Liver Disease Evaluation

Liver disease diagnosis can generally be made using a carefully obtained history, physical examination, and a few laboratory tests. Initial laboratory testing should include aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin.

Diagnosis

Indications for Testing

  • Acute presentation of jaundice, suspicion of hepatitis
  • Asymptomatic elevation of transaminases

Laboratory Testing

  • Initial screening for suspected liver disease should include aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin
    • Recommend repeat serum testing prior to initiation of exhaustive evaluation of modestly elevated liver function tests (<2x upper reference limit for AST, ALT, ALP)
  • Further testing based on results from initial screening
  • Patterns of elevation may suggest where abnormality exists
    • AST/ALT elevations – hepatocellular damage
    • ALP, bilirubin elevations – cholestasis
  • Elevated ALT, AST, gamma glutamyl transferase (GGT), and 5’ nucleotidase (5’ NT) – combined elevation highly suggestive of liver disease
  • AST, ALT
    • Modest elevation – <10x upper reference limit (URL); seen in many types of liver disorders
    • Striking elevation (<20x URL)
      • Acute hepatitis
      • Toxin/drug-induced hepatitis
      • Ischemic damage to the liver
    • AST/ALT ratios
      • Normal – 0.8-1.0
      • Alcoholic liver disease – >2.0
  • ALP
    • Up to 3-fold elevation may be seen in liver disease – not specific for cholestasis
    • Multiple isoenzymes – liver, bone, intestinal, placental
    • Elevation of ALP exclusive of other enzymes may indicate bone disease
      • ALP isoenzyme testing – differentiates between bone and liver as source of ALP elevation
      • GGT/5’ NT – distinguish elevated ALP as liver related
        • Elevated GGT/5’ NT – liver
        • Normal GGT/5’ NT – bone
    • Isolated elevation of the liver isoenzyme – suspicious for early cholestasis but may also reflect tumor or granulomatous disease (eg, Mycobacterium tuberculosissarcoidosis)
    • Level of elevation – not helpful in distinguishing intrahepatic from extrahepatic causes of cholestasis
  • Total bilirubin
    • Elevated unconjugated (indirect) bilirubin – rarely reflects liver disease; commonly found in hemolytic disease
    • Elevated conjugated (direct) bilirubin – reflects hepatobiliary disease
    • Elevated delta bilirubin – reflects hepatobiliary disease and remains elevated longer than other bilirubin fractions during the convalescent phase of liver disease
    • Urine bilirubin – water-soluble conjugated fraction that implies hepatobiliary disease

Histology

Definitive diagnosis of fibrosis requires biopsy and pathologist examination.

Differential Diagnosis

Background

Epidemiology

  • Prevalence – chronic liver disease is the 12th most common cause of death in U.S.
  • Age – incidence of chronic disease increases with age
  • Sex – M>F

Pathophysiology

  • Biochemical tests of liver function
    • May be normal in the presence of liver disease
    • Do not suggest a specific disease or accurately assess degree of liver function
    • Do suggest a category of liver disease (eg, cholestatic versus hepatocellular patterns) and order as groups of tests for better categorization
  • Tests to Assess Liver Disease
    Hepatocellular Damage
    AST
    • Found in numerous tissues, including the liver, cardiac muscle, skeletal muscle, kidneys, brain, and pancreas
    ALT
    • Found primarily in the liver
      • Considered most specific laboratory test for liver injury
      • Release of enzymes into the blood occurs when liver-cell membrane is damaged
        • Sensitive indicator of liver-cell injury; however, may not be elevated in 10-15% of patients with chronic disease
        • Poor correlation exists between degree of liver damage and level of aminotransferases
        • Level of aminotransferases does not provide prognosis for liver necrosis or permanent damage
    Cholestasis
    ALP
    • Isoenzymes include liver, bone, placental, and intestinal forms of ALP
    • Usually increased during periods of growth (eg, children and teenagers) and during pregnancy
    GGT
    • Very sensitive indicator of liver injury (even minor injury)
    • Clinical value – determine origin of elevated ALP
    5’ NT
    • Very sensitive and specific for hepatobiliary disease
    • Clinical value – determine origin of elevated ALP
    Excretory Function
    Serum bilirubin
    • Heme product from catalysis and conjugation with glucuronic acid
    • 3 fractions – conjugated, unconjugated, and delta bilirubin (albumin bound)
    • Causes jaundice when concentrations exceed 1.5 mg/dL
    • Conjugated hyperbilirubinemia indicates liver disease
    Urine bilirubin
    • Performed qualitatively using a urine dipstick
    Blood ammonia
    • Liver converts ammonia to urea – significant liver dysfunction results in elevated serum ammonia
    • Poor correlation between ammonia level and degree of liver disease
    Biosynthetic Function (Proteins)
    Markers of nutrition
    • Albumin (not liver specific but does mirror long-term hepatic synthetic function)
    • Prealbumin
    • Retinol binding protein
    Alpha and beta globulins
    Coagulation factors
    • Most factors are produced in the liver
    • Factors II, VII, IX, and X are vitamin-K dependent (factors require adequate quantities of vitamin K for production of functional factors)
    • PT is a collective measure of factors II, V, VII, and X
      • Elevated PT unresponsive to vitamin K supplementation suggests poor liver functionality
      • PT is not sensitive to mild decreases in factor activity
    5’ NT, 5’ nucleotidase, ALP, alkaline phosphatase, ALT, alanine aminotransferase, AST, aspartate aminotransferase, GGT, gamma glutamyl transferase, PT, prothrombin time,

