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Hepatic fibrosis is overly exuberant wound healing in which excessive connective tissue builds up in the liver. The extracellular matrix is either overproduced, degraded deficiently, or both. The trigger is chronic injury, especially if there is an inflammatory component. Fibrosis itself causes no symptoms but can lead to portal hypertension (the scarring distorts blood flow through the liver) or cirrhosis (the failure to properly replace destroyed liver cells results in liver dysfunction). Diagnosis is based on liver biopsy. Treatment involves correcting the underlying condition when possible.

Various types of chronic liver injury can cause fibrosis (see Table 1: Fibrosis and Cirrhosis: Disorders and Drugs that Can Cause Hepatic Fibrosis). Self-limited, acute liver injury (eg, acute viral hepatitis A), even when fulminant, does not necessarily distort the scaffolding architecture and hence does not cause fibrosis, despite loss of hepatocytes. In its initial stages, hepatic fibrosis can regress if the cause is reversible (eg, with viral clearance). After months or years of chronic or repeated injury, fibrosis becomes permanent. Fibrosis develops even more rapidly in mechanical biliary obstruction.

Table 1
Disorders and Drugs that Can Cause Hepatic Fibrosis Disorders with direct hepatic effects Certain storage diseases and inborn errors of metabolism α 1-Antitrypsin deficiency Copper storage diseases (Wilson's disease) Fructosemia Galactosemia Glycogen storage diseases (especially types III, IV, VI, IX, and X) Iron-overload syndromes (hemochromatosis) Lipid abnormalities (eg, Gaucher's disease) Peroxisomal disorders (eg, Zellweger syndrome) Tyrosinemia Congenital hepatic fibrosis Infections Bacterial (eg, brucellosis) Parasitic (eg, echinococcosis) Viral (eg, chronic hepatitis B or C) Disorders affecting hepatic blood flow Budd-Chiari syndrome Heart failure Hepatic veno-occlusive disease Portal vein thrombosis Drugs and chemicals Alcohol Amiodarone Some Trade Names CORDARONE Click for Drug Monograph Chlorpromazine Some Trade Names THORAZINE Click for Drug Monograph Isoniazid Some Trade Names INH NYDRAZID Click for Drug Monograph Methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph Methyldopa Some Trade Names ALDOMET Click for Drug Monograph Oxyphenisatin Tolbutamide Some Trade Names ORINASE Click for Drug Monograph Mechanical obstruction

Pathophysiology

Activation of the hepatic perivascular stellate cells (Ito cells, which store fat) initiates fibrosis. These and adjacent cells proliferate, becoming contractile cells termed myofibroblasts. These cells produce excessive amounts of abnormal matrix (consisting of collagen, other glycoproteins, and glycans) and matricellular proteins. Kupffer cells (resident macrophages), injured hepatocytes, platelets, and leukocytes aggregate. This releases reactive O₂ species and inflammatory mediators (eg, platelet-derived growth factor, transforming growth factors, and connective tissue growth factor). Thus, stellate cell activation results in abnormal extracellular matrix, both in quantity and composition.

Myofibroblasts, stimulated by endothelin-1, contribute to increased portal vein resistance and increase the density of the abnormal matrix. Fibrous tracts join branches of afferent portal veins and efferent hepatic veins, bypassing the hepatocytes and limiting their blood supply. Hence, fibrosis contributes both to hepatocyte ischemia (causing hepatocellular dysfunction) and portal hypertension. The extent of the ischemia and portal hypertension determines how the liver is affected. For example, congenital hepatic fibrosis affects portal vein branches, largely sparing the parenchyma. The result is portal hypertension with sparing of hepatocellular function.

Symptoms and Signs

Hepatic fibrosis itself does not cause symptoms. Symptoms may develop secondary to the primary disorder or to portal hypertension. Portal hypertension with splenomegaly is often asymptomatic unless complications develop, such as variceal GI bleeding, ascites, or portal-systemic encephalopathy. Eventually, cirrhosis supervenes.

Diagnosis

Hepatic fibrosis is suspected in patients who have an underlying disorder or take a drug that could cause fibrosis or who have unexplained abnormalities in liver function or enzymes. Noninvasive tests (eg, serologic markers) are under study but are not yet ready for routine clinical use. Imaging tests such as ultrasonography, CT, and MRI may detect findings associated with fibrosis (eg, portal hypertension, splenomegaly, cirrhosis) but are not sensitive to parenchymal fibrosis itself. Liver biopsy is currently the only means of detecting hepatic fibrosis. Biopsy is indicated to clarify the diagnosis (eg, nonalcoholic steatohepatitis, primary biliary cirrhosis) and stage its progress (eg, in chronic hepatitis C, whether fibrosis is present or whether it has progressed to cirrhosis).

Treatment

Because fibrosis represents a response to hepatic damage, primary treatment should focus on the underlying cause-removing the basis of the liver injury. This would include eliminating HBC or HCV in chronic viral hepatitis; abstaining from alcohol in alcoholic liver disease; removing heavy metals such as iron or copper in hemochromatosis and Wilson's disease, respectively; or decompressing bile ducts in biliary obstruction.

Treatments aimed at reversing the fibrosis are usually too toxic for long-term use (eg, corticosteroids, penicillamine Some Trade Names
CUPRIMINE
Click for Drug Monograph
) or have no proven efficacy (eg, colchicine Some Trade Names
No US trade name
Click for Drug Monograph
). Other antifibrotic treatments are under study. Simultaneous use of multiple antifibrotic drugs may eventually prove most beneficial.

Last full review/revision August 2007 by Eldon A. Shaffer, MD

Content last modified August 2007