FitSugar

Health Headlines

FitSugar — Wed, 10 Oct 2007 02:00:00 -0700

There are some health headlines that are worth sharing. Often the stories behind the headlines live up to their tag lines. Check out these three stories with "double take" deserving headlines.

Nutrition: An Up Side to Hard Times – New York Times
An interesting analysis of the health benefits of Cuba's economic crisis. The average daily calories consumption per person dropped by almost 1000 calories and people started walking more. There were significant decreases in the rates of obesity, diabetes, coronary heart disease and stroke.

Sales Call Leads to Kidney Donation – CNN
A door-to-door vacuum cleaner salesman donated one of his kidneys to a potential client too broke to use a vacuum cleaner due to his illness.

And this just in time for Halloween...

Hair-Raising Ideas to Cure Baldness – USA Today
Could scalp transplants, donated from corpses, be the next cure for baldness? Hair restoration specialists explore the possibilities.

Source

Kidney transplant

admin — Thu, 04 Sep 2008 19:03:33 -0700

Illustrations

Kidney anatomy

Kidney - blood and urine flow

Kidneys

Kidney transplant - series

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

A kidney transplant is surgery to place a healthy kidney into a person with kidney failure.

Alternative Names

Renal transplant; Transplant - kidney

Description

Kidney transplants are one of the most common transplant operations in the United States.

A donated kidney is needed to perform a kidney transplant.

The donated kidney may be from:

Living related donor -- related to the recipient, such as a parent, sibling, or child
Living unrelated donor -- such as a friend or spouse
Deceased donor -- a person who has recently died and who has no known chronic kidney disease

People with chronic kidney disease can receive lifesaving dialysis until a donated kidney becomes available. The healthy kidney is transported in cool salt water (saline) that preserves the organ for up to 48 hours. This gives the health care providers time to perform tests that match the donor's and recipient's blood and tissue before the operation.

PROCEDURE FOR A LIVING KIDNEY DONOR

If you are donating a kidney, you will be placed under general anesthesia before surgery. This means you will be asleep and pain-free. The surgeon makes a cut in the side of your abdomen, removes the proper kidney, and then closes the wound. The procedure used to require a long surgical cut. However, today surgeons can use a short surgical cut (mini-nephrectomy) or laparoscopic techniques.

PROCEDURE FOR THE KIDNEY RECIPIENT

People receiving a kidney transplant are given general anesthesia before surgery. The surgeon makes a cut in the lower belly area and stitches the new kidney into place. The wound is then closed.

Indications

A kidney transplant may be recommended if you have kidney failure caused by:

Diabetes
Glomerulonephritis
Severe, uncontrollable high blood pressure
Certain infections

A kidney transplant alone may NOT be recommended if you have:

Certain infections, such as TB or osteomyelitis
Difficulty taking medications several times each day for the rest of your life
Heart, lung, or liver disease
Other life-threatening diseases

Risks

The risks for any anesthesia are:

Problems breathing
Reactions to medications

The risks for any surgery are:

Bleeding
Infection

Other risks include:

Infection due to medications that suppress the immune response that must be taken to prevent transplant rejections

Expectations after surgery

Kidney transplants generally offer the best outlook for patients with end-stage kidney disease. Kidneys from living related donors do better than from donors who have died. (If you donate a kidney, you can usually live safely without complications with your one remaining kidney.)

People who receive a transplanted kidney may reject the new organ. This means that their immune system sees the new kidney as a foreign substance and tries to destroy it.

In order to avoid rejection, almost all kidney transplant recipients must take medicines that suppress their immune response for the rest of their life. This is called immunosuppressive therapy. While the treatment helps prevent organ rejection, it also puts patients at a higher risk of infection and cancer. If you take this medicine, you need to be regularly screened for cancer. The medicines may also cause high blood pressure and high cholesterol and increase the risk of diabetes.

A successful kidney transplant requires close follow-up with your doctor and always taking your medicine as directed.

Convalescence

The recovery period is 4 - 6 weeks for people who donate a kidney. If you've done so, you should avoid heavy activity during this time. Your doctor removes the stitches after a week or so.

If you received a donated kidney, you will need to stay in the hospital for about a week. Afterwards, you will need close follow-up by a doctor and regular blood tests.

Review Date: 2/7/2008

Reviewed By: Parul Patel, MD, Private Practice specializing in Nephrology and Kidney and Pancreas Transplantation, Affiliated with California Pacific Medical Center, Department of Transplantation, San Francisco, CA. Review provided by VeriMed Healthcare Network.Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows rigorous standards of quality and accountability. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial policy, editorial process and privacy policy. A.D.A.M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

A.D.A.M. Copyright

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2009 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

adam.com

Source Doc: 1_003005

Kidney removal

admin — Thu, 04 Sep 2008 19:03:27 -0700

Overview

Definition
Alternative Names
Description
Indications
Risks
Expectations after surgery
Convalescence

Illustrations

Kidneys

Kidney removal - series

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Kidney removal, also called nephrectomy, is a surgical procedure to remove a kidney.

Alternative Names

Nephrectomy

Description

This surgery is done under general anesthesia (asleep and pain-free). The surgeon makes a cut in the abdomen or in the side of the abdomen (flank area). A rib may need to be removed to perform the procedure.

The ureter (the tube that carries urine from the kidney to the bladder) and the blood vessels are cut away from the kidney and the kidney is removed. The cut is then closed.

Kidney removal may be done as open surgery, which involves a large cut in the side of the abdomen. Some patients may have laparoscopic surgery, which is less invasive and involves three or four small cuts, usually no more than an inch each, in the abdominal and flank areas.

Indications

Kidney removal may be recommended for:

Birth defects (congenital abnormalities)
Injury (trauma)
Infection
Hypertension
Tumor
Chronic bleeding

Kidney removal is also performed on someone who donates a kidney for a kidney transplant.

Risks

Risks for any anesthesia include the following:

Reactions to medications
Problems breathing

Risks for any surgery include the following:

Bleeding
Infection

Expectations after surgery

Outcome is usually good in the case of the removal of a single kidney. If both kidneys are removed or if the remaining kidney does not function well enough, hemodialysis or kidney transplantation will be necessary to maintain life.

Convalescence

You will be given fluids through an IV and pain medication. Kidney removal surgery is often very painful because of the location.

The health care team will carefully watch your blood pressure and electrolytes and fluid balance. These body functions are controlled in part by the kidneys. You will most likely have a urinary catheter (tube to drain urine) in place for a short time during your recovery.

You will probably remain in the hospital for 2 to 7 days, depending on the method of surgery used. You will be encouraged to return to light activities as soon as you feel up to it. Strenuous activity should be avoided for 6 weeks following the procedure.

Review Date: 8/15/2006

Reviewed By: David R. Knowles, M.D., Advanced Urologic Surgeons, Mt. Vernon, IL. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Source Doc: 1_003001

Rapidly progressive glomerulonephritis

admin — Wed, 03 Sep 2008 17:49:58 -0700

Overview

Definition
Alternative Names
Causes, incidence, and risk factors
Symptoms
Signs and tests
Treatment
Expectations (prognosis)
Complications
Calling your health care provider
Prevention

Illustrations

Kidney anatomy

Kidney - blood and urine flow

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Rapidly progressive glomerulonephritis is a form of kidney disease that causes damage to the small structures (glomeruli) inside the kidneys that help filter waste and fluids from blood to form urine. The disease leads to a rapid loss of kidney function.

Alternative Names

Necrotizing glomerulonephritis; Glomerulonephritis - crescentic; Crescentic glomerulonephritis

Causes, incidence, and risk factors

Many conditions are known to cause or increase the risk for developing rapidly progressive glomerulonephritis. These include:

Abscess of any internal organ
Anti-glomerular basement membrane antibody disease
Blood vessel diseases such as vasculitis or polyarteritis
Collagen vascular disease such as lupus nephritis and Henoch-Schonlein purpura
Goodpasture syndrome
IgA nephropathy
Membranoproliferative GN

The following increase your risk of developing this condition:

History of cancer
Blood or lymphatic system disorders
Exposure to hydrocarbon solvents

Rapidly progressive glomerulonephritis includes any type of glomerulonephritis (inflammation of the glomerulus) in which progressive loss of kidney function occurs over weeks to months.

The disorder is more common in certain geographic areas. Mini-epidemics of this disorder have also occurred. Rapidly progressive glomerulonephritis is most common in people age 40-60, and slightly more common in men. It is unusual in preschool children, and slightly more common in later childhood.

Symptoms

Common symptoms include the following:

Edema (swelling) of the face, eyes, ankles, feet, legs, or abdomen
Blood in the urine
Dark or smoke-colored urine
Decreased urine volume

Symptoms that may also appear include the following:

Signs and tests

A physical examination reveals edema (swelling). The doctor will listen to your heart and lungs with a stethoscope. Abnormal heart and lung sounds may be present. Blood pressure may be high.

Rapid, worsening loss of kidney function may be present. This disease may show up as an acute nephritic syndrome or unexplained kidney failure.

Tests that may be done include:

Anti-glomerular basement membrane antibody tests
Antineutrophil cytoplasmic antibodies (ANCAs)
BUN and creatinine
Complement levels
Creatinine clearance
Urinalysis

Other tests for suspected causes may be done. A kidney biopsy confirms the diagnosis. Most pathologists define crescentic glomerulonephritis when 50% or more glomeruli have an abnormal crescent shape on a kidney biopsy.

Treatment

Treatment depends on the underlying cause.

Corticosteroids may relieve symptoms in some cases. Medications that suppress the immune system may also be prescribed, depending on the cause.

A procedure called plasmapheresis may relieve the symptoms in some cases. The fluid part of the blood containing antibodies is removed and replaced with intravenous fluids or donated plasma (without antibodies). The removal of antibodies may reduce inflammation in the kidney tissues.

Persons with this condition should be closely watched for signs of progression to kidney failure. Dialysis or a kidney transplant may ultimately be necessary.

Expectations (prognosis)

Without treatment, crescentic glomerulonephritis often worsens rapidly to kidney failure and end-stage kidney disease in 6 months or less, although a few cases may just go away on their own.

Those who receive treatment may recover some or rarely all of their original kidney function. The extent of recovery is related to the degree of kidney function at diagnosis and degree of crescent formation. The disorder may recur.

If the disease occurs in childhood, it is likely that kidney failure will eventually develop.

Complications

Calling your health care provider

Call your health care provider if symptoms indicate rapidly progressive glomerulonephritis may be present.

If you have this disorder, call if new symptoms develop, especially irregular heartbeat, difficulty breathing, increased edema, or decreased urine production.

Prevention

The prompt treatment of disorders that can cause rapidly progressive glomerulonephritis may prevent the development of this disease.

Review Date: 8/14/2007

Reviewed By: Charles Silberberg, DO, Private Practice specializing in Nephrology, Affiliated with New York Medical College, Division of Nephrology, Valhalla, NY. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Source Doc: 1_000469

Sickle cell disease

FitSugar — Wed, 08 Oct 2008 17:35:29 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Complications
Treatment
Prevention and Lifestyle Ch...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Screening for Sickle Cell Disease

The United States Preventive Services Task Force’s 2007 guidelines recommend that all newborn infants be screened for sickle cell disease. (In the United States, most states require hospitals to perform this test.) Early detection of sickle cell disease ensures that babies will be given treatment to prevent infections. Sickle cell disease is an inherited condition. About 1 in 375 African-American babies are born with sickle cell disease, but children of other ethnicities are also at risk.

Infections and Sickle Cell Disease

Children with sickle cell disease are highly susceptible to many life-threatening infections, including those caused by the pneumococcus bacterium. Pneumococcal vaccinations are an important protection against this bacterium. Research published in 2007 in Clinical Infectious Diseases indicates that the introduction of the pneumococcal conjugate vaccine has helped reduce by 90% the rate of pneumococcal infections in children with sickle cell disease. Four doses of this vaccine are given from age 2 - 15 months. A second type of pneumococcal vaccine, pneumococcal saccharide, is given when the child reaches 2 years of age.
Daily antibiotics given from age 2 months through 5 years can help prevent many other types of bacterial infections, such as meningitis and blood infections.

Introduction

Blood has two major components:

Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.
White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.

Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million red blood cells per cubic millimeter of blood. To understand red blood cells and their role in anemia, it is useful to know certain facts about them.

Hemoglobin and Iron. Each red blood cell contains about 280 million hemoglobin molecules. Hemoglobin is a complex molecule and the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The red blood cells carry the oxygen to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.

Structure and Shape. Red blood cells are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

It provides a large surface area to absorb oxygen and carbon dioxide.
Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.
Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

Blood Cell Production (Erythropoiesis). The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red" and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky (viscous).
Most of the work of erythropoiesis occurs in the bone marrow.
If the body needs more oxygen (at high altitudes, for instance), the kidney triggers the release of erythropoietin (EPO), a hormone that increases production of red blood cells in the bone marrow.
The lifespan of a red blood cell is 90 - 120 days. The liver and spleen remove old red blood cells from the blood.
When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Sickle cell disease occurs from genetic changes which causes a portion of the hemoglobin molecules to be abnormal:

Hemoglobin A (HbA). HbA is the hemoglobin molecule found in normal red blood cells during childhood and adulthood. People without sickle cell anemia have primarily this type of hemoglobin in their blood cells.
Hemoglobin S (HbS). HbS (S is for sickle) is the abnormal variant of hemoglobin A, which occurs in sickle-red blood cells and is the primary characteristic of the disease. The difference between hemoglobin A (HbA) and hemoglobin S (HbS) lies in only one protein out of about 300 that are common to both. This protein lies along an amino-acid chain called beta-globin, where even a tiny abnormality has disastrous results.

Hemoglobin is the most important component of red blood cells. It is composed of a protein called heme, which binds oxygen. In the lungs, oxygen is exchanged for carbon dioxide. Abnormalities of an individual's hemoglobin value can indicate defects in red blood cell balance. Both low and high values can indicate disease states.

Hemoglobin F (HbF) is a form of hemoglobin that is produced during fetal development in the womb. (The F in HbF stands for fetal.) It is usually present for only a short time after birth. Normally, most HbF is later replaced by HbA, although some HbF may persist throughout life. Importantly, HbF is able to block the sickling action of red blood cells. Infants who have inherited sickle cell disease do not develop symptoms of the illness while they still have HbF present in their blood. People with the sickle cell gene who continue to carry some fetal hemoglobin are better protected, therefore, from severe forms of the disease. This knowledge is being used as the basis for therapies used in treating sickle cell disease.

The symptoms and problems of sickle cell disease are a result of the hemoglobin S (HbS) molecule:

When the sickle hemoglobin molecule loses its oxygen, it forms rigid rods called polymers that change the red blood cells into a sickle or crescent shape.
These abnormally sickle-shaped cells are both rigid and sticky. They stick to the walls and cannot squeeze through the capillaries. Blood flow through tiny blood vessels becomes slowed or stopped throughout the body. This deprives tissues and organs of oxygen.
In the immediate setting, oxygen deprivation (hypoxia) can cause severe pain (the sickle cell crisis). Over time, it leads to gradual destruction in organs and tissues throughout the body.

Click the icon to see an image of sickle cells.

In a vicious cycle, oxygen deprivation in cells leads to more polymerization and increased production of sickle cells. The higher the concentration of sickle hemoglobin and the more acidic the environment, the faster the sickle cell process.
Cell dehydration (not enough water molecules) is another major destructive factor in the sickling process of red blood cells. Dehydration increases the density of hemoglobin S within the cell, thereby speeding up the sickling process.
Sickle cells also have a shorter life span (10 - 20 days) than that of normal red blood cells (90 - 120 days). Every day the body produces new red blood cells to replace old ones, but sickle cells become destroyed so fast that the body cannot keep up. The red blood cell count drops, which results in anemia. This gives sickle cell disease its more common name, sickle cell anemia.

The severity of sickle cell disease generally depends on a number of factors:

The extent of oxygen loss. Prolonged oxygen deprivation contributes to the severe pain experienced as a sickle cell crisis. It also produces both short- and long-term organ damage. The lungs are specifically critical targets of the disease process. Because they supply oxygen, they can restore the sickle molecules to a normal form. Unfortunately, once the process occurs, the lungs become major sites for sickle cell damage, particularly for dangerous acute episodes of chest pain.
The acidity of the environment. The lower the better. The organs most seriously affected are those with an acidic environment (such as the spleen and bone marrow).
The concentration of hemoglobin S within the cell. The lower the better.
The amount of a protective hemoglobin F (for fetal). The more the better.

Risk Factors

Sickle cell disease is inherited. People at risk for inheriting the gene for sickle cell descend from people who are or were originally from Africa and parts of India and the Mediterranean. The sickle cell gene also occurs in people from South and Central America, the Caribbean, and the Middle East. The high incidence of the sickle cell gene in these regions of the world is due to the sickle cell's ability to make red blood cells resistant to the malaria parasite:

People who inherit just a single gene are referred to as having the sickle trait. These people are protected against malaria and do not develop sickle cell disease. About 40% of people in certain parts of Africa and about 9% of African-Americans have the trait.
Those who inherit both copies of the HbS gene develop sickle cell disease. They are not protected from malaria, however. In fact, malaria is more serious in these individuals. An estimated 1 in 500 African-Americans and 1 in 1,000 - 1,400 Hispanic Americans are born with sickle cell disease.

The sickle cell gene for hemoglobin S (HbS) is the most common inherited blood condition in America. About 72,000 Americans -- mostly African-Americans -- have sickle cell disease. The risk for inheriting sickle cell disease from parents with the sickle cell gene is as follows:

One parent has only one copy of the sickle cell gene and the other parent has two normal hemoglobin genes, and the child inherits a healthy gene from each parent. The child will not inherit either the disease or the trait.
The child inherits one copy of the sickle cell gene. The child has the trait (HbS) only. The other, healthy hemoglobin gene overrides HbS and blocks the development of sickle cell disease. Such people lead normal lives.
The child inherits the hemoglobin S gene from both parents (HbSS). The child develops the full-blown disease. (If each parent has one copy of the gene, the child has a 25% chance of acquiring the disease.)
The child inherits one hemoglobin S gene and one abnormal hemoglobin gene from other causes (such as one form called HbSC). Such children may develop a form of sickle cell disease. It is often a milder variant, but children can experience severe symptoms. They are also at risk for some of the complications of sickle cell disease, although their risks for serious problems are lower than in children with the full-blown disease.

Symptoms

General Symptoms in Infants. In infants, symptoms do not usually appear until late in the baby's first year. Most commonly, they include:

Fever
Swelling of the hands and feet
Pain in the chest, abdomen, limbs, and joints
Nosebleeds and frequent upper respiratory infections

General Symptoms in Childhood. Pain is the most common complaint. It can be acute and severe or chronic, usually from orthopedic problems in the legs and low back. Other symptoms include:

Anemia
Fatigue
Irritability
Jaundice (yellowish discoloration of the skin and eyes)
Bedwetting

Additional Symptoms in Adolescence or Adulthood. Symptoms of childhood continue in adolescence and adulthood. In addition, patients may experience:

Delayed puberty (in young teenagers)
Severe joint pain
Progressive anemia
Leg sores
Gum disease

The hallmark of sickle cell anemia is a group of devastating symptoms known collectively as a sickle cell crisis (also sometimes known as a vaso-occlusive crisis). Sickle cell crises are episodes of pain that occur with varying frequency and severity in different patients and are usually followed by periods of remission. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. It most commonly occurs in the lower back, leg, abdomen, and chest, usually in two or more locations. Episodes usually recur in the same areas.

The risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half the cases, however, the trigger is unknown. Acute chest syndrome is a particularly serious complication of sickle cell crisis. It occurs in the lungs and can be extremely serious and even life threatening.

Diagnosis

Prenatal diagnosis of sickle cell disease is now possible for women who may be at risk for having a child with the disease. A positive result for sickle cell disease, however, poses extremely difficult questions even for parents who are not opposed to abortion.

A genetic test known as preimplantation genetic diagnosis (PGD) may prove to determine the presence or absence of the sickle cell mutation in embryos (fertilized eggs) before they are implanted in the mother during assisted fertilization techniques. This genetic tool may eventually help avoid the often emotionally devastating effects of abortion.

In the United States, most hospitals screen newborn babies for sickle cell disease. To perform the test, a blood sample is taken from the baby's heel using a simple needle prick. Early detection of sickle cell disease can help reduce the risk for life-threatening infections and increase the odds for survival. Babies who are diagnosed with sickle cell disease are given daily antibiotics to help prevent infections.

Unfortunately, no tests can definitely determine which children are at highest risk for a stroke and, therefore, would be candidates for ongoing blood transfusions. The following are diagnostic tools currently used or under investigation:

Transcranial Doppler (TCD) ultrasonography measures the speed of blood flow in the brain and is the most sensitive method to date for identifying children at risk for stroke. However, high-risk children are still vulnerable to stroke even if the TCD screening diagnosed normal blood flow velocities.
The use of follow-up magnetic resonance imaging (MRI) to detect small blockages in blood vessels may help confirm high risk in patients identified by TCD ultrasound.
Some patients may need to undergo angiography, an invasive diagnostic technique useful for detecting aneurysms.
Researchers are also beginning to uncover possible genetic markers that may eventually be used to help identify sickle cell patients at higher risk for stroke.

Outlook

New and aggressive treatments for sickle cell disease are prolonging life and improving its quality. As recently as 1973, the average lifespan for people with sickle cell disease was only 14 years. Currently, life expectancy for these patients can reach 50 years and over. Early studies showed that women had a greater risk for death from sickle cell disease than men, but experts now believe this was due to high mortality during pregnancies before the mid-1970s. Women with sickle cell disease now actually live longer than their male counterparts.

The damage and durability of sickle cell disease occurs because the logjam that sickle cells cause in the capillaries slows the flow of blood and reduces the supply of oxygen to various tissues. Not only does pain occur when body tissues are damaged by lack of oxygen, but serious and even life-threatening complications can result from severe or prolonged oxygen deprivation. Sickle cell disease is referred to in some African languages as "a state of suffering," but the disease has a wide spectrum of effects, which vary from patient to patient. In some people, the disease may trigger frequent and very painful sickle cell crises that require hospitalization. In others, it may cause less frequent and milder attacks.

Children with sickle cell disease are very susceptible to infections, usually because their damaged spleens are unable to protect the body from bacteria. A recent study suggested that signs of impaired lung function occur even in very early years. As medical progress has increased the lifespan of children with sickle cell disease, older patients are now facing medical problems related to the long-term adverse effects of the disease process. The most serious dangers are acute chest syndrome, long-term damage to major organs, stroke, and complications during pregnancy such as high blood pressure in the mother and low birth weight.

Complications

There is still no cure for sickle cell disease other than experimental transplantation procedures, but treatments for complications of sickle cell have prolonged the lives of many patients who are now living into adulthood.

The hallmark of sickle cell disease is the sickle cell crisis (also sometimes known as a vaso-occlusive crisis), which is an episode of pain. It is the most common reason for hospitalization in sickle cell disease. The pattern may occur as follows:

In general, the risk for a sickle cell crisis is increased by any activity that boosts the body's requirement for oxygen, such as illness, physical stress, or being at high altitudes. In more than half of episodes, however, the trigger is unknown.
Episodes typically begin at night and last 3 - 14 days, accelerating to a peak over several days and then declining.
The pain is typically described as sharp, intense, and throbbing. Severe sickle cell pain has been described as being equivalent to cancer pain and more severe than postsurgical pain. Shortness of breath is common.
Pain most commonly occurs in the lower back, leg, hip, abdomen, or chest, usually in two or more locations. Episodes usually recur in the same areas. Pain in the bones (usually occurring symmetrically on both sides) is common because blood obstruction can directly damage bone and because bone marrow is where red blood cells are manufactured.
The liver or spleen may become enlarged, causing pain in the upper right or upper left sides of the abdomen. Liver involvement may also cause nausea, low-grade fever, and increasing jaundice.
Males of any age may experience prolonged, often painful erections, a condition called priapism.

Episodes cannot be predicted, and they vary widely among different individuals. In one study, nearly 40% of patients reported no painful episodes over a 5-year period. About 5% of patients experienced severe and frequent episodes (more than three a year). They sometimes become less frequent with increasing age. Generally, people can resume a relatively normal life between crises. Most patients are pain-free between episodes although pain can be chronic in some cases.

Acute chest syndrome (ACS) occurs when the lungs are deprived of oxygen during a crisis. It can be very painful, dangerous, and even life threatening. It is a leading cause of illness among sickle cell patients and is the most common condition at the time of death. At least one whole segment of a lung is involved, and the following symptoms may be present:

Fever of 101.3°F degrees (38.5°C) or above
Rapid or labored breathing
Wheezing or cough
Acute chest pain

Pain often lasts for several days. In about half of patients, severe pain develops about 2 - 3 days before there are any signs of lung or chest abnormalities. Acute chest syndrome is often accompanied by infections in the lungs, which can be caused by viruses, bacteria, or fungi. Pneumonia is often present. A dull, aching pain usually follows, which most often ends after several weeks, although it may persist between crises.

Air is breathed in (inhaled) through the nasal passageways, and travels through the trachea and bronchi to the lungs.

Causes of Acute Chest Syndrome. Primary causes of acute chest syndrome include:

Infection. Infection from viruses or small atypical organisms (Chlamydia and Mycoplasma) is the most common cause of the oxygen deprivation that leads to acute chest syndrome.
Blockage of blood vessels. Blockage in the blood vessels (called infarction) that cuts off oxygen in the lungs is another important cause of acute chest syndrome. Blockage may be produced by blood clots or fat embolisms. (Fat embolisms are particles formed from fatty tissue in the bone marrow that enter and travel through the blood vessels.)
Asthma. Asthma can increase the frequency and pain of acute chest syndrome episodes in children, according to an important 2006 study. The researchers recommended that all children with sickle-cell disease who have frequent acute chest syndrome attacks should be evaluated for asthma.

In about 45% cases, the cause cannot be established. Some cases of acute chest syndrome may result from treatments of the crisis, including from administration of opioids (which reduce oxygen) or excessive use of intravenous fluids. Other lung diseases may also trigger ACS.

Severity of Acute Chest Syndrome. The mortality rates for ACS are around 2% in children and 4% in adults. The syndrome and its long-term complications are the major causes of death in older patients. The condition is four times more deadly in adults than in children. The longer a patient survives, the greater is the damage done by repetitive sickle cell crises in the chest and lungs.

The following destructive effects can occur:

Damage in the chest area from recurrent episodes increases susceptibility to invading infections, even those that are ordinarily not harmful. Infections frequently clear up if they are limited to small areas of the lung, but if they spread, they can progress very quickly and become life threatening.
Lung damage over time can lead to obstruction in the airways in lungs, causing asthma-like conditions.

Infections are common and an important cause of severe complications in sickle cell patients. Before early screening for sickle cell disease and the use of preventive antibiotics in children, 35% of infants with sickle cell died from infections. Fortunately, with screening tests for sickle cell now required for newborns in most states, and with the use of preventive antibiotics in babies who are born with the disease, this terrible mortality rate has dropped significantly.

Infections in Infants and Toddlers with Sickle Cell Disease. The most common organisms causing infection in children with sickle cell disease include:

Streptococcus pneumoniae (can cause blood infections or meningitis)
Haemophilus influenza (a cause of meningitis)

Such infections pose a grave threat to infants and very young children with sickle cell disease. They can progress to fatal pneumonia with devastating speed in infants, and death can occur only a few hours after onset of fever. The risk for pneumococcal meningitis, a dangerous infection of the central nervous system, is also significant.

Infections in Children and Adults. Infections are also common in older children and adults with sickle cell disease, particularly respiratory infections such as pneumonia, kidney infections, and osteomyelitis, a serious infection in the bone. (The organisms causing them, however, tend to differ from those in young children.) Infection-causing organisms include:

Chlamydia and Mycoplasma pneumoniae. These are the important infections in acute chest syndrome (see above).
Gram-negative bacteria. This group of bacteria mostly infects hospitalized patients and can cause serious pneumonias and other infections.

About 30% of patients with sickle cell disease have pulmonary hypertension. Pulmonary hypertension is a serious and potentially deadly condition that develops when pressure in the arteries of the lungs increases. It is an often unrecognized complication and cause of death in sickle cell disease. Many doctors recommend that all adults with sickle cell disease undergo echocardiographic testing to identify if they are at risk for pulmonary hypertension and require treatment.

Researchers are developing new types of tests that may help with early identification of pulmonary hypertension. For example, some studies indicate that a simple blood test for the hormone brain natriuretic peptide (BNP) could help identify patients with sickle cell pulmonary hypertension. Higher levels of BNP are associated with increased pressure in the pulmonary (lung) arteries. A blood test measuring levels of the enzyme lactate dehydrogenase (LDH) may also help identify patients at risk for pulmonary hypertension, as well as leg ulcerations and priapism (persistent and painful erection of the penis). Echocardiography or other tests would still need to be performed to confirm results from these blood tests.

The primary symptom of pulmonary hypertension is shortness of breath, which is often severe. Pulmonary hypertension can be very serious and life threatening in the short- and long-term. If pulmonary hypertension develops suddenly it can cause respiratory failure, which is life threatening. Over time, pulmonary hypertension may cause a condition called cor pulmonale, in which the right side of the heart increases in size. In some cases, this enlargement can lead to heart failure.

Click the icon to see an image of cor pulmonale.

After acute chest syndrome, stroke is the most common killer of patients with sickle cell disease who are older than 3 years old. Between 8 - 10% of patients suffer strokes, typically at about age 7. Patients may also suffer small strokes that may not be immediately noticeable. However, patients who have many of these small strokes may over time start behaving differently or have worsening mental functioning.

Strokes are usually caused by blockages of vessels carrying oxygen to the brain. Patients with sickle cell disease are also at high risk for stokes caused by aneurysm, a weakened blood vessel wall that can rupture and hemorrhage. Multiple aneurysms are common in sickle cell patients, but they are often located where they cannot be treated surgically.

Click the icon to see an image of stroke.

Anemia is a significant characteristic in sickle cell disease (which is why the disease is commonly referred to as sickle cell anemia).

Severe worsening of anemia. Children, adolescents, and possibly young adults may experience what is called splenic sequestration. This happens when a large amount of the sickled red blood cells collect in the patient's spleen. Symptoms may include pain in the right abdomen below the ribs and a large mass (the swollen spleen) may be felt.

Chronic Anemia. Because of the short lifespan of the sickle red blood cells, the body is often unable to replace red blood cells as quickly as they are destroyed. This causes a particular form of anemia called hemolytic anemia. Most patients with sickle cell disease have a hemoglobin levels of 8 g/dL, much lower than people without sickle cell anemia. Chronic anemia reduces oxygen and increases the demand on the heart to pump more oxygen-bearing blood through the body. Eventually, this can cause the heart to become dangerously enlarged, with an increased risk for heart attack and heart failure.

On occasion, patients may experience what is called an aplastic crisis. This happens when the cells in the bone marrow that are normally trying to make new red blood cells suddenly stop working. This sudden stopping is often triggered by a virus called human parvovirus B19.

The kidneys are particularly susceptible to damage from the sickling process. Persistent injury can cause a number of kidney disorders, including infection. Problems with urination are very common, particularly uncontrolled urination during sleep. Patients may have blood in the urine, although this is usually mild and painless and resolves without damaging consequences. Kidney failure is a major danger in older patients and accounts for 10 - 15% of deaths in sickle cell patients. Renal medullary carcinoma is an aggressive, rapidly destructive tumor in the kidney that is rare but can occur as a result of sickle cell disease.

Click the icon to see an image of kidney anatomy.

A reported 38 - 42% of males, including children, with sickle cell disease suffer from priapism. Priapism causes prolonged and painful erections that can last from several hours to days. Experts think that priapism in sickle cell disease may be caused by the destruction of red blood cells and subsequent reduction of nitric oxide. If priapism is not treated, partial or complete impotence can occur in 80% of cases.

Click the icon to see an image of the male reproductive anatomy.

Enlargement of the liver occurs in over half of sickle cell patients, and acute liver damage occurs in up to 10% of hospitalized patients. Because sickle cell patients often need transfusions, they have been at higher risk for viral hepatitis, an infection of the liver. This risk, however, has decreased since screening procedures for donated blood have been implemented.

