Liver Disease Evaluation

Clinical Background

In most cases, the diagnosis of liver disease can 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
  • Do not usually suggest a specific disease
  • Do suggest a category of liver disease (eg, cholestatic versus hepatocellular patterns)
  • Can be normal in the presence of liver disease
  • Do not accurately assess the functionality of the liver
  • Best used in groups as a battery of tests to assess:
    • Hepatocellular damage
    • Cholestasis
    • Excretory function
    • Biosynthetic function
• Tests of 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 the 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 the degree of liver damage and the level of aminotransferases
    • Level of aminotransferases does not provide prognosis for liver necrosis or permanent damage
• Tests of 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
  • Gammaglutamyl 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
• Tests of 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
• Tests of biosynthetic function
  • Albumin (proteins)
    • Not liver specific
  • Globulins
  • Coagulation factors
    • Most factors are produced in the liver
    • Factors II, VII, IX and X are vitamin K dependent (meaning they 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% 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

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
• AST, ALT
  • Modest elevation (<300 U/L – seen in any type of liver disorder)
    • Alcoholism
    • Gallstone-induced
    • Metabolic diseases
    • Acute and chronic hepatitis
  • Striking elevation (>1000 U/L)
    • Acute hepatitis
    • Toxin/drug-induced hepatitis
    • Ischemic damage to the liver
• ALP
  • Up to 3-fold elevation may be seen in any liver disease – not specific for cholestasis
  • Sole elevation of ALP may indicate bone disease
    • ALP isoenzymes can differentiate between bone and liver as source of ALP elevation
    • GGT/5’ NT can solely distinguish elevated ALP as liver-related
  • Isolated elevation of the liver isoenzyme is suspicious for early cholestasis but may also reflect tumor or granulomatous disease
  • Level of elevation is not helpful in distinguishing intrahepatic from extrahepatic causes of cholestasis
• GGT/5’ NT – can distinguish solely elevated ALP as liver related
• Elevated ALT, AST, GGT and 5’ NT
  • If all are elevated, highly suggestive of liver as source of disease
• Total bilirubin 
  • Elevated unconjugated bilirubin – rarely reflects liver disease; commonly found in hemolytic disease
  • Elevated conjugated 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
• Further testing based on results from initial screening battery
  • If patient has suspected chronic disease, consider noninvasive testing for fibrosis (cirrhosis)
• Recommend repeat serum testing prior to initiation of exhaustive evaluation of modestly elevated liver function tests (<2 times above normal for AST, ALT, ALP)

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

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: Enzymatic
Alanine Aminotransferase, Serum or Plasma 0020008 Method: Enzymatic
Alkaline Phosphatase, Serum or Plasma 0020005 Method: Enzymatic
Bilirubin, Direct & Total, Serum or Plasma 0020426 Method: Spectrophotometry
Alkaline Phosphatase Isoenzymes 0021020 Method: Heat Inactivation/Enzymatic
Bone Specific Alkaline Phosphatase 0070053 Method: Chemiluminescent Immunoassay
Bilirubin, Direct, Body Fluid 0020511 Method: Spectrophotometry
Bilirubin, Direct, Serum or Plasma 0020033 Method: Spectrophotometry
Bilirubin, Total (Neonatal), Plasma or Serum 0020114 Method: Spectrophotometry
Albumin, Serum by Nephelometry 0050671 Method: Nephelometry
Albumin, Serum or Plasma by Spectrophotometry 0020030 Method: 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: Enzymatic/Electrophoresis