Cirrhosis

Diagnosis

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
      • FibroMeter VIRUS (EASL-ALEH, 2015)
        • 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
      • FibroMeter VCTE
        • For chronic viral hepatitis (B and C)
        • Combines platelet count, prothrombin index, aspartate aminotransferase, alpha-2-macroglobulin, GGT, and liver stiffness
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity
    • Hepatitis B virus (HBV) fibrosis tests (EASL-ALEH, 2015)
      • FibroMeter VCTE
        • For chronic viral hepatitis (B and C)
        • Combines platelet count, prothrombin index, aspartate aminotransferase, alpha-2-macroglobulin, GGT, and liver stiffness
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity
    • HIV/HCV fibrosis tests
      • FibroMeter VCTE
        • For chronic viral hepatitis (B and C)
        • Combines platelet count, prothrombin index, aspartate aminotransferase, alpha-2-macroglobulin, GGT, and liver stiffness
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity​
    • NAFLD fibrosis tests
      • FibroMeter NAFLD (EASL-ALEH, 2015)
        • 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
      • FibroMeter VCTE
        • For chronic viral hepatitis (B and C) and metabolic steatosis
        • Combines platelet count, prothrombin index, aspartate aminotransferase, alpha-2-macroglobulin, GGT, and liver stiffness
        • Interpreted according to value range and given a METAVIR score for fibrosis and inflammatory activity
• 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

Background

Epidemiology

• Prevalence
  • Chronic HBV or HCV infection – leading cause of chronic liver disease; affects >4 million people in the U.S.
  • Alcohol-related liver disease results in >12,000 deaths annually in U.S.
  • Fatty liver disease
    • Estimated prevalence of NAFLD worldwide – 6.3-33%
    • Prevalence of NASH – 3-5% (AASLD, 2012)
• Age – unusual in patients <40 years, unless in combination with a genetic disease associated with cirrhosis
• Sex – M>F

Etiology

• Infectious – viral (HCV, HBV), parasitic, bacterial
• Chemical/toxin – alcohol, drugs (eg, methotrexate, amiodarone, methyldopa)
• Metabolic – NAFLD
• Autoimmune disorders – autoimmune hepatitis, PBC
• Genetic – Wilson disease, hemochromatosis, alpha-1-antitrypsin deficiency

Pathophysiology

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

Clinical Presentation

• May be asymptomatic until late-stage disease
• Hepatocellular dysfunction – jaundice, coagulation problems, encephalopathy
• Portal hypertension – varices, splenomegaly, ascites, palmar erythema, spider angiomata
• Hepatorenal syndrome

Prognosis

• Model for end-stage liver disease (MELD) score
  • Based on creatinine, bilirubin, and international normalized ratio (INR)
• Degree of fibrosis by transient elastography (TE)
• Fibrosis scoring systems