Cirrhosis

Chronic liver disease without intervention often progresses to liver fibrosis and cirrhosis, in which active, healthy hepatocytes are replaced by fibrotic tissue and damaged by ongoing inflammation. Liver fibrosis and cirrhosis can progress to end-stage liver disease and to hepatocellular cancer.

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

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

ARUP Lab Tests

Noninvasive, serum surrogate marker test for assessment of liver fibrosis in patients with chronic viral hepatitis

Noninvasive assessment of liver fibrosis in patients with chronic viral hepatitis B or C (with or without HIV coinfection) and in patients with hepatic steatosis​

Test can performed only if the patient has a FibroScan score

Result based on both a panel of serum biomarkers (FibroMeter) and the FibroScan Vibration Controlled Transient Elastography (VCTE), a noninvasive, diagnostic ultrasound-based test that measures liver fibrosis

Only intended for use in patients with NAFLD; results may be inaccurate in patients with other etiologies of liver disease

Screen for genetic susceptibility to NAFLD and cirrhosis progression in alcoholic liver disease

Related Tests

Noninvasive assessment of liver status

Results obtained with different assay methods or kits cannot be used interchangeably

Initial test for suspected bleeding disorder

May be used as marker of membrane permeability in urine or as indirect marker for liver fibrosis

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite) but only when concentrations are at or above those expected during acetaminophen overdose

Medical Experts

Contributor

Slev

Patricia R. Slev, PhD
Associate Professor of Clinical Pathology, University of Utah
Section Chief, Immunology; Medical Director, Immunology Core Laboratory, ARUP Laboratories

References

Additional Resources