Cirrhosis

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Overview
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrotic scar tissue as well as regenerative nodules, leading to progressive loss of liver function. Cirrhosis is most commonly caused by alcoholism and hepatitis C, but has many other possible causes.

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 once it occurs, and treatment generally focuses on preventing progression and complications. In advanced stages of cirrhosis the only option is a liver transplant.

Etymology
The word "cirrhosis" is a neologism that derives from Greek kirrhos, meaning "tawny" (the orange-yellow colour of the diseased liver). While the clinical entity was known before, it was René Laennec who gave it the name "cirrhosis" in his 1819 work in which he also describes the stethoscope.

Epidemiology
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. 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.

Little is known on modulators of cirrhosis risk. Studies have recently suggested that coffee consumption may protect against cirrhosis, especially alcoholic cirrhosis.

Miscellaneous syndromes

 * Cruveilhier-Baumgarten syndrome
 * Haemosiderosis
 * Steatohepatitis, non-alcoholic

Biochemical abnormalities

 * Cholestatic jaundice

Congenital conditions

 * Biliary atresia

Mendelian inherited conditions

 * Carbohydrate-deficient glycoprotein syndrome type 1b
 * Caroli disease
 * Hemochromatosis
 * Sickle cell disease

Autosomal dominant conditions

 * Alagille syndrome
 * Porphyria cutanea tarda type 2 (familial)

Autosomal recessive conditions

 * Alpers disease
 * Alpha-1-antitrypsin deficiency
 * Alström syndrome
 * Berardinelli lipodystrophy syndrome
 * Carbohydrate deficient glycoprotein syndrome type 1a
 * Cerebrohepatorenal syndrome
 * Cholestasis-oedema syndrome, Norwegian type
 * Cholesterol ester storage disease
 * Cystic fibrosis
 * Galactosemia type 1
 * Glycogenosis type 3
 * Glycogenosis type 4
 * Hepatic venoocclusive disease with immunodeficiency
 * Indian familial childhood cirrhosis
 * Keratitis-ichthyosis-deafness syndrome, autosomal recessive
 * Polycystic kidney disease, autosomal recessive
 * Tyrosinaemia type 1
 * Wilson disease

Cardiac and vascular conditions

 * Cardiac failure, right sided
 * Hepatic vein thrombosis

Autoimmune conditions

 * Primary biliary cirrhosis
 * Primary sclerosing cholangitis

Trauma, mechanical and physical conditions

 * Bile duct stricture

Helminths and helminthic conditions

 * Fasciola hepatica
 * Schistosoma haematobium
 * Schistosoma japonicum
 * Schistosoma mansoni

Protozoa and protozoal conditions
 * Visceral leishmaniasis

Viruses and viral conditions

 * Hepatitis B
 * Hepatitis C

Iatrogenic conditions

 * Graft versus host disease
 * Parenteral nutrition

Drugs, hormones and mediators

 * Ethanol
 * Isoniazid
 * Methotrexate
 * Methyldopa
 * Methyldopate

Common 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 in 15% of individuals who drink heavily for more than a decade. There is great variability in the amount of alcohol needed to cause cirrhosis (as little as 3-4 drinks a day in some men and 2-3 in some women). 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 this virus causes inflammation of and low grade damage to the liver that over several decades can lead to cirrhosis. 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 is probably the most common cause of cirrhosis worldwide, especially South-East Asia, but it is less common in the United States and the Western world. Hepatitis B 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 +/- 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
 * Drugs or toxins
 * Certain parasitic infections (such as schistosomiasis)

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 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-β1, 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.

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.

Diagnosis
The gold standard for diagnosis of cirrhosis is a liver biopsy, through a percutaneous, transjugular, laparoscopic, or fine-needle approach. Histologically cirrhosis can be classified as micronodular, macronodular, or mixed, but this classification has been abandoned since it is nonspecific to the etiology, it may change as the disease progresses, and serological markers are much more specific. However, 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.

Symptoms and signs
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 central arteriole surrounded by many smaller vessels due to an increase in estradiol. These occur in about 33% of cases.
 * Palmar erythema. Exaggerations of normal speckled mottling of the palm, due to altered sex hormone metabolism.
 * Nail changes.
 * Muehrcke's nails - paired horizontal bands separated by normal color due to hypoalbuminemia (low production of albumin).
 * Terry's nails - proximal two thirds of the nail plate appears white with distal one-third red, also due to hypoalbuminemia
 * 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 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. 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 due to collateral connections between portal system and the remnant of the umbilical vein in portal hypertension.
 * Fetor hepaticus. Sweet pungent smell in breath due to increased dimethyl sulfide due to severe portal-systemic shunting.
 * Jaundice. Yellow discoloring of the skin, eye, and mucus membranes due to increased bilirubin (at least 2-3 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.

