Cirrhosis

On this page:

What is cirrhosis? What causes cirrhosis? What are the symptoms of cirrhosis? What are the complications of cirrhosis? How is cirrhosis diagnosed? How is the severity of cirrhosis measured? How is cirrhosis treated? When is a liver transplant indicated for cirrhosis? Points to Remember Hope through Research For More Information Acknowledgments

What is cirrhosis?
Cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injury. Scar tissue replaces healthy liver tissue, partially blocking the flow of blood through the liver. Scarring also impairs the livers ability to

control infections remove bacteria and toxins from the blood process nutrients, hormones, and drugs make proteins that regulate blood clotting produce bile to help absorb fatsincluding cholesteroland fat-soluble vitamins

A healthy liver is able to regenerate most of its own cells when they become damaged. With end-stage cirrhosis, the liver can no longer effectively replace damaged cells. A healthy liver is necessary for survival.

The liver and digestive system. Cirrhosis is the twelfth leading cause of death by disease, accounting for 27,000 deaths each year.1 The condition affects men slightly more often than women.
1

Minio AM, Heron MP, Murphy SL, Kochanek KD. Deaths: Final data for 2004. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/nchs/data/nvsr/nvsr55/nvsr55_19.pdf. Updated October 10, 2007. Accessed January 20, 2008. [Top]

What causes cirrhosis?

Cirrhosis has various causes. In the United States, heavy alcohol consumption and chronic hepatitis C have been the most common causes of cirrhosis. Obesity is becoming a common cause of cirrhosis, either as the sole cause or in combination with alcohol, hepatitis C, or both. Many people with cirrhosis have more than one cause of liver damage. Cirrhosis is not caused by trauma to the liver or other acute, or short-term, causes of damage. Usually years of chronic injury are required to cause cirrhosis.

Alcohol-related liver disease. Most people who consume alcohol do not suffer damage to the liver. But heavy alcohol use over several years can cause chronic injury to the liver. The amount of alcohol it takes to damage the liver varies greatly from person to person. For women, consuming two to three drinksincluding beer and wineper day and for men, three to four drinks per day, can lead to liver damage and cirrhosis. In the past, alcohol-related cirrhosis led to more deaths than cirrhosis due to any other cause. Deaths caused by obesity-related cirrhosis are increasing. Chronic hepatitis C. The hepatitis C virus is a liver infection that is spread by contact with an infected persons blood. Chronic hepatitis C causes inflammation and damage to the liver over time that can lead to cirrhosis. Chronic hepatitis B and D. The hepatitis B virus is a liver infection that is spread by contact with an infected persons blood, semen, or other body fluid. Hepatitis B, like hepatitis C, causes liver inflammation and injury that can lead to cirrhosis. The hepatitis B vaccine is given to all infants and many adults to prevent the virus. Hepatitis D is another virus that infects the liver and can lead to cirrhosis, but it occurs only in people who already have hepatitis B. Nonalcoholic fatty liver disease (NAFLD). In NAFLD, fat builds up in the liver and eventually causes cirrhosis. This increasingly common liver disease is associated with obesity, diabetes, protein malnutrition, coronary artery disease, and corticosteroid medications. Autoimmune hepatitis. This form of hepatitis is caused by the bodys immune system attacking liver cells and causing inflammation, damage, and eventually cirrhosis. Researchers believe genetic factors may make some people more prone to autoimmune diseases. About 70 percent of those with autoimmune hepatitis are female. Diseases that damage or destroy bile ducts. Several different diseases can damage or destroy the ducts that carry bile from the liver, causing bile to back up in the liver and leading to cirrhosis. In adults, the most common condition in this category is primary biliary cirrhosis, a disease in which the bile ducts become inflamed and damaged and, ultimately, disappear. Secondary biliary cirrhosis can happen if the ducts are mistakenly tied off or injured during gallbladder surgery. Primary sclerosing cholangitis is another condition that causes damage and scarring of bile ducts. In infants, damaged bile ducts are commonly caused by Alagille syndrome or biliary atresia, conditions in which the ducts are absent or injured. Inherited diseases. Cystic fibrosis, alpha-1 antitrypsin deficiency, hemochromatosis, Wilson disease, galactosemia, and glycogen storage diseases are inherited diseases that interfere with how the liver produces, processes, and stores enzymes, proteins, metals, and other substances the body needs to function properly. Cirrhosis can result from these conditions.

