Author/s: David E. Johnston
Issue: April 15, 1999
A number of pitfalls can be encountered in the interpretation
of common blood liver function tests. These tests can be normal
in patients with chronic hepatitis or cirrhosis. The normal
range for aminotransferase levels is slightly higher in males,
nonwhites and obese persons. Severe alcoholic hepatitis is
sometimes confused with cholecystitis or cholangitis.
Conversely, patients who present soon after passing common bile
duct stones can be misdiagnosed with acute hepatitis because
aminotransferase levels often rise immediately, but alkaline
phosphatase and g-glutamyltransferase levels do not become
elevated for several days. Asymptomatic patients with isolated,
mild elevation of either the unconjugated bilirubin or the g-glutamyltransferase
value usually do not have liver disease and generally do not
require extensive evaluation. Overall hepatic function can be
assessed by applying the values for albumin, bilirubin and
prothrombin time in the modified Child-Turcotte grading system.
The commonly used liver function tests (LFTs) primarily
assess liver injury rather than hepatic function. Indeed, these
blood tests may reflect problems arising outside the liver, such
as hemolysis (elevated bilirubin level) or bone disease
(elevated alkaline phosphatase [AP] level).
Abnormal LFTs often, but not always, indicate that something
is wrong with the liver, and they can provide clues to the
nature of the problem. However, normal LFTs do not always mean
that the liver is normal. Patients with cirrhosis and bleeding
esophageal varices can have normal LFTs. Of the routine LFTs,
only serum albumin, bilirubin and prothrombin time (PT) provide
useful information on how well the liver is functioning.
The general subject of LFTs1,2 and the differential diagnosis
of abnormal LFTs in asymptomatic patients3-5 have been well
reviewed. This article discusses some common pitfalls in the
interpretation of LFTs. Hints for interpreting these tests are
presented in Table 1.
Markers of Hepatocellular Injury
The most commonly used markers of hepatocyte injury are
aspartate aminotransferase (AST, formerly serum
glutamic-oxaloacetic transaminase [SGOT]) and alanine
aminotransferase (ALT, formerly serum glutamate-pyruvate
transaminase [SGPT]). While ALT is cytosolic, AST has both
cytosolic and mitochondrial forms.
Hepatocyte necrosis in acute hepatitis, toxic injury or
ischemic injury results in the leakage of enzymes into the
circulation. However, in chronic liver diseases such as
hepatitis C and cirrhosis, the serum ALT level correlates only
moderately well with liver inflammation. In hepatitis C, liver
cell death occurs by apoptosis (programmed cell death) as well
as by necrosis. Hepatocytes dying by apoptosis presumably
synthesize less AST and ALT as they wither away. This probably
explains why at least one third of patients infected with
hepatitis C virus have persistently normal serum ALT levels
despite the presence of inflammation on liver biopsy.6,7
Patients with cirrhosis often have normal or only slightly
elevated serum AST and ALT levels. Thus, AST and ALT lack some
sensitivity in detecting chronic liver injury. Of course, AST
and ALT levels tend to be higher in cirrhotic patients with
continuing inflammation or necrosis than in those without
continuing liver injury.
As markers of hepatocellular injury, AST and ALT also lack
some specificity because they are found in skeletal muscle.
Levels of these aminotransferases can rise to several times
normal after severe muscular exertion or other muscle injury, as
in polymyositis,8 or in the presence of hypothyroidism, which
can cause mild muscle injury and the release of
aminotransferases. In fact, AST and ALT were once used in the
diagnosis of myocardial infarction.
Slight AST or ALT elevations (within 1.5 times the upper
limits of normal) do not
necessarily indicate liver disease. Part of this ambiguity
has to do with the fact that unlike the values in many other
biochemical tests, serum AST and ALT levels do not follow a
normal bell-shaped distribution in the population.9 Instead, AST
and ALT values have a skewed distribution characterized by a
long "tail" at the high end of the scale (Figure 1).5 For
example, the mean values for ALT are very similar from one
population to another, but the degree to which the distribution
is skewed varies by gender and ethnicity. The ALT distributions
in males and nonwhites (i.e., blacks and Hispanics) tend to have
a larger tail at the high end, so that more values fall above
the upper limits of normal set for the average population.10,11
AST and ALT values are higher in obese patients, probably
because these persons commonly have fatty livers.12 ALT levels
have been noted to decline with weight loss.13 Depending on the
physician's point of view, the upper limits of normal for AST
and ALT levels could be set higher for more obese persons.
