Wallach: Hepatic

LIVER FUNCTION TESTS

COMMON TEST PATTERNS

Patterns of abnormalities rather than changes in single test results are particularly
useful despite sensitivities of only 65% in some cases.
Test results may be abnormal in many conditions that are not primarily hepatic (e.g.,
heart failure, sepsis, infections such as brucellosis, SBE), and individual test
results may be positive in conditions other than liver disease. Results on individual tests
are normal in a high proportion of patients with proven specific liver diseases,
and normal values may not rule out liver disease.

Serum bilirubin (direct/total ratio)

<20% direct.
Constitutional (e.g., Gilbert's disease, Crigler-Najjar syndrome).
Hemolytic states.
20–40% direct.
Favors hepatocellular disease rather than extrahepatic obstruction.
Disorders of bilirubin metabolism (e.g., Dubin-Johnson, Rotor's syndromes).
40–60% direct: Occurs in either hepatocellular or extrahepatic type.
>50% direct: Favors extrahepatic obstruction rather than hepatocellular disease.
Serum total bilirubin
Not a sensitive indicator of hepatic dysfunction; may not reflect degree of liver damage.
Must be >2.5 mg/dL to produce clinical jaundice.
>5 mg/dL seldom occurs in uncomplicated hemolysis unless hepatobiliary disease is
also present.
Is generally less markedly increased in hepatocellular jaundice (<10 mg/dL) than in
neoplastic obstructions (£20 mg/dL) or intrahepatic cholestasis.
In extrahepatic biliary obstruction, bilirubin may rise progressively to a plateau of 30–40
mg/dL (due in part to balance between renal excretion and diversion of
bilirubin to other metabolites). Such a plateau tends not to occur in hepatocellular
jaundice, and bilirubin may exceed 50 mg/dL (partly due to concomitant renal
insufficiency and hemolysis).
Concentrations are generally higher in obstruction due to carcinoma than that due to
stones.
In viral hepatitis, higher serum bilirubin suggests more liver damage and longer clinical
course.
In acute alcoholic hepatitis, >5 mg/dL suggests a poor prognosis.
Increased serum bilirubin with normal ALP suggests constitutional hyperbilirubinemias
or hemolytic states.
Normal serum bilirubin, AST, and ALT with increased ALP (of liver origin) and LD
suggests obstruction of one hepatic duct or metastatic or infiltrative disease of
liver. Metastatic and granulomatous lesions of liver cause 1.5–3.0× increase of serum
ALP and LD.
Due to renal excretion, maximum bilirubin = 10–35 mg/dL; if renal disease is present,
level may reach 75 mg/dL.
Direct bilirubin >1.0 mg/dL in an infant always indicates disease.

AST and ALT

Most sensitive tests for acute hepatocellular injury (e.g., viral, drug related). >500 U/L
suggests such a diagnosis. Seldom >500 U/L in obstructive jaundice,
cirrhosis, viral hepatitis in AIDS, alcoholic liver disease.
Most marked increase (100–2000 U/L) occurs in viral hepatitis, drug injury, carbon
tetrachloride poisoning.
>4000 indicates toxic injury, e.g., from acetaminophen.
Patient is rarely asymptomatic with level >1000 U/L.
AST >10× normal indicates acute hepatocellular injury but lesser increases are
nonspecific and may occur with virtually any other form of liver injury.
Usually <200 U/L in posthepatic jaundice and intrahepatic cholestasis.
<200 U/L in 20% of patients with acute viral hepatitis.
Usually <50 U/L in fatty liver.
<100 U/L in alcoholic cirrhosis; ALT is normal in 50% and AST is normal in 25% of these
cases.
<150 U/L in alcoholic hepatitis (may be higher if patient has delirium tremens).
<200 U/L in 65% of patients with cirrhosis.
<200 U/L in 50% of patients with metastatic liver disease, lymphoma, and leukemia.
Normal values may not rule out liver disease: ALT is normal in 50% of cases of alcoholic
cirrhosis and AST is normal in 25% of cases.
AST soaring to peak of 1000–9000 U/L and declining by 50% within 3 days and to <100
U/L within a week suggests shock liver with centrolobular necrosis (e.g.,
due to congestive heart failure, arrhythmia, sepsis, GI hemorrhage); serum bilirubin and
ALP reflect underlying disease.
Rapid rise of AST and ALT to very high levels (e.g., >600 U/L and often >2000 U/L)
followed by a sharp fall in 12–72 hrs is said to be typical of acute biliary duct
obstruction.
Abrupt AST rise may also be seen in acute fulminant viral hepatitis (rarely >4000 U and
declines more slowly; positive serologic tests) and acute chemical injury.
Degree of increase has low prognostic value.
Serial determinations reflect clinical activity of liver disease.
Mild increase of AST and ALT (usually <500 U/L) with ALP increased >3× normal
indicates cholestatic jaundice, but more marked increase of AST and ALT
(especially >1000 U/L) with ALP increased <3× normal indicates hepatocellular
jaundice.
Increased concentration has poor correlation with extent of liver cell necrosis and has
little prognostic value.
AST/ALT ratio >2 with ALT <300 U/L is suggestive of alcoholic hepatitis, and ratio >3 is
highly suggestive, in cases of liver disease. Greater increase in AST than in
ALT also occurs in cirrhosis and metastatic liver disease. In patients with cirrhosis or
portal hypertension, AST/ALT ratio ³3 suggests primary biliary cirrhosis. Greater
increase in AST than in ALT favors viral hepatitis, posthepatic jaundice, intrahepatic
cholestasis. AST is increased in AMI and in muscle diseases, but ALT is normal.
ALT is more specific for liver disease than AST.