Drugs, toxins, and infections. Other causes of cirrhosis include drug reactions, prolonged exposure to toxic chemicals, parasitic infections, and repeated bouts of heart failure with liver congestion. [Top]

What are the symptoms of cirrhosis?

Many people with cirrhosis have no symptoms in the early stages of the disease. However, as the disease progresses, a person may experience the following symptoms:

weakness fatigue loss of appetite nausea vomiting weight loss abdominal pain and bloating when fluid accumulates in the abdomen itching spiderlike blood vessels on the skin

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What are the complications of cirrhosis?

As liver function deteriorates, one or more complications may develop. In some people, complications may be the first signs of the disease. Edema and ascites. When liver damage progresses to an advanced stage, fluid collects in the legs, called edema, and in the abdomen, called ascites. Ascites can lead to bacterial peritonitis, a serious infection. Bruising and bleeding. When the liver slows or stops producing the proteins needed for blood clotting, a person will bruise or bleed easily. Portal hypertension. Normally, blood from the intestines and spleen is carried to the liver through the portal vein. But cirrhosis slows the normal flow of blood, which increases the pressure in the portal vein. This condition is called portal hypertension. Esophageal varices and gastropathy. When portal hypertension occurs, it may cause enlarged blood vessels in the esophagus, called varices, or in the stomach, called gastropathy, or both. Enlarged blood vessels are more likely to burst due to thin walls and increased pressure. If they burst, serious bleeding can occur in the esophagus or upper stomach, requiring immediate medical attention.

Splenomegaly. When portal hypertension occurs, the spleen frequently enlarges and holds white blood cells and platelets, reducing the numbers of these cells in the blood. A low platelet count may be the first evidence that a person has developed cirrhosis. Jaundice. Jaundice occurs when the diseased liver does not remove enough bilirubin from the blood, causing yellowing of the skin and whites of the eyes and darkening of the urine. Bilirubin is the pigment that gives bile its reddish-yellow color. Gallstones. If cirrhosis prevents bile from flowing freely to and from the gallbladder, the bile hardens as gallstones. Sensitivity to medications. Cirrhosis slows the livers ability to filter medications from the blood. When this occurs, medications act longer than expected and build up in the body. This causes a person to be more sensitive to medications and their side effects. Hepatic encephalopathy. A failing liver cannot remove toxins from the blood, and they eventually accumulate in the brain. The buildup of toxins in the braincalled hepatic encephalopathycan decrease mental function and cause coma. Signs of decreased mental function include confusion, personality changes, memory loss, trouble concentrating, and a change in sleep habits. Insulin resistance and type 2 diabetes. Cirrhosis causes resistance to insulina hormone produced by the pancreas that enables the body to use glucose as energy. With insulin resistance, the bodys muscle, fat, and liver cells do not use insulin properly. The pancreas tries to keep up with the demand for insulin by producing more, but excess glucose builds up in the bloodstream causing type 2 diabetes. Liver cancer. Hepatocellular carcinoma is a type of liver cancer that can occur in people with cirrhosis. Hepatocellular carcinoma has a high mortality rate, but several treatment options are available. Other problems. Cirrhosis can cause immune system dysfunction, leading to the risk of infection. Cirrhosis can also cause kidney and lung failure, known as hepatorenal and hepatopulmonary syndromes. [Top]

How is cirrhosis diagnosed?

The diagnosis of cirrhosis is usually based on the presence of a risk factor for cirrhosis, such as alcohol use or obesity, and is confirmed by physical examination, blood tests, and imaging. The doctor will ask about the persons medical history and symptoms and perform a thorough physical examination to observe for clinical signs of the disease. For example, on abdominal examination, the liver may feel hard or enlarged with signs of ascites. The doctor will order blood tests that may be helpful in evaluating the liver and increasing the suspicion of cirrhosis.

To view the liver for signs of enlargement, reduced blood flow, or ascites, the doctor may order a computerized tomography (CT) scan, ultrasound, magnetic resonance imaging (MRI), or liver scan. The doctor may look at the liver directly by inserting a laparoscope into the abdomen. A laparoscope is an instrument with a camera that relays pictures to a computer screen. A liver biopsy can confirm the diagnosis of cirrhosis but is not always necessary. A biopsy is usually done if the result might have an impact on treatment. The biopsy is performed with a needle inserted between the ribs or into a vein in the neck. Precautions are taken to minimize discomfort. A tiny sample of liver tissue is examined with a microscope for scarring or other signs of cirrhosis. Sometimes a cause of liver damage other than cirrhosis is found during biopsy. [Top]

How is the severity of cirrhosis measured?