About 30% of children with sickle cell disease have gallstones, and by age 30, 70% of patients have them. In most cases, gallstones do not cause symptoms for years. When symptoms develop, patients may feel overly full after meals, have pain in the upper right quadrant of the abdomen, or have nausea and vomiting. Acute attacks can be confused with a sickle cell crisis in the liver. Ultrasound is usually used to confirm a diagnosis of gallstones. If the patient does not have symptoms, no treatment is usually necessary. If there is recurrent or severe pain from gallstones, the gallbladder may need to be removed. Minimally invasive procedures (using laparoscopy) reduce possible complications. [For more information, see In-Depth Report #10: Gallstones.]

Click the icon to see an image of cholithiasis.

The spleen of most adults with sickle cell anemia is nonfunctional due to recurrent episodes of oxygen deprivation that eventually destroy it. Injury to spleen causes problems in immune function and increases the risk for serious infection. A very serious anemic condition called acute splenic sequestration crisis (sudden spleen enlargement) can occur if the damaged spleen suddenly becomes enlarged from trapped blood.

Click the icon to see an image of an enlarged spleen.

In some children with sickle cell disease, excessive production of blood cells in the bone marrow causes bones to grow abnormally, resulting in long legs and arms or misshapen skulls. Sickling that blocks oxygen to the bone can also cause bone loss and pain. Sickling that affects the hands and feet of children causes a painful condition called hand-foot syndrome. A condition called avascular necrosis of the hip occurs in about half of adult sickle cell patients when oxygen deprivation causes tissue death in the bone. Eventually adult patients may require surgery to remove diseased and dead bone tissue. Joint replacement may be required in severe cases. X-rays are not very useful for detecting early disease in the bones. MRI may be important.

Click the icon to see an image of the blood supply to bone.

Leg sores and ulcers occur in up to 10% of sickle cell patients and usually affect patients older than 10 years.

Women with sickle cell disease who become pregnant are at higher risk for complications, but serious problems have dropped significantly over the past decades. One study reported a higher risk for premature birth and low birth weight in the baby, and a higher risk for infections and hospital visits in the mother after delivery. Pain crises occurred in nearly half of the women, and nearly 60% required transfusions. The study also reported, however, that, in general, the outcome for pregnancy is favorable. Still, pregnancy during sickle cell is high-risk and carries a mortality rate of about 1%.

Older children and adult patients with sickle cell are subject to other medical problems, including impaired physical development, gum disease, and scarring and detachment of the retina.

Treatment

Research is ongoing toward identifying the biologic and chemical activities that promote or protect against the sickle cell process. Currently, experimental treatments focus on the basic processes that cause the red blood cells to sickle in the first place. There are three basic modes of treatment:

Stimulation of production of healthy fetal hemoglobin in order to inhibit the sickling process
Blocking dehydration in the cells
Transplantation of bone marrow or stem cells from healthy donors so that normal hemoglobin is produced rather than hemoglobin S

Hemoglobin F (HbF), also called fetal hemoglobin, is the form of hemoglobin in the fetus and small infants. Most HbF is later replaced by the hemoglobin that is present in the growing child and adult, although some HbF may persist. Fetal hemoglobin is able to block the sickling action of red blood cells so that infants with sickle cell disease do not develop symptoms of the illness while they still have hemoglobin F. Adults who have sickle cell disease but still retain high levels of hemoglobin F generally have mild disease.

Studies now suggest that the severity of sickle cell disease can be reduced by using drugs that stimulate production of HbF. Even increases as modest as 4% may have significant benefits for these patients.

Hydroxyurea. Hydroxyurea (Droxia, Hydrea) destroys cells in the bone marrow, which results in an increase in special cells that can produce HbF. It is currently the only drug in general use to prevent acute sickle cell crises.

Hydroxyurea is used to treat adults and adolescents with moderate-to-severe recurrent pain (occurring three or more times a year). Hydroxyurea reduces sickling crises and pain, priapism, the number of transfusions, and life-threatening complications in this group. The benefits appear to be long-lasting. Hydroxyurea is not a cure-all. Not all patients respond to hydroxyurea, and the best candidates for the treatment are not yet clear. Small studies have reported no protection from damage in the spleen or bones and joints. Effects on stroke and complications in the eye or kidney are not yet known.

Hydroxyurea is still being investigated in young people. To date, the response to the drug in children and teenagers with sickle cell disease is similar to the response in adults, and few severe adverse effects are being reported. Recent research also suggests that hydroxyurea is safe and beneficial for infants. A 2005 study indicated that long-term hydroxyurea treatment can improve height, weight, and spleen function, and reduce episodes of acute chest syndrome. Patients in the study started the treatment as babies, and most patients took the drug for at least 4 years. The drug was given by mouth in a flavored liquid form.

Side effects include gastrointestinal problems, headache, drowsiness, and skin and nail changes. In rare cases, there have been reports of hallucinations and seizures. The drug may also cause leg ulcers and gangrene in some patients. Patients should handle hydroxyurea with care and wash their hands before and after touching the bottle or capsules. Household members who are not taking hydroxyurea (such as caregivers) should wear disposable gloves when handling the medicine or its bottle.

Cytidine Analogues. Cytidine analogues increase HbF production by affecting the genes that regulate it. Decitabine is one such drug that was developed to treat leukemia and other blood malignancies. Early studies are suggesting that it significantly increases HbF production, even in patients in whom treatment with hydroxyurea failed. Only minor toxic side effects have been reported to date.

Butyrates. Butyrates are natural fatty acids, the end-products of fermented carbohydrates in the intestinal tract that are also metabolized from fiber. One derivative, arginine butyrate, has been under investigation for some time in sickle cell for its role in stimulating production of HbF. Because its actions are different from hydroxyurea, experts hope the two drugs may eventually be used in combination. However, arginine butyrate is difficult to administer, and different forms that might make it simpler to use are needed.

General Guidelines for Managing a Sickle Cell Crisis. The basic objectives for managing a sickle cell crisis are control of pain and rehydration by administration of fluids. Oxygen is typically given for acute chest syndrome. Effective pain medications are available to help reduce the severe pain of sickle cell crises.

Accurate and continually updated assessment of pain determined by patient input and participation is at the crux of effective care for children with sickle cell disease. Often, however, patients are not given the treatment they require.

Many patients, their families, and even doctors are hesitant to use opioids aggressively because of fear of addiction. This fear, however, is nearly always unwarranted. Addiction occurs in only about 1 - 3% of patients with sickle cell disease who are taking opioids.
Many patients use emergency rooms of large hospitals for treating acute pain. Waiting times are long, and there is no single health care provider who knows the patient and can offer consistent assessment and management of pain.
Many doctors do not understand the nature of sickle cell pain. For example, early phases of sickle cell crisis can cause severe pain before test results confirm a diagnosis of a crisis. In such cases, health professionals may question the patient's self-reporting and withhold appropriate pain medication.
Patients may behave normally (talking on the phone, sleeping) and not appear to be in pain, but have actually developed coping behaviors to allow them to function in spite of severe pain.
Children and adults report pain differently, with children tending to report less pain than they actually feel. (One way of determining the severity of pain that a child feels is to show pictures of faces demonstrating degrees of pain and asking the child to point to the one that best expresses his or her experience.)

Adult patients and parents of children with the disease should insist on aggressive pain-relief treatment. If doctors show any reluctance to administer medications after the onset of pain, patients or caregivers should not hesitate to seek a more responsive health care professional.

All patients should have a treatment plan that helps guide them and their families during a pain episode. Plans should outline which medicines to take and when to seek medical help. Patients and families should learn to recognize symptoms early and begin managing with an appropriate amount of pain medication.

Opioids. Severe pain should be treated with strong painkillers, usually opioids. Opioids are generally given orally to adults and adolescents and intravenously to children. Nevertheless, there are exceptions. Studies indicate that oral medications are also effective in children.

Morphine is often used for frequent or prolonged episodes of pain. Unfortunately, its effectiveness is not as long-lasting in sickle cell patients as it is in other patients with severe pain, such as those with cancer.
The opioid meperidine (Demerol) is also used for sickle cell crises. Meperidine is not as powerful as morphine, however, and, if used for prolonged periods, may cause twitches, tremors, and disturbed mental states including seizures.
Some newer synthetic opioids such as fentanyl (Duragesic) or hydromorphone(Dilaudid) have a rapid onset and possibly fewer side effects than morphine. Fentanyl can be applied using a patch, which may help some patients who have difficult receiving intravenous drugs. It takes 12 hours to be effective, however.
Oral drugs, such as methadone, oral morphine, codeine, and oxycodone, are useful for home management of chronic pain and for transitional treatments between the hospital and home. Tramadol (Ultram) is a potent oral painkiller that has opioid-like properties but is not as addictive. (Dependence and abuse have been reported, however.) It may be very useful for sickle cell patients who need painkillers outside the hospital. It has minimal effects on respiratory function and has a low potential for addiction.

Possible side effects of opioids are vomiting and nausea, itching, constipation, itching, skin rashes, and problems urinating. If the patient vomits or becomes nauseated, the doctor may prescribe prochlorperazine (Compazine). Devices have been developed to allow patients to administer their own painkillers as needed.

Anti-Inflammatory Drugs. Because of the potentially serious side effects of opioids, doctors are constantly searching for safer and easier ways of reducing the severity of pain of sickle cell crises. Because experts believe that inflammation is a major contributor to the pain of sickle cell disease, drugs that reduce inflammation are being studied:

Prescription-strength NSAIDs include diflunisal (Dolobid) and ketorolac (Toradol). Ketorolac may be particularly helpful in relieving bone pain, and may be effective for individuals who cannot tolerate opioids. In one study, it was superior to meperidine and had fewer side effects. Studies have suggested, however, that when used as first-line therapy in an acute crisis, ketorolac is effective only in about half of episodes.
Corticosteroids are powerful anti-inflammatory drugs that are commonly used to treat pain caused by inflamed muscles and joints. Such drugs include methylprednisolone (Medrol) and dexamethasone (Decadron, Hexadrol). Studies suggest that using these drugs along with opioids may help some sickle cell patients. Because steroids can suppress the body's infection fighters, they should not be given to patients with bacterial infections or any serious medical complication.

Epidural Anesthesia. An epidural analgesia (injection of an anesthetic into the spinal fluid) may be very effective for pain that is unresponsive to the usual therapies.

Initial Management. Acute chest syndrome can be fatal and must be treated immediately. Basic treatments include the following:

Supplementary oxygen -- this is critical and life saving.
Administration of fluids -- overhydration should be avoided to reduce the risk of fluid in the lungs.
Pain relievers
Bronchoscopy (a diagnostic procedure involving insertion of a tube into the lower airways) may be needed to identify infection.

Other Treatments. Other treatments include:

High-dose intravenous corticosteroids (usually dexamethasone) may hasten recovery from acute chest syndrome and reduce the duration of hospitalization. They are also important if fat embolisms develop.
Antibiotics that specifically target the organisms ( Chlamydia, Mycoplasma) that commonly trigger acute chest syndrome. Such antibiotics include erythromycin, azithromycin, clarithromycin, and various tetracyclines.
Transfusions are important early on for rapid improvement in severe cases, especially if fat embolisms have developed.

To increase oxygen levels in children hospitalized for acute chest syndrome, a simple breathing technique known as incentive spirometry may also be beneficial. A spirometer is a hand-held plastic device commonly used by asthma patients to measure their lung capacity and by patients after surgery to increase intake of oxygen. Patients with sickle cell disease are asked to inhale and exhale into this device every 2 hours during the day and when wake at night until their chest pain subsided. This device forces more air into the lungs, and may help prevent the serious drop in oxygen levels and the risk for infection caused by acute chest syndrome. Spirometry leads to slower rates of collapsed lung tissue and infections. This very inexpensive and simple treatment might have beneficial long-term effects.

General Approach to Treating Infections. Fever in any sickle cell patient should be considered an indication of infection. Temperatures over 101°F in children warrant a call to the doctor. Adults with sickle cell should call the doctor if they have a have fever over 100°F and any signs of infection, including chest pain, productive cough, urinary problems, or any other symptoms. Some approaches for treating infections include:

Hospitalization for infections. When sickle cell patients develop infections, they are nearly always hospitalized immediately and treated with intravenous or high-dose injections of antibiotics in order to prevent septicemia, the dangerous spread of the infection throughout the body. Antibiotics called cephalosporins [cefotaxime (Claforan), ceftriaxone (Rocephin), or cefuroxime (Ceftin)] are typically used. Repeated hospitalizations are very disruptive for both children and adults. Studies have found that older children whose fever is below 38.5°C (101°F) and who have no serious infection or other complications may not need hospitalization. Children who have indications of serious complications of infection (higher fevers, pain, a history of pneumonia, and signs of dehydration) should remain in the hospital.
Treatment of osteomyelitis. If osteomyelitis, an infection in the bone, occurs, a 6-week antibiotic course is needed, most of it intravenous. An accurate diagnosis of osteomyelitis is sometimes difficult to make, because bone damage from sickling can cause similar symptoms. It should be strongly considered in children with signs of pain and swelling in the legs, a high white blood cell count, high fever, and high levels of a test that measures so-called sedimentation rates. It is important, however, to confirm the presence of an actual infection before administering antibiotics, because the antibiotic treatment required for osteomyelitis is so intensive and prolonged. The most common cause of osteomyelitis in children is Salmonella.
Treatment of urinary tract infections. Urinary tract infections may be difficult to manage and can be a serious problem for pregnant women with sickle cell disease. Doctors should take a urine culture before beginning antibiotic treatment and another culture 1 - 2 weeks after treatment to be sure the infection has cleared up.

Bosentan (an endothelin receptor antagonist) and other drugs are used to treat this condition. Investigational therapies include nitric oxide, L-arginine (which converts to nitric oxide), blood transfusions, warfarin, vasodilators, and sildenafil (Viagra). Hydroxyurea does not appear to help.

Folic acid and possibly iron supplements are often given to help treat the anemia that occurs in patients with sickle cell disease. (Patients who are given multiple transfusions may experience iron overload, and iron supplements should be avoided in such cases. Also, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.)

Kidney damage in patients with sickle cell disease can cause bleeding into the urine. Mild episodes can usually be treated with bed rest and fluids. Severe bleeding may require transfusions. ACE inhibitors are drugs commonly used to control high blood pressure and are proving to be important for preventing hypertension and kidney failure in sickle cell patients. Such drugs include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), and lisinopril (Prinivil, Zestril).

Priapism causes prolonged and painful erections that can last from several hours to days. It is best to relieve this problem within 12 hours. Relief within 36 hours is important to avoid permanent impotence. Pain relief and intravenous fluids are the initial steps. Exchange transfusions may be used to reduce the hemoglobin S and sickling that cause this condition. Drugs used to prevent priapism include terbutaline and phenylephrine, which help restrict blood flow to the penis. Hormonal treatments such as leuprolide (Lupron) and diethylstilbestrol may prevent repetitive and prolonged episodes of priapism in severely affected teenage boys with sickle cell disease. A surgical procedure that implants a shunt to redirect blood flow is sometimes performed. Inflatable penile implants may help maintain potency without causing priapism. Researchers are also investigating other treatments including inhaled nitric oxide, arginine, and sildenafil (Viagra).

The spleen is often removed (splenectomy) in children who have one or two acute splenic sequestration crises. Transfusion therapy is an alternative for preventing acute splenic sequestration in high-risk patients. At this time there are no studies comparing overall survival and benefits between the two approaches.

Leg ulcers are difficult to treat. Simple treatment with a moist dressing usually provides the best results. To treat mild ulcers, the leg should be gently washed with cotton gauze soaked in mild soap or a solution of one tablespoon of household bleach to one gallon of water. A dressing soaked in diluted white vinegar may be applied every 3 - 4 hours.

More severe ulcers require debridement, which is the removal of injured tissue until only healthy tissue remains. Debridement may be accomplished using chemical (enzymes), surgical, or mechanical (irrigation) means. Hydrogels (Nu-Gel, Intrasite Gel, Scherisorb, Clearsite, Duoderm, Geliperm) are helpful in healing ulcers and are noninvasive and soothing. Topical antibiotics, saline or zinc oxide dressings, or cocoa butter or oil are also used depending on severity. The leg should be elevated. Bed rest for a week or more is sometimes required for severe ulcers.

Skin grafts and transfusions have been helpful in some extreme cases. In one promising study administering arginine butyrate for many weeks improved ulcer healing by 10-fold. (This drug is also under investigation for other beneficial effects in patients with sickle cell disease.)

Women who are pregnant should be treated at a high-risk clinic. They should take folic acid in addition to multivitamins and iron. Standard treatment is given for sickle cell crises, which may occur more frequently during pregnancy. The benefits of transfusions to prevent crises during pregnancy are not yet clear and experts recommend them only for women who experience frequent complications during pregnancy.

Women with sickle cell disease should talk to their doctors before becoming pregnant. Sexually active women should use contraception at all times.

At this time, the only true cure for sickle cell disease is bone marrow or stem cell transplantation. The bone marrow nurtures stem cells, which are early cells that mature into red and white blood cells and platelets. By destroying the sickle cell patient's diseased bone marrow and stem cells and transplanting healthy bone marrow from a genetically-matched donor, normal hemoglobin may be produced. Clinical studies using a few carefully selected patients have reported very successful results.

Up to 80 - 85% of patients who meet criteria for receiving a transplant receive remain disease free. Unfortunately, only about 7% meet the criteria for transplantation, including those who:

Are age 16 or younger (generally considered the better candidates, but patients in their 20s have had successful transplants)
Have severe symptoms but no long-term organ or neurologic damage
Have a genetically matched brother or sister who will donate their marrow

Complications. Bone marrow transplant carries its own dangers and limitations. About 10% of those who have bone marrow transplants die from the treatment. Some complications include:

In patients who do not receive a bone marrow donation from a matched sibling, the transplanted cells from a donor (called allogeneic grafts) may attack the patient's own tissues, a potentially fatal condition called graft-versus-host disease (GVHD). Drugs that destroy bone marrow and suppress immunity must be administered before the procedure so that the body's immune system does not attack the transplanted tissue. Still, this does not always prevent the problem.
Other very serious complications include bleeding, pneumonia, and severe infection.
Those who live but are not cured face long-term problems caused by the drugs used in transplantation and by the disease itself.
Even in those who are cured, long-term consequences may include a higher risk for cancer and infertility.

The use of umbilical cord blood and cells from placentas is showing promise for providing healthy stem cells to patients who do not have genetically matched donors for bone marrow transplant. Cord blood has certain advantages over stem cell transplantation, including the capacity to produce more cells quickly. Because immune factors in cord blood are immature, the risk and severity of graft-versus-host disease may be reduced.

Early clinical trials are also reporting some success with a process called partial chimerism, in which a mixture of the patient's and a donor's bone marrow is used. The procedure has far fewer side effects because all the bone marrow is not destroyed. Although some sickle blood cells remain, small studies indicate that the patients are still free of the typical infections and pain of the disease.

Transfusions are often critical for treating sickle cell disease. In some cases, they may be given on a regular basis to prevent stroke or other life-threatening complications of the disease. Ongoing transfusions can reduce episodes of pain and acute chest syndrome. They can also help improve height and weight in children with sickle cell disease. Regular transfusions, however, can have severe side effects. Normal hemoglobin levels for patients with sickle cell disease are around 8 g/dL. Doctors will try to keep the hemoglobin level no higher than 10 g/DL after transfusion.

Transfusions may be required by sickle cell patients either for specific episodes (used only for specific events) or as chronic transfusions (ongoing transfusions).

Episodic Transfusions. Episodic transfusions are needed in the following situations:

To manage sudden severe events, including acute chest syndrome, stroke, widespread infection (septicemia), and multi-organ failure.
To manage severe anemia, usually caused by splenic sequestration (dangerously enlarged spleen) or aplasia (halting of red blood cell production, most often caused by parvovirus). Transfusions are generally not required for mild or moderate anemia.
Before major surgeries. Some evidence suggests that a conservative transfusion regime is as effective as aggressive transfusions in these cases, but more research is needed. Transfusions are generally not required for minor surgeries.

Chronic Transfusions. Chronic (on-going) transfusions are used for:

Stroke Prevention. Chronic transfusions are also used to prevent first or recurrent strokes. Evidence shows that regular (every 3 - 4 weeks) blood transfusions can reduce the risk of a first stroke by 90% in high-risk children. The objective of such transfusions is to reduce hemoglobin S concentrations to less than 30% of total hemoglobin. In addition, studies indicate that as many as 90% of patients who have experienced a stroke do not experience another stroke after 5 years of transfusions. In 2004, the National Heart, Lung, and Blood Institute (NHLBI) issued a clinical alert strongly advising doctors against terminating regular transfusions for high-risk children.
Pulmonary hypertension and chronic lung disease
Heart failure
Chronic kidney failure and severe anemia
Unusually severe and protracted episodes of pain

Chronic blood transfusions carry their own risks, including iron overload, alloimmunization (an immune response reaction), and exposure to bloodborne pathogens. Still, data from large-scale trials suggest that the risks for stroke outweigh the risks associated with transfusions. Researchers are working on ways to reduce the side effects associated with transfusion treatment.

Kinds of Transfusions. Transfusions may be either simple or exchange.

Simple Transfusion. Simple transfusions involve the infusion of one or two units of donor blood to restore blood volume levels and oxygen flow. It is used for moderately severe anemia, severe fatigue, and nonemergency situations when there is a need for increased oxygen. It is also used for acute chest syndrome.
Exchange Transfusion. Exchange transfusion involves drawing out the patient's blood while exchanging it for donor red blood cells. It can be done as manual procedure or as automatic one called erythrocytapheresis. Exchange transfusions should be used promptly if there is any evidence that the patient's condition is deteriorating. It prevents stroke and also may be used in patients with severe acute chest syndrome and to reduce the risk of iron overload in patients who require chronic transfusion therapy. Studies suggest that it may improve oxygenation and reduce hemoglobin S levels. Exchange transfusion may also reduce the risk of heart failure and help prevent fat embolism, a life-threatening condition in which fatty tissue from the bone marrow travels to blood vessels in the lungs and cuts off oxygen.

Iron Overload and Chelation Therapy. Iron overload increases risk for complications, including liver cancer and heart failure. A liver biopsy accurately determines whether excess iron levels are present. A non-invasive test called a superconducting quantum interference device (SQUID) should be used if available.

Chelation therapy is used to remove excess iron stores in the body that can harm the liver, heart, and other organs. The drug deferoxamine (Desferal) is commonly used during such therapy. Unfortunately, deferoxamine has some severe side effects and must be used with a pump for about 12 hours each day. Many patients do not continue treatment. In 2005, the drug deferasirox (Exjade) was approved for the treatment of transfusion-related iron overload in patients ages 2 and older. It is taken once a day by mouth. Patients mix the pills in liquid and drink the mixture. This new treatment may make chelation therapy much easier and less painful for patients.

Other Complications of Transfusion Therapy.

Immune reactions. An immune reaction may occur in response to donor blood. In such cases, the patient develops antibodies that target and destroy the transfused cells. This reaction, which can occur 5 - 20 days after transfusion, can result in severe anemia and may be life-threatening in some cases. It can be generally prevented with careful screening and matching of donor blood groups before the transfusion.
Hyperviscosity. With this condition, a mixture of hemoglobin S and normal hemoglobin causes the blood to become sticky. The patient is at risk for high blood pressure, altered mental status, and seizures. Careful monitoring can prevent this condition.
Transmission of viral illness. Before widespread blood screening, transfusions were highly associated with a risk for hepatitis and HIV. This complication has decreased considerably.

Nitric oxide, a soluble gas, is a natural chemical in the body that relaxes smooth muscles and expands blood vessels. Hemoglobin removes nitric oxide. Because sickle cells release hemoglobin, patients with the disease are deficient in nitric oxide. This lack of nitric oxide constricts blood vessels and causes pain in sickle cell diseases. In adult patients, men may be more susceptible to this effect than women. Some studies indicate that inhaling nitric oxide may slow the disease process and improve symptoms in acute sickle cell crises. It is difficult to administer, however. More studies are needed. (Nitric oxide is not the same substance as nitrous oxide, the so-called laughing gas used in dentistry.)

Sickle cell disease can cause red blood cells to break apart. This process is called hemolysis. Hemolysis causes a lack of the amino acid arginine. Arginine is involved in producing nitric oxide. Recent research suggests that a lack of arginine may contribute to the development of pulmonary hypertension, a leading cause of death in patients with sickle cell disease. Pulmonary hypertension causes high blood pressure in the arteries that carry blood to the lungs.

A 2005 study found that patients with sickle cell who had low levels of arginine were 3.6 times more likely to die than patients with high arginine levels. Most patients in the study died from pulmonary hypertension. Scientists are working on developing a blood test that could measure amino acid levels and help identify patients at greatest risk of death. They are also working on developing drugs that could block arginase, a protein in cells that is released during hemolysis, which consumes arginine. There is no evidence indicating that arginine nutritional supplements are helpful or harmful for patients with sickle cell disease. Patients should talk to their doctor before taking these or other supplements.

Researchers are studying the mechanisms behind cell membrane damage, dehydration, and potassium loss in order to develop drugs that will inhibit these processes. Drugs under investigation include those that specifically block the Gardos channel, which is an important route for potassium loss and dehydration. Researchers are also studying specific types of mineral supplements, such as magnesium pidolate and zinc sulfate. Initial studies have shown promising results for zinc’s efficacy in preventing red blood cell dehydration, but more research is needed.

Prevention and Lifestyle Changes

No o proven methods prevent either sickle cell crises or long-term complications of sickle cell disease. By taking precautions and aggressively managing problems that occur, however, patients are now living longer, with a better quality of life.

To prevent or reduce the severity of long-term complications, a number of precautions may be helpful:

Have regular physical examinations every 3 - 6 months.
Have periodic and careful eye examinations.
Have sufficient rest, warmth, and increased fluid intake. (These are critical precautions for reducing oxygen loss and the risk for dehydration.)
Avoid conditions, such as crowds, that increase risk for infections.
Avoid excessive demands on the body that would increase oxygen needs (physical overexertion, stress). Low impact exercise (leg lifts, light weights) may be useful and safe for maintaining strength, particularly in the legs and hips, but patients should consult their doctor about any exercise program.
Avoid high altitudes if possible. If flying is necessary, be sure that the airline can provide oxygen.
Do not smoke, and avoid exposure to second-hand smoke. Both active and passive smoking may promote acute chest syndrome in patients with sickle cell disease.

Vaccinations. Everyone with sickle cell disease should have complete regular immunizations against all common infections. Children should have all routine childhood vaccinations. The following are important vaccinations for everyone with sickle cell disease:

Pneumococcal vaccines. All sickle cell patients should be vaccinated with the pneumococcal vaccine. There are two types of pneumococcal vaccines; the choice between them depends on the age of the patient. Infants and children less than 2 years of age should receive 4 doses of the pneumococcal conjugated vaccine (Prevnar) between 2 - 15 months of age. (This vaccine has helped reduce the rate of serious pneumococcal disease by more than 90%.) The pneumococcal polysaccharide vaccine should be administered at age 2 years or older, repeated after 3 - 5 years for patients younger than age 10, or in 5 years for patients older than age 10.
Vaccination against Haemophilus influenza, the major cause of childhood meningitis, starting at age 2 months.
Influenza vaccines should be given every winter, starting at age 6 months.
Meningococcal vaccination for patients age 5 and older.
Hepatitis B vaccine. Anyone starting transfusion therapy should receive this vaccine.

Tuberculosis skin testing should be performed every year.

Antibiotics. In addition to regular immunizations, preventive (prophylactic) antibiotics are the best approach for protection against pneumonia and other serious infections among children with sickle cell disease. Babies diagnosed with sickle cell are given daily antibiotics, starting at 2 months of age and continuing through 5 years of age. Penicillin is usually the antibiotic given, unless a child is allergic to it.

Many patients stop taking their antibiotics or the parents stop giving them to their children. Doctors are concerned about developing bacterial resistance to common antibiotics and researchers warn that patients might experience breakthrough infections as resistance becomes more frequent.

Foods. Good nutrition, while essential for anyone, is critical for patients with sickle cell disease. Some dietary recommendations include:

Fluids are number one in importance. The patient should drink as much water as possible each day to prevent dehydration.
Diet should provide adequate calories, protein, fats, and vitamins and minerals. Patients and families should discuss vitamin and mineral supplements with their doctors and nurses.
Studies on omega-three fatty acids, found in fish and soybean oil, suggest that they might make red blood cell membranes less fragile, and possibly less likely to sickle, although no studies have proven this definitively. Fish and soy products have health benefits in any case. In one small study, fish oil supplements reduced the frequency of painful episodes over the course of a year.

Vitamins. Patients should take daily folic acid and vitamin B12 and B6 supplements. Vitamin B6 may have specific anti-sickling properties. Some experts recommend 1 mg folic acid, 6 microgram vitamin B12, and 6 mg vitamin B6. Foods containing one or all of these vitamins include meats, oily fish, poultry, whole grains, dried fortified cereals, soybeans, avocados, baked potatoes with skins, watermelon, plantains, bananas, peanuts, and brewer's yeast. Of note, folic acid can mask pernicious anemia, which is caused by deficiency of vitamin B12 and is more common in African-Americans than other populations.

Click the icon to see an image of vitamin B6 sources.

Note on Iron. Although sickle cell disease is often referred to as anemia, patients should avoid iron supplements or iron rich foods when receiving multiple transfusions, which increase the risk for iron-overload.

In assessing the seriousness of this disease, no one should underestimate its emotional and social impact. For the family, nothing is more heartbreaking than watching their child endure extreme pain and life-threatening medical conditions. The patient endures not only the pain itself but also the emotional strain from unpredictable bouts of pain, fear of death, and lost time and social isolation at school and work. Academic grades among patients average less than C, even in children with a low frequency of hospitalization (averaging 17 days a year).

These problems continue over the years, and both children and adults with sickle cell disease often suffer from depression. The financial costs of medical treatments combined with lost work can be very burdensome.

Any chronic illness places stress on the patient and family, but sickle cell patients and caregivers often face great obstacles in finding psychological support for the disease. Communities in which many sickle cell patients live generally lack services that can meet their needs, and professionals who work in their medical facilities are often overworked. In a study comparing patients with different kinds of long-term illnesses, those with sickle cell disease gave the lowest scores to their doctors and other professional caregivers for compassion, and were least satisfied with their medical care.

It is very important for patients and their caregivers to find emotional and psychological support. No one should or can endure this life-long disease alone. Unfortunately, studies indicate that most patients do not receive even basic supportive care that could help reduce the anxiety and intensity of pain that occurs when a sickle cell crisis erupts.

The following are some measures that some people find helpful in dealing with this disease:

Stress Reduction. Stress reduction techniques and relaxation methods appear to be helpful. Breathing and mediation techniques may be very helpful.
Cognitive-Behavioral Therapy. Studies suggest that cognitive behavioral therapies that teach coping skills can result in less negative thinking and even less pain. Coping skills refer to the patient's ability to respond to symptoms, such as pain.
On-Line Support Help. Computer on-line services are now valuable sources of support groups and access to research. They are particularly valuable for patients who cannot easily leave home or for patients who are ill.
Support Associations. Parent and professional support associations still offer the best and least expensive sources of help.

Other important factors are those that help maintain positive attitudes including spirituality, humor, or having important life goals (such as having children or pursuing a career).

Resources

www.sicklecelldisease.org -- Sickle Cell Disease Association of America
www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute (NHLBI)
www.scinfo.org -- Sickle Cell Information Center
www.sicklecellsociety.org -- Sickle Cell Society (UK)
www.sicklecell-info.org -- NHLBI Comprehensive Sickle Cell Centers
www.clinicaltrials.gov -- Find clinical trials

References

Adams RJ, Brambilla D; Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005 Dec 29;353(26):2769-78.

Al Hajeri AA, Fedorowicz Z, Omran A, Tadmouri GO. Piracetam for reducing the incidence of painful sickle cell disease crises. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD006111.

Bernaudin F, Socie G, Kuentz M, et al Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. Epub 2007 Jul 2.

Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003350.

Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program. 2006:58-62.

Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis. 2007 Jun 1;44(11):1428-33. Epub 2007 Apr 18.

Hankins JS, Wynn LW, Brugnara C, Hillery CA, Li CS, Wang WC. Phase I study of magnesium pidolate in combination with hydroxycarbamide for children with sickle cell anemia. Br J Haematol. 2008 Jan;140(1):80-5. Epub 2007 Nov 7.

Lee MT, Piomelli S, Granger S, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1;108(3):847-52.

