Cirrhosis

Indications for Testing

Known liver disease or newly discovered disease – testing to assess presence of fibrosis

Laboratory Testing

• Indirect fibrosis markers
  • Markers of hepatocellular damage
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT)
      • Elevated when healthy hepatocytes are present and undergoing damage
      • After fibrotic replacement of normal cells, levels decline to normal
  • Markers of synthetic function
    • Albumin and prothrombin time (PT)
      • Evaluate ability of damaged liver to function
• Direct fibrosis markers
  • Multiple biomarkers have been identified and are being evaluated for clinical use
  • None recommended for clinical use by American Association for the Study of Liver Diseases (AASLD)
  • Use is limited by lack of sensitivity and specificity
  • Combining serum markers or panels with noninvasive scans may improve sensitivity
  • Direct fibrosis markers include (Liu, 2012)
    • Liver function
      • ALT, AST
    • Extracellular matrix (ECM) formation
      • PIIINP, PINP, type IV collagen, P4NP 7S, PVCP, HA, YKL-40, MFAP
    • Fibrolytic process
      • MMP-1/MMP-13, MMP-2, MMP-9, TIMP-1
    • ECM degradation
      • CO3-610, CO6-MMP, C01-764, C4M
    • Cytokines
      • TGF-β, CTGF, PDGF, TNF-α, interleukin (IL) 4, 6, 8, and 18
• Fibrosis scoring systems
  • Combination of indirect markers in panels
  • Markers included in scoring algorithms include standard liver tests, synthetic markers, and markers of inflammation or other damage
  • Preferred for assessment of liver fibrosis and cirrhosis because of higher sensitivity/specificity
  • Some scoring systems created based on etiology of cirrhosis (eg, nonalcoholic fatty liver disease [NAFLD], hepatitis C virus [HCV]-induced cirrhosis)
  • May aid in identifying which patients need liver biopsy​
    • HCV fibrosis tests (European Association for the Study of the Liver- Asociación Latinoamericana para el Estudio del Hígado, 2015)

      • FibroMeter
        • For chronic viral hepatitis
        • Combines platelet count, prothrombin index,  ALT, AST, gamma glutamyl transferase (GGT), alpha-2-macroglobulin, blood urea nitrogen (BUN), and age
        • High diagnostic accuracy confirmed by rules-based system
        • No interference from patients with Gilbert disease or hemolysis (eg, induced by ribavirin)
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity
      • AST platelet ratio index (APRI)
        • Uses AST, upper limit of normal (ULN), platelet count
        • APRI = AST (/ULN) / platelet count (10⁹/L) x 100
      • Enhanced Liver Fibrosis (ELF) score
        • Combines hyaluronate, age, MMP-3, and TIMP-1
      • Fibrosis Probability Index (FPI)
        • Combines AST, homeostatic model assessment of insulin resistance (HOMA-IR), cholesterol, past alcohol abuse, and age
        • 10.929 + (1.827 x Ln[AST]) + (0.081 x age) + (0.768 x past alcohol use [graded as 0-2]) + (0.385 x HOMA-IR) - (0.447 x cholesterol)
    • Hepatitis B virus (HBV) fibrosis tests (EASL-ALEH, 2015)

      • Hui score
        • Uses body mass index (BMI), bilirubin, albumin, and platelet count
        • 3.148 + 0.167 x BMI + 0.088 x bilirubin - 0.151 x albumin - 0.019 x platelet count
      • Zeng score
        • Uses gamma glutamyl transferase (GGT), alpha-2-macroglobulin, hyaluronate, and age
        • 13.995 + 3.220 log(alpha-2-macroglobulin) + 3.096 log(age) + 2.254 log(GGT) + 2.437 log(hyaluronate)
    • HIV/HCV fibrosis tests (EASL-ALEH, 2015)

      • FIB-4
        • Uses AST, ALT, platelet count, age
        • Age (years) x AST [U/L]/platelet count x [10⁹/L] x (ALT [U/L])^1/2
      • SHASTA index
        • Uses hyaluronic acid (HA), albumin, and AST
        • -3.84 + 1.70 (1 if HA 41-85 ng/mL, 0 otherwise) + 3.28 (1 if HA >85 ng/mL, 0 otherwise) + 1.58 (albumin <3.5 g/dL, 0 otherwise) + 1.78 (1 if AST >60 IU/L, 0 otherwise)​
    • ​NAFLD fibrosis tests (EASL-ALEH, 2015)

      • FibroMeter
        • Combines ALT, AST, ferritin, glucose, platelet count, age, sex, and weight
        • High diagnostic accuracy confirmed by rules-based system
        • No interference from patients with Gilbert disease or hemolysis (eg, induced by ribavirin)
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity
      • NAFLD fibrosis score (NFS)
        • Combines AST/ALT ratio, platelet count, albumin, age, diabetes mellitus, BMI
        • (-1.675 + 0.037 x age [year] + 0.094 x BMI (kg/m²) + 1.13 x IFG/diabetes (yes = 1, no = 0) + 0.99 x AST/ALT ratio - 0.013 x platelet count (x 10⁹/L) - 0.66 x albumin [g/dL])
• Genetic testing
  • Carriers of PNPLA3 I148M and TM6SF2 E167K variants may be at increased risk for nonalcoholic steatohepatitis (NASH)
  • Genetic testing may be considered, but is not routinely recommended

Histology

• Liver biopsy (invasive)
  • Considered gold standard for diagnosis of fibrosis
  • Remains important in cases with diagnostic uncertainty with coexisting disorders (HIV and HCV) and overlapping syndromes (primary biliary cholangitis [PBC] and autoimmune hepatitis) when there is an absolute necessity for diagnosis
  • Limitations
    • Costly, painful, subject to sampling error (identifies hepatic disease in only 65-75%); 0.3% associated morbidity rate, 0.01% mortality rate
• Pathologists have developed scoring systems such as METAVIR in an attempt to quantify liver fibrosis
• Immunohistochemistry (IHC) staining of cellular markers provides additional information
  • Smooth muscle actin expression –  identifies hepatic stellate cell activation
  • Cytokeratin 7 – identifies ductular proliferation
  • CD34 – identifies sinusoidal endothelial capillarization
• Advanced microscopic techniques are used for visualization of fibrillar collagen

Other Assessment Modalities

• Ultrasound
  • May help in diagnosis of fibrosis
• FibroScan vibration-controlled transient elastography
  • Measures liver stiffness in kPa
  • Has been evaluated for fibrosis and cirrhosis assessment in chronic HBV and HCV, HIV/HCV coinfection, NAFLD, alcoholic liver disease, and biliary diseases (eg, PBC, primary sclerosing cholangitis [PSC])
• Magnetic resonance elastography – rarely used in clinical practice
• Acoustic radiation force impulse