Rare individuals have chronically elevated AST levels because
of a defect in clearance of the enzyme from the circulation.14
For both AST and ALT, the average values and upper limits of
normal in patients undergoing renal dialysis are about one half
of those found in the general population.15 Mild elevations of
ALT or AST in asymptomatic patients can be evaluated efficiently
by considering alcohol abuse, hepatitis B, hepatitis C and
several other possible diagnoses (Table 2).5
Various liver diseases are associated with typical ranges of
AST and ALT levels (Figure 2). ALT levels often rise to several
thousand units per liter in patients with acute viral hepatitis.
The highest ALT levels-often more than 10,000 U per L-are
usually found in patients with acute toxic injury subsequent to,
for example, acetaminophen overdose or acute ischemic insult to
the liver. AST and ALT levels usually fall rapidly after an
acute insult.
Lactate dehydrogenase (LDH) is less specific than AST and ALT
as a marker of hepatocyte injury. However, it is worth noting
that LDH is disproportionately elevated after an ischemic liver
injury.16
It is especially important to remember that in patients with
acute alcoholic hepatitis, the serum AST level is almost never
greater than 500 U per L and the serum ALT value is almost never
greater than 300 U per L. The reasons for these limits on AST
and ALT elevations are not well understood. In typical viral or
toxic liver injury, the serum ALT level rises more than the AST
value, reflecting the relative amounts of these enzymes in
hepatocytes. However, in alcoholic hepatitis, the ratio of AST
to ALT is greater than 1 in 90 percent of patients and is
usually greater than 2.17 The higher the AST-to-ALT ratio, the
greater the likelihood that alcohol is contributing to the
abnormal LFTs. In the absence of alcohol intake, an increased
AST-to-ALT ratio is often found in patients with cirrhosis.
The elevated AST-to-ALT ratio in alcoholic liver disease
results in part from the depletion of vitamin B6 (pyridoxine) in
chronic alcoholics.18 ALT and AST both use pyridoxine as a
coenzyme, but the synthesis of ALT is more strongly inhibited by
pyridoxine deficiency than is the synthesis of AST. Alcohol also
causes mitochondrial injury, which releases the mitochondrial
isoenzyme of AST.
Patients with alcoholic hepatitis can present with jaundice,
abdominal pain, fever and a minimally elevated AST value,
thereby leading to a misdiagnosis of cholecystitis. This is a
potentially fatal mistake given the high surgical mortality rate
in patients with alcoholic hepatitis.19
Markers of Cholestasis
Cholestasis (lack of bile flow) results from the blockage of
bile ducts or from a disease that impairs bile formation in the
liver itself. AP and g- glutamyltransferase (GGT) levels
typically rise to several times the normal level after several
days of bile duct obstruction or intrahepatic cholestasis. The
highest liver AP elevations-often greater than 1,000 U per L, or
more than six times the normal value-are found in diffuse
infiltrative diseases of the liver such as infiltrating tumors
and fungal infections.
Diagnostic confusion can occur when a patient presents within
a few hours after acute bile duct obstruction from a gallstone.
In this situation, AST and ALT levels often reach 500 U per L or
more in the first hours and then decline, whereas AP and GGT
levels can take several days to rise.
Both AP and GGT levels are elevated in about 90 percent of
patients with cholestasis.20 The elevation of GGT alone, with no
other LFT abnormalities, often results from enzyme induction by
alcohol or aromatic medications in the absence of liver disease.
The GGT level is often elevated in persons who take three or
more alcoholic drinks (45 g of ethanol or more) per day.21 Thus,
GGT is a useful marker for immoderate alcohol intake.