Mehta SR, Afenyi-Annan A, Byrns PJ, Lottenberg R. Opportunities to improve outcomes in sickle cell disease. Am Fam Physician. 2006 Jul 15;74(2):303-10.

Singh PC, Ballas SK. Drugs for preventing red blood cell dehydration in people with sickle cell disease. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003426.

Tanabe P, Myers R, Zosel A, et al. Emergency department management of acute pain episodes in sickle cell disease. Acad Emerg Med. 2007 May;14(5):419-25. Epub 2007 Mar 26.

U.S. Preventive Services Task Force. Screening for Sickle Cell Disease in Newborns: U.S. Preventive Services Task Force Recommendation Statement. AHRQ Publication No. 07-05104-EF-2, September 2007. Agency for Healthcare Research and Quality, Rockville, MD.

Review Date:
3/11/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (1/1/2008).

A.D.A.M. Copyright

adam.com

Goodpasture syndrome

admin — Wed, 03 Sep 2008 17:47:33 -0700

Overview

Definition
Alternative Names
Causes, incidence, and risk factors
Symptoms
Signs and tests
Treatment
Expectations (prognosis)
Complications
Calling your health care provider
Prevention

Illustrations

Kidney blood supply

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Goodpasture syndrome is a disease that affects the kidneys and lungs. It usually involves rapidly progressive kidney failure that develops in days to weeks along with lung disease (cough, shortness of breath, and blood in the sputum).

Some forms of the disease involve just the lung or kidney, not both.

Alternative Names

Anti-glomerular basement membrane antibody disease; Rapidly progressive glomerulonephritis with pulmonary hemorrhage; Pulmonary renal syndrome; Glomerulonephritis - pulmonary hemorrhage

Causes, incidence, and risk factors

Goodpasture syndrome is an autoimmune disorder. This means your body makes antibodies that attack your own body tissues. In this case, antibodies form against a certain type of protein called collagen. The collagen is present in the alveoli (tiny air sacs in the lungs) and in the glomeruli (the filtering units of the kidney). These antibodies are called anti-glomerular basement membrane antibodies (or anti-GBM antibodies).

Sometimes the disorder is triggered by a viral respiratory infection or by inhaling hydrocarbon solvents. In such cases, the immune system may attack organs or tissues because it mistakes them for these viruses or foreign chemicals.

The antibody attack leads to bleeding in the air sacs, which causes shortness of breath, cough, and bloody sputum. It also causes inflammation in the glomeruli of the kidney, which causes blood in urine (hematuria), protein in the urine (proteinuria), or kidney failure.

Symptoms

Bloody urine
Dark colored urine
Decreased urine output
Foamy urine
Cough with bloody sputum (coughing up blood)
Difficulty breathing after exertion
Weakness
Nausea and vomiting
Chest pain
Pale skin

Signs and tests

During a physical examination, the health care provider will usually discover that the patient has high blood pressure. The patient usually has signs of fluid overload, such as swelling, gallop rhythms of the heart, and crackle sounds in the lungs. The crackles may also be from blood in the air sacs.

The following are relevant test results:

Urinalysis shows blood and protein in the urine. Abnormal red blood cells may be seen.
BUN and creatinine levels are elevated.
Chest x-ray shows diseased alveoli.
Arterial blood gas analysis may show low oxygen in the blood.
Lung biopsy shows damaged alveoli.
Kidney biopsy shows damaged glomeruli.
Anti-GBM antibody levels are elevated.

Treatment

The main goal is to remove the circulating antibodies from the blood. An early diagnosis is very important. The patient's outlook is much worse if the kidneys are already severely damaged when treatment begins.

Plasmapheresis is a procedure where blood plasma is removed from the circulation and replaced by fluid, protein, or donated plasma. This helps to make sure that harmful antibodies are removed.

Anti-inflammatory and cytotoxic agents (such as prednisone or cyclophosphamide) may be needed.

If kidney failure becomes severe, dialysis may be needed to substitute for the kidney's normal functioning.

Kidney transplantation may be performed in patients who suffer irreversible loss of kidney function. The nephrologist (a specialist physician) would usually wait for the levels of circulating anti-GBM antibodies to drop before proceeding with the transplant.

Expectations (prognosis)

The outlook varies. Early diagnosis and treatment tend to have better outcomes.

Complications

Rapidly progressive glomerulonephritis
Chronic kidney failure
End-stage kidney disease
Severe pulmonary hemorrhage (lung bleeding)
Respiratory failure

Calling your health care provider

Call for an appointment with your health care provider if the amount of urine you produce drops, or if you have any other symptoms of Goodpasture syndrome.

Prevention

Never sniff glue or siphon gasoline, which expose the lungs to hydrocarbon solvents and can cause the disease. Early diagnosis and treatment may slow the progression of the disorder.

Review Date: 11/16/2006

Reviewed By: David M. Charytan, MD,Department of Medicine, Division of Nephrology, Brigham and Women's Hospital, Boston, MA. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Source Doc: 1_000142

Rheumatoid arthritis

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Complications
Diagnosis
Treatment
Medications
Surgery
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Treatment Approaches

Patients with rheumatoid arthritis who do not respond to single-drug therapy often do better when a combination of drugs is used, indicates a review of 23 clinical trials published in 2007 in the Annals of Internal Medicine. However, the researchers were unable to determine which combinations of drugs work best or which individual drugs are more effective than others.
Combination drug treatment is now becoming a standard approach to treating rheumatoid arthritis while it is still in its early stages. Another 2007 Annals of Internal Medicine study indicated that initial combination therapies slow progression of joint damage more rapidly than single-drug therapy but, after several years, all treatment strategies produce benefits.

Fish Oil for Joint Pain

The omega-3 fatty acids found in fish oil may have anti-inflammatory properties that can help relieve joint pain, indicates a 2007 review in Pain. The researchers found that taking omega-3 fatty acids for 3 - 4 months helped reduce joint pain intensity, minutes of morning stiffness, the number of painful or tender joints, and consumption of non-steroidal anti-inflammatory drugs (NSAIDs). Salmon, mackerel, and herring are types of fish that are particularly high in these fatty acids. Fish oil can also be taken through dietary supplements, but these can interact with some types of prescription medications and may not be safe or appropriate for all patients. (Check with your doctor before taking these or any other supplements.)

Introduction

Rheumatoid arthritis (RA) is a chronic disease in which various joints in the body are inflamed, leading to swelling, pain, stiffness, and the possible loss of function.

Rheumatoid arthritis is an autoimmune disease in which the body's immune system attacks itself. The pattern of joints affected is usually symmetrical, involves the hands and other joints, and is worse in the morning. Rheumatoid arthritis is a systemic (body-wide) disease, involving other body organs, whereas osteoarthritis is limited to the joints. Both forms of arthritis can be crippling.

The process probably develops in the following way:

The disease process leading to rheumatoid arthritis begins in the synovium, the membrane that surrounds a joint and creates a protective sac.
This sac is filled with lubricating liquid called the synovial fluid. In addition to cushioning joints, this fluid supplies nutrients and oxygen to cartilage, a slippery tissue that coats the ends of bones.
Cartilage is composed primarily of collagen, the structural protein in the body, which forms a mesh to give support and flexibility to joints.
In rheumatoid arthritis, an abnormal immune system produces destructive molecules that cause continuous inflammation of the synovium. Collagen is gradually destroyed, narrowing the joint space and eventually damaging bone.
If the disease develops into a form called progressive rheumatoid arthritis, destruction to the cartilage accelerates. Fluid and immune system cells accumulate in the synovium to produce a pannus, a growth composed of thickened synovial tissue.
The pannus produces more enzymes that destroy nearby cartilage, aggravating the area and attracting more inflammatory white cells, thereby perpetuating the process.

This inflammatory process not only affects cartilage and bones but can also harm organs in other parts of the body.

Click the icon to see an image of rheumatoid arthritis.

Causes

Although much has been learned about the process leading to rheumatoid arthritis, researchers have yet to uncover all the factors that lead to this devastating disease. One prevalent theory is that a combination of factors triggers rheumatoid arthritis, including an abnormal autoimmune response, genetic susceptibility, and some environmental or biologic trigger, such as a viral infection or hormonal changes.

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight any infections.
In the process the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting off any bleeding blood vessel and initiating fiber-like patches to the tissue.
Under normal conditions, the immune system has other special factors that control and limit this inflammatory process.

The Infection Fighters. Two important components of the immune system that play a role in the inflammation associated with rheumatoid arthritis are B cells and T cells, both of which belong to a family of immune cells called lymphocytes.

When macrophages recognize foreign particles entering the bloodstream, they are programmed to ingest them, split them into pieces, and bring specific sections of them (antigens) into contact with the surface of the T cell. These antigens are placed within specialized proteins on the surface of the T cell that signal to a T cell and begin a process of immune system inspection. This process involves the interaction of several proteins on B cells and T cells, which seem to signal back and forth.

If the T cell recognizes an antigen as "non-self," it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion. T cells can be further categorized as killer T cells or helper T cells. Killer T cells directly attack antigens, such as viruses and tumor cells. Helper T cells recognize antigens that are presented to them by macrophages (or other specialized cells), and can stimulate B cells to mount various kinds of attacks on the antigen. They also produce chemicals (cytokines) that can have a more direct role in the inflammatory process.

For reasons that are still not completely understood, both the T cells and the B cells become overactive in patients with RA. In an immune response it is normal for the antibody response to change over time, particularly if the first antibodies that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes in an attempt to achieve better recognition and a stronger inflammatory response against a recalcitrant invader. In RA, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal repertoire of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Cytokines. Cytokines are very important in the destructive process of rheumatoid arthritis, particularly those known as interleukins (ILs) -- notably IL1 and IL6 -- and tumor necrosis factor (TNF). TNF is now known to be the major cause of joint damage and various systemic manifestations of RA, including weight loss.

Leukocytes. The leukocytes, the other major white blood cells in the body, are also spurred into action by the over-zealous T cells. Leukocytes stimulate the production of key players in the inflammatory process, including leukotrienes, prostaglandins, and nitric oxide.

The Hypothalamic-Pituitary-Adrenal Axis and Stress Hormones. Some research suggests that abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) may contribute to RA. The HPA system includes two parts of the brain (the hypothalamus and the pituitary) and the adrenal gland.

Click the icon to see an image of the adrenal glands.

The HPA axis regulates a person's response to stress, which includes the release of cortisol (an important stress hormones) and DHEA (a weak male hormone). The cytokines interleukin-6 and TNF-alpha normally stimulate a surge in these hormones, which then block further release of the cytokines. Research suggests, however, that in RA, a defective HPA axis responds to the cytokines with a lower-than-normal release of cortisol and DHEA. Without a strong stress response, the cytokine levels remain high and become destructive, causing inflammation.

Genetic factors play some role in RA, but are clearly not the only important factor. The presence of certain genetic mutations, however, may worsen the disease process. It should be pointed out that defective genes not only can be inherited but they may be changed and mutated by environmental or other factors. More research is needed to determine the specific genetic contributions to this disease.

HLA. HLA (human leukocyte antigen) is a genetically regulated molecule that traps part of antigens and presents them on the surface of cells for destruction by antibodies and T cells. It is designed to recognize self- from non-self cells. A number of HLA genetic forms called HLA-DRB1 alleles are referred to as the RA-shared epitope because of their association with rheumatoid arthritis. These genetic factors do not cause RA, but they may make the disease more severe once it has developed. Genetic variations in the HLA region may also predict drug treatment response to etanercept and the disease-modifying anti-rheumatic drug methotrexate.

Lack of Corticotropin-Releasing Hormone. Some people with RA may have a genetic deficiency of a hormone known as corticotropin-releasing hormone (CRH), which produces corticosteroids, hormones that suppress the inflammatory process.

Infections. Although many bacteria and viruses have been studied, no single organism has been proven to be the primary trigger for the autoimmune response and subsequent damaging inflammation. Higher than average levels of antibodies that react with the common intestinal bacteria E. coli have appeared in the synovial fluid of people with RA. Some experts think they may stimulate the immune system to prolong RA once the disease has been triggered by some other initial infection. Other potential triggers include Mycoplasma, parvovirus B19, retroviruses, mycobacteria, and Epstein-Barr virus.

Chemicals. A number of chemicals are being investigated as triggers of rheumatoid arthritis, but it is very difficult to determine causal effects of any specific trigger.

Risk Factors

Rheumatoid arthritis (RA) is an ancient disease. The condition has been identified in skeletons thousands of years old. According to the Arthritis Foundation, RA affects an estimated 2.1 million Americans.

Although the disease can occur at any age from childhood to old age, it usually starts in young adulthood, with onset peaking between the ages of 20 - 45. Still, about 50,000 children may be afflicted with juvenile rheumatoid arthritis.

Women are more likely to have RA than men. (The risk for women is slightly lower if they have been pregnant.) Women are also at higher risk for the severe type 2 rheumatoid arthritis.

Some people may inherit genes that make them susceptible to RA, but a family history of RA does not appear to increase an individual's risk.

Other factors may place certain susceptible individuals at higher risk for developing RA:

Heavy long-term smoking is a very strong risk factor for RA, particularly in patients without a family history of the disease.
Women who have a shorter fertility time (and so lower levels of reproductive hormones) may be at higher risk.
History of blood transfusions.

Most studies have not found any association between silicone breast implants and rheumatoid arthritis or other autoimmune disease (except possibly Sjögren syndrome).

Reports from a Dutch study suggest that hay fever sufferers have a reduced risk of developing rheumatoid arthritis, and, conversely, arthritis patients are less likely to have hay fever.

Symptoms

The hallmark symptom of rheumatoid arthritis is morning stiffness that lasts for at least an hour. (Stiffness from osteoarthritis, for instance, usually clears up within half an hour.) Even after remaining motionless for a few moments, the body can stiffen. Movement becomes easier again after loosening up.

Swelling and pain in the joints must occur for at least 6 weeks before a diagnosis of rheumatoid arthritis is considered. The inflamed joints are usually swollen and often feel warm and "boggy" when touched. The pain often occurs symmetrically but may be more severe on one side of the body, depending on which hand the person uses more often.

Although rheumatoid arthritis almost always develops in the wrists and knuckles, the knees and joints of the ball of the foot are often affected as well. Indeed, many joints may be involved, including those in the cervical spine, shoulders, elbows, tips, temporomandibular joint (jaw), and even joints between very small bones in the inner ear. Rheumatoid arthritis does not usually show up in the fingertips, where osteoarthritis is common, but joints at the base of the fingers are often painful.

In about 20% of people with RA, inflammation of small blood vessels can cause nodules, or lumps, under the skin. They are about the size of a pea or slightly larger, and are often located near the elbow, although they can show up anywhere. Nodules can occur throughout the course of the disease. Rarely, nodules may become sore and infected, particularly if they are in locations where stress occurs, such as the ankles. On rare occasions, nodules can reflect the presence of rheumatoid vasculitis, a condition that can affect blood vessels in the lungs, kidneys, or other organs.

Fluid may accumulate, particularly in the ankles. In rare cases, the joint sac behind the knee accumulates fluid and forms what is known as a Baker cyst. This cyst feels like a tumor and sometimes extends down the back of the calf causing pain.

Symptoms such as fatigue, weight loss, and fever may accompany early rheumatoid arthritis. Some people describe them as being similar to those of a cold or flu except, of course, RA symptoms can last for years.

In children, juvenile rheumatoid arthritis, also known as Still's disease, is usually preceded by high fever and shaking chills along with pain and swelling in many joints. A pink skin rash may be present.

Complications

Rheumatoid arthritis is not fatal, but complications of the disease may shorten survival by a few years in some individuals. Although type 2 rheumatoid arthritis is progressive and there is no cure, over time the disease becomes less aggressive, and symptoms may even improve.

Treatments for RA are increasingly effective in slowing this debilitating disease, and some may even prevent initial destruction by aggressively reducing inflammation. If bone and ligament destruction and any deformities have occurred, however, the effects are permanent. It is essential, therefore, to seek a doctor's help as soon as symptoms develop. Side effects of the treatments often contribute to the severity of the disease.

Affected joints can become deformed, and the performance of even ordinary tasks may be very difficult or impossible. According to one survey, 70% of patients with rheumatoid arthritis feel the disease prevents them from living a fully productive life. A 2000 study found that about one-third of people with RA stop working within 5 years of onset of the disease.

Rheumatoid arthritis can affect other parts of the body as well as the joints. Some patients with severe disease may then be at higher risk for complications, such as the following:

Peripheral Neuropathy. This condition affects the nerves, most often those in the hands and feet. It can result in tingling, numbness, or burning.
Muscle problems. Many patients have weakness of the muscles.
Anemia. People with RA may develop anemia, which involves a decrease in the production of red blood cells.
Scleritis and Episcleritis. This is an inflammation of the blood vessels in the eye that can result in corneal damage. Symptoms include redness of the eye and a gritty sensation.
Infections. Patients with RA have a higher risk for infections, particularly from some of the immune-suppressing drugs (corticosteroids, anti-tumor necrosis factors, disease modifying drugs) that they take.
Skin Problems. Skin problems are common, particularly on the fingers and under the nails. Some patients develop severe skin complications that include rash, ulcers, blisters (which may bleed in some cases), lumps under the skin, and other problems. Severe skin disease can reflects a more serious case of RA in general.
Osteoporosis. Osteoporosis, a disorder in which bone density decreases, is more common than average in postmenopausal women with RA. The hipbone is particularly affected. The risk for osteoporosis also appears to be higher than average in men with RA who are over 60 years old.
Lung Disease. Patients with RA are susceptible to chronic lung diseases, including interstitial fibrosis, pulmonary hypertension, and other problems. Both rheumatoid arthritis itself and some treatments may cause this damage.
Kidney. Although rheumatoid arthritis only rarely involves the kidney, many of the drugs used to treat it can damage kidneys.
Vasculitis. Vasculitis involves autoimmune inflammatory abnormalities in very small vessels and can affect many organs in the body. Manifestations of vasculitis include mouth ulcers, nerve disorders, rapid worsening of the lungs, inflammation of coronary arteries, and inflammation of the arteries supplying blood to the intestines.
Heart Disease. Inflammation of the heart muscle itself in the sac around the heart can cause many problems. Mounting evidence suggests that RA can increase the risk for heart disease, possibly because of the inflammatory response in RA, which may also injure arteries and heart muscle tissue. Some studies have reported that people with RA are 30 - 50% more likely to suffer heart vessel blockages and 60 - 70% more likely to die as result than people without RA.
Lymphoma and Other Cancers. Research suggests that patients with RA are four times more likely than healthy patients to develop non-Hodgkin’s lymphoma. There has also been concern that some RA treatments may increase the risk for lymphoma. Studies from 2006 indicate that RA’s chronic inflammatory process may play a role in the development of lymphoma. Researchers found that patients with very severe and long-term RA had a substantially increased risk of developing lymphoma. Other 2006 research suggests that RA drugs, such as biologic response modifiers, do not increase lymphoma risk, although they do increase skin cancer risk.
Periodontal Disease. People with RA may be twice as likely as non-arthritic individuals to have periodontal disease. Chronic inflammation and immune dysfunction are central to both diseases.
Pregnancy. Women with RA have an increased risk for premature delivery. They are also three times more likely than healthy women to develop hypertension during the last trimester of pregnancy.

Juvenile rheumatoid arthritis often resolves before adulthood. Patients who experience arthritis in only a few joints do better than those with more widespread (systemic) disease, which is very difficult to treat. Although it can be very serious, very few people die from this condition.

MAS. Macrophage activation syndrome (MAS) is a life-threatening complication of this disorder and requires immediate treatment with high-dose steroids and cyclosporin A. Parents should be aware of symptoms, which include persistent fever, weakness, drowsiness, and lethargy.

Diagnosis

Rheumatoid arthritis can be difficult to diagnose. Many other conditions resemble it and its symptoms can develop insidiously. Blood tests and x-rays may show normal results for months after the onset of joint pain. Even after rheumatoid arthritis has been diagnosed, it is extremely important to determine whether the course of the disease is benign (type 1) or aggressive (type 2) in order to treat the problem appropriately.

Specific findings or presentation more likely to suggest the diagnosis of rheumatoid arthritis include morning stiffness, involvement of three joints at the same time, involvement of both sides of the body, subcutaneous nodules, positive rheumatoid factor, changes in x-rays.

Various blood tests may be used to help diagnose RA, determine its severity, and detect complications of the disease.

Rheumatoid Factor. In RA, antibodies that collect in the synovium of the joint are known as rheumatoid factor. In about 80% of cases of RA, blood tests reveal rheumatoid factor. It can also show up in blood tests of people with other diseases. However, when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of type 2 RA. The presence of rheumatoid factor plus evidence of bone damage on x-rays also suggests a significant chance for progressive joint damage.

Erythrocyte Sedimentation Rate Test. An erythrocyte sedimentation rate (ESR or sed rate) measures how fast red blood cells (erythrocytes) fall to the bottom of a fine glass tube that is filled with the patient's blood. The higher the sed rate the greater the inflammation. In addition to rheumatoid arthritis, the sed rate can be high in many conditions ranging from infection to inflammation to tumors. The test is used, then, not for diagnosis, but to help determine how serious the condition is.

C-Reactive Protein. High levels of C-reactive protein (CRP) are also indicators of active inflammation. However, because obesity also increases CRP levels, the doctor should consider a patient’s body mass index when evaluating CRP levels during RA diagnosis.

Anti-CCP Antibody Test. The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop. In combination with the test for rheumatoid factor, the CCP antibody test is the best predictor of which patients will go on to develop severe RA. Used in Europe, the test is now beginning to be used somewhat more commonly in the U.S. U.S. laboratories have not yet developed consistent standards for interpreting the test, however.

Tests for Anemia. Anemia is a common complication. Blood tests are needed often to determine the amount of red blood cells (hemoglobin and hematocrit) and iron (soluble transferrin receptor and serum ferritin) in the blood.

Analyzing the synovial fluid might prove to be helpful in detecting markers of joint destruction, but this is not commonly performed. Some investigational examples include the following:

An enzyme called MMP-3 (matrix metalloproteinase 3) is involved with the degradation of cartilage. Its presence in synovial fluid is strongly associated with progressive joint destruction in patients with chronic RA.
High levels urocortin, a member of the peptide family involved in the stress response, may also be a major player in the RA inflammation.

X-Rays. X-rays generally have not been helpful to detect the presence of early rheumatoid arthritis because they cannot show images of soft tissue. The use of a technique known as dual energy x-ray absorptiometry, however, may be useful in detecting early bone loss in rheumatoid arthritis (2 - 27 months after onset). Evidence of damage on x-rays along with elevated rheumatoid factor is a significant predictor for progressive joint destruction.

Ultrasound. Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. PDUS may be reliable for monitoring inflammatory activity in the joint. QUS, which is used for osteoporosis, can detect bone loss in fingers, which may prove to be a good indicator of early RA.

Magnetic Resonance Imaging. Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays cannot. Further evaluation is necessary.

Symptoms of rheumatoid arthritis can be mimicked by things as benign as a bad mattress or as serious as cancer. A number of rare genetic diseases attack the joints. Physical injuries, infections, and poor circulation are among the many problems that can cause aches and pains. It would be impossible to discuss in this report the dozens of all conditions with symptoms of joint aches and pains.

Osteoarthritis. Osteoarthritis requires some special mention because it is the most common form of arthritis. It differs from RA in several important respects.

Osteoarthritis usually occurs in older people.
It is located in only one or a few joints. (In fact, osteoarthritis is probably most often confused with rheumatoid arthritis if it affects multiple joints in the body.)
The joints are less inflamed.
Progression of pain is almost always gradual.

Gout. Gout also causes swelling and severe pain in a joint, although most commonly starting in one joint. It is particularly difficult to distinguish chronic gout in older people from rheumatoid arthritis, however, since gout in this population can occur in a number of joints. A proper diagnosis can be made with a detailed medical history, laboratory tests, and detection in the affected joint of a salt called monosodium urate (MSU), which identifies gout.


Disease	Specific Subtypes
Osteoarthritis
Infectious Arthritis	Lyme disease, septic arthritis, bacterial endocarditis, mycobacterial and fungal arthritis, viral arthritis
Postinfectious or Reactive Arthritis	Reiter syndrome (a disorder characterized by arthritis and inflammation in the eye and urinary tract), rheumatic fever, inflammatory bowel disease
Crystal Induced Arthritis	Gout and pseudogout
Other Rheumatic Autoimmune Diseases	Systemic vasculitis, systemic lupus erythematosus, scleroderma, Still's Disease (also called juvenile rheumatoid arthritis), Behcet's disease
Other Diseases	Chronic fatigue syndrome, hepatitis C, familial Mediterranean fever, cancers, AIDS, leukemia, bunions, Whipple's disease, dermatomyositis, Henoch-Schonlein purpura, Kawasaki's disease, erythema nodosum, erythema multiforme, pyoderma gangrenosum, pustular psoriasis

Treatment

The treatment of rheumatoid arthritis involves medications and lifestyle changes.

Many drugs are used for managing the pain and slowing the progression of rheumatoid arthritis, but none completely cure the disease. Some experts believe that no single drug will ever cure rheumatoid arthritis because of the many factors that affect the disease at various times. The goals of drug treatment for rheumatoid arthritis include:

Reduce inflammation
Prevent damage to the bones and ligaments of the joint
Preserve movement
To be as inexpensive and as free from side effects as possible over the long-term

The drug categories used for RA include:

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) are the least potent drugs used for RA. These drugs relieve pain by reducing inflammation, but do not affect the course of the disease.
Disease-Modifying Anti-Rheumatic Drugs (DMARDs) are the main drugs used for treating rheumatoid arthritis. They slow the progression of the disease. They are much more effective than NSAIDs but also have more side effects. Methotrexate (Rheumatrex, Trexall) is the most widely used of these drugs.
Biologic Response Modifiers (also known as Biologic DMARDs) are often prescribed to patients who have failed to respond to DMARDs. They may be used alone or in combination with DMARDs such as methotrexate. They modify or block destructive immune factors such as tumor-necrosis factor (TNF). Current anti-TNF drugs include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). Other biologic response modifiers include the interleukin-1 antagonist anakinra (Kineret), the T cell co-stimulation modulator abatacept (Orencia), and rituximab (Rituxan), which targets CD20-positive B cells.
Corticosteroids, or steroids, are powerful anti-inflammatory drugs that are used to quickly reduce inflammation. These drugs include prednisone and prednisolone.

The question of how early and how aggressively to treat RA has been the subject of great debate. Among patients with RA, some will go into remission and remain in remission for the length of their lives even in the absence of treatment, while others will go on to develop active, sometimes severe RA.

Current practice has moved towards treating the disease aggressively while it is in its early stages to help prevent it from reaching a more severe and chronic state. Studies have found less joint damage in patients with early, aggressive treatment, particularly with the use of DMARDs and TNF modifiers in combination with methotrexate. Intensive early dosing of methotrexate may help slow progression of rheumatoid arthritis. Early combination therapy with DMARDs and corticosteroids is also showing good results.

During the first year of treatment, combination therapy appears to reduce the progression of joint deterioration more rapidly and effectively than single drug treatment. In addition, patients who have not been helped by one drug often benefit from a combination of drugs. However, over a longer period of time, it is not clear whether a drug combination approach offers many advantages over single drugs. It is also not certain which combination of drugs works best. Depending on your particular health condition, and how you respond to the drugs prescribed, your doctor may try various treatment strategies.

Medications

Two-thirds of people with RA rank pain as their primary reason for seeking professional help. The most common pain relievers for RA are nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs:

Over-the-counter NSAIDs include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), ketoprofen (Actron, Orudis KT).
Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), dexibuprofen (Seractil). In 2004, a new NSAID, meloxicam (Mobic) was approved in the U.S. for the management and treatment of rheumatoid arthritis.

Studies suggest that the best times for taking an NSAID may be after the evening meal and then again on awakening. RA symptoms increase gradually during the night, reaching their greatest severity at the time of awakening. Taking NSAIDs with food can reduce stomach discomfort, although it may slow down the pain-relieving effect.

In April 2005, the Food and Drug Administration (FDA) asked drug manufacturers of prescription NSAIDs to include with their products the same warning label used for the COX-2 inhibitor celecoxib (Celebrex). This "black box" warning, the FDA's strongest warning, emphasizes the increased risks for cardiovascular events and gastrointestinal bleeding associated with these drugs’ use. The FDA also requested manufacturers of OTC NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and gastrointestinal risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions. In December 2006, the FDA proposed even stronger labeling changes to highlight these drugs’ risk for liver damage as well as alcohol and drug interactions.

Long-term, regular use of NSAIDs can increase the risk for heart attack, especially for people who have a heart condition. Long-term use of NSAIDs is also the second most common cause of ulcers and gastrointestinal bleeding. To reduce the risks associated with NSAIDs, take the lowest dose possible for pain relief.

Other possible side effects of NSAIDs may include:

Upset stomach
Dyspepsia (burning, bloated feeling in pit of stomach)
Drowsiness
Skin bruising
High blood pressure
Fluid retention
Headache
Rash
Reduced kidney function

Long-term use of NSAIDs is the second most common cause of ulcers. Ulcers caused by NSAIDs are more likely to bleed than those caused by the bacteria Helicobacter pylori.

NSAID-related bleeding and stomach problems may be responsible for 107,000 hospital admissions and 16,500 deaths each year. Those at high risk for bleeding include people over age 60, anyone with a history of ulcers of gastrointestinal bleeding, patients with serious heart conditions, people who abuse alcohol, and those who take medications such as anticoagulants (blood thinners) and corticosteroids.

Proton-pump inhibitor (PPI) drugs may help prevent and heal ulcers caused by NSAIDs. PPIs include omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid).

COX-2 Inhibitors (Coxibs). Coxibs inhibit an inflammation-promoting enzyme called COX-2. This drug class was initially thought to provide benefits equal to NSAIDs but cause less gastrointestinal distress. However, following numerous reports of heart problems, skin rashes, and other adverse effects, the FDA re-evaluated the risks and benefits of this drug class. This lead to the removal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the United States market. Celecoxib (Celebrex) is still available, but patients should ask their doctor whether the drug is appropriate and safe for them. In December 2006, the FDA approved celecoxib for the relief of symptoms of juvenile rheumatoid arthritis in patients ages 2 years and older.

Disease-modifying anti-rheumatic drugs (DMARDs) are the standard treatments for RA. They are used either alone or in combination with newer biologic DMARDs.

DMARDs do not have any common properties other than their ability to slow down the progression of rheumatoid arthritis. Many were used for other diseases and were found accidentally to help RA. DMARDs include:

Methotrexate (considered to be the current standard of care)
Leflunomide
Hydroxychloroquine
Sulfasalazine
Gold
Minocycline
Azathioprine
Cyclosporine

Unfortunately, all DMARDs tend to lose effectiveness over time, even methotrexate. Patients rarely use one drug for more than 2 years. Combining DMARDs with each other or with drugs in other categories offers the best approach for many patients. The addition of a corticosteroid to any combination may also be helpful.

All DMARDs may produce stomach and intestinal side effects, and, over the long-term, each poses some risk for rare but serious reactions. (In some cases, however, they may be less harmful than long-term NSAID treatment.)

Methotrexate. Methotrexate (Rheumatrex, Trexall) acts as an anti-inflammatory drug and is now the most frequently used DMARD, particularly for severe disease. It has a faster mode of action than other DMARDs, (it starts working within 3 - 6 weeks), and its effectiveness as a well proven in studies.

Even this drug loses effectiveness, however, when used alone. It may be more effective when used in combination with other DMARDs or other drugs. Recent studies have focused on combining methotrexate with various biological response modifier drugs, especially for treatment of patients with early aggressive arthritis. The combination appears to work better than single drug therapy.

About 20% of patients withdraw from methotrexate because of its side effects. They include nausea and vomiting, rash, mild hair loss, headache, mouth sores, and muscle aches. Methotrexate reduces levels of folic acid (folate) in the body, which can lead to some of these side effects. Doctors may prescribe folic acid supplements to prevent side effects. However, some research suggests that folic acid may interfere with methotrexate’s effectiveness.

Methotrexate is usually given as pills. Patients who need higher doses can take it as an injection. Methotrexate has fewer serious toxic effects than many DMARDs. Although these severe reactions are rare, they may include:

Kidney and liver damage. People at particular risk for liver damage from methotrexate include those with diabetes, obesity, and alcoholism.
Increased risk for infections
Lung disease occurs in up to 5% of people. People who have poor lung function are most at risk.
The drug increases the risk for birth defects and should not be taken by pregnant women. However, methotrexate will not harm a woman’s chance for future healthy pregnancy.