Clinical Presentation

  • Acute liver disease
    • Generally hepatitis – may be any etiology
    • Fever, anorexia, fatigue, jaundice
    • Fulminant failure – encephalopathy, coagulopathy
  • Chronic liver disease
    • Frequently asymptomatic until late stage of disease (up to 40% of patients with cirrhosis)
    • Constitutional – fatigue, weight loss, anorexia
    • Late stage – ascites, spider angiomata, jaundice, pedal edema, esophageal varices, splenomegaly, encephalopathy

ARUP Laboratory Tests

Initial screening for hepatobiliary inflammation

Panel includes albumin; alkaline phosphatase (ALP); aspartate aminotransferase (AST); alanine aminotransferase (ALT); bilirubin, direct; protein, total; and bilirubin, total

Initial test for suspected bleeding disorder

Initial screen for infectious process

May be useful as an indirect marker of alcohol abuse, nonalcoholic fatty liver disease, drug intoxication, or other liver diseases

Determine whether enzyme elevation is due to hepatocellular or cholestatic pattern

Preferred single screening test for one-time screening of population born between 1945-1965 and individuals at risk for hepatitis C virus (HCV)

Positive results require confirmation by molecular testing (eg, HCV by quantitative PCR or HCV by quantitative PCR with reflex to HCV genotype by sequencing)

Evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Panel includes hepatitis A virus (HAV) IgM, hepatitis B virus (HBV) core antibody IgM, HBV surface antigen (HBsAg), HCV antibody

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation will be added

Related Tests

Aid in the diagnosis of iron deficiency anemia and iron overload

Aid in the diagnosis of iron deficiency anemia and iron overload

Monitor treatment of hemochromatosis

Use when total alkaline phosphatase activity is elevated to determine amounts contributed by bone and liver isoenzymes

For information on body fluid reference ranges and/or interpretive guidance, visit http://aruplab.com/bodyfluids/

 May assist in assessing nutritional status or in indicating a possible chronic process

Initial screen for inhibitor in plasma

Reflex pattern: if the prothrombin time (PT) is prolonged, a PT 1:1 mix will be added

Do not use to detect myocardial injury; troponin I and troponin T are the recommended tests for diagnosis and management of acute coronary syndrome

In rare cases, this test may be used to evaluate elevated lactate dehydrogenase associated with noncardiac muscle injury

May be helpful as an indicator of malnutrition, acute and chronic hepatic disease, advanced chronic renal insufficiency, or cystic fibrosis

Assess nephrotic syndrome and protein-losing enteropathy

Determine alpha-1-antitrypsin (AAT) enzyme plasma concentration for the initial evaluation of AAT deficiency

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD
Associate Professor of Clinical Pathology, University of Utah
Chief Operations Officer: Medical Director, Automated Core Laboratory, ARUP Laboratories
Contributor

Slev

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

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®