The model for end-stage liver disease (MELD) score measures the severity of cirrhosis. The MELD score was developed to predict the 90-day survival of people with advanced cirrhosis. The MELD score is based on three blood tests:

international normalized ratio (INR)tests the clotting tendency of blood bilirubintests the amount of bile pigment in the blood creatininetests kidney function

MELD scores usually range between 6 and 40, with a score of 6 indicating the best likelihood of 90-day survival. [Top]

How is cirrhosis treated?

Treatment for cirrhosis depends on the cause of the disease and whether complications are present. The goals of treatment are to slow the progression of scar tissue in the liver and prevent or treat the complications of the disease. Hospitalization may be necessary for cirrhosis with complications. Eating a nutritious diet. Because malnutrition is common in people with cirrhosis, a healthy diet is important in all stages of the disease. Health care providers recommend a meal plan that is well balanced. If ascites develops, a sodium-restricted diet is recommended. A person with cirrhosis should not eat raw shellfish, which can contain a bacterium that causes serious infection. To improve nutrition, the doctor may add a liquid supplement taken by mouth or through a nasogastric tubea tiny tube inserted through the nose and throat that reaches into the stomach.

Avoiding alcohol and other substances. People with cirrhosis are encouraged not to consume any alcohol or illicit substances, as both will cause more liver damage. Because many vitamins and medicationsprescription and over-the-countercan affect liver function, a doctor should be consulted before taking them. Treatment for cirrhosis also addresses specific complications. For edema and ascites, the doctor will recommend diureticsmedications that remove fluid from the body. Large amounts of ascitic fluid may be removed from the abdomen and checked for bacterial peritonitis. Oral antibiotics may be prescribed to prevent infection. Severe infection with ascites will require intravenous (IV) antibiotics. The doctor may prescribe a beta-blocker or nitrate for portal hypertension. Beta-blockers can lower the pressure in the varices and reduce the risk of bleeding. Gastrointestinal bleeding requires an immediate upper endoscopy to look for esophageal varices. The doctor may perform a band-ligation using a special device to compress the varices and stop the bleeding. People who have had varices in the past may need to take medicine to prevent future episodes. Hepatic encephalopathy is treated by cleansing the bowel with lactulosea laxative given orally or in enemas. Antibiotics are added to the treatment if necessary. Patients may be asked to reduce dietary protein intake. Hepatic encephalopathy may improve as other complications of cirrhosis are controlled. Some people with cirrhosis who develop hepatorenal failure must undergo regular hemodialysis treatment, which uses a machine to clean wastes from the blood. Medications are also given to improve blood flow through the kidneys. Other treatments address the specific causes of cirrhosis. Treatment for cirrhosis caused by hepatitis depends on the specific type of hepatitis. For example, interferon and other antiviral drugs are prescribed for viral hepatitis, and autoimmune hepatitis requires corticosteroids and other drugs that suppress the immune system. Medications are given to treat various symptoms of cirrhosis, such as itching and abdominal pain. [Top]

When is a liver transplant indicated for cirrhosis?

A liver transplant is considered when complications cannot be controlled by treatment. Liver transplantation is a major operation in which the diseased liver is removed and replaced with a healthy one from an organ donor. A team of health professionals determines the risks and benefits of the procedure for each patient. Survival rates have improved over the past several years because of drugs that suppress the immune system and keep it from attacking and damaging the new liver.

The number of people who need a liver transplant far exceeds the number of available organs. A person needing a transplant must go through a complicated evaluation process before being added to a long transplant waiting list. Generally, organs are given to people with the best chance of living the longest after a transplant. Survival after a transplant requires intensive follow-up and cooperation on the part of the patient and caregiver. [Top]

