Liver Enzyme Abnormalities:What to Do for the Patient

Authors: 

By ALLEN L. GINSBERG, MD

You routinely order laboratory screening
panels, including serum liver enzyme
measurements, for nearly every
patient who has a complete physical
examination or who is seen for any of
a host of other complaints. If you find
abnormal liver enzyme levels, your familiarity
with the common causes and
the settings in which they occur may
enable you to avoid costly diagnostic
studies or biopsy.

In this article, I present brief case
histories of patients who have similar
liver enzyme abnormalities but quite
dissimilar clinical backgrounds. These
differences can help guide you in the
interpretation of laboratory findings in
your own patients.

AN APPROACH
TO INTERPRETING LIVER
ENZYME ELEVATIONS

I find it helpful to divide patients
with liver enzyme deviations into 2 categories,
according to the predominant
elevation: alkaline phosphatase or the
transaminases—aspartate aminotransferase
(AST) and alanine aminotransferase
(ALT). When alkaline
phosphatase elevations are the main
feature, patients generally have either
cholestatic disease (with bile duct injury
or obstruction) or infiltrative disease—
neoplastic or granulomatous
(eg, sarcoidosis or tuberculosis).
When transaminase elevation is the
predominant abnormality, the usual
cause is hepatocellular injury—typified
by viral hepatitis, autoimmune hepatitis,
or injury from medications or toxins
(eg, halothane(, acetaminophen, or
poisonous mushrooms).

An alkaline phosphatase elevation
can be induced by liver or bone disease.
When it arises from the liver, the
other liver enzymes, such as AST and
ALT, are usually mildly elevated as
well; it is unusual for them to be completely
normal. Bone disease, however,
cannot account for even mild AST or
ALT elevation.

γ-Glutamyl transpeptidase (GGT)
levels tend to parallel alkaline phosphatase
elevations that stem from the
liver. Measurement of GGT can be a
useful confirmatory test, but it is an inducible
enzyme. Its levels rise (in the
absence of liver disease) in persons
who are accustomed to drinking excessive
quantities of alcohol or who
take certain medications, such as phenobarbital(
or phenytoin(.1,2 Some patients
have a mixed (cholestatic and
hepatocellular) injury, but most can be
categorized in the above manner.

PREDOMINANT
ALKALINE PHOSPHATASE
ELEVATION

Let us consider the cases of 8 patients,
all of whom have the same abnormal
liver enzyme levels: AST, 75
U/L (normal, 5 to 35 U/L); ALT, 90
U/L (normal, 5 to 40 U/L); and alkaline
phosphatase, 450 U/L (normal,
less than 85 U/L). (These values are
considered the norm in my laboratory.)
With the exception of one, all patients
have total bilirubin levels of 1.3 mg/dL
(normal, up to 1.1 mg/dL). This is a
typical pattern in which the alkaline
phosphatase concentration is the predominant
abnormality. The mild or trivial
transaminase elevations strongly
suggest that the increased alkaline
phosphatase level is from liver rather
than bone.

Because this liver enzyme pattern
is inconsistent with primary hepatocellular
injury, such as that typically
seen in viral hepatitis, it would be a
waste of money to order hepatitis serologic
tests. Nevertheless, you must
consider a differential diagnosis that
includes a wide range of cholestatic
and infiltrative disorders (Table).

  Table — Common causes of
hepatic alkaline
phosphatase elevation
Extrahepatic obstruction
Choledocholithiasis
Carcinoma: head of pancreas,
ampulla of Vater,
cholangiocarcinoma
Pancreatitis
 

Intrahepatic cholestasis
Drugs: chlorpromazine(, erythromycin(,
anabolic and contraceptive
steroids, propylthiouracil(,
amoxicillin(-clavulanate
Primary biliary cirrhosis
Sclerosing cholangitis
 

Infiltrative disorders
Metastatic malignancy
Sarcoidosis
Infections: eg, tuberculosis,
histoplasmosis, cytomegalovirus
infection, mononucleosis
 

Not every patient, of course, requires
extensive evaluation with invasive
radiologic studies or liver biopsy.
Consider first the clinical setting in
which the abnormalities occur. Information
garnered from the history and
physical examination will enable you to
focus on the likely diagnosis, and only
one or two confirmatory tests may be
required.

