Liver Disease Evaluation

Diagnosis

Indications for Testing

  • Acute presentation of jaundice, suspicion of hepatitis

Laboratory Testing

  • Initial screening for suspected liver disease should include AST, ALT, 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 battery
    • Initial testing – consider PT, albumin, HCV antibodies, HBsAg, HAV IgM, CBC, iron, total iron binding capacity and ferritin
    • If patient has suspected chronic disease, consider noninvasive testing for fibrosis (cirrhosis)
  • Patterns of elevation may suggest where abnormality exists
    • AST/ALT elevations – hepatocellular damage
    • ALP, bilirubin elevations – cholestasis
  • AST, ALT
    • Modest elevation – <10x upper reference limit (URL); seen in many types of liver disorders
      • Alcoholism
      • Gallstone-induced
      • Metabolic diseases
      • Acute and chronic hepatitis
    • Striking elevation (<20x URL)
    • AST/ALT ratio
      • Normal – 0.8-1.0
      • Alcoholic liver disease – >2.0
  • ALP
    • Up to threefold 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 – differentiate 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 is suspicious for early cholestasis but may also reflect tumor or granulomatous disease (eg, M. tuberculosis, sarcoidosis)
    • Level of elevation is not helpful in distinguishing intrahepatic from extrahepatic causes of cholestasis
  • Elevated ALT, AST, GGT and 5’ NT
    • If all are elevated, highly suggestive of liver as source of disease
  • Total bilirubin 
    • Elevated unconjugated (indirect) bilirubin – rarely reflects liver disease; commonly found in hemolytic disease
    • Elevated conjugated (direct) bilirubin – almost always reflects hepatobiliary disease
    • Elevated delta bilirubin – reflects hepatobiliary disease and remains elevated longer than other bilirubin fractions during the convalescent phase of liver disease
    • Any bilirubin found in the urine is the water-soluble conjugated fraction and implies hepatobiliary disease

Differential Diagnosis

Clinical Background

Liver disease diagnosis can generally be made using a carefully obtained history, physical examination, and a few laboratory tests.

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
    • Can be normal in the presence of liver disease
    • Do not usually suggest a specific disease or accurately assess liver function
    • Do suggest a category of liver disease (eg, cholestatic versus hepatocellular patterns) and are best ordered as groups of tests
    • Tests to assess liver disease

      Tests to Assess Liver Disease 

      Hepatocellular Damage

      Aspartate aminotransferase (AST)
      • Found in numerous tissues, including the liver, cardiac muscle, skeletal muscle, kidneys, brain and pancreas
      Alanine aminotransferase (ALT)
      • Found primarily in the liver; considered best 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

      Alkaline phosphatase (ALP)
      • Isoenzymes include liver, bone, placental, and intestinal forms of ALP
      • Usually increased during periods of growth (eg, children, teenagers) and during pregnancy
      Gamma glutamyl transferase (GGT)
      • Very sensitive to small liver insults (eg, alcohol consumption)
      • May be elevated in hepatocellular disease
      5’ nucleotidase (5’ NT)
      • Very sensitive and specific for hepatobiliary disease

      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
      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)
      • 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)
      • Prothrombin time (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

Clinical Presentation

  • Chronic
    • 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
  • Acute
    • Fever, anorexia, fatigue
    • Fulminant failure – encephalopathy, coagulopathy

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
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Initial screen for hepatobiliary disease

Panel includes albumin; ALP; AST; ALT; bilirubin, direct; protein, total; and bilirubin, total

   
Prothrombin Time 0030215
Method: Electromagnetic Mechanical Clot Detection

Assess liver synthetic capacity (synthesis of coagulation factors)

PT is not sensitive to mild/moderate decreases in factor activity

 
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Initial screen for infectious process

   
Gamma Glutamyl Transferase, Serum or Plasma 0020009
Method: Quantitative Enzymatic

Determine if enzyme elevation is due to hepatocellular or cholestatic pattern

   
5'Nucleotidase 0080235
Method: Quantitative Enzymatic

Determine if enzyme elevation is due to hepatocellular or cholestatic pattern

  If 5' NT is normal but ALP is elevated, perform bone-specific ALP testing
Hepatitis C Virus Antibody by CIA 2002483
Method: Qualitative Chemiluminescent Immunoassay

Confirm HCV as infectious agent in patient with acute hepatitis

   
Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457
Method: Qualitative Chemiluminescent Immunoassay

Order when patient has had clinical acute hepatitis of unknown origin for less than 6 months

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen, HCV antibody

Positive HAV IgM shows current or recent infection with 98% sensitivity and specificity

   
Iron and Iron Binding Capacity 0020420
Method: Quantitative Spectrophotometry

Assess for iron storage disease

   
Ferritin 0070065
Method: Quantitative Chemiluminescent Immunoassay

Assess for iron storage disease

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Aspartate Aminotransferase, Serum or Plasma 0020007
Method: Quantitative Enzymatic
Alanine Aminotransferase, Serum or Plasma 0020008
Method: Quantitative Enzymatic
Alkaline Phosphatase, Serum or Plasma 0020005
Method: Quantitative Enzymatic
Bilirubin, Direct and Total, Serum or Plasma 0020426
Method: Quantitative Spectrophotometry
Alkaline Phosphatase Isoenzymes, Serum or Plasma 0021020
Method: Quantitative Heat Inactivation/Enzymatic
Bone Specific Alkaline Phosphatase 0070053
Method: Quantitative Chemiluminescent Immunoassay
Bilirubin, Total, Body Fluid 0020510
Method: Quantitative Spectrophotometry
Bilirubin, Direct, Serum or Plasma 0020033
Method: Quantitative Spectrophotometry
Bilirubin, Total, Serum or Plasma 0020032
Method: Spectrophotometry
Albumin by Nephelometry 0050671
Method: Quantitative Nephelometry
Albumin, Serum or Plasma by Spectrophotometry 0020030
Method: Quantitative Spectrophotometry
Inhibitor Assay, PT with Reflex to PT 1:1 Mix 2003260
Method: Electromagnetic Mechanical Clot Detection
Ammonia, Plasma 0020043
Method: Colorimetry
Lactate Dehydrogenase, Isoenzymes 0020413
Method: Quantitative Enzymatic/Electrophoresis
Retinol Binding Protein 0050467
Method: Quantitative Nephelometry
Alpha-1-Antitrypsin 0050001
Method: Quantitative Immunoturbidimetry
Sex Hormone Binding Globulin 0099375
Method: Quantitative Electrochemiluminescent Immunoassay