Cirrhosis

Diagnosis

Indications for Testing 

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

Laboratory Testing

  • Serum testing (noninvasive)
    • Indirect markers
      • Main initial markers – aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, prothrombin time (PT)
        • Imprecise – when abnormal, frequently indicates decompensation
        • Albumin, PT, bilirubin, alpha-2 macroglobulin, and platelets may all be abnormal
      • Combination of indirect markers in panels may be more helpful
          • AST platelet ratio index (APRI)
            • APRI = (AST/upper limit normal) x 100/platelet count
            • Score <0.5 excludes fibrosis
            • Score >2 suggests fibrosis
          • FibroIndex
            • FibroIndex = 1.738-0.064 x platelets + 0.005 x AST (IUs) + 0.463 x gammaglobulin
            • Less accurate than FibroSURE
          • FibroMeter
            • Alpha-2-macroglobulin, ALT, AST, blood urea nitrogen (BUN), gamma glutamyl transferase (GGT), platelets, and prothrombin index
          • FIB4
            • Age (years) x AST (IUs)/platelets x 109/L x ALT (IUs)
          • FibroSURE/FibroTest
            • Uses alpha-2 macroglobulin, haptoglobin, apolipoprotein A-1, total bilirubin, GGT (gamma glutamyl transpeptidase), and ALT
            • Interpreted according to value range and given a METAVIR and Ishak score for cirrhosis
          • ActiTest – adds ALT into FibroTest
          • FibroSpect
            • Uses hyaluronic acid, TMP-1, and alpha-2 macroglobulin
            • Performance has not been measured against FibroSURE or FibroMeter
          • Forns index
            • Uses age, platelet count, AST, cholesterol
          • Hepascore
            • Uses age, sex, bilirubin, GGT, alpha-2 macroglobulin, hyaluronic acid
            • <0.5 – extensive fibrosis
            • >0.84 – excludes fibrosis
            • Lower sensitivity than FibroSURE or FibroMeter
          • Nonalcoholic fatty liver disease (NAFLD) fibrosis score
          • Sequential algorithm for fibrosis evaluation (SAFE)
            • Combines APRI and FibroSURE/FibroTest
    • Direct markers
      • Multiple biomarkers exist – most have relatively low specificity and sensitivity if used alone
        • Sensitivity and specificity based on disease process involved in fibrosis
        • No evidence to support use of collagen or metalloprotease measurements
      • Hyaluronic acid
        • Unsulfated, highly-polymerized glycosaminoglycan
        • Endogenous ligand for toll-like receptor of Kupffer cells
        • Synthesized by activated hepatic stellate cells
        • Most useful in nonalcoholic liver fibrosis
        • Negative predictive value is 93-99%
          • <55 µg/L excludes patients unlikely to have extensive fibrosis or cirrhosis
        • May avoid or postpone need for liver biopsy
        • Has been combined in panel testing with other markers in attempts to improve sensitivity (Fibrospect, HepaScore)

Histology

  • Liver biopsy (invasive)
    • Remains important in cases with diagnostic uncertainty with coexisting disorders (HIV and hepatitis C), overlapping syndromes (primary biliary cirrhosis and autoimmune hepatitis), when there is an absolute necessity for diagnosis
    • Considered gold standard for diagnosis of fibrosis
    • Recommended sample size – at least 15 mm long and containing >5 portal tracts
    • Limitations – costly, painful, subject to sampling error (identifies hepatic disease in only 65-75%), morbidity (0.3%), mortality (0.01%)

Other

  • Ultrasound – may help in diagnosis of NAFLD
  • FibroScan – measures liver stiffness (transient elastography)
    • Uses mild-amplitude, low-frequency vibration
      • Wave travels faster through stiffer lines (fibrosis)
    • Has been evaluated for use in hepatitis B virus (HBV), hepatitis C virus (HCV), and alcohol-related cirrhosis
      • Use limited by technical issues in up to 15-20% of patients
      • Comparison of performance to indirect markers (eg, serology tests)
        • AUROC curves vary from 0.8 to 0.94
        • Studies demonstrating lower sensitivity results – sensitivity comparable to indirect markers
        • Studies demonstrating higher sensitivities (AUROC >0.85) – sensitivity superior to indirect markers
  • Magnetic resonance elastography
    • Same principal as FibroScan

Clinical Background

Chronic liver disease is a common problem worldwide.

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.
  • 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 an increase in interstitial fibrous tissue
  • Widespread disruption and secondary attempts at repair by the liver cause irreversible histologic changes leading to cirrhosis

Clinical Presentation

  • May be asymptomatic until late-stage disease
  • Hepatocellular dysfunction – jaundice, hepatomegaly
  • Portal hypertension – varices, splenomegaly, ascites, palmar erythema, spider angiomata

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Quantitative Enzymatic

Indirect marker for liver fibrosis

   
Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic

Indirect marker for liver fibrosis

   
Albumin, Serum or Plasma by Spectrophotometry 0020030
Method: Quantitative Spectrophotometry

Indirect marker for liver fibrosis

   
Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Indirect marker for liver fibrosis

   
Bilirubin, Direct and Total, Serum or Plasma 0020426
Method: Quantitative Spectrophotometry

Indirect marker for liver fibrosis

   
Alpha-2-Macroglobulin 0050005
Method: Quantitative Nephelometry

Indirect marker for liver fibrosis

   
Platelets 0040235
Method: Automated Cell Count

Indirect marker for liver fibrosis

   
Hyaluronic Acid, Serum 0081138
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Noninvasive assessment of liver status

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

Fasting specimens best, as eating slightly increases hyaluronic acid (HA)

If elevated may need to perform liver biopsy
Liver Fibrosis, Chronic Viral Hepatitis (Echosens FibroMeter) 2005661
Method: Quantitative Nephelometry/Quantitative Enzymatic/Quantitative Spectrophotometry/Automated Cell Count/ Electromagnetic Mechanical Clot Detection

Not a substitute for liver biopsy; may be considered for the following

  • Assess liver status in individuals at increased risk of complications from liver biopsy
  • Determine liver status before beginning hepatitis C virus (HCV) treatment
  • Assess liver status after completion of HCV treatment

Surrogate marker of liver fibrosis, cirrhosis, and necroinflammatory activity

Proprietary algorithm calculates and compares results from 7 blood markers along with age and gender to provide a patient score and a correlated fibrosis stage and activity grade

  • Alpha-2-macroglobulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), gamma glutamyl transferase (GGT), platelets, and prothrombin index

Results should be interpreted in conjunction with the patient’s clinical history, particularly when the rules-based system has modified the scores

Test is not validated for individuals <18 years

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Nonalcoholic steatohepatitis (NASH) FibroSURE 2008868
Method: Semi-Quantitative Immunologic/Colorimetry/Kinetic/Nephelometry

Identify liver disease in individuals with nonalcoholic fatty liver disease (NAFLD)

Not recommended for individuals with other liver diseases due to potentially inaccurate quantitative predictions of fibrosis

Haptoglobin 0050280
Method: Quantitative Immunoturbidimetry

Use to calculate indirect marker index

Cholesterol, Serum or Plasma 0020031
Method: Quantitative Enzymatic

Use to calculate indirect marker index