Case 1:
Young, Asymptomatic Woman

During the course of a routine
physical examination, a 30-year-old
African American woman is found to
have the following liver enzyme levels:
AST, 75 U/L; ALT, 90 U/L; alkaline
phosphatase, 450 U/L. Her serum bilirubin
level is 1.3 mg/dL. She is asymptomatic
and is taking no medications.

An infiltrative disorder, such as
sarcoidosis, rarely causes symptoms,
yet it often produces this enzyme pattern.
In this setting, obtain a chest film.
The finding of bilateral hilar adenopathy
might suffice to diagnose sarcoidosis
(which occurs 10 times more frequently
in black persons). Some physicians
might also look for an elevation in
serum angiotensin-converting enzyme.
If still in doubt, they might perform a
liver biopsy; in the case of sarcoidosis,
this would almost certainly show noncaseating
granulomas (Figure).

If the chest film shows no abnormalities,
consider the possibility of the
earliest stage of primary biliary cirrhosis—
a rare disorder found more
often in middle-aged women (see Case
5). Abnormal liver enzyme concentrations
(predominantly an increase in alkaline
phosphatase) in a young woman
who is asymptomatic is now a common
presentation for primary binary
cirrhosis. A positive test for antimitochondrial
antibodies would strongly
support this diagnosis.

Case 2:
Ill, Feverish College Student

A 20-year-old college student is
feverish and has a sore throat and cervical
lymphadenopathy. Serum levels
include AST, 75 U/L; ALT, 90 U/L; alkaline
phosphatase, 450 U/L; and bilirubin,
1.3 mg/dL.

In this setting, the diagnosis is almost
certainly mononucleosis or a re-
lated viral disease, such as cytomegalovirus
(CMV) infection. You may
find that her spleen is palpable, and
you should expect to see atypical lymphocytes
on a peripheral smear.
A spot test for mononucleosis or an
Epstein-Barr virus titer should be
diagnostic.

Mononucleosis commonly produces
this liver enzyme pattern. The
characteristic predominant alkaline
phosphatase elevation is presumed to
be caused by sinusoidal infiltration
with atypical lymphocytes.3 No additional
studies should be necessary.

Case 3:
Woman With Acute
Abdominal Pain

A 40-year-old woman seen in the
emergency department has had severe
right upper quadrant pain for the
past 3 hours. Her blood studies reveal
AST, 75 U/L; ALT, 90 U/L; alkaline
phosphatase, 450 U/L; and bilirubin,
1.3 mg/dL.

Numbers 1, 2, and 3 on your differential
diagnosis should be cholelithiasis,
which should be confirmed with
an ultrasonogram. If no gallstones are
visualized (small stones may be
missed on the ultrasonogram or CT
scan), but this patient continues to
have similar attacks, cholecystectomy—
with operative cholangiogram or
preoperative endoscopic retrograde
cholangiopancreatography (ERCP)—
will still be necessary.

Case 4:
HIV-positivity, Low-grade Fever,
Weight Loss

A 30-year-old man who is HIVpositive
has had a low-grade fever and
weight loss for several weeks. His liver
enzyme studies are as follows: AST, 75
U/L; ALT, 90 U/L; alkaline phosphatase,
450 U/L. His serum bilirubin
level is 1.3 mg/dL.

Until it is proved otherwise, abnormal
liver enzyme levels in an HIVpositive
patient are consicaused by an opportunistic infection
(eg, tuberculosis, candidiasis, CMV
infection), which may involve the
liver. A drug reaction must also be
considered.

Moreover, HIV-positive patients
are susceptible to bile duct infection
caused by Microsporidia, Cryptosporidium,
or CMV.4,5 Obtain a CT scan
to search for focal lesions in the liver
and bile duct dilation. A liver biopsy
may be necessary to identify the
pathogen.

Case 5:
Middle-aged Woman With
Pruritus and Xanthelasma

A 40-year-old woman complains
of pruritus, and you note that she has
xanthelasma. Her serum values include
AST, 75 U/L; ALT, 90 U/L; alkaline
phosphatase, 450 U/L; and bilirubin,
1.3 mg/dL.

