Cirrhosis

Indications for Testing

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

Laboratory Testing

Serum testing (non-invasive)
- Indirect markers
  - Main markers used – aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, prothrombin time (PT)
    - Imprecise; when abnormal, may indicate decompensation
    - Albumin, PT, bilirubin, alpha-2 macroglobulin and platelets may all be abnormal
    - Amino transferase levels – do not correlate with fibrosis
      - Ratio of AST/ALT in fibrosis tends to be >1.0 (normal ratio 0.8)
  - 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
    - FibroSURE™/FibroTest
      - Uses alpha macroglobulin, haptoglobin, apolipoprotein A2, total bilirubin, GGT (gamma glutamyl transpeptidase) and ALT
      - Sensitivity 75%; specificity 85% (platelet count, AST, gammaglobulin)
    - ActiTest – adds ALT into FibroTest
    - FibroIndex
      - FibroIndex = 1.738-0.064 x platelets + 0.005 x AST (IUs) + 0.463 x gammaglobulin
      - Less accurate than FibroSURE
    - FibroMeter – platelet count, prothrombin, AST, alpha macroglobulin
    - FIB4 = age (years) x AST (IUs)/platelets x 10⁹/L x ALT (IUs)
    - Forns index
      - Uses age, platelet count, AST, cholesterol
    - Nonalcoholic fatty liver disease (NAFLD) fibrosis score
      - Uses age, diabetes mellitus, BMI, AST/ALT ratio, platelet count, albumin
    - 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 metalloproteases
  - 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 extensive fibrosis)
      - 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)
      - HepaScore uses age, sex, bilirubin, alpha GT, alpha-2 macroglobulin and hyaluronic acid
        <0.5 – extensive fibrosis
        >0.84 – excludes fibrosis
        Lower sensitivity than FibroSURE or FibroMeter
      - FibroSpect uses hyaluronic acid, TMP-1 and alpha-2 macroglobulin
        No comparison to FibroSURE or FibroMeter has been performed

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) and 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%), definite morbidity (0.3%), mortality (0.01%)

Imaging Studies

Not recommended in diagnosis of fibrosis; may be helpful if uncertain of diagnosis
- Ultrasound – may help in diagnosis of NAFLD
- FibroScan^® measures liver stiffness
  - Uses mild-amplitude, low-frequency vibration
  - Wave travels faster through stiffer lines (fibrosis)
- Magnetic resonance elastography
  - Same principal as FibroScan^®

Chronic liver disease is a common problem worldwide.

Epidemiology

Prevalence
- Chronic viral hepatitis (B or C) infection, a 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 the U.S.
Age – unusual in patients <40 years unless combined with a genetic disease associated with cirrhosis
Sex – M>F

Etiology

Infectious – viral, parasitic, bacterial
Chemical/toxin – alcohol, drugs (eg, acetaminophen)
Autoimmune disorders – autoimmune hepatitis, primary biliary cirrhosis
Genetic – Wilson disease, hemochromatosis, alpha-1-antitrypsin deficiency

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

Tests generally appear in the order most useful for common clinical situations

Test name: Aspartate Aminotransferase, Serum or Plasma

ARUP #: 0020007

Methodology: Quantitative Enzymatic

Use:

Indirect marker for fibrosis

Test name: Alanine Aminotransferase, Serum or Plasma

ARUP #: 0020008

Methodology: Quantitative Enzymatic

Use:

Indirect marker for fibrosis

Test name: Albumin, Serum or Plasma by Spectrophotometry

ARUP #: 0020030

Methodology: Quantitative Spectrophotometry

Use:

Indirect marker for fibrosis

Test name: Prothrombin Time

ARUP #: 0030215

Methodology: Electromagnetic Mechanical Clot Detection

Use:

Indirect marker for fibrosis

Test name: Bilirubin, Direct & Total, Serum or Plasma

ARUP #: 0020426

Methodology: Quantitative Spectrophotometry

Use:

Indirect marker for fibrosis

Test name: Alpha-2-Macroglobulin

ARUP #: 0050005

Methodology: Quantitative Nephelometry

Use:

Indirect marker for fibrosis

Test name: Platelets

ARUP #: 0040235

Methodology: Automated Cell Count

Use:

Indirect marker for fibrosis

Test name: Hyaluronic Acid, Serum

ARUP #: 0081138

Methodology: Quantitative Protein Binding

Use:

Noninvasive assessment of liver status

Exclude presence of hepatic fibrosis
Assess likelihood of liver fibrosis in newly diagnosed chronic HCV infection
Estimate fibrosis severity in alcoholic liver disease
Substantiate mildly fibrotic liver biopsy results that lack sensitivity for cirrhosis due to sampling error

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

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

Follow-up: If elevated may need to perform liver biopsy

Test name: FibroSURE

ARUP #: 2004745

Methodology: Semi-Quantitative Immunologic/Colorimetry/Kinetic/Nephelometry

Use:

Noninvasive assessment of liver status following diagnosis of HCV, as well as baseline determination of liver status before initiating HCV therapy

Also used for post-treatment assessment of liver status 6 months after completion of therapy and noninvasive assessment of liver status in patients who are at increased risk of complications from a liver biopsy

Limitations:

Requires 8 hours of fasting prior to test

Patient must be greater than or equal to 14 years of age

Additional Tests Available

Test name: Haptoglobin

ARUP #: 0050280

Methodology: Quantitative Immunoturbidimetric

Comments:

Use to calculate indirect marker index

Test name: Apolipoprotein A-1

ARUP #: 0050030

Methodology: Quantitative Nephelometry