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
      • HCV, HBV, HDV
  • Striking elevation (<20x URL)
    • Acute hepatitis
    • Toxin/drug-induced hepatitis
    • Ischemic damage to the liver
  • 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

• Autoimmune
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Autoimmune hepatitis
• Genetic
  • Wilson disease
  • Alpha-1-antitrypsin deficiency
  • Hemochromatosis
  • Crigler-Najjar syndrome
• Viral infection
  • Hepatitis A, B, C or D
  • Cytomegalovirus
  • Epstein-Barr virus
  • Herpes simplex virus
• Nonalcoholic liver disease
  • Congestive heart failure
  • Biliary disease
  • Nonalcoholic steatohepatitis
• Toxins
  • Alcohol
  • Aflatoxin
  • Acetaminophen
  • Other drugs
• Hematologic syndromes
  • HELLP
  • Ischemia
  • Budd-Chiari syndrome

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	Alpha globulin Alpha-1-antitrypsin  Ceruloplasmin  Beta globulin Transferrin  Sex hormone binding globulin
    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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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 & 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, Serum 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