This is the classic presentation of
primary biliary cirrhosis. As previously
mentioned, this almost always affects
middle-aged women. You would
expect this patient to test strongly positive
for antimitochondrial antibody. If
this antibody is absent, have her bile
ducts evaluated by means of ERCP or
percutaneous transhepatic cholangiography.
Patients with primary biliary cirrhosis
benefit from therapy with ursodeoxycholic
acid.6

Case 6:
Enlarged, Nodular Liver and
Anemia in Older Man

A 60-year-old man complains of
decreased energy. His liver is large,
hard, and nodular. His hematocrit is
29%; mean corpuscular volume, 60 fL;
stool test, positive for occult blood. The
patient’s liver enzyme levels are AST,
75 U/L; ALT, 90 U/L; alkaline phosphatase,
450 U/L. His serum bilirubin
level is 1.3 mg/dL.

These findings immediately suggest
colon cancer with metastasis to
the liver. Cancer in the cecum and
right side of the colon commonly presents
with occult blood in the stools
and iron deficiency anemia. This patient’s
liver enzyme pattern is typical of
metastatic infiltration of the hepatic
parenchyma. The diagnosis can be
confirmed with colonoscopy.

Case 7:
Young Man With
Ulcerative Colitis

A 30-year-old man with ulcerative
colitis in remission is receiving sulfasalazine(
maintenance therapy. His
serum values include AST, 75 U/L;
ALT, 90 U/L; alkaline phosphatase,
450 U/L; and bilirubin, 1.3 mg/dL.

This is a textbook case of sclerosing
cholangitis. Although it is
seen in association with ulcerative
colitis, this condition does not correlate
with the activity or extent of colitis.
The diagnosis can be confirmed
with ERCP.

Case 8:
Elderly Woman With Jaundice

Painless jaundice develops in a
70-year-old woman. She had a sinus infection
a month earlier, for which she
was given amoxicillin-clavulanate. Her
liver enzyme values are AST, 75 U/L;
ALT, 90 U/L; and alkaline phosphatase,
450 U/L. Her serum bilirubin
level is 6 mg/dL.

When you find clinical and laboratory
evidence of cholestasis in an elderly
patient, you must consider malignancy
as well as drug-induced
cholestasis. Painless jaundice associated
with this liver enzyme profile constitutes
a classic presentation of cancer
of the head of the pancreas.

Remember, however, that medications
(typically phenothiazines) may
also produce this clinical and laboratory
picture. Amoxicillin-clavulanate occasionally
causes intrahepatic cholestasis,
which may appear even after the
drug is discontinued.7 Obtain an ultrasonogram
or CT scan of the liver and
pancreas to exclude tumor in the head
of the pancreas and/or bile duct dila-
tion. If there is any doubt, ERCP may
be necessary.

PREDOMINANT
TRANSAMINASE
ELEVATION

AST and ALT elevations can be
marked or mild. Very high levels usually
indicate acute hepatocellular
necrosis, as seen in viral- or drug-induced
hepatic injury. Extremely high
levels (5000 to 10,000 U/L or higher)
suggest an overdose of acetaminophen.8 As you will see in the following
4 cases, the laboratory data and the
clinical history often point to the correct
diagnosis.

Case 9:
Sudden Illness in Day-care Teacher

A 30-year old teacher in a day-care
center abruptly becomes feverish, with
a temperature of 38.9ºC (102ºF); she suffers
headache and myalgias, followed by
nausea and anorexia. The fever subsides
after 48 hours and she feels better,
but then she notices that her urine is
dark and her scleras are yellow. Her
liver enzyme levels are AST, 1200 U/L;
ALT, 1500 U/L; and alkaline phosphatase,
150 U/L. Her serum bilirubin
concentration is 5 mg/dL.

This is a truly representative case
of hepatitis A, epidemics of which have
been reported in day-care centers. In
contrast to other forms of viral hepatitis,
hepatitis A typically presents with
the sudden onset of a flu-like illness
featuring headache, fever, and myalgias.
The appropriate confirmatory test
is IgM antibody to hepatitis A, an acute
phase reactant. Other hepatitis serologic
tests would be superfluous.

Case 10:
Arthritis, Nausea, and Anorexia
in Homosexual Man

A 30-year-old man describes the
recent occurrence of arthritis in his fingers
and knees and a rash on his legs.
Over the following 2 weeks, he experiences
an insidious onset of nausea and
anorexia. The patient then notes that
his urine is dark and the whites of his
eyes are yellow. His serum values include
AST, 1200 U/L; ALT, 1500 U/L;
alkaline phosphatase, 150 U/L; and
bilirubin, 5 mg/dL.