Leflunomide. Leflunomide (Arava) blocks autoimmune antibodies and reduces inflammation. It also may inhibit metalloproteinases (MMP), which are involved in cartilage destruction. It has the following benefits:

It slows disease progression as early as 6 months into treatment.
Comparison studies with methotrexate report a better quality of life with leflunomide, including more energy, greater vitality, and fewer emotional side effects. (Studies comparing their risk for serious adverse effects are mixed. One, for example, showed fewer problems with leflunomide, while another reported identical rates.)

The combination of methotrexate and leflunomide (which has different effects on the immune system) is very effective compared to either drug alone. (This combination poses a risk for liver toxicity and requires monitoring.)

Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and liver injury. Everyone taking leflunomide should be monitored regularly, including blood tests for liver function, and anyone with liver problems should not take this drug. Monitoring of serum concentrations of the most active metabolite of leflunomide may help predict treatment response.

Hydroxychloroquine. Hydroxychloroquine (Plaquenil) was originally used for preventing malaria and is now also used for mild, slowly progressive arthritis. It can help relieve pain and improve mobility. It has one of the least toxic profiles of the DMARDs. The downside is that this drug can take up to 6 months to achieve full benefit. It also does not appear to slow disease progression. One study concluded that joint erosion after 2 years was worse than with no DMARD at all.

As with all DMARDs, gastrointestinal complaints are fairly common. This drug used to be associated with eye and vision problems, but with current lower doses this side effect is rare. If vision problems occur, it is usually with people taking very high doses, those with kidney disease, or those over 60 years of age. Still, you should have regular eye exams while taking this drug and notify your doctor if you experience any sudden changes in vision.

Sulfasalazine. Sulfasalazine (Azulfidine) was developed in the 1930s for treating rheumatoid arthritis, but fell into disfavor when gold treatment emerged. It has regained popularity, however, and is now used for both adult and juvenile RA. It works best when the disease is confined to the joints. Symptom relief occurs within 1 - 3 months.

Side effects are common, particularly stomach and intestinal distress, which usually occur early in the course of treatment. (However, serious gastrointestinal side effects, such as stomach ulcers, occur less frequently with sulfasalazine than with NSAIDs.) A coated-tablet form may help reduce side effects. Other side effects include skin rash and headache. Sulfasalazine increases sensitivity to sunlight. Be sure to wear sunscreen (SPF 15 or higher) while taking this drug. People with intestinal or urinary obstructions or who have allergies to sulfa drugs or salicylates should not take sulfasalazine.

Gold. Gold has been a long-standing DMARD for rheumatoid arthritis, although its use has decreased with the development of disease modifying and biologic drugs. Gold is usually administered in an injected form because the oral form, auranofin (Ridaura), is much less effective. There are two injectable forms of gold: Gold sodium thiomalate (Myochrysine) and aurothioglucose (Solganal). It can take 3 - 6 months before injections have an effect on RA symptoms.

Gold injections cause mouth sores in about a third of patients. Skin side effects include itching and rash, which can be severe in some patients. . The most serious side effects of gold injections, while rare, are kidney damage and decreased white blood cell count. Gold injections are not usually given to pregnant women. It is not definite that gold causes birth defects but doctors generally recommend that women use birth control while receiving this drug.

Minocycline. Minocycline (Minocin) is a tetracycline antibiotic that is usually prescribed for patients with mild RA. It can take 2 - 3 months before symptoms begin to improve and up to a year for full benefit. Side effects include upset stomach, dizziness, and skin rash. Long-term use of minocycline can cause changes in skin color, but this side effect usually disappears once the medication is stopped. Minocycline can cause yeast infections in women. Minocycline increases sensitivity to sunlight and patients should be sure to wear sunscreen. In rare cases, minocycline can affect the kidneys and liver.

Azathioprine. Azathioprine (Imuran) suppresses immune system activity. It takes 6 - 8 weeks for early symptom improvement and up to 12 weeks for full benefit. Azathioprine can cause serious problems with the gastrointestinal tract. About 10 - 15% of patients experience nausea and vomiting, often accompanied by stomach pain and diarrhea. (Taking the medication twice daily, instead of once daily, or taking it after eating may help avoid this problem.) Azathioprine can also cause problems with liver function and pancreas gland inflammation, and can reduce white blood cell count.

Cyclosporine. Like azathioprine, cyclosporine (Sandimmune, Neoral) is an immunosuppressant. It is used for people with RA who have not responded to other drugs. It can take a week before symptoms improve and up to 3 months for full benefit. The most serious and common side effects of cyclosporine are high blood pressure and kidney function problems. While kidney function usually improves once the drug is stopped, mild-to-moderate high blood pressure may continue. Cyclosporine can also cause gout or worsen gout in people who have this condition.

Other common side effects include headache, nausea, vomiting, stomach pain and upset, and swelling of hands and feet. About 10% of patients who take cyclosporine develop tremors, increased hair growth, muscle cramps, and numbing or tingling in hands and feet (neuropathy). Swelling of the gums is also common. Patients should practice good dental hygiene, including regular brushing and flossing.

Biologic response modifiers are drugs made from living cells. These drugs target specific components of the immune system that contribute to the joint inflammation and damage that are part of the rheumatoid arthritis disease process.

Currently approved biologic response modifiers include:

Etanercept (Enbrel). Etanercept is an anti-tumor necrosis factor (anti-TNF) drug. Approved in 1998, etanercept was the first biologic response modifier drug for treatment of rheumatoid arthritis. It is also approved for juvenile RA and psoriatic arthritis.
Infliximab (Remicade). Approved in 1999, infliximab is also an anti-TNF drug. It is used in combination with methotrexate.
Adalimumab (Humira). Adalimumab is another anti-TNF drug. First approved in 2002 as a second-line treatment for RA, adalimumab received additional approvals in 2005 as a first-line treatment for RA and psoriatic arthritis. It is used alone or in combination with methotrexate or other DMARDs. It is also showing promising results in clinical trials for juvenile rheumatoid arthritis.
Anakinra (Kineret). Approved in 2001, anakinra targets interleukin-1 (IL-1), another type of immune factor.
Abatacept (Orencia). Approved in 2005 for adults with moderate-to-severe RA who have not responded to DMARD or anti-TNF drugs. Abatacept is known as a T cell co-stimulation modulator. It blocks T cell activation. It is used alone or in combination with other DMARDs aside from anti-TNF drugs.
Rituximab (Rituxan). Approved in 2006, rituximab targets CD20-positive B cells and blocks their activation. It is used in combination with methotrexate for patients with moderate-to-severe RA who have not responded to anti-TNF therapies.

Some of these drugs are used as first-line treatments for RA. Others are used for patients who have not responded to DMARDs or other types of treatment. Depending on the specific drug, they may be used alone or in combination with the DMARD methotrexate. However, biologic response modifiers are not used in combination with each other, as they can lead to serious infections.

As with other rheumatoid arthritis drugs, these drugs do not cure the disease but can help slow progression and joint damage. In recent clinical trials, some patients have achieved remission using methotrexate in combination with infliximab, adalimumab, or rituximab.

Side Effects and Complications. Etanercept, adalimumab, and anakinra are given by injection and may cause pain at the injection site. To prevent injection reactions, patients are sometimes pretreated with betamethasone, a corticosteroid drug, but some research suggests that the steroid does little good. Infliximab, abatacept and rituximab are given by intravenous infusion. Common infusion reactions include headache, nausea, and flu-like symptoms. Because biologic response modifiers affect the immune system, patients who take these drugs have an increased risk for infections.

Other risks associated with these drugs include:

Anti-TNF drugs (etanercept, infliximab, adalimumab) have been associated with sepsis, pneumonia, and tuberculosis; non-melanoma skin cancer, lymphoma, and other malignancies; lupus; heart failure; blood disorders (including aplastic anemia); palmoplantar psoriasis; lung disease; and liver damage.
Anakinra may cause a sudden drop in white blood cells (leukopenia) that increases the risk for infections.
Abatacept should be used cautiously in patients with chronic obstructive pulmonary disorder (COPD) as it may increase the risk for respiratory complications.
Rituximab has been associated with cases of a rare and deadly brain infection called progressive multifocal leukoencephalopathy (PML). It also may cause hepatitis B reactivation, viral infections, and heart rhythm disturbances and other heart problems.

Corticosteroids work rapidly to control inflammation and pain. Long-time use, however, can have severe adverse effects. Still, they are often used under the following conditions:

Oral corticosteroids, such as prednisolone and prednisone (Deltasone, Orasone), are most often used in combination with DMARDs, which significantly enhances the benefits of DMARDs.
Oral corticosteroids are sometimes used in early stage-RA for patients who cannot tolerate NSAIDs. Studies, in fact, suggest that low-dose corticosteroids may significantly slow joint pain when it is the first drug administered and then used for 2 years. (Even low-dose oral steroids have adverse effects on bone density, blood sugar, and weight.)
Higher doses of corticosteroids are used for flareups of vasculitis and severe reactions to medications.
Corticosteroids may also be used during pregnancy to avoid exposure to more toxic drugs.
Daily, low-dose corticosteroids are also needed in some patients to control their rheumatoid arthritis symptoms.
Corticosteroids are sometimes injected directly into joints for relief of flare-ups when only one or a few joints are affected. Experts suggest no more than three or four injections into a specific joint a year. Steroid injections in the joints may be a safe and effective treatment for juvenile rheumatoid arthritis and reduce the need for oral medication.
Corticosteroid pulse therapy (intravenous administration) may work as well as DMARDs.

Side Effects of Oral Corticosteroids. Serious side effects are associated with long-term use of oral steroids. (Low doses may reduce these risks, but they do not eliminate them.) Osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, or bisphosphonates (alendronate etidronate, risedronate). Other adverse effects include cataracts, glaucoma, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and, rarely, psychosis. Recent research suggests that prednisone can increase the risk of developing non-melanoma skin cancer.

Withdrawal from Long-Term Use of Oral Corticosteroids. Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. There have been a few cases of severe adrenal insufficiency that occurred when switching from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first, and if steroids are withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctor measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times, when the risk increases.

Biologic Drugs. For many years, therapeutic treatment of rheumatoid arthritis focused on T cell mediation. New research is now examining the role of B cells, which become overactive in autoimmune disease, and how B cell depletion may help to reduce disease activity. Other areas of intense research include interleukin receptor antagonists, which target cytokines involved in the inflammatory process.

Many of the current investigational drugs are monoclonal antibodies (MAbs), biologic drugs that are designed to target specific receptors. Promising candidates in late-stage research include tocilizumab (Actemra), golimumab, denosumab, ocrelizumab, ofatumumab, and certolizumab.

Statins. Some research suggests that compounds derived from statins, the highly regarded cholesterol-lowering drugs, may suppress the inflammation responsible for RA damage.

Stem cell transplantation. Stem cells are the early versions of mature, specialized blood cells. Investigators are reporting that transplantation of donated hemopoietic stem cells, which mature into various blood cells, has induced remission in a few children with severe juvenile rheumatoid arthritis. The procedure is promising in select cases, but it can be highly toxic. More studies are needed to determine risks and benefits for RA patients.

Plasmapheresis. A device called the Prosorba column is used to remove inflammatory antibodies from the patient's blood. Small, short-term studies have shown that this therapy may slow or even halt the progression of the disease in a third to a half of patients. Side effects from the Prosorba column may include anemia, fatigue, itching, fever, a drop in blood pressure, and nausea. Nearly all patients experience an immediate flare-up of joint pain that lasts a few days. Some patients develop infection from the catheter used to remove blood. Long-term studies are needed.

Surgery

Certain surgical techniques may be helpful for people with severe deformities or disabilities.

Arthroscopy. Arthroscopy is performed to clean out bone and cartilage fragments that cause pain and inflammation. It is usually performed on the knee, but it also may be done on the hip:

The surgeon makes a small incision and injects a sterile solution to make the joint swell for easier viewing.
A lighted tube, called an arthroscope (which enables the surgeon to view the joint), is then inserted through another small incision.
Through a third incision, the surgeon trims, shaves, or stitches the damaged tissue. (Arthroscopy is most successful when the removal of cartilage only, and not bone, is involved.)

In many cases, the procedure can be done using local anesthetic, and the patient can go home within a day. In the case of knee operations, patients can resume mild activity in a couple of days, but full recovery can take up to 3 months.

Osteotomy. If only a certain section (the medial compartment) of the knee is damaged and deformed, the surgeon may choose to perform osteotomy:

The knee is opened.
A debridement (removal of damaged tissue) is performed in the joint to eliminate the loose or torn fragments that are causing pain and inflammation.
The bone is then reshaped to remove the deformity.

The procedure is best used in heavier adults who are under 60 years old.

Unicompartmental Knee Arthroplasty. Unicompartmental knee arthroplasty (also called unicondylar knee arthroplasty) may be a useful procedure in some cases of limited damage in the knee. It is intended to relieve pain and preserve function as long as possible before a total knee replacement is necessary. The procedure involves a small incision and insertion of small implants. It retains important knee ligaments, which should preserve more movement than a total knee replacement. The procedure is not widely available and is somewhat controversial, since the implants may not be as reliable as those in total knee replacement.

Synovectomy. Synovectomy is a procedure whereby the diseased joint lining is removed. It is used when more conservative measures fail, particularly in the wrist. Studies are suggesting, however, that with the use of lasers for the procedure, eventually synovectomy may prove to be an alternative to DMARD treatments in reducing symptoms and achieving long-term remission.

Joint Replacement Surgery. Eventually, even after these procedures, rheumatoid arthritis may progress to the point that normal functioning is impossible. In such cases, artificial (prosthetic) replacement joint implants may be considered for knees, hips, or other joints. The prosthesis is usually made of a chromium alloy and plastic and may be attached to the adjoining bones using a cement, polymethyl methacrylate, or the prosthesis may be composed of a porous material that allows bone to grow into and eventually adhere to the device.

Although this procedure has usually been performed in people over 60, implants are now lasting 20 years and more and younger patients with severe disability are finding them useful. Uncemented arthroplasty using porous material is showing particularly good results. Studies on hip replacement, for example, now report that after 10 years, 5% of patients require reoperation and 12% of patients report some pain.

Lifestyle Changes

It is important to maintain a balance between rest (which will reduce inflammation) and exercise (which will relieve stiffness and weakness). Studies have suggested that even as little as 3 hours of physical therapy over 6 weeks will help people with RA, and that these benefits are sustained.

The goal of exercise is to:

Maintain a wide range of motion
Increase strength, endurance, and mobility
Improve general health
Promote well-being

In general, doctors recommend the following approaches:

Start with the easiest exercises, stretching and tensing of the joints without movement.
Next attempt mild strength training. (One study found that people with RA who exercised with machines that use compressed air for gentle resistance experienced less pain and increased muscle tone.)
The next step is to try aerobic exercises. These include walking, dancing, or swimming, particularly in heated pools. Avoid heavy impact exercises, such as running, downhill skiing, and jumping.
Tai chi, which uses graceful slow sweeping movements, is an excellent method for combining stretching and range-of-motion exercises with relaxation techniques. It is of particularly value for elderly RA patients who report significantly less pain after practicing this technique.

While traditional guidelines have restricted RA patients to only gentle exercise, recent research suggests that more intense exercise may not only be safe, but may actually produce greater muscle strength and overall functioning. Common sense is the best guide:

If exercise is causing sharp pain, stop immediately.
If lesser aches and pains continue for more than 2 hours afterwards, try a lighter exercise program for a while.
Using large joints instead of small ones for ordinary tasks can help relieve pressure, for instance, closing a door with the hip or pushing buttons with the palm of the hand.

Many patients with RA try dietary approaches, such as fasting, vegan diets, or eliminating specific foods, that seem to worsen RA symptoms. There is little scientific evidence to support these approaches but some patients report anecdotally that they are helpful.

In recent years, a number of studies have suggested that the omega-3 fatty acids contained in fish oil may have anti-inflammatory properties useful for RA joint pain relief. The best source of fish oil is through increased consumption of fatty fish such as salmon, mackerel, and herring. Fish oil supplements are another option, but they may interact with certain medications. If you are thinking of trying fish oil supplements, talk to your doctor first.

Various ointments, including Ben Gay and capsaicin (a cream that use the active ingredient in chilli peppers), may help soothe painful joints.

Orthotic devices are specialized braces and splints that support and help align joints. Many such devices made from a variety of light materials are available and can be very helpful when worn properly.

A number of specially designed appliances and devices are available to ease daily activities.

Although the influence of stress or emotions on the progression of RA is not fully known, having a history of major depression that persists or reoccurs seems to increase the pain, disability, and fatigue. Stress management alone cannot reduce pain, but it may be very helpful in helping people deal with their condition.

One study found that people with RA reported significant clinical improvement after writing about their pain, stress, or other traumatic experiences. Writing for 20 minutes, just a few days a week, resulted in improvement that lasted for months. One study found that spirituality (defined as "a belief in a power outside oneself and one's own existence," as opposed to the practice of any specific religion) is associated with better health, happiness and well-being among RA patients. (Spiritual healing does not appear to offer any advantages.)

People often turn to alternative therapies or nontraditional remedies to relieve the pain of rheumatoid arthritis. Some alternative procedures, such as acupuncture, massage, relaxation techniques, biofeedback, and hypnosis, are not harmful and may be a useful adjunct to standard treatments.

In a small study, acupuncture reduced pain by a third in 73% of patients, and more than half reported at least a 50% improvement in pain. Patients also reduced their use of pain medications. Research presented at the 2006 American College of Rheumatology annual meeting suggested that both electroacupuncture and traditional acupuncture may help reduce joint tenderness.
Balneotherapy, also known as hydrotherapy or spa therapy, is an ancient form of therapy that involves mineral baths to soothe pain, and some patients have reported relief using such baths.
The NIH is conducting clinical trials to examine whether relaxation response, tai chi, stress management, and cognitive-behavioral therapy can help patients with RA feel better.

Herbal remedies used for RA include boswellia, equisetum arvense (horsetail), devil's claw, borage seed oil, and many others. To date, no evidence supports their efficacy.

Researchers are currently conducting studies in animals to determine if supplements extracted from the turmeric spice can help prevent joint inflammation. The U.S. National Institutes of Health is also conducting a clinical trial to compare the clinical effects of the Chinese herb Tripterygium wilfordii Hook F (TwHF) with the pharmaceutical drug sulfasalazine. TwHF is traditionally used in Chinese medicine for its anti-inflammatory properties.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

Resources

www.niams.nih.gov -- The National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.rheumatology.org -- American College of Rheumatology
www.arthritis.org -- The Arthritis Foundation
www.fda.gov/cder/drug/infopage/cox2 -- FDA information on COX-2 inhibitors and NSAIDs
www.clinicaltrials.gov -- Find a clinical trial

References

Chen YF, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess. 2006 Nov;10(42):iii-iv, xi-xiii, 1-229.

Donahue KE, Gartlehner G, Jonas DE, Lux LJ, Thieda P, Jonas BL, et al. Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis. Ann Intern Med. 2007 Nov 19 [Epub ahead of print]

Firestein GS. In: Harris ED Jr, ed. Kelley's Textbook of Rheumatology. 7th ed. Saunders; 2005.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Sieper J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis. 2007 Nov;66 Suppl 3:iii2-22.

Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM,, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007 Mar 20;146(6):406-15.

Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007 May;129(1-2):210-23. Epub 2007 Mar 1.

Harris ED Jr. In: Harris ED Jr, ed. Kelley's Textbook of Rheumatology. 7th ed. Saunders; 2005. O’Dell JR. In: Goldman, ed. Cecil Medicine. 23rd ed. Saunders; 2007.

Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007 Dec 1;370(9602):1861-74.

Smolen JS, Keystone EC, Emery P, Breedveld FC, Betteridge N, Burmester GR,. et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2007 Feb; 66(2): 143-50.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Cirrhosis

FitSugar — Wed, 08 Oct 2008 17:35:41 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Complications
Diagnosis
Treatment
Lifestyle Changes
Abdominal Infections
Encephalopathy
Ascites
Bleeding Episodes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In 2007, the Food and Drug Administration approved HepaGram B, an injectable immune globulin that can help prevent recurrence of hepatitis B following liver transplantation.

Primary Biliary Cirrhosis

Primary biliary cirrhosis is an autoimmune liver disease that increases the risk for liver cancer. According to a 2007 study, specific risk factors may help predict which patients with primary biliary cirrhosis are at particularly high risk of developing liver cancer. These risk factors include older age, being male, history of blood transfusion, and any signs of portal hypertension (high pressure of the blood in the portal vein, which leads to the liver) or cirrhosis.

Hepatitis C and Cirrhosis

Patients with cirrhosis who are infected with a particular hepatitis C genotype (1b) have a high risk of developing liver cancer, indicates a 2007 study. These patients should receive regular monitoring so that liver cancer can be detected in its earliest stages.
Interferon drug therapy can help reduce -- but not entirely eliminate -- the risk of liver cancer developing in patients with hepatitis C-related cirrhosis.

Hemochromatosis

Hemochromatosis, also called “iron overload,” is an iron disorder that increases the risk for cirrhosis. Hereditary hemochromatosis is one of the most common genetic diseases in the United States, and experts have debated whether all people should get screened for it. In 2006, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines concerning hemochromatosis screening. The USPSTF does not recommend routine screening in the general population. However, people who have family histories of hemochromatosis, or who show signs or symptoms of this disorder, should get tested.

Encephalopathy

Lactulose, a drug that helps remove ammonia from the body, can help improve cognitive function and quality of life for people with hepatic encephalopathy, suggests a 2007 study. Hepatic encephalopathy, a complication of liver disease, affects the brain and nervous system.

Introduction

Cirrhosis is an irreversible result of various disorders that damage liver cells over time. Eventually, damage becomes so extensive that the normal structure of the liver is distorted and its function is impaired.

Cirrhosis is a chronic liver disease that causes damage to liver tissue, scarring of the liver (fibrosis - nodular regeneration), progressive decrease in liver function, excessive fluid in the abdomen (ascites), bleeding disorders (coagulopathy), increased pressure in the blood vessels (portal hypertension), and brain function disorders (hepatic encephalopathy). Excessive alcohol use is the leading cause of cirrhosis.

The disease process often takes the following path:

Scarring. The main damage in cirrhosis is triggered by scarring (fibrosis) that occurs from injuries due to alcohol, viruses, or other assaults. Normal clumps and form nodules around the scarred areas. The scar tissue and regenerated nodules act like small dams and alter the flow of blood and bile in and out of the liver.

Altered Blood and Bile Flow. The changes in blood and bile flow have significant consequences, with both the liver and other organs responding to the altered flow:

The spleen overproduces nitric oxide, a gas that causes blood vessels in the spleen to relax and open.
The small blood vessels and bile ducts in the liver itself, however, narrow (constrict). (Blood vessels in other organs, including the kidney, also narrow.)
Blood flow coming from the intestine into the liver is slowed by the narrow blood vessels. It backs up through the portal vein and seeks other routes.
New, abnormally twisted and swollen veins called varices form in the stomach and lower part of the esophagus in order to compensate for the backup blood.
Bile also builds up in the bloodstream, resulting in high levels of bilirubin, which causes a yellowish cast in the skin called jaundice.
Fluid buildup also occurs in the abdomen (called ascites), and swelling in the arms and legs is common.

Changes in Liver Size. The liver enlarges in the first phases of the disease. In advanced stages, the liver sometimes shrinks, a condition called postnecrotic cirrhosis.

The liver is the largest organ in the body. In the healthy adult, it weighs about 3 pounds. The liver is wedge-shaped, with the top part wider than the bottom. It is located immediately below the diaphragm and occupies the entire upper right quadrant of the abdomen.

Vital Functions. The liver performs over 500 vital functions. Damage to the liver can impair these and many other processes. Among them are the following:

Processing Healthful Nutrients. It processes all of the nutrients the body requires, including proteins, glucose, vitamins, and fats.

Bile Production. The liver produces bile, a green-colored fluid that helps the body absorb fats and fat-soluble vitamins. Bile is formed from bilirubin, a yellow-green pigment produced from the breakdown of hemoglobin, the oxygen-carrying component in red blood cells. Bile contains bile salts, fatty acids, cholesterol, and other substances. Bile travels from the liver to the gallbladder, where it is stored until after a meal. It is then secreted into the intestines where it helps digest fat.

Eliminating Toxins. One of the liver's major functions is to render harmless potentially toxic substances, including alcohol, ammonia, nicotine, drugs, and harmful by-products of digestion.

Recycling Blood. The liver and spleen removes old red blood cells from the blood. The iron contained in them is recycled in the bone marrow to make new red blood cells.

The Liver's Architecture. The vital processes the liver performs rely on well-organized liver architecture.

The Building Blocks. The basic building blocks of the liver are the following structures:

Bile ducts
Blood vessels
Working liver tissue (called the parenchyma)
Supportive (connective) tissue

The Architecture. The liver is a built on a framework of lobes:

The lobes. The liver is divided into two major lobes, a right and a smaller left, that are separated by tough, fibrous connective tissue.
The lobules. The liver's two major lobes contain about 100,000 smaller lobes, called lobules. Each lobule contains microscopic columns of liver cells and blood vessels. Bracing the corners of each lobule column are an artery and a vein that carry blood and a bile duct that drains bile.
The arteries and veins. The arteries bring oxygen-rich blood to nourish the liver cells. The veins supply the liver cells with blood containing the nutrients and toxins that the liver cells process. A central vein runs through each column and collects the processed blood from both sources. These veins join to form the hepatic vein.
The bile ducts. The bile ducts in the column corners collect bile draining from tiny canals around the liver cells. These ducts eventually join to form the large common bile duct that leads from the liver to the gallbladder.

The Liver's Blood Supply. The liver is rich in blood. It holds about a pint, or 13% of the body's supply. It is furnished with blood from two large vessels, the hepatic artery and the portal vein, and is drained of blood by the hepatic vein. (The word "hepatic" derives from the Latin word for liver.)

The hepatic artery. This artery supplies blood from the heart directly to the liver. This blood nourishes the liver.

The portal vein. The portal vein carries to the liver blood that has been circulating through the stomach, spleen, and intestine. The liver processes this blood, extracting nutrients and toxins.

The hepatic vein. This vein carries blood from the liver and connects to the inferior vena cava, a large vein that carries blood back to the heart.

Click the icon to see an image of the liver.

Causes

Several processes can lead to cirrhosis.

Alcoholism particularly endangers the liver. Alcoholic cirrhosis (also sometimes referred to as portal, Laennec's, nutritional, or micronodular cirrhosis) is the primary cause of cirrhosis in the U.S. It is estimated to be responsible for 44% of deaths from cirrhosis in North America. Some experts believe this estimate is low. One Canadian study found alcohol to be the major contributor in 80% of all cirrhosis deaths.

The relationship between alcohol and cirrhosis is generally as follows:

Alcohol is absorbed from the small intestine, and the blood carries it directly into the liver, where it becomes the preferred energy source.
In the liver, alcohol converts to toxic chemicals, such as acetaldehyde (AcH), which trigger the production of powerful immune factors called cytokines. These molecules in large amounts can cause inflammation and tissue injury. They are proving to be major culprits in the destructive process in the liver. AcH is particularly being researched because it plays a role in most actions of alcohol, including damaging effects on the liver that may lead to cirrhosis.
The injured liver eventually is unable to break down fatty acids, compounds that make up fat. Over time, then, fat accumulates, further impairing the liver's ability to absorb oxygen and increasing its susceptibility to injury. During the initial phase, the fat-laden liver becomes greatly enlarged, but it eventually shrinks as cirrhosis develops.

Chronic hepatitis, both hepatitis B and hepatitis C, is the second leading cause of cirrhosis. Chronic hepatitis C is the more dangerous form and accounts for one-third of all cirrhosis cases. About 5 - 20% of patients with chronic hepatitis C, and 5 - 10% of patients with chronic hepatitis B, eventually develop cirrhosis over the course of several decades. The longer a patient has had chronic hepatitis, the greater the risk for eventually developing cirrhosis. A 2005 study indicated that cirrhosis develops in 70% of patients who have had hepatitis C for more than 60 years.

The hepatitis virus can produce inflammation in liver cells, causing injury or destruction. If the condition is severe enough, the cell damage becomes progressive, building a layer of scar tissue over the liver. In advanced cases, as with alcoholic cirrhosis, the liver shrivels in size, a condition called postnecrotic or posthepatic cirrhosis.

Hepatitis C is a virus-caused liver inflammation which may lead to jaundice, fever, and cirrhosis. The people most at risk for contracting and spreading hepatitis C are those who share needles for injecting drugs and health care workers or emergency workers who may be exposed to contaminated blood.

Autoimmune liver diseases include autoimmune hepatitis and primary biliary cirrhosis. Like other autoimmune disorders, these conditions most likely develop because a genetically defective immune system attacks the body's own cells and organs. People who have one of these liver diseases also often have other autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, scleroderma, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia.

Autoimmune Hepatitis. Autoimmune chronic hepatitis occurs when an abnormal immune response causes an attack on the liver cells. It accounts for about 20% of all chronic hepatitis cases. Autoimmune chronic hepatitis typically occurs in women age 20 - 40 who have other autoimmune diseases. Some research indicates that the postmenopausal period may be another peak in incidence of AIH among women. About 30% of patients are men, however, and in both genders there is often no relationship to another autoimmune disease. In general, no major risk factors have been discovered for this condition.

Suspects for triggering this hepatitis include the measles virus, a hepatitis virus, or the Epstein-Barr virus, which causes mononucleosis. It is also possible that a reaction to a drug or other toxin that affects the liver also triggers an autoimmune response in some people.

Click the icon to see an image of mononucleosis.

Primary Biliary Cirrhosis. Up to 95% of primary biliary cirrhosis (PBC) cases occur in women, usually around age 50. In people with PBC, the immune system attacks and destroys cells in the liver’s bile ducts. Like many autoimmune disorders, the causes of PBC are unknown. Recent research indicates the following risk factors:

Family history of PBC
Family history of Sjögren syndrome (another autoimmune disorder)
Individual history of urinary tract infections (UTI)
History of smoking
History of nail polish use
Hormone replacement therapy
Exposure to toxins from hazardous waste sites

This research suggests that environmental factors (chemicals, cigarette smoke) or infectious organisms (bacteria that causes UTI) may trigger PBC in patients who are genetically susceptible to the disease. Women who have never been pregnant appear less likely to develop PBC.

Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease, but it occurs in people who do not drink a lot of alcohol. Obesity and type 2 diabetes are the two main causes of a fatty liver. Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver. A diet high in fatty foods may also be a risk factor, as dietary fat accumulates in the liver. Due to the recent rise in childhood obesity, NAFLD is increasingly occurring in children. In fact, NAFLD is now the most common liver disease in American children.

Nonalcoholic fatty liver disease can lead to nonalcoholic steatohepatitis (NASH). Liver inflammation and injury, as well as a fatty liver, characterize NASH. NASH occurs in about half of people with diabetes and up to 75% of obese people.

Nonalcoholic fatty liver disease is usually benign and very slowly progressive. But, in certain patients it can lead to cirrhosis, liver failure, or liver cancer. About 8 - 20% of people with nonalcoholic steatohepatitis go on to develop cirrhosis. A 2006 study indicated that NASH-related cirrhosis causes fewer deaths than cirrhosis that is caused by chronic hepatitis C. However, many patients with NASH have coronary artery disease and heart failure and have a high risk of dying from heart disease.

Weight reduction and diabetes and cholesterol management are the primary approaches to controlling these diseases.

Hemochromatosis is a disorder of iron metabolism. This disease interferes with the way the body normally gets rid of iron. People with hemochromatosis absorb too much more iron from the food that they eat. The iron overload accumulates in organs in the body. When excess iron deposits accumulate in the liver, they can cause cirrhosis.

There are two main forms of hemochromatosis:

Primary hemochromatosis, also called hereditary hemochromatosis, is an inherited genetic disease.
Secondary hemochromatosis results from other conditions, such as anemia and alcoholism.

Hereditary hemochromatosis is one of the most common genetic diseases, especially among Caucasians. About 1 in every 200 Americans carries the gene that causes this disease. Although experts do not recommend that everyone get screened for hemochromatosis, people who have a family history of this disease, or who show symptoms (joint pain, fatigue, abdominal pain), should get tested. Left untreated, hemochromatosis can lead to serious damage of the liver, heart, and pancreas.