Phenobarbital, phenytoin (Dilantin) and other aromatic drugs
typically cause GGT elevations of about twice normal. A mildly
elevated GGT level is a typical finding in patients taking
anticonvulsants and by itself does not necessarily indicate
liver disease.22,23
Serum AP originates mostly from liver and bone, which produce
slightly different forms of the enzyme. The serum AP level rises
during the third trimester of pregnancy because of a form of the
enzyme produced in the placenta. When serum AP originates from
bone, clues to bone disease are often present, such as recent
fracture, bone pain or Paget's disease of the bone (often found
in the elderly). Like the GGT value, the AP level can become
mildly elevated in patients who are taking phenytoin.22,23
If the origin of an elevated serum AP level is in doubt, the
isoenzymes of AP can be separated by electrophoresis. However,
this process is expensive and usually unnecessary because an
elevated liver AP value is usually accompanied by an elevated
GGT level, an elevated 5[acute accent]-nucleotidase level and
other LFT abnormalities.
In one study,24 isolated AP elevations were evaluated in an
unselected group of patients at a Veterans Affairs hospital.
Most mild AP elevations (less than 1.5 times normal) resolved
within six months, and almost all greater elevations had an
evident cause that was found on routine clinical evaluation.
Persistently elevated liver AP values in asymptomatic
patients, especially women, can be caused by primary biliary
cirrhosis, which is a chronic inflammatory disorder of the small
bile ducts. Serum antimitochondrial antibody is positive in
almost all of these patients.
Indicators of How Well the Liver Functions
Bilirubin
Bilirubin results from the enzymatic breakdown of heme.
Unconjugated bilirubin is conjugated with glucuronic acid in
hepatocytes to increase its water solubility and is then rapidly
transported into bile. The serum conjugated bilirubin level does
not become elevated until the liver has lost at least one half
of its excretory capacity. Thus, a patient could have
obstruction of either the left or right hepatic duct without a
rise in the bilirubin level.
Because the secretion of conjugated bilirubin into bile is
very rapid in comparison with the conjugation step, healthy
persons have almost no detectable conjugated bilirubin in their
blood. Liver disease mainly impairs the secretion of conjugated
bilirubin into bile. As a result, conjugated bilirubin is
rapidly filtered into the urine, where it can be detected by a
dipstick test. The finding of bilirubin in urine is a
particularly sensitive indicator of the presence of an increased
serum conjugated bilirubin level.
In many healthy persons, the serum unconjugated bilirubin is
mildly elevated to a concentration of 2 to 3 mg per dL (34 to 51
[micro sign]mol per L) or slightly higher, especially after a
24-hour fast. If this is the only LFT abnormality and the
conjugated bilirubin level and complete blood count are normal,
the diagnosis is usually assumed to be Gilbert syndrome, and no
further evaluation is required. Gilbert syndrome was recently
shown to be related to a variety of partial defects in uridine
diphosphate-glucuronosyl transferase, the enzyme that conjugates
bilirubin.25
Mild hemolysis, such as that caused by hereditary
spherocytosis and other disorders, can also result in elevated
unconjugated bilirubin values, but hemolysis is not usually
present if the hematocrit and blood smear are normal. The
presence of hemolysis can be confirmed by testing other markers,
such as haptoglobin, or by measuring the reticulocyte count.
Severe defects in bilirubin transport and conjugation can
lead to markedly elevated unconjugated bilirubin levels, which
can cause serious neurologic damage (kernicterus) in infants.
However, no serious form of liver disease in adults causes
elevation of unconjugated bilirubin levels in the blood without
also causing elevation of conjugated bilirubin values.
When a patient has prolonged, severe biliary obstruction
followed by the restoration of bile flow, the serum bilirubin
level often declines rapidly for several days and then slowly
returns to normal over a period of weeks. The slow phase of
bilirubin clearance results from the presence of delta-bilirubin,
a form of bilirubin chemically attached to serum albumin.26
Because albumin has a half-life of three weeks, delta-bilirubin
clears much more slowly than bilirubin-glucuronide. Clinical
laboratories can measure delta-bilirubin concentrations, but
such measurements are usually unnecessary if the physician is
aware of the delta-bilirubin phenomenon.
