Liver Disease Evaluation

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

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

Tests generally appear in the order most useful for common clinical situations

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

Initial screen for hepatobiliary disease

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

Test name: Prothrombin Time

ARUP #: 0030215

Methodology: Electromagnetic Mechanical Clot Detection

Use:

Assess liver synthetic capacity (synthesis of coagulation factors)

Limitations:

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

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Initial screen for infectious process

Test name: Gamma Glutamyl Transferase, Serum or Plasma

ARUP #: 0020009

Methodology: Quantitative Enzymatic

Use:

Determine if enzyme elevation is due to hepatocellular or cholestatic pattern

Test name: 5'Nucleotidase

ARUP #: 0080235

Methodology: Quantitative Enzymatic

Use:

Determine if enzyme elevation is due to hepatocellular or cholestatic pattern

Follow-up: If 5' NT is normal but ALP is elevated, perform bone-specific ALP testing

Test name: Hepatitis C Virus Antibody by CIA

ARUP #: 2002483

Methodology: Qualitative Chemiluminescent Immunoassay

Use:

Confirm HCV as infectious agent in patient with acute hepatitis

Test name: Hepatitis Panel, Acute with Reflex to HBsAg Confirmation

ARUP #: 0020457

Methodology: Qualitative Chemiluminescent Immunoassay/Qualitative Enzyme Immunoassay

Use:

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

Test name: Iron & Iron Binding Capacity

ARUP #: 0020420

Methodology: Quantitative Spectrophotometry/Calculation

Use:

Assess for iron storage disease

Test name: Ferritin

ARUP #: 0070065

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Assess for iron storage disease

Additional Tests Available

Test name: Aspartate Aminotransferase, Serum or Plasma

ARUP #: 0020007

Methodology: Quantitative Enzymatic

Comments:

Test name: Alanine Aminotransferase, Serum or Plasma

ARUP #: 0020008

Methodology: Quantitative Enzymatic

Comments:

Test name: Alkaline Phosphatase, Serum or Plasma

ARUP #: 0020005

Methodology: Quantitative Enzymatic

Comments:

Test name: Bilirubin, Direct & Total, Serum or Plasma

ARUP #: 0020426

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Alkaline Phosphatase Isoenzymes, Serum or Plasma

ARUP #: 0021020

Methodology: Quantitative Heat Inactivation/Enzymatic

Comments:

Test name: Bone Specific Alkaline Phosphatase

ARUP #: 0070053

Methodology: Quantitative Chemiluminescent Immunoassay

Comments:

Test name: Bilirubin, Total, Body Fluid

ARUP #: 0020510

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Bilirubin, Direct, Serum or Plasma

ARUP #: 0020033

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Bilirubin, Total, Serum or Plasma

ARUP #: 0020032

Methodology: Spectrophotometry

Comments:

Test name: Albumin, Serum by Nephelometry

ARUP #: 0050671

Methodology: Quantitative Nephelometry

Comments:

Test name: Albumin, Serum or Plasma by Spectrophotometry

ARUP #: 0020030

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Inhibitor Assay, PT with Reflex to PT 1:1 Mix

ARUP #: 2003260

Methodology: Electromagnetic Mechanical Clot Detection

Comments:

Test name: Ammonia, Plasma

ARUP #: 0020043

Methodology: Colorimetry

Comments:

Test name: Lactate Dehydrogenase, Isoenzymes

ARUP #: 0020413

Methodology: Quantitative Enzymatic/Electrophoresis

Comments:

Test name: Retinol Binding Protein

ARUP #: 0050467

Methodology: Quantitative Nephelometry

Comments:

Test name: Alpha-1-Antitrypsin

ARUP #: 0050001

Methodology: Quantitative Immunoturbidimetric

Comments:

Test name: Sex Hormone Binding Globulin

ARUP #: 0099375

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

General

ARUP Institute for Clinical and Experimental Pathology®

Akerley W, Boucher KM, Bentz JS, Arbogast K, Walters T. A phase II study of erlotinib as initial treatment for patients with stage IIIB-IV non-small cell lung cancer. J Thorac Oncol. 2009; 4 (2) :214-219.PubMed

Comprehensive Review: November 2011
Last Update: November 2011

Alcohol Abuse

Alpha-1-Antitrypsin Deficiency

Hepatitis, Autoimmune

Hepatitis A Virus

Hepatitis B Virus

Hepatitis C Virus

Hepatitis Delta Virus

Hepatocellular Carcinoma

Primary Biliary Cirrhosis

Wilson Disease