Hemochromatosis is treated with phlebotomy, a procedure that involves removing about a pint of blood once or twice a week. Starting phlebotomy treatment before organ damage occurs can help prevent cirrhosis. If, however, cirrhosis has already developed, patients have a high risk for developing liver cancer even if iron levels are normalized.

Inherited Diseases. Cirrhosis can be caused by several inherited diseases, including:

Cystic fibrosis
Alpha-1 antitrypsin deficiency
Galactosemia
Glycogen storage diseases
Wilson's disease

Other Rare Causes. Rare causes of cirrhosis include:

Schistosomiasis, caused by a parasite found in the Far East, Africa, and South America.
Small intestine bypass surgery (rarely, if ever, performed anymore).
Long-term or high level exposure to certain chemicals and drugs can cause cirrhosis, including arsenic, methotrexate, and toxic doses of vitamin A.

Cancers that have metastasized to the liver, blood clots in the hepatic or portal vein, or obstructions in the bile duct can cause changes that resemble cirrhosis.

Risk Factors

Cirrhosis affects about 3 million Americans a year. However, because about 2.7 - 4 million people harbor hepatitis C, the rates of cirrhosis could dramatically increase over the next few years.

Only 10% of heavy drinkers develop advanced liver disease. Not eating when drinking and consuming a variety of alcoholic beverages are factors that increase the risk for liver damage. Still, the amount of alcohol consumed and the patterns of drinking are only weak predictions of risk. Other risk factors have been identified that may increase the danger to the liver:

Obesity is a major factor for all stages of liver disease.
Women develop liver disease at lower quantities of alcohol intake than men. The reason for this may be due to women's inability to metabolize alcohol as quickly as men, so it stays in the bloodstream longer.
Genetic factors that regulate the immune responses in the intestine also play a role in increasing the risk for liver injury from alcoholism.

Risk Factors for Developing Cirrhosis from Hepatitis C. Overall, between 10 - 15% of patients with chronic hepatitis C develop cirrhosis. The risk varies widely, however. The following conditions put people with hepatitis C at higher risk for liver damage:

Overall the risk for progression is highest in men -- particularly African-Americans -- who were older at the time of infection. The risk is much lower in women and children (2 - 4%).
Moderate-to-heavy alcohol users. (Even one or two alcoholic drinks a day increase the risk for liver injury in hepatitis C patients.)
Having a specific genetic type of the virus. There are six main genetic types and more than 90 subtypes, which can differ significantly in their effects and response to treatment. Genotype 1 is the most serious and is the cause of up to three quarters of the cases in the U.S. The other common forms are types 2 (15%) and 3 (7%), which pose less danger.
Co-infection with hepatitis B. Co-infection with B significantly affects the outcome of these patients and may be more common than previously believed. This co-condition may cause superinfections with very serious consequences, reduce these patients' responses to interferon therapy, and increase their risk of liver cancer. Patients with hepatitis C should be immunized against hepatitis B.
Co-infection with HIV.
A history of transfusions. (In one report, the risk in middle-aged patients with a history of transfusions was 20 - 30%).
Being diabetic and overweight, particularly if fat is distributed in the abdomen (an apple-shape). This condition poses a higher risk for nonalcoholic fatty liver disease (NASH), which in turn is apt to become scarred and cirrhotic.

Weight gain in the area of and above the waist (apple type) is more dangerous than weight gained around the hips and flank area (pear type). Fat cells in the upper body have different qualities than those found in hips and thighs.

Having large iron stores in the liver.
High exposure to toxic chemicals or environmental contaminants.

Because there are millions of Americans now infected with chronic hepatitis C, doctors have been justifiably concerned that there will be a significant number of cases of liver failure and liver cancer in the coming years. Computer analyses have suggested that mortality rates from hepatitis C-related cirrhosis or liver cancer will double or triple over the next 20 years. Fortunately, improved therapies may significantly reduce these discouraging estimates.

Researchers are working on developing a genetic test to identify patients with chronic hepatitis C who are most at risk of developing cirrhosis. In 2007, scientists announced they had made progress on a test that measures variations in seven genes to calculate a “Cirrhosis Risk Score.” The researchers hope that this experimental test may eventually help doctors decide which patients should receive early treatment with alpha-interferon and ribavirin.

Risk Factors for Developing Cirrhosis from Hepatitis B. The great majority of people with chronic persistent hepatitis B have a good long-term outlook. Between 5 - 10%, however, become carriers of the virus, and 5 - 10% of these individuals eventually develop cirrhosis. The addition of hepatitis D is a particular danger and increases the risk for cirrhosis. Seven genetic types of hepatitis B virus (designated A to G) have now been identified, which may help researchers determine the patients who may have a better outlook than others. Genotype C is the most common form and is more aggressive than genotype B, which also responds better to treatment.

Primary biliary cirrhosis accounts for only 0.6 - 2% of deaths from cirrhosis. In patients with chronic persistent autoimmune hepatitis, the outlook is very favorable, and survival rates are equal to the general population. If it becomes active, it must be treated. Left untreated, the 5-year survival rates of primary biliary cirrhosis are 50%.

Obesity increases the risk for nonalcoholic fatty liver disease (NAFLD), a condition that can lead to nonalcoholic steatohepatitis (NASH). Studies estimate that 8 - 20% of people with NASH eventually develop cirrhosis. A 2006 study found that people with NAFLD and elevated liver enzymes have a high risk of developing end-stage liver disease. People with NASH had an especially poor prognosis for survival. Losing weight is important for overweight people with NASH and may help to delay disease progression. A 2003 study of more than 11,000 patients indicated that obesity increases the risk of death from cirrhosis in people who drink little or no alcohol, but not among those who drink alcohol.

Symptoms

Many people experience few symptoms at the onset of cirrhosis.

Early symptoms include:

Fatigue and loss of energy.
Loss of appetite and nausea.
Spider angiomas may develop on the skin. These are pinhead-sized red spots from which tiny blood vessels radiate.

Patients in later stages may develop the following symptoms:

Jaundice. This yellowish cast to the skin and eyes occurs because the liver cannot process bilirubin for elimination from the body.

Jaundice is a condition produced when excess amounts of bilirubin circulating in the bloodstream dissolve in the subcutaneous fat (the layer of fat just beneath the skin), causing a yellowish appearance of the skin and the whites of the eyes. With the exception of normal newborn jaundice in the first week of life, all other jaundice indicates overload or damage to the liver, or inability to move bilirubin from the liver through the biliary tract to the gut.

The palms of the hands may be reddish and blotchy, a condition known as palmar erythema.
Loss of body hair.
Abnormalities in hormone-affected organs. In men with alcoholic cirrhosis, the testicles may atrophy, and their breasts may become swollen, sometimes painfully.
Ascites. A swollen belly is a sign of ascites, the most common major complication of cirrhosis, which occurs when fluid accumulates in the abdomen. Fever, abdominal pain, and tenderness when the belly is pressed indicate that the fluid is infected, but infection can occur without any symptoms.
Fluid buildup and swelling (edema) in legs.

People with primary biliary cirrhosis may have severe generalized itching and often develop small fatty yellow lumps called xanthomas on the eyelids, hands, and elbows. They may have an unpleasant condition called steatorrhea, in which the feces contain excessive fat, causing them to float and to be very foul smelling.

Click the icon to see an image of a xanthoma.

Complications

Cirrhosis is the eleventh leading cause of death by disease in the United States, killing more than 25,000 people each year. A damaged liver affects almost every bodily process, including the functions of the digestive, hormonal, and circulatory systems. The most serious complications are those associated with so-called decompensation, which occur when cirrhosis progresses. They include the following:

Bleeding and fluid buildup (ascites).
Infections.
Damage to the brain (encephalopathy). Impaired brain function occurs when the liver cannot detoxify harmful substances.

Liver cancer is also a long-term risk with cirrhosis.

Cirrhosis is irreversible, but the rate of progression can be very slow, depending on its cause and other factors. Five-year survival rates are about 85% and can be lower or higher depending on severity.

For example, alcoholics with cirrhosis who abstain can have a 5-year or more survival rate of as high as 85%. For those who continue drinking, the chance for living beyond 5 years is no higher than 60%.
In patients with hepatitis B or C, the 5-year survival rate after a diagnosis of cirrhosis is 71 - 85%.
About two-thirds of patients with primary biliary cirrhosis never develop symptoms and can have a normal lifespan. Once symptoms of liver damage, such as jaundice, occur, however, the average survival time declines. In one study of women diagnosed with primary biliary cirrhosis, about 36% developed symptoms over an 11-year period, and 11% either died or required liver transplantation.

Unfortunately, doctors are usually unable to determine when cirrhosis first occurred, which makes it difficult to determine prognosis.

In cirrhosis, liver cell damage slows down blood flow. This causes a backup of blood through the portal vein, a condition called portal hypertension. The effects of portal hypertension can be widespread and serious, including fluid buildup and bleeding.

Ascites and Fluid Buildup. Ascites is fluid buildup in the abdomen. It is uncomfortable and can reduce breathing function and urination. Ascites is usually caused by portal hypertension, but it can result from other conditions. Swelling can also occur in the arms, legs, and spleen. Although ascites itself is not fatal, it is a marker for severe progression. Once ascites occurs, only half of patients survive after 2 years. Some doctors refer to the phases of cirrhosis as preascitic and ascitic. Some doctors even believe that ascites signals the need for liver transplantation, particularly in alcoholic cirrhosis.

Variceal Bleeding. One of the most serious repercussions of portal hypertension is the development of varices, blood vessels that enlarge to provide an alternative pathway for blood diverted from the liver. In about two-thirds of patients, they form in esophagus. Varices pose a high risk for rupture and bleeding because of the following characteristics:

They are thin-walled.
They are often twisted.
They are subject to high pressure.
Internal bleeding from these varices (variceal bleeding) occurs in 20 - 30% of patients with cirrhosis. The risk of death from a single episode can reach 70%.

Bleeding commonly recurs within 2 weeks of the first episode, but after 6 weeks, the risk for recurrence is the same as for patients who have not had a bleeding event.

Factors that predict variceal bleeding include:

Ascites
Encephalopathy
Large veins

Factors that can increase the danger for a bleeding episode in high-risk individuals include the following:

Moderate-to-intense exercise
Bacterial infection
Certain times of the day. Eating increases portal pressure, and there is a greater risk for bleeding in the evening. A lesser but still significant risk occurs in the early morning.

It is important for patients to be screened for esophageal varices and treated with preventive beta blockers if they show signs of risk. Between 30 - 40% of patients with cirrhosis have bleeding. The risk of dying from this complication is 20 - 35%. Some doctors recommend that all newly diagnosed patients be screened using endoscopy. Screening should also be considered for all previously diagnosed patients who have not been screened but would benefit from preventive treatments.

Portal hypertension can cause several secondary complications, including kidney failure. Non-steroidal anti-inflammatory drugs, such as naproxen, may increase the risk for kidney failure.

Gastrointestinal bleeding can occur from abnormal blood clotting, which can be a result of a combination of complications associated with cirrhosis. They include vitamin K deficiencies and thrombocytopenia -- a drop in platelets (the blood cells that normally initiate the clotting process). Some research now suggests that thrombocytopenia itself may be associated with more advanced liver failure.

Bacterial infections are very common in advanced cirrhosis, and may even increase the risk for bleeding. Most bacterial infections, including those in the urinary, respiratory, or gastrointestinal tracts, develop when patients are in the hospital. Abdominal infections are a particular problem in cirrhosis and occur in up to 25% of patients with cirrhosis within a year of diagnosis.

Mental impairment is a common event in advanced cirrhosis. In severe cases, the disease causes encephalopathy (damage to the brain), with mental symptoms that range from confusion to coma and death. A combination of conditions associated with cirrhosis causes this serious complication:

Buildup in the blood of harmful intestinal toxins, particularly ammonia.
An imbalance of amino acids that affect the central nervous system.

Encephalopathy is often triggered by certain conditions, including:

Gastrointestinal bleeding
Constipation
Excessive dietary protein
Infection
Surgery
Dehydration

Alcoholics with cirrhosis are believed to be at higher risk for this complication than are nonalcoholic cirrhosis, but one study suggested that alcoholics simply tend to have more severe cirrhosis. Even minimal hepatic encephalopathy (MHE) can have detrimental effects on functional ability. One study suggested that MHE impairs the ability to safely drive a car, and that all patients with cirrhosis be tested for MHE.

Symptoms of Encephalopathy. Early symptoms of hepatic encephalopathy include forgetfulness, unresponsiveness, and trouble concentrating. Sudden changes in the patient's mental state, including agitation or confusion, may indicate an emergency condition. Other symptoms include bad fruity-smelling breath and tremor. Late stage symptoms of encephalopathy are stupor and eventually coma.

Hepatorenal syndrome occurs if the kidneys drastically reduce their own blood flow in response to the altered blood flow in the liver. It is a life-threatening complication of late-stage liver disease that occurs in patients with ascites. Symptoms include dark colored urine and a reduction in volume, yellowish skin, abdominal swelling, mental changes (delirium, confusion), jerking or coarse muscle movement, nausea, and vomiting.

People with cirrhosis have an increased risk for liver cancer. Hepatitis B and C themselves increase the risk for liver cancer, regardless of the presence of cirrhosis. Hepatitis B infection is the leading cause of liver cancer.

For hepatitis C-related cirrhosis, a 2007 study indicated that patients with cirrhosis who are infected with genotype 1b hepatitis C have a greater risk of developing liver cancer than patients infected with other types of hepatitis C genotypes. (Genotype 1 is the most common type of hepatitis C in the United States.)

People with primary biliary cirrhosis also face a high risk of liver cancer. According to a 2007 study, several factors can indicate the increased likelihood of developing liver cancer. These factors include older age, male gender, history of blood transfusion, and signs of portal hypertension or cirrhosis.

About 30% of patients with chronic liver disease develop osteoporosis (loss of bone density), which is twice the usual incidence. Patients with primary biliary cirrhosis have a particularly high risk for osteoporosis. Treating osteoporosis in patients with cirrhosis can be complicated. One study found that calcitriol (a form of vitamin D) is especially helpful in preventing bone loss in patients with cirrhosis.

Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue, and increased vulnerability to fractures. Osteoporosis may result from disease, dietary or hormonal deficiency, or advanced age. Regular exercise and vitamin and mineral supplements may reduce and even reverse loss of bone density.

Nearly all patients with cirrhosis are insulin resistant. Insulin resistance is a primary feature in type 2 diabetes and occurs when the body is unable to use insulin. This hormone is important for delivering blood sugar and amino acids into cells and helps determine whether these nutrients will be burned for energy or stored for future use.

One study reported that nearly a quarter of patients with cirrhosis had gallstones.

Click the icon to see an image of gallstones.

They may also face a higher than average risk for certain abnormal heart rhythms. Peptic ulcers, sleep disorders, and respiratory problems are also more common in people with cirrhosis than in the general population.

Diagnosis

A physical examination may reveal the following in a patient with cirrhosis:

The cirrhotic liver is firm and often enlarged. The liver may feel rock-hard. (In advanced stages of cirrhosis, the liver may become small and shriveled.)
The left side can often be felt by the doctor when pressing on the abdomen.

If the abdomen is swollen, the doctor will check for ascites by tapping the flanks and listening for a dull thud and feeling the abdomen for a shifting wave of fluid.

Measuring Liver Enzymes (Aminotransferases). Enzymes known as aminotransferases, including aspartate (AST) and alanine (ALT), are released when the liver is damaged. Measurements of these enzymes, particularly ALT, are the least expensive and most noninvasive tests for determining severity of the underlying liver disease and monitoring treatment effectiveness. Enzyme levels vary, however, and are not always an accurate indicator of disease activity. (For example, they are not useful in detecting progression to cirrhosis.)

Radioimmunoassays. To identify a particular virus that may be causing hepatitis, blood tests called radioimmunoassays are performed. Typically, radioimmunoassays identify particular antibodies, which are molecules in the immune system that attack specific antigens. (Antigens are any molecules that the body considers threatening or dangerous, and can be targeted by antibodies.)

An antigen is a substance that can provoke an immune response. Typically antigens are substances not usually found in the body.

Some of these tests can pinpoint hepatitis antigens directly. These tests, however, have limitations:

There may not be enough antibodies for blood tests to detect for up to weeks or months after hepatitis develops. Blood tests that are taken too early, then, may miss these signs of infection.
Antibodies also persist after patients recover, so a positive antibody test can indicate a previous infection but does not necessarily determine if the infection is active.

The assays for individual hepatitis viruses may differ.

Polymerase Chain Reaction. In some cases of hepatitis C, a polymerase chain reaction (PCR), may be performed. A PCR is able to make multiple copies of the genetic material (the RNA) of the virus to the point where it is detectable.

Screening for Hepatitis C Virus. In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against routine screening for the hepatitis C infection in the general population due to low prevalence of the disease. In addition, it "found no evidence that screening for HCV infection in adults at high risk leads to improved long-term health outcomes" and found insufficient evidence to recommend for or against such screening. However, the USPSTF did advise testing in those with signs or symptoms of liver disease. The failure to recommend testing in the high-risk population goes against current recommendations made by the Centers for Disease Control and Prevention, the National Institutes of Health, and other professional organizations. In response to the study, published in the Annals of Internal Medicine, the American Association for the Study of Liver Diseases issued a statement saying that halting such screening would be a "terrible mistake with grave consequences," pointing out that the study itself underscored some key infection-related data that strongly emphasizes the need for screening in high-risk populations.

A liver biopsy is the only definite method for diagnosing cirrhosis. It also helps determine its cause, treatment possibilities, the extent of damage, and the long-term outlook. For example, hepatitis C patients who show no significant liver scarring when biopsied appear to have a low risk for cirrhosis.

The biopsy may be performed using various approaches, including:

Percutaneous Liver Biopsy. This approach uses a needle inserted through the abdomen to obtain a tissue sample from the liver. Various forms of needles are used, including those that use suction or those that cut out the tissue. If cirrhosis is suspected, a cutting needle is the better tool. This approach should not be used in patients with bleeding problems, and it must be used with caution in patients with ascites or severe obesity.

Click the icon to see an image of liver biopsy.

Transjugular Liver Biopsy. This approach uses a catheter (a thin tube) that is inserted in the jugular vein in the neck and threaded through the hepatic vein (which leads to the liver). A needle is passed through the tube, and a suction device collects liver samples. This procedure is risky but may be used for patients with severe ascites.
Laparoscopy. This procedure requires a small abdominal incision through which the doctor inserts a thin tube that contains small surgical instruments and a tiny camera to view the surface of the liver. This is generally reserved for staging cancer or for ascites with unknown causes.

Biopsies can be dangerous, so they cannot be performed on patients who have test results that indicate clotting problems, on those who have had previous liver biopsies, or who have ascites.

Certain blood tests are used to determine liver function. They include the following:

Serum albumin concentration. Serum albumin measures protein in the blood (low levels indicate poor liver function).
Prothrombin time (PT). The PT test measures in seconds the time it takes for blood clots to form (the longer it takes the greater the risk for bleeding).
Bilirubin. One of the most important factors indicative of liver damage is bilirubin, a red-yellow pigment that is normally metabolized in the liver and then excreted in the urine. In patients with hepatitis, the liver cannot process bilirubin, and blood levels of this substance rise, sometimes causing jaundice.

The results of these tests along with the presence of specific complications (ascites and encephalopathy) are used for calculating the Child-Pugh Classification. This is a staging system (A to C) that helps doctors determine the severity of cirrhosis.

Very high levels of serum alkaline phosphatase, an enzyme produced in the liver, and high levels of immune factors called mitochondrial antibodies are usually present in blood tests of patients with primary biliary blood cirrhosis. Bilirubin measurements appear to be important factors in determining its severity.

Fatty liver is suspected when a patient has elevated liver enzymes. The doctor will take imaging tests of the liver using ultrasound, computed tomography, or magnetic resonance imaging. A liver biopsy is the standard test for confirming a diagnosis of fatty liver disease and for distinguishing NAFLD from nonalcoholic steatohepatitis (NASH). Several studies in 2006 and 2007 suggested that a blood test for cytokeratin-18 (CK-18), a protein found in liver cells, may be an effective noninvasive approach for diagnosing NASH. Doctors hope that this simple blood test may eventually be able to replace liver biopsy.

Several imaging tests can be used to diagnose cirrhosis and its complications.

Imaging Techniques. Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound are all imaging techniques that are useful in detecting and defining the extent of cirrhosis. Such tests can reveal ascites, an enlarged spleen, an irregular liver surface, reversed portal vein blood flow, and liver cancer. Sometimes they can even detect abnormally large blood vessels in the liver. In some cases, images from ultrasound and CT can be misinterpreted as cancer. MRI is most useful for ruling out or confirming cancer.

Click the icon to see an image of an MRI scan.

Click the icon to see an image of a CT scan.

Liver Scans. Sometimes liver scans are performed using a small radioactive tracer and a special camera that records information provided by the tracer as it passes through the liver:

Arteriography uses dye injected into the hepatic arteries that show up on x-ray.
Splenoportography uses dye injected into the spleen, which allows the doctor to measure portal vein pressure. This procedure is risky.

Hepatic vein wedge pressure involves insertion of a catheter into the hepatic veins. The blood pressure in the veins of the liver is then measured. The result is an indicator of portal vein pressure. If pressure is high, cirrhosis is likely. A low measurement is a favorable sign.

Endoscopy. Some doctors recommend endoscopy for patients newly diagnosed with mild-to-moderate cirrhosis in order to screen for esophageal varices. (These are abnormal blood vessels in the esophagus that increase the risk for bleeding). In this test, a fiber optic tube is inserted down the throat. The tube contains tiny cameras to view the inside of the esophagus, where varices are most likely to develop. Endoscopy is the only procedure for detecting varices, but it is not clear if screening for varices in patients without severe cirrhosis is any more beneficial than simply putting them immediately on preventive drugs -- whether or not varices have been identified.

Paracentesis. If ascites is present, paracentesis is performed to determine its cause. This procedure involves using a thin needle to withdraw fluid from the abdomen. The fluid is tested for different factors to determine the cause of ascites:

Bacteria cultures and white blood cell counts. (These are used to determine the presence of infection.)
Protein levels. Low levels of protein in the fluid plus a low white blood cell count suggest that cirrhosis is the cause of the ascites.

The appearance of the fluid is helpful in determining problems:

A cloudy fluid plus a high white blood cell count means an infection is present.
Bloody fluid suggests the presence of a tumor.

Screening for Liver Cancer. Patients with cirrhosis are usually screened for liver cancer using ultrasound and tests for a substance called alpha-fetoprotein (AFP). It is not known whether such screening has much impact on survival, because it is not very sensitive and has a high rate of false positives (suggesting the presence of cancer when it is not actually present). Screening is not necessary in patients without cirrhosis.

Treatment

The only treatment for alcoholic cirrhosis is to stop drinking. Individuals with alcoholic cirrhosis are typically malnourished and require increased calories and rigorous nutritional support, which can improve survival rates.

Interferons Alone and in Combination with Ribavirin. Pegylated interferon combined with ribavirin is the gold standard treatment for chronic hepatitis C in both adults and children. It achieves response rates of up to 50% for patients infected with HCV genotype 1 (the most common genotype form in the U.S.) and up to 80% for patients infected with genotypes 2 or 3. Interferon alone is usually reserved for patients who cannot tolerate ribavarin.

A 2005 clinical trial of patients with chronic hepatitis C and cirrhosis found that interferon treatment reduced the risk of liver cancer and significantly improved chance of survival. The study emphasizes the importance and substantial benefits of interferon therapy. A 2007 study of patients with hepatitis C-related cirrhosis also indicated that interferon therapy can help reduce the risk of liver cancer and overall risk of death from liver disease.

A number of natural and synthetic interferons are available:

Natural interferons include interferon alfa-2a (Intron) and interferon alfa-2b (Roferon).
Pegylated interferons (PegINF) are long-acting formulations of interferon. They include alfa-2b (Peg-Intron) or alfa-2a (Pegasys). These drugs are used in combination with ribavarin (Copegus, Rebetol).
Alfacon-1 (Infergen), also called consensus interferon, is a genetically modified interferon. A combination of alfacon-1 with ribavirin is proving to help some patients who had been resistant to ribavirin with interferon.

A 2005 study suggested that some patients with hepatitis C genotypes 2 or 3 may be able to benefit from a shorter course of combination treatment (12 weeks) than the standard 24-week treatment duration. A shorter treatment time may reduce the risk of side effects. However, a 2007 study in the New England Journal of Medicine found that 16 weeks of combination therapy in patients with these genotypes did not work as well as the 24-week regimen. Given the significant side effects associated with combination pegylated interferon and ribavarin treatment, particularly anemia, researchers are actively investigating how to identify which patients may be able to succeed with shorter treatment duration.

PegINF combinations are proving to slow progression of scarring, and have even achieved improvement in some patients who already have cirrhosis. Whether the combination treatment protects against future liver cancer is still unclear. (A higher total dose, rather than a longer duration of treatment, may be the critical factor for protection.)

Side Effects of Combination Treatment. The side effects of the combination include those of both interferon and ribavirin. Interferon side effects may occur more often in the combination treatment. Combination treatment side effects may include:

Anemia occurs in about 22% of patients who take combination treatment versus 1% who take interferon alone. This complication is reversible and usually stabilizes after 1 - 2 months of treatment. However, some patients may become so anemic that they have to stop the medication. Since anemia can worsen heart disease, patients with a history of significant heart problems should not be treated with ribavirin. Other nucleoside analogues are being investigated that may have a lower risk for anemia than ribavirin.
Flu-like symptoms, such as fever, headaches, and muscle aches, are the most common side effect.
Reduced white blood cell count.
Skin disorders, such as dry skin and rash.
Coughing and shortness of breath.
Gastrointestinal symptoms (nausea, indigestion, lack of appetite).
Emotional and psychological symptoms, such as severe sleep disturbances, depression, irritability, and anxiety.
Combination treatment in pregnant women poses a very high risk for birth defects.

The current drugs used for hepatitis C still do not meet the needs of all patients. They are expensive, have significant side effects, do not work in half the patients who take them, and are unsuitable in many others. Investigation is ongoing to find better solutions. Drugs showing promise include:

Albinterferon alfa-2b (Albuferon). This long-acting form of interferon-alfa may have fewer side effects and require less dosing than pegylated interferons. It is currently being tested in combination with ribavarin in Phase II trials for patients with genotype 1 chronic hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a peptide derived from the thymus gland (which is responsible for maturation of immune factors called T-cells). It is being used for hepatitis B and is under investigation for hepatitis C in combination with interferon.
Celgosivir. Celgosivir is a new type of antiviral drug, which blocks alpha-glucosidase, an enzyme involved in viral replication. Celgosivir is being studied in combination with pegylated interferon alfa-2b and ribavirin. The drug is derived from the Australian chestnut tree.
Eltrombopag (Revolade). Thrombocytopenia, reduced production of blood platelets, is a condition that affects patients with hepatitis C and cirrhosis. Patients with thrombocytopenia cannot tolerate standard antiviral therapy. Researchers hope that eltrombopag, a drug that stimulates platelet production, may help normalize platelet levels so that they can start antiviral drug treatment.
Statins. Statin drugs are used for the treatment and management of cholesterol. Researchers are studying whether they may help improve liver enzyme levels in patients with hepatitis C.

Of interest are studies using phlebotomy (which is simply drawing blood) to reduce iron levels. In one study, maintenance therapy with this procedure reduced liver inflammation and possibly slowed progression of cirrhosis.

An ounce of prevention is worth a pound of cure, and the phrase resoundingly holds true in the case of hepatitis B. Today, a vaccine against hepatitis B is available. It can prevent hepatitis B and, therefore, also prevent liver cancer. The American Academy of Pediatrics and the Centers for Disease Control and Prevention currently recommend that all babies born in the United States receive a hepatitis B vaccine at birth.

Six drugs are currently approved in the United States for treatment of chronic hepatitis B:

Peginterferon alfa-2a (Pegasys)
Interferon-alfa-2b (Intron)
Adefovir (Hepsera)
Lamivudine (Epivir)
Entecavir (Baraclude)
Telbivudine (Tyzeka)

These drugs block the replication of hepatitis B in the body. Some also help boost the immune system. A doctor will decide which drug to prescribe based on a patient’s age, disease severity, and other factors. Each drug has various advantages and disadvantages in terms of cost, efficacy, side effects, and likelihood of drug resistance. A combination of drugs may also be prescribed.

Peginterferon alfa-2a. Peginterferon alfa-2a (Pegasys) was approved in 2005 for treatment of chronic hepatitis B. (Peginterferon is also called pegylated interferon.) The drug was previously approved in 2002 for treatment of chronic hepatitis C. Pegasys prevents the hepatitis B virus from replicating and also helps boost the immune system. It is given as a weekly injection. Peginterferon is sometimes prescribed in combination with lamivudine (Epivir).

Interferon Alpha. For many years, interferon alfa-2b (Intron) was the standard drug for hepatitis B. The drug is usually taken by injection every day for 16 weeks. (It does not appear to help hepatitis D.) Unfortunately, even in hepatitis B, the virus recurs in almost all cases, although this recurring mutation may be weaker than the original strain. Administering the drug for longer periods may produce sustained remission in more patients while still being safe. Interferon is also effective in eligible children, although long-term effects are unclear.

Lamivudine, Entecavir, and Telbivudine. These drugs are classified as nucleoside analogs. Lamivudine (Epivir or 3TC) is an antiretroviral drug that is used to treat human immunodeficiency virus (HIV) as well as hepatitis B. Studies suggest that lamivudine reduces viral count in over half of hepatitis B patients who take it as sole therapy for about a year. It is less expensive than interferon-alfa and has fewer side effects, but may not work as well as interferon-alfa for long-term therapy. A major problem with lamivudine is the development of mutated viral strains that become resistant to the drug, particularly in areas where the virus is common. About 20% of patients who take lamivudine develop drug resistance.

In 2005, the Food and Drug Administration (FDA) approved entecavir (Baraclude) for treatment of adults with chronic hepatitis B. In clinical trials, entecavir worked better than lamivudine for treating hepatitis B. Entecavir appears to have less risk of drug resistance than lamivudine. Studies also suggest that it may be a good alternative treatment for patients who have developed resistance to lamivudine. Questions have been raised about the drug’s possible cancer risks. Ongoing studies are evaluating this risk.

In 2006, the FDA approved telbivudine (Tyzeka), the newest nucleoside analog drug, for treatment of chronic hepatitis B.

Adefovir. Adefovir (Hepsera) belongs to a class of antiviral drugs called nucleotide analogs. (Nucleotides are related to nucleosides but have a slightly different chemical structure.) Nucleotide analogs block an enzyme involved in the replication of viruses. Adefovir costs more than lamivudine, but may be effective against lamivudine-resistant strains of hepatitis B. The drug must be taken on a long-term basis. A 2006 study indicated that when patients stopped taking adefovir after 48 weeks, the hepitatis B virus resumed replication. Patients who took the drug for a longer period (144 weeks) continued to benefit from treatment. Another 2006 study indicated that for some patients, adefovir remains effective for up to 5 years, although resistance occurs in about 20% of patients.

Drug Warnings. In 2004, the FDA issued two drug warnings for patients with hepatitis B. The HIV drug tenofovir (Viread) should not be used to treat patients with HIV who are co-infected with hepatitis Bas the drug may increase hepatitis severity. The lymphoma drug rituximab (Rituxan) may reactivate hepatitis B. Patients with lymphoma should be screened for hepatitis B. In 2007, the FDA revised the label for entecavir (Baraclude); patients who are co-infected with hepatitis Band HIV should take entecavir only if they are also taking antiviral HIV drugs.

Emtricitabine is a nucleoside analog drug used to treat HIV and AIDS. It is being investigated for chronic hepatitis B.
Pegylated interferon alfa-2b (Peg-Intron) and alfa-2a (Pegasys) are approved for treatment of chronic hepatitis C. They are being investigated alone and in combination with other drugs, such as ribavirin (Copegus, Rebetol), for treatment of hepatitis B. The combination of pegylated interferon and ribavirin is the standard treatment for hepatitis C.
Thymosin Alpha 1 (Zadaxin), also called thymalfasin, is a synthetic version of a substance derived from the thymus gland (which is responsible for maturation of immune factors called T-cells). It appears to be safe for hepatitis B patients when used alone or in combination with interferon. It is approved in many countries, but not the United States.

