Cirrhosis

Clinical Background

Chronic liver disease is a common problem worldwide.

Epidemiology

• Prevalence
  • Chronic viral hepatitis (B or C) infection, a leading cause of chronic liver disease, affects >4,000,000 people in the U.S.
  • Alcohol-related liver disease results in >12,000 deaths annually in the U.S.
• Age – unusual in patients <40 years unless combined with a genetic disease associated with cirrhosis
• Sex – M>F

Etiology

• Infectious – viral, parasitic, bacterial
• Chemical/toxin – alcohol, drugs (eg, acetaminophen)
• Autoimmune disorders – autoimmune hepatitis, primary biliary cirrhosis
• Genetic – Wilson disease, hemochromatosis, alpha-1-antitrypsin deficiency

Pathophysiology

• Chronic liver inflammation leads to an increase in interstitial fibrous tissue
• Widespread disruption and secondary attempts at repair by the liver cause irreversible histologic changes leading to cirrhosis

Clinical Presentation

• May be asymptomatic until late-stage disease
• Hepatocellular dysfunction – jaundice, hepatomegaly
• Portal hypertension – varices, splenomegaly, ascites, palmar erythema, spider angiomata

Diagnosis

Indications for Testing 

• Assess presence of fibrosis in patients with known liver disease or newly discovered disease

Laboratory Testing

• Serum testing (non-invasive)
  • Indirect markers
    • Main markers used – aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, prothrombin time (PT)
      • Albumin, PT, bilirubin, alpha-2 macroglobulin and platelets may all be abnormal
      • Amino transferase levels – do not correlate with fibrosis
        • Ratio of AST/ALT in fibrosis tends to be >1.0
    • Combination of indirect markers in panels may be more helpful
      • AST platelet ratio index (APRI)
        • APRI = (AST/upper limit normal) x 100/platelet count
        • Score <0.5 excludes fibrosis
        • Score >2 suggests fibrosis
      • FibroTest
        • Uses alpha-2 macroglobulin, haptoglobin GGTP, total bilirubin and apolipoprotein-A1
      • FibroIndex
        • FibroIndex = 1.738-0.064 x platelets + 0.005 x AST (IUs) + 0.463 x gammaglobulin
        • Less accurate than FibroTest
      • FibroMeter
        • FIB4 = age (years) x AST (IUs)/platelets x 10⁹/L x ALT (IUs)
      • Forns score
        • Uses age, platelet count, AST, cholesterol
      • Nonalcoholic fatty liver disease (NAFLD) fibrosis score
        • Uses age, diabetes mellitus, BMI, AST/ALT ratio, platelet count, albumin
  • Direct markers
    • Multiple biomarkers exist – most have relatively low specificity and sensitivity if used alone
      • Sensitivity and specificity based on disease process involved in fibrosis
      • No evidence to support use of collagen or metalloproteases
    • Hyaluronic acid
      • Unsulfated, highly-polymerized glycosaminoglycan
      • Endogenous ligand for toll-like receptor of Kupffer cells
      • Synthesized by activated hepatic stellate cells
      • Most useful in nonalcoholic liver fibrosis
      • Negative predictive value is 93-99% (<60 µg/L excludes extensive fibrosis)
        • Excludes patients unlikely to have extensive fibrosis or cirrhosis
      • May avoid or postpone need for liver biopsy
      • Has been combined in panel testing with other markers in attempts to improve sensitivity (Fibrospect, HepaScore)
        • HepaScore uses age, sex, bilirubin, alpha GT, alpha-2 macroglobulin and hyaluronic acid
          • <0.5 – extensive fibrosis
          • >0.84 excludes fibrosis
          • Lower sensitivity than FibroTest or FibroMeter
        • FibroSpect uses hyaluronic acid, TMP-1 and alpha-2 macroglobulin
          • No comparison to FibroTest or FibroMeter has been performed

Histology

• Liver biopsy (invasive)
  • Considered the gold standard for diagnosis of fibrosis
  • Recommended sample size – at least 15 mm long and containing >5 portal tracts
  • Limitations – costly, painful, subject to sampling error (identifies hepatic disease in only 65-75%), definite morbidity (0.3%), mortality (0.01%)

Imaging Studies

• Not recommended in diagnosis of fibrosis; may be helpful if uncertain of diagnosis
  • Ultrasound – may help in diagnosis of NAFLD
  • FibroScan® measures liver stiffness

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Haptoglobin 0050280 Method: Immunoturbidimetric	Use to calculate indirect marker index
Apolipoprotein A-1 0050030 Method: Nephelometry	Use to calculate indirect marker index
Cholesterol, Serum or Plasma 0020031 Method: Enzymatic	Use to calculate indirect marker index