Points to Remember

Cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injury. Scar tissue replaces normal, healthy liver tissue, preventing the liver from working as it should. In the United States, heavy alcohol consumption and chronic hepatitis C have been the most common causes of cirrhosis. Obesity is becoming a common cause of cirrhosis, either as the sole cause or in combination with alcohol, hepatitis C, or both. Many people with cirrhosis have more than one cause of liver damage. Other causes of cirrhosis include hepatitis B, hepatitis D, and autoimmune hepatitis; diseases that damage or destroy bile ducts, inherited diseases, and nonalcoholic fatty liver disease; and drugs, toxins, and infections. Many people with cirrhosis have no symptoms in the early stages of the disease. As the disease progresses, symptoms may include weakness, fatigue, loss of appetite, nausea, vomiting, weight loss, abdominal pain and bloating, itching, and spiderlike blood vessels on the skin. As liver function deteriorates, one or more complications may develop. In some people, complications may be the first signs of the disease. The goals of treatment are to stop the progression of scar tissue in the liver and prevent or treat complications. Treatment for cirrhosis includes avoidance of alcohol and other drugs, nutrition therapy, and other therapies that treat specific complications or causes of the disease. Hospitalization may be necessary for cirrhosis with complications. A liver transplant is considered when complications of cirrhosis cannot be controlled by treatment.

[Top]

Hope through Research

The National Institute of Diabetes and Digestive and Kidney Diseases Division of Digestive Diseases and Nutrition supports basic and clinical research into liver diseases including cirrhosisand liver transplantation. Researchers are also studying

the mechanisms of cirrhosis reversal in the early stages of the disease potential new approaches to the management of complications of cirrhosis the long-term outcome of new drugs to treat portal hypertension

the development of therapies to prevent and treat the recurrence of hepatitis C after liver transplantation

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research. For information about current studies, visit www.ClinicalTrials.gov. [Top]

For More Information

American Liver Foundation 75 Maiden Lane, Suite 603 New York, NY 100384810 Phone: 1800GOLIVER (4654837) or 2126681000 Fax: 2124838179 Email: info@liverfoundation.org Internet: www.liverfoundation.org Hepatitis Foundation International 504 Blick Drive Silver Spring, MD 209042901 Phone: 18008910707 or 3016224200 Fax: 3016224702 Email: hfi@comcast.net Internet: www.hepfi.org United Network for Organ Sharing P.O. Box 2484 Richmond, VA 23218 Phone: 18888946361 or 8047824800 Fax: 8047824817 Internet: www.unos.org You may also find additional information about this topic by visiting MedlinePlus at www.medlineplus.gov. This publication may contain information about medications. When prepared, this publication included the most current information available. For updates or for questions about any medications, contact the U.S. Food and Drug Administration toll-free at 1 888INFOFDA (18884636332) or visit www.fda.gov. Consult your doctor for more information. [Top]

Acknowledgments
Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts. This publication was reviewed by Bruce A. Runyon, M.D., Loma Linda University Medical Center. [Top]

National Digestive Diseases Information Clearinghouse

2 Information Way Bethesda, MD 208923570 Phone: 18008915389 TTY: 18665691162 Fax: 7037384929 Email: nddic@info.niddk.nih.gov Internet: www.digestive.niddk.nih.gov The National Digestive Diseases Information Clearinghouse (NDDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health of the U.S. Department of Health and Human Services. Established in 1980, the Clearinghouse provides information about digestive diseases to people with digestive disorders and to their families, health care professionals, and the public. The NDDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about digestive diseases. This publication is not copyrighted. The Clearinghouse encourages users of this publication to duplicate and distribute as many copies as desired.

Cirrhosis
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Cirrhosis
Classification and external resources

Micrograph showing cirrhosis. Trichrome stain. ICD-10 ICD-9 DiseasesDB eMedicine MeSH K70.3, K71.7, K74. 571 2729 med/3183 radio/175 D008103

Cirrhosis (pronounced /sross/) is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated),[1][2][3] leading to loss of liver function. Cirrhosis is most commonly caused by alcoholism, hepatitis B and C, and fatty liver disease but has many other possible causes. Some cases are idiopathic, i.e., of unknown cause. Ascites (fluid retention in the abdominal cavity) is the most common complication of cirrhosis and is associated with a poor quality of life, increased risk of infection, and a poor long-term outcome. Other potentially life-threatening complications are hepatic encephalopathy (confusion and coma) and bleeding from esophageal varices. Cirrhosis is generally irreversible, and treatment usually focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant. The word "cirrhosis" derives from Greek , meaning tawny (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was Ren

Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.[4]

Contents
[hide]