Ursodeoxycholic Acid (UDCA) and Drugs Used to Slow Progression. At this time no medication can cure primary biliary cirrhosis. Ursodiol, ursodeoxycholic acid (Actigall), or UDCA has been the standard drug used for primary biliary cirrhosis. Several studies have reported that it slows progression and helps prevent the need for liver transplantation.

It has no effect on symptoms, including itching and fatigue. Some drugs, such as colchicine, corticosteroids, or immunosuppressants, are being investigated for use in combination with UDCA. Long-term controlled trials are needed to determine the value of UDCA alone or with other drugs.

Drugs for Itching. Itching is a major problem with this disease. Cholestyramine, taken with meals, is the first choice for relieving itching. Several other drugs have been used or investigated, including low doses of the drug naltrexone and phototherapy.

Drugs for Impaired Fat Absorption. Because primary biliary cirrhosis affects fat absorption, patients may need high doses or injections of important fat-soluble vitamins, including K, D, A, and E.

Treatment of Nonalcoholic Fatty Liver Disease. Weight loss is the most important method for managing nonalcoholic fatty liver disease (NAFLD) and preventing progression to nonalcoholic steatohepatitis (NASH) and, eventually, cirrhosis. Diabetes and cholesterol control are also important. Investigators are studying whether various drugs used to treat type 2 diabetes may help treat NAFLD and NASH.

Other research is focusing on antioxidant vitamins, such as vitamin E.

In 2005, the National Institutes of Health launched two trials to study treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitisin adults and children. Children with NAFLD will receive vitamin E, metformin, or placebo. In the adult trial, patients with NASH will receive vitamin E, pioglitazone, or placebo.

Secondary Biliary Cirrhosis. Secondary biliary cirrhosis caused by blockage in the bile ducts can be relieved by surgery.

Autoimmune Hepatitis. Autoimmune hepatitis is treated with the corticosteroid prednisone and also sometimes immunosuppressants, such as azathioprine (Imuran).

Hemochromatosis. For hemochromatosis, weekly bleedings (phlebotomies) may be performed until iron levels are normal, then repeated as needed. If treatment is given before cirrhosis develops, life expectancy may be normal.

Wilson's Disease. D-penicillamine is the drug most used for Wilson's disease.

There are no current safe and effective therapies for liver scarring (fibrosis). However, recent insights into the cellular and molecular mechanisms responsible for scarring have led to the development of specific, antifibrotic drugs that target the primary injury and inhibit abnormal cell mechanisms. Such drugs, now in very early testing, could one day help prevent or reduce the progression of liver scarring or the progression to liver cancer.

Liver transplantation may be indicated for the following:

Patients who have developed life-threatening cirrhosis and who have a life expectancy of more than 12 years.
Patients with liver cancer that has not spread beyond the liver.

Survival rates after transplantation are similar among those who have hepatitis B, hepatitis C, or alcoholic liver disease. Current 5-year survival rates after liver transplantation are about 75%. Patients also report improved quality of life and mental functioning after liver transplantation. Patients should seek medical centers that perform more than 50 transplants per year and produce better-than-average results.

Unfortunately, there are many more patients waiting for liver transplants than there are available organs. Fortunately, more procedures are now being performed using liver tissue from a living donor. In these cases, surgeons replace the patient’s diseased liver with a part of the liver taken from a donor. The donor’s liver regenerates to full size within a few weeks of surgery, and the recipient’s liver also regrows.

Transplantation surgery generally takes 4 - 12 hours to perform, and patients stay in the hospital for up to 3 weeks after the surgery. Most patients return to normal or near-normal activities 6 - 12 months following the transplant. For the rest of their lives, patients need to take immunosuppressive medication to prevent rejection.

Liver Transplantation in Patients with Hepatitis. One of the primary problems with many hepatitis patients is recurrence of the virus after transplantation.

One study of patients with hepatitis C reported 5-year risks of 80% for viral recurrence and 10% for cirrhosis. A 2004 study found that the hepatitis C virus recurs with more severity with liver donations from living donors than livers taken from cadavers.
Viral recurrence is also high in patients with hepatitis B. In 2007, the FDA approved HepaGram B, an immune globulin, to prevent recurrence of hepatitis B after transplantation. Patients need to receive HepaGram B injections on a lifelong basis.

Liver Transplantation in Autoimmune Liver Diseases. Patients who require transplantation for primary biliary cirrhosis are those who develop major complications of portal hypertension and liver failure or who have poor quality of life and short survival without the procedure. Survival rates after transplantation are excellent.

The outlook is also good for patients who have autoimmune hepatitis who require a transplant. Survival rates are about 90% after 1 year, and 70 - 80% after 5 years. Rejection usually occurs in those patients whose immune systems are very compromised.

Liver Transplantation in Alcoholism. There is considerable controversy over whether liver transplantation should be performed in alcoholics with cirrhosis who are unlikely to abstain. One French study reported no differences in survival, transplant rejection, and other indicators of success and failure after transplantation between alcoholics and non-alcoholics and between alcoholics who abstained and those who relapsed after the procedure.

Click the icon to see an illustrated series detailing a liver transplant.

Lifestyle Changes

A healthy lifestyle is particularly important for people with cirrhosis.

Healthy Foods. Because important antioxidant vitamins are depleted in the cirrhotic liver, patients should maintain a diet rich in fresh fruits, vegetables, and whole grains.

Coffee and Tea. Coffee appears to help lower the risk of cirrhosis, especially among heavy drinkers. A 2006 study indicated that people who drank 1 - 3 cups of coffee a day reduced their risk of alcoholic cirrhosis by 40%. Those who drank 4 or more cups reduced their risk by 80%. Researchers think that there is some ingredient in coffee (other than caffeine) that is responsible for this apparent protection. Studies on tea have been mixed. Some studies report that tea also lowers the risk of chronic liver disease, while others have found no effect.

Antioxidant Supplements. There is some preliminary laboratory evidence that various antioxidant supplements -- including vitamin E, selenium, and S-adenosylmethionine (SAMe) -- may help protect against liver damage and cirrhosis. Supplements, however, are not recommended for people with liver disease except with the advice of a doctor. Some vitamins, such as vitamins D and A, are metabolized in the liver and can be toxic.

Iron Restrictions. Elevated iron levels have been associated with cirrhosis from many causes. Patients should avoid iron-rich foods, such as red meats, liver, and iron-fortified cereals, and should avoid cooking with iron-coated cookware and utensils.

Supplemental Nutritional Products. Supplemental nutritional beverages may be helpful, particularly for patients with both alcoholism and cirrhosis. In one study, patients with both alcoholism and cirrhosis drank Ensure every day as a supplement to their regular diet. After 6 months they showed significant improvement in many signs of overall health compared to those who did not consume the beverage.

Vitamin B1 (Thiamine). Thiamine binds to iron and helps reduce iron load in the liver. One small study suggested it may be helpful for patients with chronic hepatitis B. It is not known if it has any benefit for cirrhosis. Pork is high in the vitamin, but more healthful sources include dried fortified cereals, oatmeal, corn, nuts, cauliflower, sunflower seeds and vitamin pills.

Like most vitamins, vitamin B1 may be obtained in the recommended amount with a well-balanced diet, including some enriched or fortified foods.

Omega-3 Fatty Acids. Some research suggests that supplements of omega-3 fatty acids (found in fish oil and evening primrose oil) may help protect the diseased liver.

Click the icon to see an image of omega-3 fatty acids.

Protein and Soy. High-quality dietary protein may be especially helpful for patients with ascites and for repairing muscle mass, but excessive protein loads may trigger encephalopathy. Protein solutions have been devised that provide beneficial amino acids without including those that increase this risk. There is no limit on vegetable proteins, such as those from soy.

Salt Restriction. Restricting salt consumption to less than 2,000 mg a day is particularly important for patients with ascites. The less salt the better.

Zinc. In some studies, taking zinc supplements have lowered ammonia levels in some patients who were zinc-deficient, a common problem in cirrhosis. Zinc replacement may reduce frequency and severity of muscle cramps and may even help protect against encephalopathy.

Fluid restriction is not usually necessary, but patients with severe ascites should discuss limiting fluid with their doctors.

Exercise increases the risk for portal pressure and variceal bleeding. One study reported that taking a beta-blocker may reduce this risk, although patients should discuss this with their doctor.

Infections can have a severe impact on the liver. Although most respiratory infections generally affect only the lungs, one small study suggested influenza may directly affect the liver in patients with cirrhosis and exacerbate the disease process. Researchers in the study advise annual flu shots for people with cirrhosis.

Patients should be aware that manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Patients should always check with their doctors before using any herbal remedies or dietary supplements.

Among the natural substances being investigated for liver disease are ginseng, glycyrrhizin (a compound in licorice), catechin (found in green tea), SAMe, and silymarin (found in milk thistle).

Silymarin. Silymarin is a chemical found in the milk thistle herb. It is one of the most popular, and most studied, herbal remedies for liver disease. Some studies have indicated that silymarin may help improve liver enzyme levels. However, a 2005 review found that milk thistle did not help reduce deaths from liver disease caused by alcohol or hepatitis.

S-adenosylmethionine. S-adenosylmethionine (SAMe) is a chemical found in all parts of the body, which declines with age. It has been investigated for years in Europe for arthritis, depression, and liver disease. Some preliminary studies suggest it may provide some protection against liver damage and scarring and may improve survival rates in alcoholic patients with cirrhosis. It is very expensive, however, and as with all unregulated products, long-term side effects, drug interactions, and other factors are not fully known.

The following warnings are of particular importance for people with liver disease:

Kava kava (an herb used for anxiety and tension) can be toxic to the liver and cause severe hepatitis and even liver failure if taken excessively.

Abdominal Infections

Antibiotics are administered when fluid examination and tests for ascites indicate infection. For a first episode, the antibiotic cefotaxime is typically administered intravenously, requiring hospitalization. Treatment usually lasts 10 days, but research indicates that 5 days may be sufficient for certain patients. Some research indicates that the oral antibiotic ofloxacin may work as well with fewer complications, allowing patients to be treated at home.

In advanced cirrhosis, the risk for serious abdominal infection is high, and the antibiotic norfloxacin is often prescribed preventively against specific organisms that infect the abdominal cavity. One study reported, however, that patients who took norfloxacin became susceptible to Staphylococcal infections. Long-term treatments with norfloxacin or similar antibiotics may increase the risk for fungal infections after liver transplantation.

Encephalopathy

The first step in managing encephalopathy (damage to the brain) is to treat any precipitating cause, such as:

High ammonia levels
Bleeding
Low oxygen
Dehydration
Infection
Use of sedatives

Some studies indicate that manganese poisoning may be partially responsible for encephalopathy in cirrhosis. Studies are needed to determine if drugs that remove manganese improve this complication.

Ammonia is the leading toxin in causing encephalopathy related to cirrhosis. Mild encephalopathy is managed by directing therapy toward eliminating ammonia in the intestine:

The first step is to restrict animal protein, substituting meats and dairy products with vegetable protein, such as soy, and amino acid supplements.
Enemas, which clean out the intestine, may be effective.
Lactulose (Cephulac, Chronulac, Constulose, Duphalac, Enulose) and lactitol, known as disaccharides, help lower blood ammonia levels and have been shown to be effective in improving cognitive function and quality of life in people with mild encephalopathy.
Antibiotics, such as metronidazole, rifamycin, or neomycin, are effective in reducing levels of ammonia-producing bacteria in the intestine, although long-term use of these drugs can cause toxic side effects. Rifaximin (Xifaxan), another antibiotic, was approved in 2005 for treatment of hepatic encephalopathy.
L. acidophilus is the probiotic found in live culture yogurt. Researchers are studying whether L. acidophilus food or supplements can aid in improving liver and cognitive functions.
Researchers are investigating whether exercise can help remove ammonia from the body and improve encephalopathy.

Investigational Drugs. Certain drugs, such as rifaximin (Xifaxan) and flumazenil (Mazicon, Romazicon), are under investigation for treating encephalopathy. Flumazenil is typically administered to counteract the effects of sedatives.

Ascites

Nearly all patients with ascites (fluid accumulation in the abdomen) can benefit from the following measures:

Abstaining from alcohol. (Sometimes abstaining from alcohol is enough to improve this complication.)
Restricting salt.
Taking diuretics, usually spironolactone (Aldactone) and furosemide (Lasix). Previously, spironolactone was usually given alone, but experts now use it by itself only in patients with minimal fluid buildup. Patients should be monitored carefully for excessive and too-fluid loss, which can set off complications, including hypokalemia (dangerously low potassium levels), kidney failure, or encephalopathy. Weight loss from diuretics usually should not exceed 1 - 2 pounds per day, but there is no limit for patients with massive swelling.

Doctors often recommend bed rest for patients with ascites, but studies do not support its benefits. Restricting fluid is not usually necessary unless sodium levels in the blood are very low.

Patients with recurring ascites, or ascites that does not respond to standard diuretics after a month (refractory ascites), may require procedures to reduce fluid.

Large-Volume Paracentesis. Large-volume paracentesis is the current standard procedure and involves the following:

Large volumes of fluid are removed through a tube in the abdomen. Research indicates that 4 - 6 liters are usually effective and safe.
Albumin (protein) may be administered intravenously. This helps prevent a sudden drop in blood flow in the arteries. One study suggested that terlipressin, a drug that constricts blood vessels, may be as effective.
If the ascites does not respond to treatments, the patient may need paracentesis every 2 weeks or more frequently, and up to 10 liters may need to be removed.

Patients who need this procedure are probably not complying with dietary requirements.

Transjugular Intrahepatic Portosystemic Shunt. Studies have been mixed on whether transjugular intrahepatic portosystemic shunt (TIPS) improves survival without transplantation compared to large-volume paracentesis. An important 2003 study reported that although TIPS reduced the number of paracenteses, there was no improvement in survival rates. In addition, patients who were given TIPS had a higher risk for encephalopathy than those given large-volume paracentesis. In general, TIPS should be a second-line option for ascites that does not respond to diuretics.

Peritoneovenous Shunting. Peritoneovenous shunting is an older, more invasive, procedure involving insertion of a tube, or shunt, under the skin that routes the fluid from the abdomen into the jugular vein. The procedure can have serious complications, including infection, blood clots, encephalopathy, and rupture of blood vessels in the esophagus. It is now generally reserved for patients who are not candidates for repeat paracentesis or liver transplantation.

Hepatorenal syndrome can occur in patients with ascites. This is a life-threatening condition in which the kidneys fail in trying to compensate for altered blood flow in the liver. Studies suggest that terlipressin may be an effective treatment in combination with albumin for hepatorenal syndrome.

Researchers are testing certain drugs that may correct the imbalances in circulation that lead to portal hypertension and ascites. Of particular interest are drugs called nonpeptide vasopressin antagonists, also referred to as aquaretics. They may reverse the dilation in blood vessels that lead to salt and fluid retention.

The prognosis for patients with ascites is poor, even with intensive procedures. Liver transplantation should be considered for patients when ascites does not respond to treatments and when poor liver function or other complications, such as peritonitis or kidney failure, are present.

Bleeding Episodes

Preventing an Initial Bleeding Episode. About half of patients with mild-to-moderate cirrhosis have esophageal varices (enlarged veins in the esophagus). In such patients, the risk for bleeding within 2 years is as high as 35%. Bleeding is fatal in half of these patients. In general, experts recommend preventive drugs for such patients, even if they have not been screened with endoscopy -- the procedure needed to actually detect varices. Beta-blockers are the only medications to date that have some preventive effects, but others are under investigation.

Guidelines for Treating Bleeding Episodes. The doctor should first be certain that bleeding is caused by portal hypertension and ruptured varices and not by other conditions. For example, patients with cirrhosis are also at higher than average risk for bleeding peptic ulcers.

Saline or Ringers solution (a fluid and electrolyte replenisher) followed by red blood cells and plasma is administered immediately to replace lost blood.

The next step is to immediately achieve normal blood clotting (hemostasis) in order to stop the current bleeding episode and prevent early recurrence, which typically occurs 3 - 5 days after a bleeding episode.

In general it is a two-pronged approach using drugs and endoscopy procedures.

Drugs. Either octreotide or vasopressin are typically used to reduce portal pressure and blood flow.
Endoscopy. Endoscopy involves insertion of a thin tube containing a tiny camera followed by surgery to make repairs. Endoscopic sclerotherapy is the most common procedure. Emergency sclerotherapy is often used as first-line therapy for variceal bleeding, but a major 2002 analysis suggested that it is no more effective than drugs for stopping bleeding, and it has potentially serious adverse effects.

A combination of drugs and endoscopy is the best approach for stopping bleeding compared to endoscopy alone. It is not clear if there is any difference in long-term survival, however.

Prevent Bleeding Recurrence. Rebleeding is common after an episode. Beta-blocker drugs are typically used, although they are not effective for many patients.

Preventing Complications. The patient who is experiencing a bleeding episode is at high risk for other complications, including pneumonia, bacterial infections, and hepatic encephalopathy. Bacterial infections can also impair blood clotting. Preventive oral antibiotics are often problematic in these patients. One study suggested that intravenous ciprofloxacin may be helpful.

Beta-Blockers. Beta-blockers, typically propranolol (Inderal) or nadolol (Corgard), reduce the heart rate and can lower portal vein pressure in many patients and so reduce variceal bleeding. Carvedilol (Coreg), a newer drug, may be even more effective, but more research is needed. Beta-blockers are also used as a primary approach for prevention of recurring bleeding. Nevertheless, they fail to reduce portal pressure in nearly 40% of patients with cirrhosis. They may not be appropriate for patients with type 1 diabetes, asthma, emphysema, and chronic bronchitis. They must be taken for at least 2 years and most likely longer to sustain a survival advantage.

Other Drugs. Other drugs are being used or investigated, mostly in combination with beta-blockers, to reduce recurrence rates.

Isosorbide mononitrate is a nitrate, a type of drug commonly used for angina. Combinations with beta-blockers appear to prevent rebleeding more effectively than beta-blockers alone. It is not clear if the combination improves any other aspects of the disease. The nitrate may also be an alternative drug for patients who cannot tolerate beta-blockers. Studies have failed to show any survival advantage, however, when isosorbide mononitrate is used alone.
The diuretic spironolactone may be helpful in combination with a beta-blocker for reducing both ascites and rebleeding after an initial episode.
Angiotensin II receptor antagonists, including losartan (Cozaar), are being studied for lowering portal pressure.

Somatostatinand Similar Drugs. Somatostatin is a natural hormone that constricts blood vessels. This drug or synthetic derivatives (octreotide and vapreotide) may be more effective than the common procedure, endoscopic sclerotherapy, for controlling bleeding. No single drug is more effective than another. Their benefits for improving overall survival, however, are still uncertain, and a major analysis of current studies found no effects on survival rates with either octreotide or somatostatin.

Somatostatin, the natural hormone, controlled variceal bleeding in 87% of patients in one study, but it is short acting.
Octreotide (Sandostatin) is a derivative of somatostatin and is longer acting. It has largely replaced the older drug. It is very safe, even for heart patients, and has few serious side effects.
Vapreotide (Octastatin) also resembles somatostatin. One study concluded that a combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone for controlling bleeding, but the combination therapy did not improve mortality rates at 42 days. The study suggested that these drugs should be taken for 5 days.

Vasoconstrictors. Vasoconstrictors narrow the blood vessels and reduce flow in the spleen. They are particularly effective when used with nitroglycerin.

Vasopressin (Pitressin) is the most commonly used vasoconstrictor. It poses a risk to the heart, however, and it is not clear whether it is actually helpful.
Terlipressin is a synthetic version of vasopressin that is proving to be as effective as sclerotherapy in controlling bleeding. It also lacks vasopressin's side effects and may prove to prolong survival and serve as a bridge for patients waiting for liver transplantation.

Endoscopic procedures use a tube inserted down through the esophagus, containing microcameras and tiny instruments. Endoscopy is used both to diagnose the disease and stop bleeding. The two standard procedures are band ligation and sclerotherapy. In general, a combination of drug therapies and an endoscopic procedure is the usual approach for preventing a bleeding recurrence.

Endoscopic Band Ligation. In endoscopic band ligation, latex bands are wrapped around the bleeding varices, shutting off the blood supply. It is the method of choice to control of bleeding and, in weekly sessions, to prevent rebleeding, because it has a lower risk for complications than sclerotherapy. Recurrence rates are higher with band ligation, however. Studies are mixed on whether weekly treatments with band ligation are any more effective in preventing rebleeding than beta-blockers plus isosorbide mononitrate. A combination of medications plus band ligation is under investigation.

Investigators are studying argon plasma coagulation (APC) after band ligation to prevent variceal recurrence and rebleeding. This procedure uses argon gas to deliver electric currents that coagulate and stop bleeding.

Endoscopic Sclerotherapy. Endoscopic sclerotherapy is only effective against bleeding in the esophagus. The endoscopic tube is inserted through the mouth. A sclerosant (a solution that toughens the tissue around the variceal blood vessels) is injected to stop the bleeding. The procedure is repeated over a period of 2 - 3 months. Repeat treatments appear to reduce rebleeding and death. Minor complications (usually ulcers in the mucus membranes) are common, and serious complications can occur (narrowing or perforation of the esophagus and leakage at the injection site.)

Balloon tamponade has been available for years, but it is now used only for bleeding that cannot be controlled by drugs or endoscopy. It uses a tube inserted through the nose and down through the esophagus until it reaches the upper part of the stomach. A balloon at the tube's end is inflated and positioned tightly against the esophageal wall. It is usually deflated in about 24 hours. Serious complications can occur, the most dangerous being rupture of the esophagus. Recurrence of bleeding is common.

Shunts are used for patients who are still bleeding in the esophagus after endoscopic sclerotherapy or who are bleeding in the stomach. Choices include the following:

Transjugular intrahepatic portosystemic shunt (TIPS)
A surgical shunt

Shunt operations usually eliminate variceal bleeding, but encephalopathy and shunt failure are frequent complications. Doctors do not recommend shunts as elective surgery for high-risk patients who are candidates for liver transplantation, since shunts make this operation more difficult.

Transjugular Intrahepatic Portosystemic Shunt.A transjugular intrahepatic portosystemic (or portal-systemic) shunt (TIPS) involves the following:

The patient only requires a local anesthetic and a sedative.
A long needle is inserted into the jugular vein in the neck and passed down through the vena cava, a large vein that conducts blood back to the heart. This serves to widen the vein.
The surgeon makes an incision in the hepatic vein in the liver and creates a connection to the portal vein.
A cylindrical wire-mesh stent is inserted into this connecting vein.
The stent now acts as a shunt, which reroutes blood around the scarred liver.

TIPS is a good choice for bleeding that is not controlled by endoscopy, particularly when it is performed shortly after a bleeding episode. It also reduces ascites.

It is not useful as the first choice for stopping an initial bleeding episode or for preventing rebleeding, however, since it poses a high risk for encephalopathy. This complication outweighs its benefits compared to endoscopy for initial treatment and to beta-blockers for preventing recurrence. Blockage or closure of the shunt can develop over time.

TIPS is generally recommended for only patients who:

Cannot tolerate sclerotherapy
Are unlikely or unable to comply with the repeated procedures necessary for sclerotherapy
Have poor blood circulation

Surgical Shunts. There are two types of surgical shunts:

A portal shunt, or portal systemic shunt. It was introduced in 1945 and was the first significant treatment for bleeding varices. It relieves pressure in the portal vein by surgically joining it to the inferior vena cava, a large vein that conducts blood back to the heart. It poses a high risk for encephalopathy and does not appear to improve survival, so is not used often.
A variation called the H-graft portacaval shunt is a partial shunt that is proving to be effective for treating bleeding. It controls bleeding in 90% of patients and has a lower encephalopathy rate than the complete portal shunt or TIPS. In fact, early studies report that it may have lower rates for transplantation and death than TIPS.
A distal splenorenal shunt (DSRS) preserves blood flow through the portal vein while relieving pressure on the varices by joining the left kidney vein to the splenic vein. (The splenic vein returns blood from the spleen and is one of two veins that form the portal vein.) Studies show that DSRS has similar mortality rates compared to the portal shunt but lower rates of encephalopathy afterwards. Patients with alcoholic cirrhosis fare worse with DSRS than nonalcoholic patients. It is probably best used as an elective operation in patients with good liver function who continue to bleed in spite of endoscopy.

Resources

www2.niddk.nih.gov -- National Institute of Diabetes and Digestive and Kidney Diseases
www.aasld.org -- American Association for the Study of Liver Diseases
www.liverfoundation.org -- American Liver Foundation
www.gastro.org -- American Gastrointestinal Association
www.cdc.gov/ncidod/diseases/hepatitis -- Centers for Disease Control and Prevention, Hepatitis
www.hepfi.org -- Hepatitis Foundation International
www.pbcers.org -- Primary Biliary Cirrhosis Organization
www.organdonor.org -- National Transplant Society
www.unos.org -- United Network for Organ Sharing
www.organdonor.gov -- US government organ donor site

References

Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli MU. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: A seventeen-year prospective cohort study. Hepatology. 2007 Aug 6; [Epub ahead of print]

Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L, Mazzella G, et al. Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007 Mar;45(3):579-87.

Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006 Oct;44(4):865-73.

Huang H, Shiffman ML, Friedman S, Venkatesh R, Bzowej N, Abar OT, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007 Aug;46(2):297-306.

Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life inpatients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007 Mar;45(3):549-59.

Suzuki A, Lymp J, Donlinger J, Mendes F, Angulo P, Lindor K. Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007 Feb;5(2):259-64. Epub 2006 Dec 15.

U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006 Aug 1;145(3):204-8.

Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2006 Aug 1;145(3):209-23.

Review Date:
8/31/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Scoliosis

FitSugar — Wed, 08 Oct 2008 17:35:13 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Prognosis
Symptoms
Diagnosis
Treatment
Managing Scoliosis
Braces
Surgery
Treatment for Adult Scolios...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Diagnosing Scoliosis

Scoliosis is diagnosed typically in children 10 - 15 years of age. However, only about 1% of cases actually require treatment. There is a large female preponderance for larger curves that do require treatment.

Defining Scoliosis

Nonstructural scoliosis is a simple side-to-side curve of the spine. Structural scoliosis adds to that simple curve a rotation of the vertebrae, resulting in a twisting of the spine.

Causes

In about 80% of scoliosis cases, the cause is unknown (idiopathic scoliosis). Research has not been able to identify any genetic abnormality that would make a person susceptible to developing scoliosis.

Treatment with Bracing

Bracing has long been the standard treatment to prevent progression of the curvature of scoliosis. However, patient compliance has been a problem, especially for younger patients. Newer braces are now more comfortable and can be worn discretely under the clothing, thus improving patient compliance and treatment results.

Introduction

Scoliosis is the abnormal curvature of the spine. While the normal spine has gentle natural curves that round the shoulders and make the lower back curve inward, scoliosis typically involves a three-dimensional deformity of the spinal column and rib cage. To varying degrees, the spine curves from side-to-side, and some of the spinal bones may rotate slightly, making the hips or shoulders appear uneven. It may develop in the following way:

As a single primary side-to-side curve (resembling the letter C), or
As two curves (a primary curve along with a compensating secondary curve that forms an S shape).

Scoliosis most commonly develops in the area between the upper back (the thoracic area) and lower back (lumbar area). It may also occur only in the upper or lower back. The doctor attempts to define scoliosis by the following characteristics:

The shape of the curve
Its location
Its direction
Its magnitude
Its causes, if possible

Click the icon to see an image of scoliosis.

The severity of scoliosis is determined by the extent of the spinal curvature and the angle of the trunk rotation (ATR) and is usually measured in degrees. Curves of less than 20 degrees are considered mild and account for 80% of scoliosis cases. Curves that progress beyond 20% require medical attention. Such attention, however, usually involves periodic monitoring to make sure the condition is not becoming worse.

Scoliosis affects about 2 - 3% of the population (about 6 million people in the United States). It can occur in adults but is more commonly diagnosed for the first time in children aged 10 - 15 years. About 10% of the adolescent population has some degree of scoliosis, but less than 1% develops scoliosis that requires treatment. The condition also tends to run in families. Among persons with relatives that have scoliosis, about 20% develop the condition.

Among adults, previous reports have indicated a prevalence of scoliosis of up to 32%. But a recent study of 75 healthy adults aged 60 years and older with no known history of scoliosis or prior spine surgery suggested a rate of 68%. However, scoliosis was not linked to physical or social impairment in this population.

Scoliosis is often categorized by the shape of the curve, usually as either structural or nonstructural.

Structural scoliosis. In addition to the spine curving from side to side, the vertebrae rotate, twisting the spine. As it twists, one side of the rib cage is pushed outward so that the spaces between the ribs widen and the shoulder blade protrudes (producing the rib-cage deformity, or hump). The other half of the rib cage is twisted inward, compressing the ribs.
Nonstructural scoliosis. The curve does not twist but is a simple side-to-side curve.

Other abnormalities of the spine that may occur alone or in combination with scoliosis include hyperkyphosis (an abnormal exaggeration in the backward rounding of the upper spine) and hyperlordosis (an exaggerated forward curving of the lower spine, also called swayback).

Click the icon to see an image of kyphosis.

The location of a structural curve is defined by the location of the apical vertebra. This is bone at the highest point (the apex) in the spinal hump. This particular vertebra also undergoes the most severe rotation during the disease process.

The direction of the curve in structural scoliosis is determined by whether the convex (rounded) side of the curve bends to the right or left. For example, a doctor will diagnose a patient as having right thoracic scoliosis if the apical vertebra is in the thoracic (upper back) region of the spine, and the curve bends to the right.

The magnitude of the curve is determined by taking measurements of the length and angle of the curve on an x-ray view.

Vertebrae. The spine is a column of small bones, or vertebrae, that support the entire upper body. The column is grouped into three sections of vertebrae:

Cervical (C) vertebrae are the 7 spinal bones that support the neck.
Thoracic (T) vertebrae are the 12 spinal bones that connect to the rib cage.
Lumbar (L) vertebrae are the 5 lowest and largest bones of the spinal column. Most of the body's weight and stress falls on the lumbar vertebrae.

Each vertebra can be designated by using a letter and number; the letter reflects the region (C=cervical, T=thoracic, and L=lumbar), and the number signifies its location within that region. For example, C4 is the fourth bone down in the cervical region, and T8 is the eighth thoracic vertebra.

Below the lumbar region is the sacrum, a shield-shaped bony structure that connects with the pelvis at the sacroiliac joints. At the end of the sacrum are 2 - 4 tiny, partially fused vertebrae known as the coccyx or "tail bone."

The Spinal Column and its Curves. Altogether, the vertebrae form the spinal column. In the upper trunk the column normally has a gentle outward curve (kyphosis) while the lower back has a reverse inward curve (lordosis).

The Disks. Vertebrae in the spinal column are separated from each other by small cushions of cartilage known as intervertebral disks. Inside each disk is a jelly-like substance called the nucleus pulposus, which is surrounded by a tough, fibrous ring called the annulus fibrosis. The disk is 80% water. This structure makes the disk both elastic and strong. The disks have no blood supply of their own, relying instead on nearby blood vessels to keep them nourished.

Processes. Each vertebra in the spine has a number of bony projections, known as processes. The spinal and transverse processes attach to the muscles in the back and act like little levers, allowing the spine to twist or bend. The particular processes form the joints between the vertebrae themselves, meeting together and interlocking at the zygapophysial joints (more commonly known as facet or z joints).

Spinal Canal. Each vertebra and its processes surround and protect an arch-shaped central opening. These arches, aligned to run down the spine, form the spinal canal, which encloses the spinal cord, the central trunk of nerves that connects the brain with the rest of the body.

Click the icon to see an image of the spine.

Click the icon to see an image of the sacrum.

Click the icon to see an image of the curves of the spine.

Click the icon to see an image of an intervertebral disk.

Click the icon to see an image of the spinal canal.

Causes

In 80% of patients, the cause of scoliosis is unknown. Such cases are called idiopathic scoliosis. (Idiopathic means without a known cause.) Idiopathic scoliosis may be due to multiple, poorly understood inherited factors, most likely from the mother's side. However, the severity often varies widely among family members who have the condition, suggesting that other factors must be present.