Here we see a typical case of hepatitis
B, which may be sexually transmitted
and is frequently encountered
among male homosexuals. Extraintestinal
manifestations, such as arthritis
and vasculitis, are common in the
late incubation period. The diagnosis is
confirmed by detection of the hepatitis
B surface antigen.

Case 11:
Arthralgias and Amenorrhea
in Young Woman

A 30-year-old woman complains
of arthralgias and amenorrhea. Her
liver enzyme pattern includes AST, 200
U/L; ALT, 200 U/L; and alkaline phosphatase,
120 U/L. Her serum bilirubin
concentration is 1.2 mg/dL.

The cause of such moderate
transaminase evaluation should be
identified if possible, whether or not
the patient has symptoms. The abnormality
is usually chronic. Document
these abnormal transaminase levels if
they persist for more than 3 months.

In this patient, the diagnosis is autoimmune
chronic hepatitis, which generally
occurs in young women and commonly
presents with arthralgias and/or
amenorrhea. Hyperglobulinemia is
common, and hypersplenism may be
present. Tests for fluorescent antinuclear
antibodies and smooth muscle antibodies
are likely to be positive. Corticosteroid
therapy, often combined with azathioprine(, may be lifesaving.9 The
differential diagnosis includes chronic
hepatitis C, drug-induced liver injury,
and such hereditary metabolic disorders
as Wilson disease, hemochromatosis,
and α1-antitrypsin deficiency.

Case 12:
Alcohol(-induced Liver Injury

A 35-year-old bartender undergoes
routine blood studies. Values include
AST, 150 U/L; ALT, 60 U/L; al-
kaline phosphatase, 85 U/L; and GGT,
300 U/L (normal, 5 to 40 U/L).

Although the patient denies
drinking heavily, alcohol-induced liver
injury is the obvious diagnosis. In
most patients thus affected, the ALT
value is normal or only minimally elevated.
The AST level is usually more
than twice that of the ALT, but it is
below 300 U/L in over 95% of cases.10,11
The GGT elevation is induced by alcohol
and is invariably marked. These
liver enzyme values suffice for the diagnosis;
it is unnecessary to order a
liver biopsy or any other tests.


References: 


1. Whitfield JB, Moss DW, Neale G, et al. Changes
in plasma y-glutamyl transpeptidase activity associated
with alterations in drug metabolism in man. Br
Med J. 1973;1:316-318.
2. Davidson DC, McIntosh WB, Ford JA. Assessment
of plasma y-glutamyl transpeptidase activity
and urinary D-glucaric acid excretion as indices
of enzyme induction. Clin Sci Mol Med. 1974;47:
279-283.
3. Shuster F, Ognibene AI. Dissociation of serum
bilirubin and alkaline phosphatase in infectious
mononucleosis. JAMA. 1969;209:267-268.
4. Cello JP. Acquired immunodeficiency syndrome
cholangiopathy: spectrum of disease. Am J Med.
1989;86:539-546.
5. Beaugerie L, Teilhoc MF, Deluol AM, et al. Cholangiopathy
associated with Microsporidia infection
of the common bile duct mucosa in the patient with
HIV infection. Ann Intern Med. 1992;117:401-402.
6. Poupon RE, Poupon R, Balkau B, et al. Ursodiol
for the long-term treatment of primary biliary cirrhosis.
N Engl J Med. 1994;330:342-347.
7. Reddy KR, Brilliant P, Schiff EF, et al. Amoxicillin/
clavulanic acid potassium-associated cholestasis.
Gastroenterology. 1989;96:1135-1141.
8. Zimmerman HJ. Hepatotoxicity. New York: Appleton-
Century-Crofts; 1978:288.
9. Johnson PJ, McFarlane IG, Williams R. Azathioprine
for long-term maintenance of remission in autoimmune
hepatitis. N Engl J Med. 1995;333:958-963.
10. Bradus S, Korn RJ, Chomet B, Zimmerman HJ.
Hepatic function and serum enzyme levels in association
with fatty metamorphosis of the liver. Am J
Med Sci. 1963;246:69-75.
11. Zimmerman HJ, Seeff LB. Enzymes in hepatic
disease. In: Coodley EL, ed. Diagnostic Enzymology.
Philadelphia: Lea & Febiger; 1970:1-38.