Albumin
Although the serum albumin level can serve as an index of
liver synthetic capacity, several factors make albumin
concentrations difficult to interpret.27 The liver can
synthesize albumin at twice the healthy basal rate and thus
partially compensate for decreased synthetic capacity or
increased albumin losses. Albumin has a plasma half-life of
three weeks; therefore, serum albumin concentrations change
slowly in response to alterations in synthesis. Furthermore,
because two thirds of the amount of body albumin is located in
the extravascular, extracellular space, changes in distribution
can alter the serum concentration.
In practice, patients with low serum albumin concentrations
and no other LFT abnormalities are likely to have a nonhepatic
cause for low albumin, such as proteinuria or an acute or
chronic inflammatory state. Albumin synthesis is immediately and
severely depressed in inflammatory states such as burns, trauma
and sepsis, and it is commonly depressed in patients with active
rheumatic disorders or severe end-stage malnutrition. In
addition, normal albumin values are lower in pregnancy.
Prothrombin time
The liver synthesizes blood clotting factors II, V, VII, IX
and X. The prothrombin time (PT) does not become abnormal until
more than 80 percent of liver synthetic capacity is lost. This
makes PT a relatively insensitive marker of liver dysfunction.
However, abnormal PT prolongation may be a sign of serious liver
dysfunction. Because factor VII has a short half-life of only
about six hours, it is sensitive to rapid changes in liver
synthetic function. Thus, PT is very useful for following liver
function in patients with acute liver failure.
An elevated PT can result from a vitamin K deficiency. This
deficiency usually occurs in patients with chronic cholestasis
or fat malabsorption from disease of the pancreas or small
bowel. A trial of vitamin K injections (e.g., 5 mg per day
administered subcutaneously for three days) is the most
practical way to exclude vitamin K deficiency in such patients.
The PT should improve within a few days.
Blood ammonia
Measurement of the blood ammonia concentration is not always
useful in patients with known or suspected hepatic
encephalopathy. Ammonia contributes to hepatic encephalopathy;
however, ammonia concentrations are much higher in the brain
than in the blood and therefore do not correlate well.28
Furthermore, ammonia is not the only waste product responsible
for encephalopathy. Thus, blood ammonia concentrations show only
a mediocre correlation with the level of mental status in
patients with liver disease. It is not unusual for the blood
ammonia concentration to be normal in a patient who is in a coma
from hepatic encephalopathy.
Blood ammonia levels are best measured in arterial blood
because venous concentrations can be elevated as a result of
muscle metabolism of amino acids. Blood ammonia concentrations
are most useful in evaluating patients with stupor or coma of
unknown origin. It is not necessary to evaluate blood ammonia
levels routinely in patients with known chronic liver disease
who are responding to therapy as expected.
Grading Liver Function by Child-Turcotte Class
In communicating among themselves, many physicians use the
Child-Turcotte class as modified by Pugh, often termed the
"Child class," to convey information about overall liver
function and prognosis (Table 3).29 This grading system can be
used to predict overall life expectancy and surgical mortality
in patients with cirrhosis and other liver diseases.30
For elective general abdominal surgery, perioperative
mortality is in the neighborhood of several percent for patients
who fall into the Child class A, 10 to 20 percent for those in
class B and approximately 50 percent for those in class C.31
These percentages must be balanced by prognostic considerations
when transplantation becomes an option. The presence of
cirrhosis by itself is not an indication for liver
transplantation, and transplantation is rarely performed in
patients who fall into Child class A. For example, the 10-year
survival rate is as high as 80 percent in patients with
hepatitis C and cirrhosis who have Child class A liver function
and no variceal bleeding.32 However, once patients with any type
of liver disease fall into the Child-Turcotte class B or class C
category, survival is significantly reduced and transplantation
should be considered.
REFERENCES
1.Kaplan MM. Laboratory tests. In: Schiff L, Schiff ER, eds.
Diseases of the liver. 7th ed. Philadelphia: Lippincott,
1993:108-44.
2.Kamath PS. Clinical approach to the patient with abnormal
liver function test results. Mayo Clin Proc 1996;71:1089-94.
