Фіброз печінки

Various types of chronic liver injury can cause fibrosis (see table Disorders and Medications/Substances 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 advanced 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.

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 oxygen 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. Once the balance is damaged between extracellular matrix production and degradation, the fibrosis progresses.

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 jaundice, variceal bleeding, ascites, and portosystemic encephalopathy. Cirrhosis can result in hepatic insufficiency and potentially fatal liver failure.

• Clinical evaluation

• Sometimes blood tests and/or noninvasive imaging tests

• Sometimes liver biopsy

Hepatic fibrosis is suspected if patients have known chronic liver disease (eg, chronic viral hepatitis C [HCV] or chronic hepatitis B [HBV], alcoholic liver disease, metabolic dysfunction–associated steatohepatitis [MASH, formerly known as nonalcoholic steatohepatitis]) or if results of liver blood 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 generally not indicated for mild or moderate fibrosis. Assessment of the degree of hepatic fibrosis helps assess the prognosis of patients with chronic viral hepatitis. However, since the widespread availability of direct-acting antiviral drugs, knowing the degree of fibrosis has become much less important in deciding when to initiate antiviral therapy.

Tests used to stage fibrosis include conventional imaging tests, blood tests, liver biopsy, and newer noninvasive imaging tests that assess liver stiffness.

Conventional imaging tests: Conventional imaging tests include ultrasonography, CT, and MRI. These tests can detect evidence of cirrhosis and portal hypertension, such as liver surface nodularity, splenomegaly, and varices. However, they are not sensitive for moderate or even advanced fibrosis and may fail to detect some cases of cirrhosis 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.

Noninvasive imaging assessment of fibrosis: Newer acoustic technologies can increase the accuracy of ultrasonography, CT, and MRI for detecting fibrosis or early cirrhosis; they include

• Transient elastography

• Acoustic radiation force impulse imaging

• Two-dimensional shear wave elastography

• Magnetic resonance elastography (MRE)

For these tests, acoustic vibrations are applied to the abdomen with a probe. How rapidly these vibrations are transmitted through liver tissue indicates how stiff (ie, fibrosed) the liver is. However, certain other conditions besides fibrosis also increase liver stiffness, including severe active hepatitis, increased right heart pressures, and the postprandial state. Also, these techniques have not been validated well in pregnancy, sustained virologic response after HCV treatment, and rare liver disorders. Thus, use of these techniques is typically not recommended in patients with one of these conditions. To improve the assessment of fibrosis, other techniques (eg, corrected T1 MRI, 3-dimensional ultrasound-based measurement) are in development and awaiting validation in different clinical settings.

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) (1). 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. Liver biopsy is usually not done solely for staging of hepatic fibrosis unless noninvasive tests do not help establish the diagnosis (eg, because different noninvasive tests yield discordant results) or for clinical trials.

The METAVIR (meta-analysis of histological data in viral hepatitis) staging system assesses inflammatory changes (histologic activity) and the level of fibrosis as follows (2):

Histologic activity

• A0 = no activity

• A1 = mild activity

• A2 = moderate activity

• A3 = severe activity

Fibrosis

• F0 = no fibrosis

• F1 = portal fibrosis without septa

• F2 = portal fibrosis with rare septa

• F3 = numerous septa without cirrhosis

• F4 = cirrhosis

Blood tests are included in clinical models (eg, APRI index, BARD score, FIB-4 score, nonalcoholic fatty liver disease [NAFLD] fibrosis score), which combine commonly available tests (AST, ALT, platelet count, albumin, INR) with demographic and clinical information (eg, age, body mass index [BMI], diabetes/impaired fasting glucose). Some commercially available panels (eg, FibroTest [known as Fibrosure in the United States], Hepascore, European Liver Fibrosis panel [ELF]) combine indirect markers (eg, serum bilirubin) and direct markers (eg, procollagen types I and III, hyaluronic acid) of hepatic function. Direct markers are substances involved in the pathogenesis of extracellular matrix deposition or cytokines that induce extracellular matrix deposition. These models and 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 the newer noninvasive imaging assessments of fibrosis, reserving liver biopsy as a last resort.

Combinations of blood tests and imaging tests may improve the fibrosis assessment. Examples include the FAST (FibroScan- AST) score, which combines FibroScan and serum AST levels; MAST (MRI-AST) score, which combines the MRI-based proton density fat fraction (MRI-PDFF), MRE, and serum AST levels; and the MEFIB, which combines MRE and the Fibrosis-4 (FIB-4) index (3). These tools have been developed for assessment of hepatic fibrosis in metabolic dysfunction–associated steatohepatitis (MASH, formerly known as nonalcoholic fatty liver disease).

• Treatment of cause

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 antiviral drugs to eliminate hepatitis B virus or hepatitis C virus in chronic viral hepatitis, abstaining from alcohol in alcoholic liver disease, weight loss in patients with metabolic dysfunction–associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis/NASH), 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 fibrosis are usually too toxic for long-term use (eg, corticosteroids, penicillamine) or have no proven efficacy (eg, colchicine, silymarin from milk thistle). Other antifibrotic treatments are under study, especially for MASH (eg, glitazone, vitamin E, GLP-1 agonist, PPAR agonist, FXR agonist, caspase inhibitor, SK1 inhibitors). Coffee has been associated with a decreased risk of cirrhosis in meta-analyses, but further study is needed.