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.

Tabs Content

Clinical Overview

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 (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

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

ARUP Lab Tests

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

Recommended Use

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

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

Recommended Use

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

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

Recommended Use

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

Medical Experts

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

References

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
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
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
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
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
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
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
Flamm SL, Yang Y, Singh S, Falck-Ytter YT, AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guidelines for the Diagnosis and Management of Acute Liver Failure. Gastroenterology. 2017; 152(3): 644-647. PubMed
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1): 328-357. 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

Kennedy P, Wagner M, Castéra L, Hong CW, Johnson CL, Sirlin CB, Taouli B. Quantitative elastography methods in liver disease: current evidence and future directions. Radiology. 2018; 286(3): 738-763. 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

Educational Videos

Content Review:

May 2018

Last Update: July 2018

Cirrhosis

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Other Assessment Modalities

Background

Epidemiology

Etiology

Pathophysiology

Clinical Presentation

Prognosis

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Cirrhosis. ARUP Consult^©. Retrieved April 17, 2019, from: https://arupconsult.com/content/cirrhosis

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Cirrhosis

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Other Assessment Modalities

Background

Epidemiology

Etiology

Pathophysiology

Clinical Presentation

Prognosis

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

ARUP Laboratories

ARUP Websites

ARUP Consult