1 Signs and symptoms o 1.1 Complications 2 Causes 3 Pathophysiology 4 Diagnosis o 4.1 Lab findings o 4.2 Imaging o 4.3 Endoscopy o 4.4 Pathology o 4.5 Grading 5 Management o 5.1 Treating underlying causes o 5.2 Preventing further liver damage o 5.3 Preventing complications 5.3.1 Ascites 5.3.2 Esophageal variceal bleeding 5.3.3 Hepatic encephalopathy 5.3.4 Hepatorenal syndrome 5.3.5 Spontaneous bacterial peritonitis o 5.4 Transplantation o 5.5 Decompensated cirrhosis 6 Epidemiology 7 See also 8 References 9 External links

[edit] Signs and symptoms

Some of the following signs and symptoms may occur in the presence of cirrhosis or as a result of the complications of cirrhosis. Many are nonspecific and may occur in other diseases and do not necessarily point to cirrhosis. Likewise, the absence of any does not rule out the possibility of cirrhosis.

Spider angiomata or spider nevi. Vascular lesions consisting of a central arteriole surrounded by many smaller vessels due to an increase in estradiol. These occur in about 1/3 of cases.[5]

Palmar erythema. Exaggerations of normal speckled mottling of the palm, due to altered sex hormone metabolism. Nail changes. o Muehrcke's lines - paired horizontal bands separated by normal color due to hypoalbuminemia (inadequate production of albumin). o Terry's nails - proximal two-thirds of the nail plate appears white with distal one-third red, also due to hypoalbuminemia o Clubbing - angle between the nail plate and proximal nail fold > 180 degrees Hypertrophic osteoarthropathy. Chronic proliferative periostitis of the long bones that can cause considerable pain. Dupuytren's contracture. Thickening and shortening of palmar fascia that leads to flexion deformities of the fingers. Thought to be due to fibroblastic proliferation and disorderly collagen deposition. It is relatively common (33% of patients). Gynecomastia. Benign proliferation of glandular tissue of male breasts presenting with a rubbery or firm mass extending concentrically from the nipples. This is due to increased estradiol and can occur in up to 66% of patients. Hypogonadism. Manifested as impotence, infertility, loss of sexual drive, and testicular atrophy due to primary gonadal injury or suppression of hypothalamic or pituitary function. Liver size. Can be enlarged, normal, or shrunken. Splenomegaly (increase in size of the spleen). Due to congestion of the red pulp as a result of portal hypertension. Ascites. Accumulation of fluid in the peritoneal cavity giving rise to flank dullness (needs about 1500 mL to detect flank dullness). Caput medusa. In portal hypertension, the umbilical vein may open. Blood from the portal venous system may be shunted through the periumbilical veins into the umbilical vein and ultimately to the abdominal wall veins, manifesting as caput medusa. Cruveilhier-Baumgarten murmur. Venous hum heard in epigastric region (on examination by stethoscope) due to collateral connections between portal system and the remnant of the umbilical vein in portal hypertension. Fetor hepaticus. Musty odor in breath due to increased dimethyl sulfide. Jaundice. Yellow discoloring of the skin, eye, and mucus membranes due to increased bilirubin (at least 23 mg/dL or 30 mmol/L). Urine may also appear dark. Asterixis. Bilateral asynchronous flapping of outstretched, dorsiflexed hands seen in patients with hepatic encephalopathy. Other. Weakness, fatigue, anorexia, weight loss.

[edit] Complications
As the disease progresses, complications may develop. In some people, these may be the first signs of the disease.

Bruising and bleeding due to decreased production of coagulation factors.

Jaundice due to decreased processing of bilirubin. Itching (pruritus) due to bile salts products deposited in the skin. Hepatic encephalopathy - the liver does not clear ammonia and related nitrogenous substances from the blood, which are carried to the brain, affecting cerebral functioning: neglect of personal appearance, unresponsiveness, forgetfulness, trouble concentrating, or changes in sleep habits. Sensitivity to medication due to decreased metabolism of the active compounds. Hepatocellular carcinoma is primary liver cancer, a frequent complication of cirrhosis. It has a high mortality rate. Portal hypertension - blood normally carried from the intestines and spleen through the hepatic portal vein flows more slowly and the pressure increases; this leads to the following complications: o Ascites - fluid leaks through the vasculature into the abdominal cavity. o Esophageal varices - collateral portal blood flow through vessels in the stomach and esophagus. These blood vessels may become enlarged and are more likely to burst. Problems in other organs. o Cirrhosis can cause immune system dysfunction, leading to infection. Signs and symptoms of infection may be aspecific are more difficult to recognize (e.g., worsening encephalopathy but no fever). o Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis). o Hepatorenal syndrome - insufficient blood supply to the kidneys, causing acute renal failure. This complication has a very high mortality (over 50%). o Hepatopulmonary syndrome - blood bypassing the normal lung circulation (shunting), leading to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.[6] o Portopulmonary hypertension - increased blood pressure over the lungs as a consequence of portal hypertension.[6] o Portal hypertensive gastropathy which refers to changes in the mucosa of the stomach in patients with portal hypertension, and is associated with cirrhosis severity.[7]