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.
 * GGT -- 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.

Other laboratory studies performed in newly diagnosed cirrhosis may include:
 * Serology for hepatitis viruses, autoantibodies (ANA, anti-smooth muscle, anti-mitochondria, 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

Electrolyte and Biomarker Studies

 * Prothrombin time, albumin
 * Platelets
 * Lytes/Creatinine (Cr)
 * Hyponatremia suggests severe disease

Imaging
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 20-80mm) along with a pressure reading (in kPa.) The test is much faster than a biopsy (usually last 2.5-5 minutes) and is completely painless. It shows reasonable corellation with the severity of cirrhosis.

Other tests performed in particular circumstances include abdominal CT and liver/bile duct MRI (MRCP).

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.

Other Diagnostic Modalities
If biliary pathology (primary sclerosing cholangitis - PSC) is suspected, ERCP may be performed.

Generally MRCP (MRI of biliary tract and pancreas) is sufficient for diagnosis, but ERCP allows for particular interventions, such as placement of a biliary stent or extraction of gallstones.

Pathology
Macroscopically, the liver may be 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.

Microscopically, cirrhosis is characterized by regeneration nodules, surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages) If it is a secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended - bile stasis. These dilated ducts contain inspissated bile which appear as bile casts or bile thrombi (brown-green, amorphous). Bile retention may be found also in the parenchyma, as the so called "bile lakes".

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.

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.

Complete Differential Diagnosis
In alphabetical order.


 * Abetalipoproteinemia
 * Alpha-1 Antitrypsin Deficiency
 * Autoimmune cholangiopathy
 * Autoimmune hepatitis
 * Budd-Chiari Syndrome
 * Congenital hepatic fibrosis
 * Constrictive pericarditis
 * Cor Pulmonale
 * Cystic Fibrosis
 * Drugs, toxins
 * Galactosemia
 * Glycogen-storage disease
 * Granulomatous cirrhosis
 * Hemochromatosis
 * Hereditary fructose intolerance
 * Hereditary tyrosinosis
 * Hypervitaminosis A
 * Indian childhood cirrhosis
 * Mitral Stenosis
 * Nutritional
 * Porphyria cutanea tarda
 * Posthepatic cirrhosis
 * Postnecrotic cirrhosis
 * Primary Biliary Cirrhosis
 * Primary sclerosing cholangitis
 * Sarcoidosis
 * Schistosomiasis
 * Secondary biliary cirrhosis
 * Sickle Cell Disease
 * Steatohepatitis
 * Thalassemia
 * Tricuspid insufficiency
 * Viral Hepatitis
 * Wilson's Disease

Treatment
Traditionally, 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.

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.

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

Varices

 * Endoscopic screening in all cirrhotic patients
 * If varices present--treat with propranolol or nadolol

Hepatocellular Cancer

 * Incidence 1-6%/year in HCV-, HBV-, EtOH-related cirrhosis
 * Screening frequency & benefit controversial
 * Serum alpha-fetoprotein (AFP) every 6 months (~60% sensitive, ~90% specific)
 * Ultrasound every 6 months (~75% sensitive, ~90% specific)

Ascites
Salt restriction is often necessary, as cirrhosis leads to accumulation of salt (sodium retention). Diuretics may be necessary to suppress ascites.

Esophageal variceal bleeding
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.

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.

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.

Spontaneous bacterial peritonitis
Cirrhotic patients with ascites are at risk of spontaneous bacterial peritonitis.

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. In the United States, the MELD score (online calculator) is used to prioritize patients for transplantation. Transplantation necessitates the use of immune suppressants (ciclosporin or tacrolimus).

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.

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 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:
 * Ascites - fluid leaks through the vasculature into the abdominal cavity.
 * 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.
 * 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).
 * Fluid in the abdomen (ascites) may become infected with bacteria normally present in the intestines (spontaneous bacterial peritonitis).
 * Hepatorenal syndrome - insufficient blood supply to the kidneys, causing acute renal failure. This complication has a very high mortality (over 50%).
 * Hepatopulmonary syndrome - blood bypassing the normal lung circulation (shunting), leading to cyanosis and dyspnea (shortness of breath), characteristically worse on sitting up.
 * Portopulmonary hypertension - increased blood pressure over the lungs as a consequence of portal hypertension.

Primary Prevention

 * Education about hepatotoxins:
 * EtOH
 * Acetaminophen
 * Herbals
 * Maintenance of adequate caloric intake: 2000-3000 kcal/d
 * Hepatitis A Virus vaccination, Pneumovax

Pathological Findings
Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Chronic active hepatitis - Cirrhosis


Micronodular cirrhosis


Primary biliary cirrhosis
