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
    • 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 are best ordered as groups of tests
      • Order as groups of tests for better categorization
    • 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 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

      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 indicator of liver injury (even minor injury)
      • Clinical value – to determine origin of elevated ALP
      5’ nucleotidase (5’ NT)
      • Very sensitive and specific for hepatobiliary disease
      • Clinical value – to 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)
      • 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

  • Liver disease
    • Acute
      • Generally hepatitis – may be any etiology
      • Fever, anorexia, fatigue, jaundice
      • Fulminant failure – encephalopathy, coagulopathy
    • 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

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

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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

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