[edit] Causes
Cirrhosis has many possible causes; sometimes more than one cause is present in the same patient. In the Western World, chronic alcoholism and hepatitis C are the most common causes.

Alcoholic liver disease (ALD). Alcoholic cirrhosis develops for between 10% and 20% of individuals who drink heavily for a decade or more.[8] Alcohol seems to injure the liver by blocking the normal metabolism of protein, fats, and carbohydrates. Patients may also have concurrent alcoholic hepatitis with fever, hepatomegaly, jaundice, and anorexia. AST and ALT are both elevated but less than 300 IU/L with a AST:ALT ratio > 2.0, a value rarely seen in other liver

diseases. Liver biopsy may show hepatocyte necrosis, Mallory bodies, neutrophilic infiltration with perivenular inflammation. Chronic hepatitis C. Infection with the hepatitis C virus causes inflammation of the liver and a variable grade of damage to the organ that over several decades can lead to cirrhosis. Cirrhosis caused by hepatitis C is the most common reason for liver transplant. Can be diagnosed with serologic assays that detect hepatitis C antibody or viral RNA. The enzyme immunoassay, EIA-2, is the most commonly used screening test in the US. Chronic hepatitis B. The hepatitis B virus causes liver inflammation and injury that over several decades can lead to cirrhosis. Hepatitis D is dependent on the presence of hepatitis B, but accelerates cirrhosis in co-infection. Chronic hepatitis B can be diagnosed with detection of HBsAG > 6 months after initial infection. HBeAG and HBV DNA are determined to assess whether patient will need antiviral therapy. Non-alcoholic steatohepatitis (NASH). In NASH, fat builds up in the liver and eventually causes scar tissue. This type of hepatitis appears to be associated with diabetes, protein malnutrition, obesity, coronary artery disease, and treatment with corticosteroid medications. This disorder is similar to that of alcoholic liver disease but patient does not have an alcohol history. Biopsy is needed for diagnosis. Primary biliary cirrhosis. May be asymptomatic or complain of fatigue, pruritus, and non-jaundice skin hyperpigmentation with hepatomegaly. There is prominent alkaline phosphatase elevation as well as elevations in cholesterol and bilirubin. Gold standard diagnosis is antimitochondrial antibodies with liver biopsy as confirmation if showing florid bile duct lesions. It is more common in women. Primary sclerosing cholangitis. PSC is a progressive cholestatic disorder presenting with pruritus, steatorrhea, fat soluble vitamin deficiencies, and metabolic bone disease. There is a strong association with inflammatory bowel disease (IBD), especially ulcerative colitis. Diagnosis is best with contrast cholangiography showing diffuse, multifocal strictures and focal dilation of bile ducts, leading to a beaded appearance. Non-specific serum immunoglobulins may also be elevated. Autoimmune hepatitis. This disease is caused by the immunologic damage to the liver causing inflammation and eventually scarring and cirrhosis. Findings include elevations in serum globulins, especially gamma globulins. Therapy with prednisone and/or azathioprine is beneficial. Cirrhosis due to autoimmune hepatitis still has 10-year survival of 90%+. There is no specific tool to diagnose autoimmune but it can be beneficial to initiate a trial of corticosteroids. Hereditary hemochromatosis. Usually presents with family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, and/or cardiomyopathy, all due to signs of iron overload. Labs will show fasting transferrin saturation of > 60% and ferritin > 300 ng/mL. Genetic testing may be used to identify HFE mutations. If these are present, biopsy may not need to be performed. Treatment is with phlebotomy to lower total body iron levels.

