Cirrhosis

Indications for Testing

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

Laboratory Testing

• Serum testing (noninvasive)
  • Indirect markers
    • Main initial markers [aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, prothrombin time (PT)] are not useful on their own
    • Combining markers with noninvasive scans may improve sensitivity
      • Not every scoring system has been validated for every etiology of cirrhosis (eg, nonalcoholic fatty liver disease vs hepatitis C virus induced cirrhosis)
      • Should serve as tool to optimize which patient needs liver biopsy
    • Combination of indirect markers in panels are preferred for assessment of liver fibrosis and cirrhosis because of higher sensitivity/specificity

      • AST platelet ratio index (APRI)
        • APRI = (AST/upper limit normal) x 100/platelet count
        • Score <0.5 excludes fibrosis
        • Score >2 suggests fibrosis
      • FibroIndex
        • FibroIndex = 1.738-0.064 x platelets + 0.005 x AST (IUs) + 0.463 x gammaglobulin
        • Less accurate than FibroSURE
      • FibroMeter
        • Alpha-2-macroglobulin, ALT, AST, blood urea nitrogen (BUN), gamma glutamyl transferase (GGT), platelets, and prothrombin index
      • FIB4
        • Age (years) x AST (IUs)/platelets x 10⁹/L x ALT (IUs)
      • FibroSURE/FibroTest
        • Uses alpha-2 macroglobulin, haptoglobin, apolipoprotein A-1, total bilirubin, GGT (gamma glutamyl transpeptidase), and ALT
        • Interpreted according to value range and given a METAVIR and Ishak score for cirrhosis
      • ActiTest – adds ALT into FibroTest
      • FibroSpect
        • Uses hyaluronic acid, TMP-1, and alpha-2 macroglobulin
        • Performance has not been measured against FibroSURE or FibroMeter
      • Forns index
        • Uses age, platelet count, GGT, cholesterol
      • HepaScore
        • Uses age, sex, bilirubin, GGT, alpha-2 macroglobulin, hyaluronic acid
        • <0.5 – extensive fibrosis
        • >0.84 – excludes fibrosis
        • Lower sensitivity than FibroSURE or FibroMeter
      • Nonalcoholic fatty liver disease (NAFLD) fibrosis score
        • Uses age, diabetes mellitus, BMI, AST/ALT ratio, platelet count, albumin
      • Sequential algorithm for fibrosis evaluation (SAFE)
        • Combines APRI and FibroSURE/FibroTest
  • 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 metalloprotease measurements
    • 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%
        • <55 µg/L 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)

Histology

• Liver biopsy (invasive)
  • Remains important in cases with diagnostic uncertainty with coexisting disorders (HIV and hepatitis C), overlapping syndromes (primary biliary cirrhosis and autoimmune hepatitis), when there is an absolute necessity for diagnosis
  • Considered 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%), morbidity (0.3%), mortality (0.01%)

Other

• Ultrasound – may help in diagnosis of NAFLD
• FibroScan – measures liver stiffness in kPa (vibration controlled transient elastography)
  • Generates mild-amplitude, low-frequency elastic waves in liver (50Hz)
    • Elastic waves travel faster through stiffer tissues (fibrotic or cirrhotic)
  • Has been evaluated for fibrosis and cirrhosis assessment in chronic HBV and HCV; HIV/HCV coinfection; nonalcoholic fatty liver disease; alcohol liver disease; and biliary diseases (eg, PBC, PSC)
  • Comparison of performance to indirect markers (eg, serology tests)
    • Studies demonstrate lower and higher sensitivity results
      • Even in studies demonstrating lower sensitivity, sensitivity is comparable to indirect markers
• Magnetic resonance elastography
  • Same principal as FibroScan
• Acoustic radiation force impulse
  • Evaluates localized tissue displacement from acoustic pulses using B-mode ultrasonography