Researchers have not been able to identify the specific genetic abnormalities that make a young person susceptible to spinal distortion. Inherited physical abnormalities, problems in coordination, abnormalities in the central nervous system, and other inherited factors may play some role either alone or in combination with other conditions to produce scoliosis.

Physical Abnormalities. Researchers are investigating possible physical abnormalities that may cause imbalances in bones or muscles that would lead to scoliosis. Among them are the following:

Imbalances in Muscles around the Vertebrae. Some research suggests that imbalances in the muscles around the vertebrae may make children susceptible to spinal distortions as they grow.
High Arches. One study showed a higher incidence of abnormally high arches in the feet in people with idiopathic scoliosis, suggesting that altered balance may be a factor in certain cases.

Problems in Coordination. Some experts are looking at inherited defects in perception or coordination that may cause asymmetrical growth in the spine of some children with scoliosis.

Genetic Abnormalities in the Central Nervous System. Genetic defects that cause altered processing in the brain may play a role in producing abnormalities in the growing spine. For example, research has implicated low levels of melatonin, a hormone secreted in the pineal gland in brain. Melatonin is involved with sleep and growth. Researchers speculate that genetic factors that cause reduced blood levels of melatonin may adversely affect muscle tone and development during sleep, perhaps contributing to scoliosis.

Other Biologic Factors. Several other biologic factors are being investigated for some contribution to scoliosis:

Abnormalities in collagen, the critical structural protein found in muscles and bones. Enzymes known as matrix metalloproteinases are involved in the repair and remodeling of collagen. Researchers have found high levels of the enzymes in the disks of patients with scoliosis, which suggests that the enzymes may contribute to curve progression. Elevated levels of the enzymes can cause abnormalities in components in the spinal disks, contributing to disk degeneration.
A possible defective gene responsible for production of fibrillin, an important component of connective tissue, which makes up bones and muscles.
Abnormalities in a protein called platelet calmodulin that binds to calcium. This protein acts like a tiny muscle and pulls clots together. Measuring levels of this protein may eventually help predict whether scoliosis will worsen.

Congenital scoliosis is caused by inborn spinal deformities that may result in the development of absent or fused vertebrae. Kidney problems, particularly having only one kidney, often coincide with congenital scoliosis. The condition usually becomes evident at either age 2 or between ages 8 and 13 as the spine begins to grow more quickly, putting additional stress on the abnormal vertebrae. It is essential to diagnose and monitor such curvatures as early as possible, since they can progress quickly. Early surgical treatment -- before age 5 -- may be important in many of these patients to prevent serious complications.

Adult scoliosis has two primary causes:

Progression of childhood scoliosis.
Degenerative lumbar scoliosis. Degenerative lumbar scoliosis is a condition that typically develops after age 50. With this condition, the lower spine is affected, usually due to disk degeneration. Osteoporosis, a serious problem in many older adults, is not a risk factor for new-onset scoliosis, but it can be a contributing factor. In most cases, however, it is not known why scoliosis occurs in adults.

Scoliosis may be a result of various conditions that affect bones and muscles associated with the spinal column. They include the following:

Muscle paralysis.
Muscle deterioration from diseases such as muscular dystrophy, polio, or cerebral palsy.
Injury to the spinal cord.
Tumors, growths, or other small abnormalities on the spinal column. For example, syringomyelia, a disorder in which cysts form along the spine, can cause scoliosis. These spinal abnormalities may play a larger role in causing some cases of scoliosis than previously thought.
Familial dysautonomia, a rare disorder in Jewish children of Ashkenazi descent. (Only about 500 cases have been reported.)
Stress fractures and hormonal abnormalities that affect bone growth in young, competitive athletes.
Birth defects, including spina bifida (an open spinal cord) and myelomeningocele (a hernia of the central nervous system).
Turner syndrome, a genetic disease in females that affects physical and reproductive development.
Other diseases that can cause scoliosis are Marfan syndrome, Aicardi syndrome, Friedreich ataxia, Albers-Schonberg disease, rheumatoid arthritis, Cushing syndrome, and osteogenesis imperfecta.

Spina bifida is a congenital disorder (birth defect) in which the backbone and spinal canal do not close before birth. In severe cases, this can result in the spinal cord and its covering membranes protruding out of an affected infant's back. Spina bifida may also be nearly inconsequential, or may be repairable through surgery.

Nonstructural scoliosis is usually not a serious problem, since the curve is side to side. It can develop from a number of physical problems, including the following:

Unequal leg length. Injury, a shortened Achilles tendon, or other structural in-born problems can cause this very common condition. Unequal leg length rarely causes any problems and in most cases requires no treatment other than a lift in one of the shoes to equalize the length.
Muscle spasms.

Risk Factors

Risk Factors for Initial Scoliosis. Idiopathic scoliosis, the most common form, occurs most often during the growth spurt right before and during adolescence. (Between 12 - 21% of idiopathic cases occur in children ages 3 - 10 years, and less than 1% in infants.) Mild curvature (under 20 degrees) occurs about equally in girls and boys, but curve progression is 10 times more likely to occur in girls. Being taller than average at earlier ages may put some girls at risk, but other factors must be present to produce scoliosis. A risk factor that affects females is a delayed onset of menstruation, which can prolong the growth spurt period, thus increasing the possibility for the development of scoliosis.

Risk Factors for Curvature Progression. Once scoliosis is diagnosed, it is very difficult to predict who is at highest risk for curve progression. About 2 - 4% of all adolescents develop curvature of 10 degrees or more, but only about 0.3 - 0.5% of teenagers have curves greater than 20 degrees, which requires some medical attention.

People with certain medical conditions that affect the joints and muscles are at higher risk for scoliosis. These conditions include rheumatoid arthritis, muscular dystrophy, polio, and cerebral palsy. Children who receive organ transplants (kidney, liver, heart) are also at increased risk.

In one study, idiopathic scoliosis occurred in about 5% of close family members of children with the condition.

Scoliosis may be evident in young athletes, with a prevalence of 2 - 24%. The highest rates are observed among dancers, gymnasts, and swimmers. The scoliosis may have been due in part to loosening of the joints, delay in puberty onset (which can lead to weakened bones), and stresses on the growing spine. There have also been other isolated reports of a higher risk for scoliosis in young athletes who engage vigorously in sports that put an uneven load on the spine. These include figure skating, dance, tennis, skiing, and javelin throwing, among other sports. In most cases, the scoliosis is minor, and everyday sports do not lead to scoliosis. Exercise has many benefits for people both young and old and may even help patients with scoliosis.

Prognosis

In general, the severity of the scoliosis depends on the degree of the curvature and whether it threatens vital organs, specifically the lungs and heart.

Mild Scoliosis (less than 20 degrees). Mild scoliosis is not serious and requires no treatment other than monitoring.
Moderate Scoliosis (between 25 and 70 degrees). It is still not clear whether untreated moderate scoliosis causes significant health problems later on. Some studies have found no difference in either back pain or survival rates in adult untreated patients versus the general population. In one study, adults with moderate scoliosis had normal lung function, although they had difficulty exercising. (This low exercise tolerance might have been because many patients with scoliosis do not engage in regular physical activity.)
Severe Scoliosis (over 70 degrees). If the curvature exceeds 70 degrees, the severe twisting of the spine that occurs in structural scoliosis can cause the ribs to press against the lungs, restrict breathing, and reduce oxygen levels. The distortions may also affect the heart and possibly cause dangerous changes.
Very Severe Scoliosis (Over 100 degrees). Eventually, if the curve reaches over 100 degrees, both the lungs and heart can be injured. Patients with this degree of severity are susceptible to lung infections and pneumonia. Curves greater than 100 degrees increase mortality rates, but this problem is very uncommon in America.

Some experts argue that simply measuring the degree of the curve may not identify patients in the moderate and severe groups who are at greatest risk for lung problems. Other factors (spinal flexibility, the extent of asymmetry between the ribs and the vertebrae) may be more important in predicting severity in this group.

Scoliosis is associated with osteopenia, a condition characterized by loss of bone mass. About 27 - 38% of adolescent girls who have scoliosis also have osteopenia. Some experts recommend measuring bone mineral density when a patient is diagnosed with scoliosis. The amount of bone loss may help predict how severely the spine will curve. Preventing and treating osteopenia may help limit further curve progression.

If not treated, osteopenia can later develop into osteoporosis. Osteoporosis is a more serious loss of bone density that is common among postmenopausal women. Adolescents who have scoliosis are at increased risk of developing osteoporosis later in life. [See In-Depth Report#18: Osteoporosis.]

After 20 years or more, scoliosis patients who were previously treated with surgery experience small but significant physical impairment, (mainly mild back problems), compared to their peers without scoliosis. In one study, 65% of patients reported some low back pain compared to 47% of people without a history of scoliosis. In general it was mild, although 45% of patients reported having to take days off from work compared to 19% of nonscolosis patients. In another study, only 1.5% of the scoliosis group had severe debilitating back pain. In general, the quality of life was similar, however. Pain also did not play a major role in social limitations.

The following are some possible causes of later back problems in people with a history of treated scoliosis:

Spinal fusion disease. Patients who are surgically treated with fusion techniques lose flexibility and may experience weakness in back muscles due to injuries during surgery.
Disk degeneration and low back pain. With disk degeneration, the disks between the vertebrae may become weakened and rupture. In some patients, years after the original surgeries, particularly with the first generation of the Harrington rods, the weight of the instrumentation can cause disk and joint degeneration severe enough to require surgery. Treatment may involve removal of the old instrumentation and extension of the fusion into the lower back. Still, most patients do not experience significant back pain from these problems.
Height loss.
Scarred regions. Pain can occur from old scars in the incision areas.
Lumbar flatback. This condition is most often the result of a scoliosis surgical procedure called the Harrington technique, which eliminated lordosis (the inward curve in the lower back). Adult patients with flatback syndrome tend to stoop forward. They may experience fatigue and back and even neck pain.
Rotational trunk shift (uneven shoulders and hips).

Evidence suggests that previous treatment with braces may also cause mild back pain and more days off, but problems appear to be less than with surgery. In one study, dysfunction was comparable to people without a history of scoliosis.

Pain in adult-onset or untreated childhood scoliosis often develops because of posture problems that cause uneven stresses on the back, hips, shoulders, necks, and legs. In one study conducted 20 years after growth had stopped, two-thirds of adults who had lived with curvatures of 20 - 55 degrees reported they experienced back pain. Other studies have reported that adults with a history of scoliosis tend to have chronic and more back pain than the general population.

Nearly all individuals with untreated scoliosis at some point develop spondylosis, an arthritic condition in the spine. The joints become inflamed, the cartilage that cushions the disks may thin, and bone spurs may develop. If the disk degenerates or the curvature progresses to the point that the spinal vertebrae begin pressing on the nerves, pain can be very severe and may require surgery. Even surgically treated patients are at risk for spondylosis if inflammation occurs in vertebrae around the fusion site.

Emotional Impact in Childhood. The emotional impact of scoliosis, particularly on young girls or boys during their most vulnerable years, should not be underestimated. Adults who have had scoliosis and its treatments often recall significant social isolation and physical pain. Follow-up studies of children who had scoliosis without having strong family and professional support often report significant behavioral problems. Fortunately, current treatments are solving many of the problems that previous generations had to deal with, including unsightly bracing and extremely painful surgeries with little pain control.

Emotional Effects in Adults. Of some concern are growing numbers of adults with scoliosis. This group experiences considerable problems in general health, social functioning, emotional and mental health, as well as pain.

Older people with a history of treated scoliosis may carry negative emotional events into adulthood that have their roots in their early experiences with scoliosis. Many studies have reported that patients who were treated for scoliosis have limited social activities and a poorer body image in adulthood. Some patients with a history of scoliosis have reported a slight negative effect on their sexual life. Pain appears to be only a minor reason for such limitation.

Women who have been successfully treated for scoliosis have only minor or no additional risks at all for complications during pregnancy and delivery. A history of scoliosis also does not endanger the child. Pregnancy itself, even multiple pregnancies, does not increase the risk for curve progression. Women who have severe scoliosis that restricts the lungs, however, should be monitored closely.

Some evidence suggests a slightly higher risk for breast cancer and leukemia in patients who had multiple x-rays. Risks are highest in patients who had the largest radiation exposure, such as those who had been surgically treated.

Patients who simply received x-ray series for untreated idiopathic scoliosis or scoliosis caused by uneven length legs or hip abnormalities have a very low risk for future complications.

Click the icon to see an image of an x-ray.

Symptoms

Scoliosis is usually painless. The curvature itself may often be too subtle to be noticed, even by observant parents. Some parents may notice abnormal posture in their growing child that includes:

A tilted head that does not line up over the hips
A protruding shoulder blade
One hip or shoulder that is higher than the other, causing an uneven hem or shirt line
An uneven neckline
Leaning more to one side than the other
In developing girls, breasts appearing to be of unequal size
One side of the upper back being higher than the other when the child bends over, knees together, with the arms dangling down

Scoliosis may be suspected when one shoulder appears to be higher than the other, there is a curvature in the spine, or the pelvis appears to be tilted. The treatment of scoliosis can involve the use of a brace or surgery. Treatment is determined by the cause of the scoliosis, the size and location of the curve, and the stage of bone growth of the patient.

With more advanced scoliosis, fatigue may occur after prolonged sitting or standing. Scoliosis caused by muscle spasms or growths on the spine can sometimes cause pain. Nearly always, however, mild scoliosis produces no symptoms, and the condition is usually detected by the pediatrician or during a school screening test.

Diagnosis

The severity of scoliosis and need for treatment is usually determined by two factors:

The extent of the spinal curvature. (Scoliosis is diagnosed when the curve measures 11 degrees or more.)
The angle of the trunk rotation (ATR).

Both are measured in degrees. These two factors are usually related. For example, a person with a spinal curve of 20 degrees will usually have a trunk rotation (ATR) of 5 degrees. These two measurements, in fact, used to be the cutoff for recommending treatment. However, the great majority of 20-degree curves do not get worse. Patients do not usually need medical attention until the curve reaches 30 degrees, and the ATR is 7 degrees.

Adam's Forward Bend Test. The screening test used most often in schools and in the offices of pediatricians and primary care doctors is called the Adam's forward bend test.

The child bends forward dangling the arms, with the feet together and knees straight. The curve of structural scoliosis is more apparent when bending over. In a child with scoliosis, the examiner may observe an imbalanced rib cage, with one side being higher than the other, or other deformities.

The forward bend test is used most often in schools and doctor's offices to screen for scoliosis. During the test, the child bends forward with the feet together and knees straight while dangling the arms. Any imbalances in the rib cage or other deformities along the back could be a sign of scoliosis.

The forward bend test, however, is not sensitive to abnormalities in the lower back, a very common site for scoliosis. Because the test misses about 15% of scoliosis cases, many experts do not recommend it as the sole method for screening for scoliosis.

Other Physical Tests.

The patient walks on the toes, then the heels, and then jumps up and down on one foot. Such activities indicate leg strength and balance.
The doctor will check leg length and look for tight tendons in the back of the leg, which may cause an uneven leg length or other back problems.
The doctor will also check for neurologic impairment by testing reflexes, nerve sensation, and muscle function.

Proper diagnosis is important. A misjudgment can lead to unnecessary x-rays and stressful treatments in children not actually at risk for progression. Unfortunately, although measurements of curves and rotation are useful, no test exists yet to determine whether a curve will progress.

Inclinometer (Scoliometer). An inclinometer, also known as a Scoliometer, measures distortions of the torso. The procedure is as follows:

The patient bends over, arms dangling and palms pressed together, until a curve can be observed in the upper back (thoracic area).
The Scoliometer is placed on the back and measures the apex (the highest point) of the upper back curve.
The patient continues bending until the curve can be seen in the lower back (lumbar area). The apex of this curve is also measured.
Measurements are repeated twice, with the patient returning to a standing position between repetitions.
If results show a deformity, x-rays probably need to be performed to determine the extent.

Some experts believe the Scoliometer would make a useful device for widespread screening. Scoliometers, however, indicate rib cage distortions in more than half of children who turn out to have very minor or no sideways curves. They are therefore not accurate enough to guide treatment.

Currently, x-rays are the most cost-effective method for diagnosing scoliosis. Experts hope that accurate, noninvasive diagnostic techniques will eventually be developed to replace some of the x-rays used to monitor the progression of scoliosis. To date, imaging techniques under investigation appear to be fairly accurate for detecting scoliosis in the upper back (the thoracic region), but not scoliosis in the lower back (the lumbar region).

X-Rays. If screening indicates scoliosis, the child may be sent to a specialist who takes an initial x-ray and monitors the child every few months using repeated x-rays. X-rays are essential for an accurate diagnosis of scoliosis in that they:

Reveal the degree and severity of scoliosis.
Identify any other spinal abnormalities, including kyphosis (hunchback) and hyperlordosis (swayback).
Help the doctor determine whether skeletal growth has reached maturity.
X-rays taken when patients are bending forward can also help differentiate between structural and nonstructural scoliosis. Structural curves persist when a person bends over, and nonstructural curves tend to disappear. (Muscle spasms or spinal growths may sometimes cause nonstructural scoliosis that shows a curve on bending.)
Children and young adolescents who have mild curves and in older adolescents who have more severe curvatures but whose growth has stopped or slowed need x-rays every few months to detect increasing severity. Young people who are diagnosed with scoliosis should keep their x-rays indefinitely in case they develop back problems later in adulthood and need to be re-examined.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) is an advanced imaging procedure that does not use radiation, as x-rays do. It is expensive, however, and not generally used for an initial diagnosis. MRI can, nevertheless, identify spinal cord and brain stem abnormalities, which some studies indicate may be more prevalent than previously believed in children with idiopathic scoliosis. It also may be particularly useful before surgery for detecting defects that could lead to potential complications.

Click the icon to see an image of a MRI scan.

Because frequent x-rays may be required for young children with scoliosis, parents should be sure that x-ray technicians take all necessary protective measures. Experts are concerned about the long-term effects of radiation on sensitive young organs, particularly about a possible increase in the risk for cancer. Studies have reported an increased risk for cancer in women and men who, because of scoliosis, had been exposed to diagnostic x-rays in their childhood and adolescence.

X-ray techniques have become safer in recent years, and technicians can reduce the hazards with the following simple measures:

Directing x-ray beams through the patient from back to front, rather than the reverse.
Using x-ray filters that absorb some of the beam.
Using fast film to reduce exposure by two to six times.
Placing lead aprons or shields over parts of the body that are not being x-rayed.

There are various methods for determining and classifying the extent of the curve.

Cobb Method. The technique known as the Cobb method nearly always calculates the degree of the curve.

On an x-ray of the spine, the examiner draws two lines: One line extends out and up from the edge of the top vertebrae of the curve. The second line extends out and down from the bottom vertebrae.
The technician then draws a perpendicular line between the two lines.
Measuring the intersecting angle determines the degree of curvature.

The Cobb method is limited because it cannot fully determine the flexibility or the three-dimensional aspect of the spine. It is not as effective, then, in defining spinal rotation or kyphosis. It also tends to over-estimate the curve. Other diagnostic tools are needed then to make a more accurate diagnosis.

Classifying the Curve.Classification of the curve allows the doctor to identify patterns that can help determine treatments, particularly specific surgical techniques. The following are examples:

King Classification. The King classification classifies scoliotic curves as one of five patterns, which can help determine surgical treatments. It has limitations, however, and is not very useful for advanced surgical techniques.
Lenke Classification. Lenke classification takes more features of the curve into consideration and is proving to be more reliable. This includes six curve patterns plus additional factors that modify each of these curves.

Three-Dimensional Modeling Techniques. Advanced computer modeling techniques are able to create three dimensional images using x-rays or other two-dimensional images. They allow doctors to observe the spinal distortions and eventually could reduce the number of x-rays currently needed to monitor scoliosis and help surgeons determine optimal surgical procedures.

Even if the curve is accurately calculated, it still remains difficult to predict whether the scoliosis will progress. A recent report indicates that measuring the nerve conduction activity of the muscles supporting the spine may help predict subsequent progression in children with scoliosis. In addition, computer models are being used to better predict risk. One approach requires measuring 21 radiographic and clinical indicators and entering them into a computer program. The technique takes less than 20 minutes per patient, and studies found it to be up to 80% accurate in determining progression of curvature.

One way of predicting whether or not the curvature will progress is knowing when the child will stop growing:

If the child has years to grow, then the spine has more time to progress.
If the child will stop growing within a year, then progression should be very slight. (However, some progression continues in nearly 70% of curves even after the spine has matured.)

Knowing the child's age is, of course, the first step in estimating the end of growth. In addition, other methods can help predict the end of the growth stage. One method is called the Risser sign, which grades the amount of bone in the area at the top of the hipbone. A low grade indicates that the skeleton still has considerable growth; a high grade means that the child has nearly stopped growing and the curve is unlikely to progress much further. The Risser scale differs between genders, and, in boys, a high grade does not always signify the end of progression.

Screening programs for scoliosis, which began in the 1940s, are now mandatory in middle or high schools in many states, but there is considerable debate over whether screening should be routine.

Arguments Against Routine Screening. The U.S. Preventive Services Task Force does not recommend routine screening to detect adolescent scoliosis for the following reasons:

Screening tests are not accurate and depend too much on the skill of the examiner.
Schools often refer children with minor curves who are not at any risk for a progressive or serious condition to doctors, and such over-referrals add considerably to the costs of the health system. In one major study, 94% of the children referred to a doctor by the school did not require treatment. (Over 2,000 children were screened in order to find only 5 children who did need treatment.)
A long-term study of untreated patients with late-onset scoliosis indicates that these patients are productive and functional at a high level at 50-year follow-up. Patients with scoliosis have no greater danger for significant lung problems than the general population until their curves reach 60 - 100 degrees, making early screening unnecessary.

Experts against screening argue that such programs result in early treatments that either will not prevent curve progression and surgery or are unnecessary in the first place since curvatures often do not progress at all.

Arguments for Routine Screening. The American Academy of Orthopaedic Surgeons recommends that girls be screened twice, at ages 10 and 12, and that boys be screened once, at 13 or 14. The American Academy of Pediatrics recommends, however, scoliosis screening at ages 10, 12, 14, and 16 years. (In one study, over 40% of high school sophomores with newly diagnosed scoliosis had shown no signs of the disorder in earlier screening tests.) Other experts make the following arguments for universal screening:

Universal screening is useful for producing information on scoliosis that may eventually lead to knowledge of its cause and ways to prevent it.
Braces have proven to be effective, and early treatment can be important.
Without screening, the chances are slim that children with scoliosis will be diagnosed at an early stage if parents rely only on examinations by a family doctor or pediatrician. Such doctors often do not even look at backs and, if they do, they tend to use only the forward bend test, which is not accurate.

Some experts argue that widespread screening would be cost effective if schools had reasonable guidelines for determining which children should see a doctor for further testing. The following are some suggested guidelines for determining the need for a doctor referral:

Children should be sent to a doctor only if they have a 30-degree curve. (A 20-degree curve with a 5-degree trunk rotation has been the criteria for recommending treatment, although up to 80% of 20-degree curves do not get worse.)
Children with curves between 20 and 30 degrees should be screened every 6 months.

Such guidelines would detect about 95% of all genuinely serious cases while referring only 3% of all children tested for follow-up, thereby cutting costs without jeopardizing children.

Treatment

The treatments for scoliosis are not always straightforward. Some young people do not need treatment at all -- only careful observation. When treatment is warranted, several options, including braces and different surgical procedures, can help.

The general rule of thumb for treating scoliosis is to monitor the condition if the curve is less than 20 degrees. Curves greater than 25 degrees, or those that progress by 10 degrees while being monitored, may require treatment. Whether scoliosis is treated immediately or simply monitored is not an easy decision, however. The percentage of cases that will progress more than 5 degrees can be as low as 5% in certain cases or as high as 50 - 90%, depending on the severity of the curve or other predisposing factors:

Age. In general, the older the child the less likely the curve will progress. Scoliosis in a child under 10, for example, is more likely to progress than scoliosis in an adolescent. Experts estimate that curves less than 19 degrees will progress 10% in girls ages 13 - 15 years and 4% in children older than 15. (In some rare, severe cases, a curve may worsen even after a child has received treatment and stopped growing because of the weight of the body pressing against the abnormal curve.)

Gender. Girls have a higher risk for progression than boys.

Location of the Curvature. Thoracic curves, those in the upper spine, are more likely to progress than thoracolumbar curves or lumbar curves, those of the middle to lower spine.

Severity of the Curvature. The higher the degree of curvature the more likely the chance of progression and the more likely the lungs will be affected. Some experts argue that the degree of the curve alone may not identify patients with moderate and severe scoliosis who are at greatest risk for complications and therefore need treatment. For example, spinal flexibility and the extent of asymmetry between the ribs and the vertebrae may be more important than the curve degree in predicting severity in this group.

Presence of Other Health Conditions. Children in poor health may suffer more from stressful scoliosis treatments than other children. On the other hand, children who have existing conditions and are predispose to lung and heart problems may warrant immediate, aggressive treatment.

For example, a young man of 18 who has a curvature of 30 degrees may require no treatment because his growth has probably almost stopped, and his gender puts him at lower risk. A young girl of 10, however, with the same curvature requires immediate treatment.

In general, the following criteria are used to determine whether a patient should receive braces and conservative therapies or surgery:

Braces tend to be used in children with curvatures between 25 - 40 degrees who still will be growing significantly.
Surgery is suggested for patients with curvatures over 50 degrees, in untreated patients, or when braces have failed. In adults, scoliosis rarely progresses beyond 40 degrees, but surgery may be required if the patient is in a great deal of pain or if the scoliosis causes neurologic problems.

The choice may not be so straightforward in certain cases, and patients should discuss all options with their doctor.

In Children and Adolescents. After a mild curve is detected, a more difficult step is required: predicting whether the curve will progress into a more serious condition. Although as many as 3 in every 100 teenagers have a condition serious enough to need at least observation, progression is highly variable and individual.

In a study of patients whose curves did progress after diagnosis, 34% progressed more than 10 degrees, 18% progressed more than 20 degrees, and 8% progressed more than 30 degrees. Doctors cannot rely on any definitive risk factors for curve progression to predict with any certainty which patients will need aggressive treatment. Some evidence suggests the following factors may help determine patients at lower or higher risk:

Being female, particularly if taller than average.
Being younger at the onset of scoliosis.
Having a greater angle of curvature. For example, at 20 degrees, only about 20% of curves progress. Young people diagnosed with a 30-degree curve, however, have a risk for progression of 60%. With a curve of 50 degrees, the risk is 90%.
Curvatures caused by congenital scoliosis (spinal problems present at birth). These may progress rapidly.
Treatment with growth hormone. (Studies are mixed on whether this treatment poses any significant risk, although strict monitoring is still essential in young patients being given growth hormone.)

Curvatures may be less likely to progress in girls whose scoliosis was low in the back and whose spine was out of balance by more than an inch. Height also comes into play. For example, a shorter-than-average girl of 14 with low-back scoliosis of 25 - 35 degrees but whose spine is imbalanced by over an inch would have almost no risk. The same degree of curvature in the chest region of a tall 10-year old girl whose spine was in balance, however, would almost certainly progress.

In Adults. In rare cases, unrecognized or untreated scoliosis in youth may progress into adulthood, with the following curvatures posing low to high risk:

Curvatures under 30 degrees almost never progress
Predicting progression at curves around 40 degrees is not clear
Curvatures over 50 degrees are at great risk for progression

Managing Scoliosis

Exercise has many health benefits and is important for maintaining strength and muscle tone and stabilizing weight. Stretching exercises may be beneficial in children whose scoliosis is due to uneven leg lengths or a shortened tendon.

Strengthening the Muscles That Turn the Torso. A promising approach focuses on training and strengthening the muscles that turn the torso. Studies using specific equipment (MedX Torso Rotation machine) are showing promise. In a 2003 study, 16 of the 20 patients experienced curve reduction, and no curves progressed. In an earlier study, patients increased strength from 12 - 40%. One girl with a severe lumbar curve required surgery, but the remaining 11 patients had no progression of curvature, and 4 of the patients experienced a reduction in their curvature. Treatment did not involve braces. Clinical trials using this approach are underway. Exercising the torso to build muscle strength is important, in any case, in conjunction with braces.

ASCO Scoliosis Treatment Method. ASCO Scoliosis Treatment Method is a Russian approach that consists of isometric and stretching exercises, vibration, spinal manipulation, and electrical muscle stimulation. Some U.S. centers are reporting success in halting curve progression, but more research is needed to determine possible benefits.

Biofeedback. Researchers have investigated biofeedback on the premise that people receiving a signal to improve posture when slumping may, in some cases, reduce their spinal deformities. (Some experts believe that braces work only because the young patients self-correct their curves by retraining their posture to avoid the discomfort of the brace.)

Chiropractic Care. Several case reports suggest that chiropractic manipulation of the spine may help stop progression of mild curves. However, no rigorous studies have proved this. One small study reported no benefits from chiropractic in girls with spinal curves less than 20 degrees. (About 80% of such curves will not progress significantly without any treatment.)

Airway Ventilation at Night. Some research has focused on the use of airway systems, such as nasal continuous positive airflow pressure, for patients with severe scoliosis and reduced lung capacity. Patients use such systems during the night to force air into the upper airways and into the lungs. In one study, the use of these devices reduced hospitalization and improved lung function, shortness of breath, and fatigue. Such systems also can treat sleep apnea, a common sleep disorder.

Breathing Exercises. Breathing exercises may help improve lung function in children with scoliosis, and signs of lung problems.

When a difference in leg lengths causes secondary scoliosis, adding lifts to the heels may decrease a mild curvature. In one study, this practice reduced the curvature by an average of 5.3 to 7.5 degrees. (Curvatures were all less than 20 degrees.) Patients with the greatest curvature experienced some muscle pain, fatigue, and even nausea during the first few days they were using the lifts, but these symptoms eased within 10 days.

Braces

A brace can prevent further progression of moderate curves of (24 - 40 degrees). However, a brace will almost never reverse an existing curve and is only used to stop progression. One study reported overall success rates of around 74%, but results vary widely depending on the length of time the brace is worn, the type of brace, and the severity of the curve. The great majority of subjects in scoliosis studies are girls. Limited data suggest that in boys compliance rates are low, and braces are not effective.

Compliance with wearing a brace correlates strongly with success rate. In analysis of 34 patients, the compliance rate for the patients whose curve progressed by more than 5 degrees was 62%, while the compliance rate for the patients who did not progress was 85%.

In overweight patients with adolescent idiopathic scoliosis, braces appear to be less effective than in those who are not overweight. In one 10-year multicenter retrospective study, overweight patients were about three times more likely to have an unsuccessful result with braces than were people of normal weight.

A brace is one type of treatment for scoliosis. The brace works by exerting pressure on the back and ribs to push the spine in a straighter position. The brace usually fits snugly around the torso and can come in many styles. In a child who is still growing, bracing is usually recommended to help slow the progression of the curve. The brace is usually worn full-time until the growth of the bones has stopped.

Many experts have questioned whether a brace is any better than nature in halting curvature progress. Early studies found that braces were successful in halting progression in only half of cases (the same rate as no treatment at all). In recent years, however, braces have improved. Many now fit under the arms and can be worn under clothing, so that patients are much more likely to use them for longer periods during the day, which greatly affects their success rates.

Wearing the brace for the prescribed time is difficult but essential for any success. A team approach, with several health professionals involved, is beneficial and often necessary to support the patient through the bracing process. An orthopedic surgeon interprets the x-rays, assesses the potential progression of the scoliosis, and plans the treatment with the patient and family. If a brace is used, an orthotist measures and fits the patient with the device. A physical therapist tailors an exercise program best suited for the patient. A nurse may also coordinate the treatment plans and provide physical and emotional support.

Milwaukee Brace. A full torso brace called the Milwaukee brace was the standard treatment until a decade ago. It is still used particularly for high curves.

The device contains a wide flat bar in front and two smaller ones in back. These bars attach to a ring around the neck that has rests for the chin and back of the head. One study determined that correcting the curve occurs best if the patient lies on their chest when wearing the brace. Some researchers suggest that increasing the tension on the chest straps might add benefit. The brace is also periodically adjusted for growth.

The brace needs to be worn 23 hours a day, with relief during bathing and exercise only. Compliance is a major problem. In one study, only 15% of patients wore the Milwaukee brace as directed. It is a particularly difficult brace to endure wearing; one woman who had worn it for 7 years during adolescence remembered being invisible during her school years, ignored and shunned by other children.

