Hepatic Fibrosis

Various types of chronic liver injury can cause fibrosis (see table Causes of Hepatic Fibrosis). Common etiologies worldwide include viral hepatitis, metabolic dysfunction-associated liver disease (MASLD), alcohol-related liver disease, and schistosomiasis (1). Self-limited, acute liver injury (eg, acute viral hepatitis A), even when fulminant, does not necessarily distort the underlying 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.

The most common causes of hepatic fibrosis are:

• Viral disorders (eg, chronic hepatitis B or C)

• Metabolic dysfunction–associated steatohepatitis (MASH)

• Alcohol-related liver disease

Activation of the hepatic perivascular stellate cells (Ito cells, which store fat) initiates fibrosis (1). 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.

• History and physical examination

• Sometimes blood tests and/or noninvasive imaging tests

• Ultrasound or magnetic resonance-based elastography (MRE)

• Sometimes liver biopsy

Hepatic fibrosis is suspected if patients have known chronic liver disease (eg, chronic hepatitis C [HCV] or chronic hepatitis B [HBV], alcohol-related liver disease, metabolic dysfunction–associated steatohepatitis [MASH, formerly known as nonalcoholic steatohepatitis (NASH)]) or if results of liver blood tests are abnormal. In such cases, tests are performed to check for fibrosis and, if fibrosis is present, to determine its severity (stage) to guide further medical decision making. For example, screening for hepatocellular carcinoma and for gastroesophageal varices is indicated if advanced fibrosis with cirrhosis is confirmed, but it is generally not indicated for mild or moderate fibrosis. Assessment of the degree of hepatic fibrosis helps determine the prognosis of patients with chronic viral hepatitis. However, since the widespread availability of direct-acting antiviral medications, 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 noninvasive imaging tests that assess liver stiffness.

The METAVIR (meta-analysis of histological data in viral hepatitis) staging system assesses inflammatory changes (histologic activity) and the level of fibrosis as follows (1):

The histologic activity parameter provides information about the current inflammatory state of the liver:

• A0 = no activity

• A1 = mild activity

• A2 = moderate activity

• A3 = severe activity

The fibrosis parameter provides information about changes to the architecture of the liver:

• F0 = no fibrosis

• F1 = portal fibrosis without septa

• F2 = portal fibrosis with rare septa

• F3 = numerous septa without cirrhosis

• F4 = cirrhosis

Conventional imaging tests: Conventional imaging tests include ultrasound, CT, and MRI. These tests can detect evidence of cirrhosis and portal hypertension, such as liver surface nodularity, splenomegaly, portal vein dilation and collateralization, ascites, and varices (2). 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 ultrasound or heterogeneity of signal on CT, these findings are nonspecific and may indicate only liver parenchymal fat.

Imaging-based noninvasive liver disease assessment: Imaging-based elastography techniques are validated for detecting fibrosis or early cirrhosis (2); they include:

• Transient elastography

• Acoustic radiation force impulse imaging

• 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, interpretation has not been well-validated in pregnancy. Thus, use of these techniques is typically not recommended in patients with one of these conditions.

Blood-based noninvasive liver disease assessment is included in clinical models (eg, AST to Platelet Ratio Index (APRI) index, BARD score, Fibrosis-4 (FIB-4) score, metabolic dysfunction–associated steatotic liver disease [MASLD] 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^TM [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.

Clinical Calculators

FIB-4 as a Marker of Fibrosis in Nonalcoholic Fatty Liver Disease (NAFLD)

Combinations of blood tests and imaging tests may improve the fibrosis assessment and are recommended for most patients with chronic liver disease (2, 3). Examples include the FAST (FibroScan and serum AST levels); Agile 3+ (AST, ALT, platelet, and FibroScan), MAST (MRI-based proton density fat fraction, magnetic resonance elastography [MRE], and serum AST levels), and the MEFIB (MRE and the FIB-4 index) (4). These tools have been developed for assessment of hepatic fibrosis in metabolic dysfunction–associated steatohepatitis (MASH, formerly known as nonalcoholic fatty liver disease [NASH]).

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 an approximately 10% risk of minor complications (eg, postprocedural pain) and an approximately 2% risk of serious complications (eg, significant bleeding, death, hospitalization, severe pain) (5). Also, liver biopsy is limited by sampling error and imperfect interobserver agreement in interpretation of histologic findings. Thus, liver biopsy may not always be performed (3). Liver biopsy is usually not performed 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.

Liver Fibrosis (Light Micrograph)

Image

JOSE CALVO / SCIENCE PHOTO LIBRARY

• 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) (1). Such treatment may include antiviral medications to eliminate hepatitis B virus or hepatitis C virus in chronic viral hepatitis, abstaining from alcohol or reducing alcohol intake, 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.

Resmetirom (thyroid hormone receptor beta agonist) may be effective for MASH and fibrosis in patients with both (Resmetirom (thyroid hormone receptor beta agonist) may be effective for MASH and fibrosis in patients with both (2). Among glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, tirzepatide, and liraglutide have been shown in trials to improve MASH without worsening fibrosis (-like peptide-1 (GLP-1) receptor agonists, semaglutide, tirzepatide, and liraglutide have been shown in trials to improve MASH without worsening fibrosis (3, 4, 5), and tirzepatide may improve fibrosis as well. Many other antifibrotic treatments are under study (eg, glitazone, vitamin E, peroxisome proliferator activated receptor [PPAR] agonist, Farnesoid X receptor [FXR] agonist, caspase inhibitor, sphingosine kinase 1 [SK1] inhibitors) (), and tirzepatide may improve fibrosis as well. Many other antifibrotic treatments are under study (eg, glitazone, vitamin E, peroxisome proliferator activated receptor [PPAR] agonist, Farnesoid X receptor [FXR] agonist, caspase inhibitor, sphingosine kinase 1 [SK1] inhibitors) (5, 6, 7). Coffee has been associated with a decreased risk of cirrhosis in meta-analyses (8, 9).