Serum ALP
Is the best indicator of biliary obstruction but does not differentiate intrahepatic
cholestasis from extrahepatic obstruction. Is increased out of proportion to other
liver function tests.
Increases before jaundice occurs.
High values (>5× normal) favor obstruction and normal levels virtually exclude this
diagnosis.
Markedly increased in infants with congenital intrahepatic bile duct atresia but is much
lower in extrahepatic atresia.
Increase (3–10× normal) with only slightly increased transaminases may be seen in
biliary obstruction and the converse in liver parenchymal disease (e.g.,
cirrhosis, hepatitis).
Increased (2–10× normal) in early infiltrative (e.g., amyloid) and space-occupying
diseases of the liver (e.g., tumor, granuloma, abscess).
Increased >3× normal in £5% of acute hepatitis.
<3× normal is nonspecific and may occur in all types of liver diseases (e.g., infiltrative
liver diseases, cirrhosis, chronic hepatitis, viral hepatitis) and in diseases
affecting the liver (e.g., congestive heart failure).
GGT/ALP ratio >5 favors alcoholic liver disease.
Isolated increase of GGT is a sensitive screening and monitoring test for alcoholism.
Increased GGT due to alcohol or anticonvulsant drugs is not accompanied by
increased ALP.
Serum 5'-NT and LAP levels parallel the increase in ALP in obstructive type of
hepatobiliary disease, but the 5'-NT is increased only in the latter and is normal in
pregnancy and bone disease, whereas the LAP is increased in pregnancy but usually
normal in bone disease. GGT is normal in bone disease and pregnancy.
Therefore, these enzymes are useful in determining the source of increased serum ALP.
Although serum 5'-NT usually parallels ALP in liver disease, it may not
increase proportionately in individual patients.

Test for antimitochondrial antibodies to rule out primary biliary cirrhosis in females
(present in >90% of cases;) and radiologic studies to rule out primary sclerosing
cholangitis.
Bilirubin (“bile”) in urine implies increased serum direct bilirubin and excludes hemolysis
as the cause. Often precedes clinical icterus. May occur without jaundice in
anicteric or early hepatitis, early obstruction, or liver metastases. (Tablets detect
0.05–0.1 mg/dL; dipsticks are less sensitive; test is negative in normal persons.)
Complete absence of urine urobilinogen strongly suggests complete bile duct
obstruction; level is normal in incomplete obstruction. Decreased in some phases of
hepatic jaundice. Increased in hemolytic jaundice and subsiding hepatitis. Increase may
indicate hepatic damage even without clinical jaundice (e.g., some patients
with cirrhosis, metastatic liver disease, congestive heart failure). Presence in viral
hepatitis depends on phase of disease. (Normal is <1 mg or 1 Ehrlich unit per 2-hr
specimen.)

Serum cholesterol
May be normal or slightly decreased in hepatitis.
Markedly decreased in severe hepatitis or cirrhosis.
Increased in posthepatitic jaundice or intrahepatic cholestasis.
Markedly increased in primary biliary cirrhosis.
PT
May be prolonged due to lack of vitamin K absorption in obstruction or lack of synthesis
in hepatocellular disease. Not useful when only slightly prolonged.
Corrected within 24–48 hrs by parenteral administration of vitamin K (10 mg/day for 3
days) in obstructive but not in hepatocellular disease. Failure to correct
suggests poor prognosis; extensive hepatic necrosis should be considered.
Markedly prolonged PT is a good index of severe liver cell damage in hepatitis and
cirrhosis and may herald onset of fulminant hepatic necrosis.

Serum gamma globulin

Tends to increase with most forms of chronic liver disease.
Increases are not specific; found in other chronic inflammatory and neoplastic diseases.
Moderate increases (e.g., >3 gm/dL) are suggestive of chronic active hepatitis; marked
increases are suggestive of autoimmune chronic hepatitis.
Polyclonal increases in IgG and IgM are found in most cases of cirrhosis.
Increased IgM alone may suggest primary biliary cirrhosis.
Increased IgA may occur in alcoholic cirrhosis.
Immunoglobulins are usually normal in obstructive jaundice.

Serum albumin is slow to reflect liver damage.

Is usually normal in hepatitis and cholestasis.
Increase toward normal by 2–3 gm/dL in treatment of cirrhosis implies improvement and
more favorable prognosis than if no increase with therapy.
Some patients do not present the usual pattern.
Liver function test abnormalities may occur in systemic diseases, e.g., SLE, sarcoidosis,
TB, SBE, brucellosis, sickle cell disease.
A confusing pattern may occur in mixed forms of jaundice (e.g., sickle cell disease
producing hemolysis and complicated by pigment stones causing duct
obstruction).