Wilson's disease. Autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy. May also have Kayser-Fleischer rings in the cornea and altered mental status. Alpha 1-antitrypsin deficiency (AAT). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking. Serum AAT levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency. Cardiac cirrhosis. Due to chronic right sided heart failure which leads to liver congestion. Galactosemia Glycogen storage disease type IV Cystic fibrosis Hepatotoxic drugs or toxins Certain parasitic infections (such as schistosomiasis)

[edit] Pathophysiology
The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting factors and complement), detoxification and storage (e.g., vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates. Cirrhosis is often preceded by hepatitis and fatty liver (steatosis), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible. The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-1, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it disturbs the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and 2), leading to matrix breakdown and replacement by connective tissue-secreted matrix.[9] The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.

[edit] Diagnosis
The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. A biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small

but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy.[10]

[edit] Lab findings

The following findings are typical in cirrhosis:

Aminotransferases - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis. Alkaline phosphatase - usually slightly elevated. Gamma-glutamyl transferase correlates with AP levels. Typically much higher in chronic liver disease from alcohol. Bilirubin - may elevate as cirrhosis progresses. Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver Prothrombin time - increases since the liver synthesizes clotting factors. Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone. Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However, this rarely results in platelet count < 50,000/mL. Leukopenia and neutropenia - due to splenomegaly with splenic margination. Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.

There is now a validated and patented combination of 6 of these markers as non-invasive biomarker of fibrosis (and so of cirrhosis) : FibroTest [11]. Other laboratory studies performed in newly diagnosed cirrhosis may include:

Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, antimitochondria, anti-LKM) Ferritin and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers of copper overload) Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes Cholesterol and glucose Alpha 1-antitrypsin

[edit] Imaging

Liver cirrhosis as seen on an axial CT of the abdomen. Ultrasound is routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein). A new type of device, the FibroScan (transient elastography), uses elastic waves to determine liver stiffness which theoretically can be converted into a liver score based on the METAVIR scale. The FibroScan produces an ultrasound image of the liver (from 20 80 mm) along with a pressure reading (in kPa.) The test is much faster than a biopsy (usually last 2.55 minutes) and is completely painless. It shows reasonable correlation with the severity of cirrhosis.[12] Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

[edit] Endoscopy
Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced. Rarely diseases of the bile ducts, such as primary sclerosing cholangitis, can be causes of cirrhosis. Imaging of the bile ducts, such as ERCP or MRCP (MRI of biliary tract and pancreas) can show abnormalities in these patients, and may aid in the diagnosis.

[edit] Pathology

Cirrhosis leading to hepatocellular carcinoma (autopsy specimen). Macroscopically, the liver is initially enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis. In micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm. In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm. The mixed cirrhosis consists in a variety of nodules with different sizes. However, cirrhosis is defined by its pathological features on microscopy: (1) the presence of regenerating nodules of hepatocytes and (2) the presence of fibrosis, or the deposition of connective tissue between these nodules. The pattern of fibrosis seen can depend upon the underlying insult that led to cirrhosis; fibrosis can also proliferate even if the underlying process that caused it has resolved or ceased. The fibrosis in cirrhosis can lead to destruction of other normal tissues in the liver: including the sinusoids, the space of Disse, and other vascular structures, which leads to altered resistance to blood flow in the liver and portal hypertension.[13] As cirrhosis can be caused by many different entities which injure the liver in different ways, different cause-specific patterns of cirrhosis, and other cause-specific abnormalities can be seen in cirrhosis. For example, in chronic hepatitis B, there is infiltration of the liver parenchyma with lymphocytes;[13] in cardiac cirrhosis there are erythrocytes and a greater amount of fibrosis in the tissue surrounding the hepatic veins;[14] in primary biliary cirrhosis, there is fibrosis around the bile duct, the presence of granulomas and pooling of bile;[15] and in alcoholic cirrhosis, there is infiltration of the liver with neutrophils.[13]

[edit] Grading
The severity of cirrhosis is commonly classified with the Child-Pugh score. This score uses bilirubin, albumin, INR, presence and severity of ascites and encephalopathy to classify patients in class A, B or C; class A has a favourable prognosis, while class C is at high risk of death. It was devised in 1964 by Child and Turcotte and modified in 1973 by Pugh et al..[16] More modern scores, used in the allocation of liver transplants but also in other contexts, are the Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, the Pediatric End-Stage Liver Disease (PELD) score.