The Boston and TLSO Braces. Molded braces called thoracolumbar-sacral orthoses (TLSOs), most often the Boston brace, come up to beneath the underarms and can be fitted close to the skin so they do not show beneath clothing. It appears to be effective for mid-back and lower curves. In one study, treatment was judged successful in 61% of adolescents who wore Boston braces, and success correlated with wearing the brace more than 18 hours a day. Wearing the brace for 16 hours a day may still be beneficial, although the risk for curve progression is significantly higher the less time the brace is worn. These braces have problems; they are hot, reduce lung capacity by nearly 20%, and cause mild, temporary changes in kidney function.

The Charleston Bending Brace. The Charleston Bending Brace is worn only at night. Some doctors question its value, although it appears to be suitable for small, flexible curves. In a 2002 study, it was equally effective as the Boston brace. Other studies have reported success rates of 56 - 66% in patients who wore the brace as directed. Still, more than 10% of the patients using either brace eventually needed surgery.

Additional Braces in Development. New braces are being developed in an attempt to improve compliance and results. Some examples are:

The Providence brace is a computer-fitted device that is worn only at night. It is specifically designed for the individual curvature abnormalities, and early studies are showing promise.
A bracing method called the SpineCor uses adjustable bands and a cotton vest that allows flexibility. A 2003 study reported that after 2 years, the brace corrected the curve by 5 degrees in more than half the patients, while 38% were stabilized and only 7% had curvature that worsened by more than 5 degrees. A recent trial of 24 girls with idiopathic scoliosis compared the SpineCor with a TLSO-type brace. The study indicated that the SpineCor did not halt curvature progression associated with idiopathic scoliosis during the pubertal growth spurt whereas the TLSO device did.
The custom-fitted TriaC brace exerts pressure in specific areas of the back to allow greater comfort and flexibility. It may be less conspicuous than some of the older braces.

Studies are needed to determine if these or other new braces provide any additional value.

According to a 2003 study, compliance in wearing the brace averages 65% (although it varied from 8 - 90%). Patients were apt to wear them at night but often wore them sporadically during the day. The quality of life can vary by the type of brace worn. In one study, patients who had the Milwaukee brace reported greater impairment than patients with the Boston, TSLO, or Charleston braces. The choice of brace should be one that will be the most effective for a particular patient with the lowest impact on quality of life. Young people often refuse to wear braces, even the newer models, and emotional support from the family and professionals is extremely important to help a child accept the process and sustain compliance. On a positive note, one study reported that brace treatment did not negatively affect the self images of the adolescents who had to wear them.

For children who require braces, an exercise program helps boost well being, improves compliance with treatment, and keeps muscles in tone so that the transition period after brace removal is easier.

An exercise and physical therapy program is important to maintain or achieve the following:

Chest mobility.
Proper breathing. In one study, young girls who wore the Boston brace and performed aerobic exercises for 30 minutes four times a week experienced improved lung function, whereas lung function declined in girls who did not exercise.
Muscle strength (especially in the abdominal muscles).
Flexibility in the spine. One small study showed that patients who performed exercises improving flexibility in the torso experienced less spinal twisting and had improved curvature.
Correct posture. Practicing correct posture, especially in front of a mirror, is an extremely important part of any physical therapy program. A patient who is accustomed to a curved spine may have the sensation of being crooked when first taught to properly align the spine. Practicing in front of a mirror provides a reality check.
Patients must also learn to conduct daily activities while wearing the brace. Patients tend to comply with physical therapy in the period when the brace is first being used. They typically stop exercising when they have gotten used to the brace, however, and resume exercising only near the time the brace is being removed. Patients who don't stay with the program throughout the duration of brace use experience a weakening in the back at the time of removal.

Surgery

The goals of scoliosis surgery are threefold:

Straighten the spine as much as possible in a safe manner
Balance the torso and pelvic areas
Maintain correction

It takes a two-part process to accomplish these goals:

Fusing (joining together) the vertebrae along the curve
Supporting these fused bones with instrumentation (steel rods, hooks, and other devices) attached to the spine

There are many surgical variations that use different instruments, procedures, and surgical approaches to treat scoliosis. All of the operations require meticulous skill. In most cases, success depends less on the type of operation than on the skill and experience of the surgeon. The cause of scoliosis often determines the type of procedure. Parents of patients or adult patients should not be shy in asking the surgeon and hospital about their experience with the specific procedures being considered.

Surgery is usually recommended for the following children and adolescents with idiopathic scoliosis:

All young people whose curve exceeds 50 degrees.
Growing children whose curve has gone beyond 40 degrees. (There is still some debate, however, about whether all children with curves of 40 degrees should have surgery.)
Older children who have surgery tend to experience improved well-being from the changes in their appearance, even if they have no actual improved physical functioning.

Surgery may be required for the following children at as early an age as possible.

Those whose scoliosis is due to inborn abnormalities. (The younger they are when surgery is performed the better their chances for success.)
Children with multiple physical handicaps.

Procedures will differ depending on whether a child has idiopathic scoliosis, or scoliosis due to muscle and nerve disorders (such as muscular dystrophy or cerebral palsy). In the latter cases, children also need a team approach to reduce their risks for serious complications.

Before the operation, a doctor conducts a complete physical examination to determine leg lengths, muscle strength, lung function, and any postural abnormalities. The patient receives training in deep breathing and effective coughing to avoid lung congestion after the operation. The patient should also receive training in turning over in bed in a single movement (called log-rolling) before the operation. Psychologic intervention using cognitive-behavioral methods that help young patients cope may be very helpful in reducing anxiety and pain after surgery.

Patients are encouraged to donate their own blood before the operation for use in possible transfusions. The patient should have no sunburn, rashes, or sores on the back before the operation, which could increase the risk for infection.

Most scoliosis operations involve fusing the vertebrae. The instruments and devices used to support the fusion vary, however.

In the fusion procedure, the surgeon will:

Slice flaps to expose the backs of the vertebrae that lie along the curve.
Remove the bony outgrowths along the vertebrae that allow the spine to twist and bend.
Lay matchstick-sized bone grafts vertically across the exposed surface of each vertebra, being careful that they touch adjoining vertebrae.
Fold the flaps back to their original position, covering the bone grafts.
These grafts will regenerate, grow into the bone, and fuse the vertebrae together.

Depending upon the severity and responsiveness to other treatment, a doctor may recommend surgery for scoliosis. Surgery involves correcting the curve (although not all the way) and fusing the bones in the curve together. The surgeon lays bone grafts across the exposed surface of each vertebra. These grafts will regenerate, grow into the bone, and fuse the vertebrae together. The bones are held in place with one or two metal rods held down with hooks and screws, helping to support the fusion of the vertebrae.

Graft Materials. A surgeon takes bone grafts from the patient's hip, ribs, spine, or other bones (called autografts). This is the best quality bone. However, because autografts are taken directly from the scoliosis patient, the operation is longer and the patient experiences more pain afterward. Researchers are investigating allografts, bone grafts taken from another person or a cadaver. This would reduce the pain and duration of the operation. Allografts, however, pose an increased risk for infection from the donor.

Some surgical centers now perform spinal fusions in adults using a biologically-manufactured human bone protein instead of bone grafts. RhBMP-2 (INFUSE Bone Graft) contains a bone morphogenetic protein (BMP) that helps the body grow its own bone. A surgeon inserts the protein into a pair of thimble-like cages, which are implanted between the spinal vertebrae. The cages help stabilize the spine, while the protein prompts new bone growth. Doctors hope that this new procedure can eliminate the pain of autografts and the risk of infection of allografts. Results from preliminary studies have been promising. BMP treatments are currently approved only for adults.

Healing. The healed fusions harden in a straightened position to prevent further curvature, leaving the rest of the spine flexible. It takes about 3 months for the vertebrae to fuse substantially, although 1 - 2 years are required before fusion is complete. Fusion stops growth in the spine, but most growth occurs in the long bones of the body (such as in the legs), anyway. Patients will most likely gain height from both growth in the legs and from the straighter spine. Patients may walk at a slightly slower pace after fusion, but balance may improve, and sports activities are not restricted after the procedure.

Harrington Procedure. Until 10 years ago, the standard instruments used in fusion procedures were those of the Harrington procedure, first developed in the 1960s:

To support the fusion of the vertebrae, the surgeon uses a steel rod, extending from the bottom to the top of the curve. (More than one rod may be used depending on the type of curve and whether outward curvature of the spine is present.)
The rod is attached by hooks that are suspended from pegs inserted into the bone.
Similar to changing a tire, the steel rod is jacked up and then locked into place to support the spine securely. The surgeon is then ready to fuse the vertebrae together.
After this operation, patients must wear a full body cast and lie in bed for 3 - 6 months until fusion is complete enough to stabilize the spine.
After 1 - 2 years, the steel rod is not really necessary, but it is almost always left in place unless infection or other complications occur.

The Harrington procedure is very difficult to undergo, particularly for young people, and although the operation can achieve a correction of the curve of over 50%, studies have reported a loss in this correction of between 10 - 25% over time. The procedure does not correct the rotation of the spine and, therefore, does not improve an existing rib hump that was caused by the rotation. The operation does not interfere with normal pregnancies and deliveries later in life.

Certain complications may occur from this procedure:

About 40% of Harrington patients have a condition called the flat back syndrome, because the procedure eliminates normal lordosis (the inward curving of the lower back). Flat back syndrome from the Harrington procedure does not cause any immediate pain. In later years, however, the disks may collapse below the fusion, making it difficult to stand erect, and the condition can cause significant pain and emotional distress.
Studies have reported that 5 - 7 years after their surgery, between a fifth and a third of patients who had the Harrington procedure experienced low back pain. (In one study, only 3% had experienced back pain before surgery.) In such cases, however, the pain was not severe enough to interfere with normal activities and did not require additional surgery.
Children younger than age 11 whose skeleton is immature and who have the Harrington procedure have a fairly high risk for a specific curve progression called the crankshaft phenomenon. This condition occurs when the front of the fused spine continues to grow after the procedure. The spine cannot grow longer, so it twists and develops a curvature. In one study that followed patients for 5 - 16 years, crankshaft curve progression was moderate, however, with the Cobb angle averaging 9 degrees and rotation averaging 7 degrees.

Cotrel-Dubousset Procedure. The Cotrel-Dubousset procedure not only corrects the curve but also may help correct rotation, and it does not cause flat back syndrome.

With this procedure, a surgeon cross links parallel rods for better stability in holding the fused vertebrae. Improvement in correction averaged 66% in one study, with a later correction loss reported to be 5%. (Other studies have reported loss of curvature correction at less than 2%.) Over 95% of patients reported the results to be good or very good (only 86% of patients who had the Harrington procedure experienced the same levels of satisfaction). Patients often go home in 5 days and may be back in school in 3 weeks.

Complication rates are similar to the Harrington procedure but with some differences:

Operation time and blood loss are greater than with the Harrington procedure.
Cotrel-Dubousset and other procedures that are designed to reverse the rotation of the spine have less risk for flat back syndrome, but they have a higher risk for spinal imbalance than the Harrington procedure.
Failure rates are about 25% after 10 years, which is very high. Experts hope that the advances in current scoliosis procedures will help reduce the long-term adverse effects.

The Texas Scottish-Rite Hospital (TSRH) Instrumentation. The Texas Scottish-Rite Hospital (TSRH) instrumentation is similar to the Cotrel-Dubousset procedure in that it uses parallel rods and other devices that reverse rotation as well as improve curvature. TSRH, however, uses smooth rods and hooks that are designed to make removal or adjustment easier later on if complications arise. Complications are similar to the Cotrel-Dubousset procedure.

Additional Forms of Instrumentation. Other instrumentation procedures have refined the hardware used in the Harrington and Cotrel-Dubousset operations.

After surgeons developed Luque instrumentation to help maintain normal lordosis, experts hoped that bracing would not be needed afterward. Several studies showed, however, that without braces, correction was lost after this operation, and the procedure may have a higher risk for spinal cord injury than other standard procedures. Luque instrumentation is used primarily in people whose scoliosis is due to problems of nerves and muscles, such as in children with cerebral palsy.
Wisconsin segmental spine instrumentation (WSSI) is as safe as the Harrington rod and nearly as strong as the Luque instrumentation.
The Dorsal Dynamic Spondylodesis (DDS) system, under testing in Germany, is a semirigid system that allows for greater flexibility of the spine.

Instrumentation for Anterior Approach. The anterior approach, in which the surgeon performs the operation by opening the chest wall, requires specific hardware. Halm-Zielke instrumentation, for example, uses TSRH instrumentation with bone grafts constructed from ribs to prop open the spaces between the disks. It allows true three-dimensional curve correction. However, it does not solve specific problems with this approach -- higher risks for kyphosis (an outward curve) and pseudoarthrosis (a false joint at the fusion site). Variants using two rod systems, fusion cages, or other instruments appear to improve this procedure.

Posterior Approach (Through the Back). Many surgeons use a posterior approach for scoliosis, which reaches the surgical area by opening the back of the patient. It has been the gold standard for decades and is generally used with Harrington instrumentation. The posterior approach has advantages and disadvantages:

Advantages. Surgeons are familiar with it, so fusion rates are excellent, curve correction is good, and it has few complications.
Disadvantages. Preadolescent children are at risk for the crankshaft phenomenon (a worsening of the curve) later on. (Newer posterior instrumentation, such as the Isola instrumentation, may prevent this occurrence.) The posterior approach also does not always correct hypokyphosis (the loss of normal outward curvature) in the thoracic (upper) spine. The procedure is not always effective for curves in the thoracolumbar region (where the upper and lower spine meet) and may cause spinal abnormalities there.

Anterior Approach (Through the Front). Increasingly, surgeons are using the anterior approach, in which the surgeon performs the operation through the chest wall (called a thoracotomy). With the anterior approach, the surgeon makes an incision in the chest, deflates the lung, and removes a rib in order to reach the spine. This rib can be used during the operation as a strut to support the spine. It also may be repositioned within the patient until it is used for bone grafting during fusion.

The anterior approach also has its advantages and disadvantages:

Advantages. Because the frontal approach allows the procedure to be performed higher up in the spine than with standard procedures, the patient may have a lower risk for lower-back injury later on. In addition, transfusion rates are much lower with the anterior approach. With increasing experience, the anterior approach is as effective as the posterior approach.
Disadvantages. It is a more recent procedure than the posterior approach, and, among inexperienced surgeons, carries a higher risk for complications than in the more standard posterior approach. One study noted poorer lung function 2 years after surgery than with the posterior approach, possibly because the wide chest incision impairs the chest muscles, which can affect lung function afterward. Anterior instrumentation poses a risk for hyperkyphosis (exaggerated outward curvature) and a higher risk for pseudoarthrosis, a painful condition in which a false joint develops at the fusion site. Hardware failure rates may also be higher in the anterior approach than in the posterior approach. Increasing experience and newer hardware designs are reducing many of these problems.

The Combined Anterior-Posterior Approach. The combination approach uses an anterior approach first, which allows better correction of the problems. The fusion part of the operation is done with the posterior approach. This is a very long and complex procedure. It appears to be safe, however, and is proving to be useful, even in very young patients, for preventing the crankshaft phenomenon. It also may correct large rigid curves and specific severe curves in the thoracic spine.

Researchers are evaluating new approaches to treating thoracic scoliosis in adolescents and children. Researchers in Germany are studying the effects of implanting a vertical expandable prosthetic titanium rib. This implant expands the thoracic cavity, thereby correcting the curvature and allowing spinal, thoracic, and lung growth. Early experience with 15 children showed improvement of thoracic insufficiency syndrome and ability to sit, in addition to greatly improvement cosmetic appearance.

Researchers in the U.S. recently compared the radiographic and clinical outcomes and pulmonary function in patients treated with either anterior thoracoscopic or traditional posterior surgery. The anterior thoracoscopic surgery uses a video-assisted anterior approach and recently developed spinal instrumentation. There were 28 patients in the thoracoscopic group (average, 14.6 years of age) and 23 patients in the posterior fusion group (average, 14.3 years of age). The researchers found no significant differences between the groups in terms of kyphosis, coronal balance, or tilt angle. Advantages of the anterior thoracoscopic approach include the need for fewer vertebral levels fused, less blood loss, and lower transfusion rate, yet the operative time was nearly 2 times longer than for the posterior approach.

While both of these new treatments have shown some early positive results, more research will be needed to determine their true value.

Complication rates are high (nearly 10%) with any of these procedures, including the standard Harrington method and the newer Cotrel-Dubousset procedure.

Complications for all procedures include allergic reactions to anesthesia and the following:

Bleeding. Standard procedures increase the risk for major blood loss during the procedure. Patients are encouraged to donate blood before the operation for use in possible transfusions. Children sometimes require more than one transfusion following surgery. Researchers are investigating various methods for reducing the need for transfusions.

In one study, patients received erythropoietin (rhEPO) before the procedure. RhEPO is a hormone that acts in the bone marrow to increase the production of red blood cells. Patients who received this hormone, particularly those with idiopathic scoliosis, needed fewer transfusions and spent less time in the hospital than those who did not receive rhEPO.

Newer endoscopic techniques are reducing the need for transfusions.

Postoperative Pain. Some pain always follows these procedures, requiring intravenous administration of potent painkillers right after the operation (endoscopic procedures may require only mild pain relievers). Of some concern is a study suggesting that the use of NSAIDs, or nonsteroidal anti-inflammatory drugs (aspirin, Motrin, Advil), for pain relief right after fusion may increase the risk for fusion failure. Until more research is conducted, these common painkillers should not be routinely used immediately after surgery.

Infection. Infection is always a risk with any operation. One study reported changes in the immune system for about 3 weeks after surgery, which indicated a greater risk for infection. Researchers recommended being very vigilant for signs of infection, including in the pancreas and urinary tract. Doctors also recommend antibiotics, given by injection for 2 - 5 days after surgery and by mouth for 1 - 2 weeks longer.

Nerve Damage. Patients often worry about neurologic injuries, but the risk is actually very low. In general, nerve injury occurs in 1% of patients, with the risk highest in adults. If neurologic damage occurs, it most often causes muscle weakness. Paralysis is very rare and can be prevented using monitoring techniques during the operation. Nearly all monitoring procedures use a so-called wake-up test, in which the patient is brought out of anesthesia during or at the end of the procedure and assessed for sensations to be sure no injury has occurred. One simple method is to wake patients up in the middle of their operations and ask them to wiggle their toes. More sophisticated methods measure the electrical activity of the spinal cord; if the monitor indicates a fall in electrical response and possible injury, the surgeon adjusts his techniques to avoid further damage to the spinal cord.

Pseudoarthrosis. If the fusion fails to heal, pseudoarthrosis, a painful condition in which a false joint develops at the site, may develop. In one study, teenagers who smoked and heavier adolescents (over 154 pounds) who had hyperkyphosis (hunchback) were at higher risk for this complication. The anterior approach may pose a higher risk for pseudoarthrosis. One study reported that pseudoarthrosis may be undiagnosed, and rates may average 20% after surgery, therefore acting as a major contributor to post-surgery pain.

Disk Degeneration and Low Back Pain. Fusion in the lumbar area produces great stress on the lower back and eventually can cause disk degeneration. Loss of trunk mobility, balance, and muscle strength from surgical treatments can also cause lower back pain and chronic problems in future years. Patients who are surgically treated with fusion techniques lose flexibility; their back muscles may be weakened if they were injured during surgery. In most cases, however, the consequences are mild to moderate.

Lung Function. Some patients may develop serious lung problems after surgery. These complications are highest in children whose scoliosis is due to neuromuscular problems, such as spina bifida, cerebral palsy, or muscular dystrophy. Lung problems can occur up to 1 week after surgery. Lung function may not become completely normal until 1 - 2 months after surgery.

Other Complications. Other problems can include, but are not limited to, the following:

Hooks dislodging or a fused vertebra fracturing
Gallstones
Pancreatitis (inflammation of the pancreas). Among adolescents, this complication tends to occur more often among those who are older or who have a lower body mass index.
Intestinal obstruction

Click the icon to see an image of gallstones.

Patients must perform breathing and coughing exercises shortly after the procedure and continue them through the recovery process to rid the lungs of congestion. The patient is usually able to sit up the day after the operation, and most patients can move on their own within a week. A brace may be necessary, depending on the procedure. With the anterior approach in the upper back, patients may have some trouble with activities involving the arms and hands -- such as tying shoes and cutting food. In one study, however, occupational therapy using stretching and strengthening exercises allowed for full resumption of daily activities, including dressing, bathing, and grooming, within 3 months.

Patients are often concerned that surgery will stiffen their backs, but most cases of scoliosis affect the upper back, which has only limited movement, so that patients do not notice much difference. It may take a year or more for muscle strength to return. In some cases, the operation cannot completely correct the curve, and one leg may be shorter than the other. Heel lifts may help in this case.

Patients may need a corrective procedure called revision or salvage surgery, usually for one of these reasons:

Failure of the previous procedure
Curvature progression around the fusion site
Disk degeneration
Poor posture alignment

Minimally invasive surgery is an alternative to spinal fusion. These types of surgeries use a few small incisions and cause less scarring than standard open approaches that require wide cuts. However, these surgeries are limited to certain patients and are not yet as frequently performed as spinal fusion surgeries.

Endoscopy. In endoscopy, the surgeon makes small incisions and inserts tubes that contain tiny instruments and cameras through the incisions in order to view and execute the procedure. In most cases, the procedure occurs in two stages:

First, the surgeon uses the anterior approach to remove disk material and loosen the spine.
They follow with a posterior for fusion and instrumentation.

Recovery after surgery is rapid. Most patients are out of bed 2 days after surgery. Endoscopy causes fewer and smaller scars, and an easier recovery, than more invasive surgical approaches.

However, the endoscopic procedure for scoliosis is complicated, and few surgeons are trained to perform it. The surgery is generally used only for single curves in the upper back or for patients with a curve in the upper back and a compensating curve in the lower back. Some surgeons are now able to operate on areas below the diaphragm, including the lumbar spine. The patients must still wear a brace for 3 months after surgery. Long-term studies are required to compare results to those of standard procedures.

Growing Rod Technique. This technique is used for very young children in whom bracing has not helped. Instead of doing spinal fusion, doctors surgically insert a rod into the patient’s back. Additional surgeries are performed every 6 months to extend the rod so that the spine can continue to grow. Some growing rod techniques use a single rod, while others use two rods. Studies suggest that dual rods are stronger than single rods, which may help provide better spinal stability and correction.

Vertebral Body Stapling. Vertebral body stapling is an experimental technique that may prevent curve progression in some young patients with curves less than 50 degrees. It involves stapling the convex (outer) curve of the anterior spine (the side of the spine facing the chest), which helps stabilize and reduce progression of the inner (concave) curve. The procedure uses a special metal device that is clamp-shaped at body temperature but can be straightened when subjected to cold temperatures and inserted into the spine. When warmed up, the staple returns to its clamp shape and supports the spine.

Treatment for Adult Scoliosis

Adults who were surgically treated for scoliosis in their youth are at risk for disk degeneration and spinal fusion failure. In most adults with previous scoliosis, moderate exercise is not harmful and is extremely important for maintaining healthy supportive muscles and preventing disk degeneration. However, people who have only one or two mobile lumbar vertebrae below the area that was fused during surgery should avoid activity or exercise that causes excessive twisting on the spine. Some experts believe this may accelerate spinal degeneration.

In most cases of adult scoliosis, nonsurgical care is preferred if possible. This can include patient education, exercises, and medical treatments. Braces are not useful.

One center reported that epidural steroid injections were a beneficial alternative to surgery in patients with degenerative lumbar scoliosis.

Candidates for Surgery. In general, pain is the most common reason for surgery in adult scoliosis. Surgery may be recommended in the following cases:

Curvatures over 50 degrees with persistent pain.
Surgery is almost always recommended for adults with curvatures over 60 degrees.
Progressive mid and low back curve or low back curve with persistent pain.
Reduced heart and lung function. Most surgeons, however, will not operate on adults with severely impaired lung function and heart failure. Once this has occurred, surgery will not help improve lung capacity and may cause the condition to worsen, at least temporarily.
Significant deformity is present. Adults should not expect to achieve a completely straight spine, however. There is a high risk for nerve damage if the spine is over-corrected, and adult spines are less flexible than children's are. Usually, however, the correction achieves an acceptable cosmetic improvement.

Surgeons prefer to operate on adults under 50 years old, although surgery may be appropriate in some older people.

Standard Scoliosis Procedures in Adult Scoliosis. The procedures involve the following depending on whether the patient had been treated previously or not:

In patients who have not had previous treatment and who have degenerative lumbar scoliosis, the procedure is often a diskectomy (removal of the diseased disks) followed by scoliosis procedures (instrumentation and fusion).
In patients with previously treated scoliosis, the only remedy is removal of the old instrumentation, extension of the fusion, and implementation of new instrumentation and bone grafts.

Surgical procedures in adult scoliosis are complex and undertaken only after careful consideration and all nonsurgical methods have been exhausted. Adults have a much higher risk than children for complications, including pneumonia, infection, poor wound healing, and persistent pain. In addition, procedures in adults often involve fusion in lumbar and sacral areas (the low back), which can cause several complications. Some experts believe that the risks of operations in this area nearly always outweigh any benefits in adults. Most studies on adults have also reported low success rates.

Others argue that without an operation, the back will become unstable and painful. In addition, most studies on adults report on procedures using the old Harrington instrumentation techniques. Advances in instrumentation are increasing success rates in adults.

In a recent study, for example, adults who underwent anterior fusion and instrumentation had excellent results. In another study of newer generation instrumentation, 87% of adult patients reported satisfaction.

Wedge Osteotomy. Researchers are investigating wedge osteotomy in patients with mature spines, as corrective surgery and as an alternative to braces. In this procedure, a surgeon cuts wedges of bone from the concave side of the curve. The surgeon then straightens the spine by inserting a temporary rod and closing the cut sections. The patient needs to wear a brace and restrict activity for about 12 weeks or until the bone has healed. The patient can resume normal activities when a surgeon removes the rod, and the spine is mobile.

Resources

www.scoliosis.org -- National Scoliosis Foundation
www.srs.org -- Scoliosis Research Society
www.scoliosis-assoc.org - - Scoliosis Association
www.aaos.org -- American Academy of Orthopaedic Surgeons
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.ispine.com -- Information on the spine

References

Akbarnia BA, Marks DS, Boachie-Adjei O, Thompson AG, Asher MA. Dual growing rod technique for the treatment of progressive early-onset scoliosis: a multicenter study. Spine. 2005;30(17 Suppl):S46-S57.

Helenius I, Jalanko H, Remes V, Sairanen H, Salminen S, Holmberg C, et al. Scoliosis after solid organ transplantation in children and adolescents. Am J Transplant. 2006;6(2):324-330.

Hell AK, Campbell RM, Hefti F. The vertical expandable prosthetic titanium rib implant for the treatment of thoracic insufficiency syndrome associated with congenital and neuromuscular scoliosis in young children. J Pediatr Orthop B. 2005;14:287-293.

Hung VW, Qin L, Cheung CS, Lam TP, Ng BK, Tse YK, et al. Osteopenia: a new prognostic factor of curve progression in adolescent idiopathic scoliosis. J Bone Joint Surg Am. 2005;87(12):2709-2716.

Lee WT, Cheung CS, Tse YK, Guo X, Qin L, Lam TP, et al. Association of osteopenia with curve severity in adolescent idiopathic scoliosis: a study of 919 girls. Osteoporos Int. 2005;16(12):1924-1932.

Lonner BS, Kondrachov D, Siddiqi F, Hayes V, Charf C. Thoracoscopic spinal fusion compared with posterior spinal fusion for the treatment of thoracic adolescent idiopathic scoliosis. J Bone Joint Surg. 2006;88A:1022-1034.

Luhmann SJ, Bridwell KH, Cheng I, Imamura T, Lenke LG, Schootman M. Use of bone morphogenetic protein-2 for adult spinal deformity. Spine. 2005;30(17 Suppl):S110-S117.

Thompson GH, Akbarnia BA, Kostial P, Poe-Kochert C, Armstrong DG, Roh J, et al. Comparison of single and dual growing rod techniques followed through definitive surgery: a preliminary study. Spine. 2005;30(18):2039-2044.

Yuan N, Fraire JA, Margetis MM, Skaggs DL, Tolo VT, Keens TG. The effect of scoliosis surgery on lung function in the immediate postoperative period. Spine. 2005;30(19):2182-2185.

Review Date:
4/6/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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Hemolytic-uremic syndrome

admin — Wed, 03 Sep 2008 17:50:14 -0700

Overview

Definition
Alternative Names
Causes, incidence, and risk factors
Symptoms
Signs and tests
Treatment
Expectations (prognosis)
Complications
Calling your health care provider
Prevention

Illustrations

Male urinary system

HEALTH GUIDE REFERENCE FROM A.D.A.M

Definition

Hemolytic-uremic syndrome (HUS) is a disorder that occurs when an infection in the digestive system produces toxic substances that destroy red blood cells. It often affects the kidneys.

Alternative Names

HUS

Causes, incidence, and risk factors

This disorder is most common in children. It often occurs after a gastrointestinal (enteric) infection, caused by a type of E. coli bacteria (Escherichia coli O157:H7). It has also been associated with other enteric infections, including Shigella and Salmonella, and some non-enteric infections.

HUS was once very rare, but it is increasing in children. It is the most common cause of acute kidney failure in children. Several large outbreaks in 1992 and 1993 were linked to undercooked hamburger meat contaminated with E. coli. Because of these outbreaks, supermarket hamburger meat now has new labeling, and there are new temperature guidelines for hamburgers cooked at fast-food chains and restaurants.

HUS is more complicated in adults. It is similar to another disease called thrombotic thrombocytopenic purpura (TTP).

Other risk factors for HUS are unknown. HUS may occur with a variety of other diseases and infections.

Symptoms

HUS often begins with vomiting and diarrhea (which may be bloody). Within a week, the person may become weak and iritable. People with HUS may urinate far less than normal. Urine output may almost stop. Because red blood cells are being destroyed (a process called hemolysis), the person quickly becomes anemic and pale.

Early symptoms:

Later developing symptoms:

Low urine output
No urine output
Paleness
Bruising
Skin rash that looks like fine red spots (petechiae)
Yellowish coloration to the skin (jaundice)
Decreased consciousness
Seizures -- rare

Signs and tests

A physical exam may show an enlarged liver or spleen. There may be abnormal changes to the nervous system. Lab tests will show signs of hemolytic anemia and acute renal failure.

A complete blood count (CBC) might show:
- Lower platelet count (thrombocytopenia)
- Rupture of red blood cells
- Anemia from loss of red blood cells (hemolytic anemia)
- Raised white blood count
Coagulation studies such as PT and PTT may be normal or abnormal.
Blood chemistry such as a chem-20 shows abnormalities, including:
- High BUN level
- High creatinine level
- High free hemoglobin level
A urinalysis shows:
- Blood in the urine
- Protein in the urine
A urine protein test can be used to show the amount of protein in the urine.

Other tests:

Stool culture may be positive for a certain type of E. coli bacteria
Kidney biopsy shows changes

Treatment

This is a serious illness in both children and adults, and it can cause death.

People with this condition receive transfusions of packed red cells and platelets as needed. Some people may need kidney dialysis. Doctors may prescribe medications such as corticosteroids.

Some people may have the liquid portion of their blood (plasma) treated with plasmapheresis or plasma exchange. The plasma is removed and replaced with fresh (donated) plasma or filtered to remove antibodies from the blood.

Expectations (prognosis)

More than half of people who get treatment will recover, and the outcome is better in children.

Complications

Chronic or relapsing HUS
Acute kidney failure
Chronic kidney failure
Uremia (symptoms caused by the build-up of nitrogen-containing wastes in the body)
Hemolytic anemia
Thrombocytopenia (lack of enough platelets)
Problems with blood coagulation
Problems with the nervous system

Calling your health care provider

Call your health care provider if you develop symptoms of HUS. If you have reduced consciousness, blood in the stool, or a lack of urination, it is an emergency situation.

Call your health care provider if you have had an episode of HUS, and your urine output decreases or you develop other new symptoms.

Prevention

You can prevent the known cause, E. coli, by cooking hamburger and ground meats well. It is not possible to prevent other, unrecognized causes at this time.

Review Date: 4/27/2007

Reviewed By: Rita Nanda, M.D., Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

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