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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 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 scarring results in disruption of normal hepatic architecture and 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 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.
Disorders and Drugs That Can Cause Hepatic Fibrosis
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. As a result, reactive O 2 species and inflammatory mediators (eg, platelet-derived growth factor, transforming growth factors, connective tissue growth factor) are released. 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.
Hepatic fibrosis itself does not cause symptoms. Symptoms may result from the disorder causing fibrosis or, once fibrosis progresses to cirrhosis, from complications of portal hypertension. These symptoms include variceal bleeding, ascites, and portosystemic encephalopathy. Cirrhosis can result in hepatic insufficiency and potentially fatal liver failure.
Hepatic fibrosis is suspected if patients have known chronic liver disease (eg, chronic viral hepatitis C) or if results of liver function tests are abnormal; in such cases, tests are done to check for fibrosis and, if fibrosis is present, to determine its severity (stage). Knowing the stage of fibrosis can guide medical decisions. For example, screening for hepatocellular carcinoma and for gastroesophageal varices is indicated if cirrhosis is confirmed, but it is not indicated for mild or moderate fibrosis. Also, if liver biopsy does not detect advanced fibrosis in patients with hepatitis C, many clinicians defer treatment with interferons because they anticipate that more effective, less toxic drugs will be available.
Tests used to stage fibrosis include noninvasive imaging tests, blood tests, liver biopsy, and newer tests that assess liver stiffness.
Noninvasive imaging tests include ultrasonography, CT, and MRI and should include cross-sectional views. These tests can detect evidence of cirrhosis and portal hypertension, such as splenomegaly and varices. However, they are not sensitive for moderate or even advanced fibrosis if splenomegaly and varices are absent. Although fibrosis may appear as altered echogenicity on ultrasonography or heterogeneity of signal on CT, these findings are nonspecific and may indicate only liver parenchymal fat.
Liver biopsy remains the gold standard for diagnosing and staging hepatic fibrosis and for diagnosing the underlying liver disorder causing fibrosis. However, liver biopsy is invasive, resulting in a 10 to 20% risk of minor complications (eg, postprocedural pain) and a 0.5 to 1% risk of serious complications (eg, significant bleeding). Also, liver biopsy is limited by sampling error and imperfect interobserver agreement in interpretation of histologic findings. Thus, liver biopsy may not always be done.
Blood tests include commercially available panels that combine indirect markers (eg, serum bilirubin) and direct markers of hepatic function. Direct markers are substances involved in the pathogenesis of extracellular matrix deposition or cytokines that induce extracellular matrix deposition. These panels are best used to distinguish between 2 levels of fibrosis: absent to minimal vs moderate to severe; they do not accurately differentiate between degrees of moderate to severe fibrosis. Therefore, if fibrosis is suspected, one approach is to start with one of these panels and then do liver biopsy only if the panel indicates that fibrosis is moderate to severe.
Tests that assess liver stiffness may be useful but are not yet commonly used clinically; they include ultrasound elastography, MRI elastography, and acoustic radiation force impulse imaging. For these tests, acoustic vibrations are applied to the abdomen with a probe. How rapidly these vibrations are transmitted through liver tissue is measured—an indication of how stiff (ie, fibrosed) the liver is. However, central obesity in a patient can decrease diagnostic accuracy, potentially limiting the usefulness of these tests in developed nations such as the US where obesity and metabolic syndrome are common.
Which tests are done may depend on the degree of clinical suspicion, based on clinical evaluation, including liver function test results. For example, noninvasive blood tests may be used to determine whether biopsy is indicated; in some of these cases, imaging tests may not be needed.
Because fibrosis represents a response to hepatic damage, primary treatment should focus on the cause (removing the basis of the liver injury). Such treatment may include eliminating hepatitis B virus or hepatitis C virus in chronic viral hepatitis, abstaining from alcohol in alcoholic liver disease, removing heavy metals such as iron in hemochromatosis or copper in Wilson disease, and decompressing bile ducts in biliary obstruction. Such treatments may stop the fibrosis from progressing and, in some patients, also reverse some of the fibrotic changes.
Treatments aimed at reversing the fibrosis are usually too toxic for long-term use (eg, corticosteroids, penicillamine) or have no proven efficacy (eg, colchicine). Other antifibrotic treatments are under study. Simultaneous use of multiple antifibrotic drugs may eventually prove most beneficial. Silymarin, present in milk thistle, is a popular alternative medicine used to treat hepatic fibrosis. It appears to be safe but to lack efficacy.
Self-limited, acute liver injury (eg, due to acute viral hepatitis A), even when fulminant, tends not to cause fibrosis.
The most common causes of hepatic fibrosis are hepatitis B and C and alcohol abuse.
Fibrosis does not cause symptoms unless it progresses to cirrhosis.
Liver biopsy, although imperfect, is the gold standard diagnostic test.
Treat the cause of fibrosis.
Drug NameSelect Brand Names
ChlorpromazineNo US brand name
MethyldopaNo brand name
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