Table 1.

Signs of Liver Disease and Related Conditions

Physical Sign Possible Condition

Jaundice, spider angiomata Cirrhosis

Pregnancy
Hyperthyroidism

Hyperpigmentation Primary biliary cirrhosis

Cutaneous excoriations Cholestasis

Dupuytren's contractures Alcoholism

White nails, clubbing Cirrhosis

Xanthomata, xanthelasma Primary biliary cirrhosis

Obesity, increased waist circumference[13] Nonalcoholic fatty liver disease

Kayser-Fleischer corneal rings Wilson's disease

Parotid enlargement Alcoholic liver disease

Signs of congestive heart failure: jugular venous Cardiac cirrhosis

distention, right pleural effusion, S3 gallop

Gynecomastia, testicular atrophy Cirrhosis

Peripheral edema, signs of ascites, Cirrhosis

hepatosplenomegaly, caput medusa

Arterial bruit heard over the liver Hepatocellular carcinoma, alcoholic hepatitis,
arteriovenous malformation (rare)

Table 2. Common Liver Tests and Associated Conditions

Liver Test Abnormal in...

Albumin Cirrhosis, severe hepatocellular injury

Alkaline Cholestasis, hepatocellular enzyme induction, canalicular injury, children

phosphatase during bone growth, bone disease, pregnancy (placenta origin)

Aminotransferases Hepatocellular injury (ethanol, drug-induced hepatitis, hepatitis B and C,

(AST, ALT) ischemic injury, chronic liver disease, NAFLD, chronic viral hepatitis,
alcoholism, nonspecific viral injury, and cholestatic or replacement disease);
acute biliary obstruction; rarely in hyperthyroidism, celiac disease, skeletal
muscle disease

Bilirubin Any acute or chronic liver disease; congenital disorders of bilirubin

metabolism.

5 nucleotidase Cholestasis

GGT Cholestasis; medications, ethanol; rarely anorexia nervosa, hyperthyroidism,

myotonic dystrophy
INR Impaired synthesis of vitamin K-dependent coagulation factors

Lactate Ischemic injury, Epstein-Barr virus infection, hemolysis, solid tumor

dehydrogenase

MCV Alcohol consumption, folic acid and B12 deficiency

Uric acid Alcohol consumption, gout

ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT =

gamma glutamyltransferase; INR = international normalized ratio; MCV = mean
corpuscular volume; NAFLD = nonalcoholic fatty liver disease
All liver tests except albumin are abnormal when elevated.

Aminotransferases
Aminotransferases are used to detect and monitor the progression and resolution
of hepatocellular injury.[16] Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels may be elevated in 8%-21% of
patients.[1,3] Elevations are more common in non-Hispanic blacks and Mexican
Americans than in non-Hispanic whites, are more common in persons 30-40
years of age, decrease in likelihood after age 60 years, and are associated with
hepatocellular injury from ethanol, medications, hepatitis B or C viruses, and,
occasionally, chronic underlying liver diseases such as hemochromatosis.[17]

In most patients, an isolated aminotransferase elevation will be unexplained.

Marked elevations of aminotransferases occur from viral infection, ischemic liver
injury, and drug-induced liver disease, and a careful history and physical
examination should assist in making a diagnosis. Moderate elevations occur in
patients with autoimmune hepatitis and some patients with cirrhosis. Minimal
elevations of aminotransferases are more frequent in NAFLD, chronic viral
hepatitis, alcoholism, nonspecific viral injury, and cholestatic or replacement
disease.[18]

The ratio of AST to ALT may indicate alcoholic liver disease when greater than
2:1.[19] Other considerations for aminotransferase elevation include Wilson's
disease, celiac disease, and hyperthyroidism. Injury to other tissues containing
aminotransferases, such as skeletal muscle, can cause an elevation of AST.

Cholestasis
Laboratory tests for cholestasis include GGT, alkaline phosphatase, and 5
nucleotidase, of which GGT and alkaline phosphatase are most widely
used.[16] These enzymes are elevated in hepatobiliary diseases, including
abnormalities of either the canaliculus or the intrahepatic and extrahepatic bile
ducts and in replacement disease from hepatic tumors or
granulomas.[20] Hepatobiliary diseases include partial biliary tract obstruction from
stones, pancreatitis, parasitic disease, acute cholecystitis, and papillary
dysfunction. With biliary disorders, the tests may fluctuate in value, suggesting
intermittent or partial blockage.

Acute biliary tract obstruction from stones can be associated with

aminotransferase levels > 500 U/L with normal or mildly elevated alkaline
phosphatase levels.[21] Medications such as ethanol, phenytoin, anabolic steroids,
and major tranquilizers can also increase GGT and alkaline phosphatase levels
due to hepatocellular enzyme induction or canalicular injury and cholestasis.
Other considerations include primary biliary cirrhosis, sclerosing cholangitis,
alcoholic liver disease, ductopenic syndromes, AIDS cholangiopathy, parenteral
nutrition, and postoperative cholestasis. GGT may also be elevated with anorexia
nervosa, hyperthyroidism, myotonic dystrophy, obesity, and diabetes mellitus. [22]

Isolated GGT elevations occur, and if other liver test results are normal and no
ethanol or medication use is evident, additional workup can generally be delayed.
Isolated alkaline phosphatase elevation occurs from bone disease, bone growth
in children, and the placenta during pregnancy. GGT levels should be normal in
these conditions. Additional evaluation of patients suspected of having
cholestasis should include a careful history and physical examination and
ultrasonography of the biliary tree or magnetic resonance cholangiography, and
endoscopic retrograde cholangiography or liver biopsy when needed.

Hyperbilirubinemia
Bilirubin elevation can develop in any acute or chronic liver disease. Congenital
disorders of hyperbilirubinemia are generally classified as unconjugated or
conjugated depending on whether the indirect fraction or direct fraction of bilirubin
is dominant.[18] Unconjugated syndromes include Gilbert's (a hepatocyte bilirubin
uptake alteration) and Crigler-Najjar's (glucuronyl transferase deficiency).
Conjugated syndromes include Dubin-Johnson's and Rotor's, both related to
impairment of hepatocyte bilirubin secretion. Unconjugated hyperbilirubinemia
also occurs with hemolysis and ineffective erythropoiesis. A direct bilirubin
fraction >0.4 mg/dL should prompt an evaluation for hepatobiliary disease,
hemolysis, or a congenital disorder of bilirubin metabolism.

Hemolysis may be identified by unconjugated hyperbilirubinemia coupled with

reticulocytosis and can occur with acute and chronic liver diseases, such as
Wilson's disease, autoimmune hepatitis, alcoholic hepatitis, and drug-induced
liver disease. Abnormal liver tests will develop in 3%-7% of women during
pregnancy and are seen in all pregnancy-related liver disorders.[23] Hyperemesis
gravidarum is most frequently associated with abnormal liver test results.
Elevated liver test results may also be associated with preeclampsia, including
the HELLP syndrome (hemolysis, elevated liver tests, and thrombocytopenia),
acute fatty liver of pregnancy (liver failure with coagulopathy and
encephalopathy), and cholestasis of pregnancy.[24]

Additional laboratory evaluation depends on suspected underlying causes, such

as hepatitis viruses (most commonly hepatitis B or C virus), iron overload
syndromes (transferrin saturation and HFEtesting), Wilson's disease
(ceruloplasmin), autoimmune disorders (antinuclear and smooth muscle
antibodies), alpha-1 antitrypsin deficiency (protease inhibitor type), or
hepatocellular carcinoma (alpha-fetoprotein).