The hepatic venous pressure gradient, i.e., the difference in venous pressure between afferent and efferent blood to the liver, also determines severity of cirrhosis, although hard to measure. A value of 16 mm or more means a greatly increased risk of dying.[17]

[edit] Management
Generally, liver damage from cirrhosis cannot be reversed, but treatment could stop or delay further progression and reduce complications. A healthy diet is encouraged, as cirrhosis may be an energy-consuming process. Close follow-up is often necessary. Antibiotics will be prescribed for infections, and various medications can help with itching. Laxatives, such as lactulose, decrease risk of constipation; their role in preventing encephalopathy is limited.

[edit] Treating underlying causes

Alcoholic cirrhosis caused by alcohol abuse is treated by abstaining from alcohol. Treatment for hepatitis-related cirrhosis involves medications used to treat the different types of hepatitis, such as interferon for viral hepatitis and corticosteroids for autoimmune hepatitis. Cirrhosis caused by Wilson's disease, in which copper builds up in organs, is treated with chelation therapy (e.g., penicillamine) to remove the copper.

[edit] Preventing further liver damage

Regardless of underlying cause of cirrhosis, alcohol and paracetamol, as well as other potentially damaging substances, are discouraged. Vaccination of susceptible patients should be considered for Hepatitis A and Hepatitis B.

[edit] Preventing complications

[edit] Ascites Main article: Ascites Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites. [edit] Esophageal variceal bleeding Main article: Esophageal varices For portal hypertension, propranolol is a commonly used agent to lower blood pressure over the portal system. In severe complications from portal hypertension, transjugular intrahepatic portosystemic shunting is occasionally indicated to relieve pressure on the portal vein. As this can worsen encephalopathy, it is reserved for those at low risk of

encephalopathy, and is generally regarded only as a bridge to liver transplantation or as a palliative measure. [edit] Hepatic encephalopathy Main article: Hepatic encephalopathy High-protein food increases the nitrogen balance, and would theoretically increase encephalopathy; in the past, this was therefore eliminated as much as possible from the diet. Recent studies show that this assumption was incorrect, and high-protein foods are even encouraged to maintain adequate nutrition.[18] [edit] Hepatorenal syndrome Main article: Hepatorenal syndrome The hepatorenal syndrome is defined as a urine sodium less than 10 mmol/L and a serum creatinine > 1.5 mg/dl (or 24 hour creatinine clearance less than 40 ml/min) after a trial of volume expansion without diuretics.[19] [edit] Spontaneous bacterial peritonitis Main article: Spontaneous bacterial peritonitis Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

[edit] Transplantation
Main article: Liver transplantation If complications cannot be controlled or when the liver ceases functioning, liver transplantation is necessary. Survival from liver transplantation has been improving over the 1990s, and the five-year survival rate is now around 80%, depending largely on the severity of disease and other medical problems in the recipient.[20] In the United States, the MELD score is used to prioritize patients for transplantation.[21] Transplantation necessitates the use of immune suppressants (cyclosporine or tacrolimus).

[edit] Decompensated cirrhosis

In patients with previously stable cirrhosis, decompensation may occur due to various causes, such as constipation, infection (of any source), increased alcohol intake, medication, bleeding from esophageal varices or dehydration. It may take the form of any of the complications of cirrhosis listed above. Patients with decompensated cirrhosis generally require admission to hospital, with close monitoring of the fluid balance, mental status, and emphasis on adequate nutrition and

medical treatment - often with diuretics, antibiotics, laxatives and/or enemas, thiamine and occasionally steroids, acetylcysteine and pentoxifylline. Administration of saline is generally avoided as it would add to the already high total body sodium content that typically occurs in cirrhosis.

[edit] Epidemiology

Disability-adjusted life year for cirrhosis of the liver per 100,000 inhabitants in 2004.[22]
no data 600-700 less than 50 50-100 700-800 800-900 100-200 900-1000 200-300 300-400 more than 1000 400-500 500-600

Cirrhosis and chronic liver disease were the 10th leading cause of death for men and the 12th for women in the United States in 2001, killing about 27,000 people each year.[23] Also, the cost of cirrhosis in terms of human suffering, hospital costs, and lost productivity is high. Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. The risk of death due to all causes is increased twelvefold; if one excludes the direct consequences of the liver disease, there is still a fivefold increased risk of death in all disease categories.[24] Little is known on modulators of cirrhosis risk, apart from other diseases that cause liver injury (such as the combination of alcoholic liver disease and chronic viral hepatitis, which may act synergistically in leading to cirrhosis). Studies have recently suggested that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis.[25]