Cirrhosis

  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

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

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
      • Extra cellular 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, IL-4,6,8,18
  • 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​
  • 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 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 cirrhosis [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%), associated morbidity rate (0.3%) and mortality rate (0.01%)
  • 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

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

Epidemiology

  • Prevalence
    • Chronic viral hepatitis (B or C) 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 nonalcoholic fatty liver disease (NAFLD) worldwide – 6.3-33%
      • Prevalence of nonalcoholic steatohepatitis (NASH) – 3-5% (American Association for the Study of LIver Diseases [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 leading 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
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.

Liver Fibrosis, Chronic Viral Hepatitis (Echosens FibroMeter) 2005661
Method: Quantitative Nephelometry/Quantitative Enzymatic/Quantitative Spectrophotometry/Automated Cell Count/ Electromagnetic Mechanical Clot Detection

Liver Fibrosis, Non-Alcoholic Fatty Liver Disease (Echosens) 2012521
Method: Quantitative Enzymatic/Quantitative Spectrophotometry/Automated Cell Count/Quantitative Chemiluminescent Immunoassay

Non-Alcoholic Fatty Liver Disease Susceptibility (PNPLA3) Genotyping 2014599
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Guidelines

Barr RG, Ferraioli G, Palmeri ML, Goodman ZD, Garcia-Tsao G, Rubin J, Garra B, Myers RP, Wilson SR, Rubens D, Levine D. Elastography Assessment of Liver Fibrosis: Society of Radiologists in Ultrasound Consensus Conference Statement. Radiology. 2015; 276(3): 845-61. PubMed

Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am J Gastroenterol. 2012; 107(6): 811-26. PubMed

European Association for Study of Liver, Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015; 63(1): 237-64. PubMed

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016; 64(6): 1388-402. PubMed

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol. 2016; 64(2): 433-85. PubMed

Liu T, Wang X, Karsdal MA, Leeming DJ, Genovese F. Molecular serum markers of liver fibrosis. Biomark Insights. 2012; 7: 105-17. PubMed

Martin P, DiMartini A, Feng S, Brown R, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014; 59(3): 1144-65. PubMed

O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Am J Gastroenterol. 2010; 105(1): 14-32; quiz 33. PubMed

Starr P, Raines D. Cirrhosis: diagnosis, management, and prevention. Am Fam Physician. 2011; 84(12): 1353-9. PubMed

General References

Adams LA. Biomarkers of liver fibrosis. J Gastroenterol Hepatol. 2011; 26(5): 802-9. PubMed

Adebajo CO, Talwalkar JA, Poterucha JJ, Kim R, Charlton MR. Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis. Liver Transpl. 2012; 18(3): 323-31. PubMed

Armutcu F, Akyol S, Ucar F, Erdogan S, Akyol O. Markers in nonalcoholic steatohepatitis. Adv Clin Chem. 2013; 61: 67-125. PubMed

Carey E, Carey WD. Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete? Cleve Clin J Med. 2010; 77(8): 519-27. PubMed

Castéra L, Le Bail B, Roudot-Thoraval F, Bernard P, Foucher J, Merrouche W, Couzigou P, de Lédinghen V. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: comparison of transient elastography (FibroScan) with standard laboratory tests and non-invasive scores. J Hepatol. 2009; 50(1): 59-68. PubMed

Chon YE, Choi EH, Song KJ, Park JY, Kim DY, Han K, Chon CY, Ahn SH, Kim SU. Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis. PLoS One. 2012; 7(9): e44930. PubMed

Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Ann Intern Med. 2013; 158(11): 807-20. PubMed

Chrostek L, Panasiuk A. Liver fibrosis markers in alcoholic liver disease. World J Gastroenterol. 2014; 20(25): 8018-23. PubMed

Degos F, Perez P, Roche B, Mahmoudi A, Asselineau J, Voitot H, Bedossa P, FIBROSTIC study group. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol. 2010; 53(6): 1013-21. PubMed

Duarte-Rojo A, Altamirano JT, Feld JJ.  Noninvasive markers of fibrosis: key concepts for improving accuracy in daily clinical practice. Ann Hepatol. 2012; 11(4): 426-39. PubMed

Enomoto M, Morikawa H, Tamori A, Kawada N. Noninvasive assessment of liver fibrosis in patients with chronic hepatitis B. World J Gastroenterol. 2014; 20(34): 12031-8. PubMed

Foucher J, Chanteloup E, Vergniol J, Castéra L, Le Bail B, Adhoute X, Bertet J, Couzigou P, de Lédinghen V. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006; 55(3): 403-8. PubMed

Lee MH, Cheong JY, Um SH, Seo YS, Kim DJ, Hwang SG, Yang JM, Han K, Cho SW. Comparison of surrogate serum markers and transient elastography (Fibroscan) for assessing cirrhosis in patients with chronic viral hepatitis. Dig Dis Sci. 2010; 55(12): 3552-60. PubMed

Martínez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology. 2011; 53(1): 325-35. PubMed

Neuman MG, Cohen LB, Nanau RM. Biomarkers in nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol. 2014; 28(11): 607-18. PubMed

Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly J, Brevet M, Grignon P, Lion S, Le Page L, Dupas J. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther. 2008; 28(10): 1188-98. PubMed

Patel K, Shackel NA. Current status of fibrosis markers. Curr Opin Gastroenterol. 2014; 30(3): 253-9. PubMed

Sebastiani G, Gkouvatsos K, Plebani M. Non-invasive assessment of liver fibrosis: it is time for laboratory medicine. Clin Chem Lab Med. 2011; 49(1): 13-32. PubMed

Medical Reviewers

Grenache, David G., PhD, Medical Director, Special Chemistry; Co-Director, Electrophoresis and Manual Endocrinology; Chief Medical Director, Clinical Chemistry at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Slev, Patricia R., PhD, Medical Director, Serological Hepatitis/Retrovirus, Immunology Core; Co-Medical Director, Microbial Immunology and Immunogenetics; Chief Medical Director, Immunology Division at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Content Reviewed: 
May 2017

Last Update: August 2017