Chronic liver disease

Chronic liver disease (CLD) is a spectrum of liver diseases that persist for ≥ 6 months. CLD is characterized by progressive liver fibrosis, steatosis, and deterioration of liver function. Cirrhosis is the final stage of CLD. The most common causes of CLD in the US include chronic HCV infection, cardiometabolic risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD), and long-term unhealthy alcohol use. The initial stages of CLD are typically asymptomatic or manifest with nonspecific features (e.g., fatigue, weight loss) before reaching the cirrhosis stage. A prompt workup of CLD is indicated in patients with abnormal liver chemistries and/or imaging findings suggestive of liver pathology (e.g., steatosis, liver nodules) or associated complications (e.g., ascites). Once a cause has been identified, disease-specific evaluation guides management. Liver biopsy is indicated in patients with inconclusive findings on noninvasive diagnostic studies. Complications include acute-on-chronic liver failure, clinically significant portal hypertension, and hepatocellular carcinoma.

• Chronic liver disease (CLD): A spectrum of liver diseases (e.g., hepatitis C, Wilson disease) that persist for ≥ 28 weeks (approx. 6 months); characterized by progressive fibrosis and/or steatosis, and deterioration of liver function ^[1][2]
• Liver fibrosis: the reversible proliferation of fibroblasts and accumulation of excessive extracellular matrix components (e.g., crosslinked type 1 collagen) in liver parenchyma in response to hepatic injury ^[3]
• Cirrhosis: the final stage of CLD; characterized by regenerative nodules and fibrous septae (usually irreversible) in liver parenchyma in response to hepatic injury ^[4][5]

Chronic hepatitis B and C, alcohol-associated liver disease, and MASH are the most common forms of CLD in the US.

The various conditions that cause CLD typically have an initial asymptomatic stage with no or mild fibrosis, which may progress to cirrhosis. ^[5]

• Hepatotoxicity
  • Alcohol-associated liver disease
  • Drug-induced liver injury; (e.g., acetaminophen, amiodarone, methotrexate)
  • Chronic ingestion of aflatoxin (produced by Aspergillus) ^[23]
  • Industrial chemicals (e.g., pesticides)

• Inflammation
  • Chronic viral infections: HBV, HDV, and HCV (most common cause of cirrhosis in the US)
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis
  • Autoimmune hepatitis
  • Parasitic infections (e.g., schistosomiasis, leishmaniasis, malaria)
  • IgG4-related sclerosing cholangitis
• Metabolic disorders
  • Metabolic dysfunction-associated steatotic liver disease
  • Hemochromatosis
  • Wilson disease
  • α1-antitrypsin deficiency
  • Porphyrias
  • Glycogen storage disorders
  • Cystic fibrosis
  • Hereditary fructose intolerance
• Hepatic vein congestion or vascular anomalies
  • Budd-Chiari syndrome
  • Cardiac cirrhosis (congestive hepatopathy)
  • Osler-Weber-Rendu syndrome ^[24]

The following is an overview of diagnostics for CLD. Disease-specific clinical evaluation and diagnostic approaches are described in other articles.

General principles ^[5][25]

The initial stages of CLD are typically asymptomatic or manifest with nonspecific features (e.g., fatigue, weight loss) before reaching the cirrhosis stage (see “Clinical features of cirrhosis”).

• Initial laboratory and imaging studies for suspected CLD are required to:
  • Assess liver function
  • Identify complications
  • Establish the underlying cause(s)
• Fibrosis assessment (e.g., fibrosis-4 score, elastography) helps to establish the prognosis and guide management.
• Liver biopsy may be considered if findings from noninvasive studies are inconclusive.

Laboratory studies ^[26][27]

Laboratory studies may be normal in the early stages of CLD.

• Liver chemistries: ↑ ALT, AST, ALP, GGT, and bilirubin
• Coagulation studies: ↑ prothrombin time
• CBC: thrombocytopenia, anemia, leukopenia
• CMP: hypoalbuminemia, hyponatremia
• HCV and HBV serology
• Additional studies based on clinical suspicion, e.g.:
  • Lipid panel and hyperglycemia tests to identify cardiometabolic risk factors for MASLD
  • Serology for type 1 autoimmune hepatitis
  • Serum ferritin and transferrin saturation for hemochromatosis
  • Serum ceruloplasmin to screen for Wilson disease
  • Serum AAT level for patients with CLD of unknown etiology ^[28]

CLD can have more than one cause, e.g., alcohol-associated liver disease with concomitant hepatitis C.

Imaging studies ^[25][29]

• Modalities: abdominal CT, MRI, or ultrasound
• Findings
  • Nodular liver surface: cirrhosis
  • Portosystemic collateral circulation: clinically significant portal hypertension
  • Dilatated intrahepatic bile ducts: intrahepatic cholestasis
  • Lesion(s) with irregular borders and possible signs of local invasion: hepatocellular carcinoma
  • Nonspecific findings: e.g., ascites, splenomegaly, portal and/or splenic vein dilatation

Noninvasive liver fibrosis assessment ^[27][30]

The following may be used alone or in combination (preferred) to predict the likelihood of advanced fibrosis in patients with CLD.

• Blood biomarker-based scores
  • Algorithms are used to predict fibrosis based on laboratory parameters and patient characteristics (e.g., fibrosis-4 score).
  • May underestimate advanced fibrosis in patients with hepatitis B or C who have received antiviral treatment ^[31]
  • Findings: See “Noninvasive liver fibrosis assessment” in “Cirrhosis.”
• Liver elastography (e.g., transient elastography, MR elastography): more accurate for predicting fibrosis than standard imaging or biomarker-based algorithms. ^[25]

Liver biopsy ^[25]

• May be considered in patients with inconclusive findings in noninvasive studies (e.g., MASLD, primary biliary cholangitis, hemochromatosis)
• See also “Diagnostics” in “Cirrhosis.”

• Initiate disease-specific management if the cause of CLD is known, e.g.:
  • Antiviral treatment of chronic hepatitis C
  • Antiviral treatment of chronic hepatitis B
• Provide patient education targeted to the cause and stage of disease, e.g.: ^[27]
  • Management of alcohol use disorder
  • Treatment for obesity and metabolic syndrome
  • Review of medications and supplements for patients with cirrhosis
• Reduce the risk of infection-associated complications, e.g., by ensuring the immunization schedule for adults is up-to-date. ^[32]
• Refer to a specialist (e.g., hepatology) to optimize the management of cirrhosis.

• Clinically significant portal hypertension
• Esophageal varices and GI bleeding
• Ascites and spontaneous bacterial peritonitis
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Hepatic encephalopathy
• Hepatocellular carcinoma
• Acute-on-chronic liver failure

We list the most important complications. The selection is not exhaustive.