Evaluating asymptomatic patients with mildly elevated

R E V I E W

Z O B A I R M . Y O U N O S S I , M D , M P H Associate Staff Physician, Department of Gastroenterology, Cleveland Clinic.

Evaluating asymptomatic patients with mildly elevated liver enzymes

ABSTRACT

Because elevated liver enzymes are found in 1 % to 4% of asymptomatic persons, extensive evaluation of all abnormal tests would expose many patients to undue risks and medical costs. On the other hand, not evaluating minor elevations of liver enzymes could result in missing the early diagnosis of potentially treatable disorders. This review discusses likely causes of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase levels and provides algorithms for evaluating abnormal liver enzyme values in apparently healthy patients in the primary care setting.

KEY POINTS Hepat i t is C virus is the most common cause o f chronic liver disease and cirrhosis, and the main ind icat ion for liver t ransp lan ta t i on in the Uni ted States.

Suspect a lcohol ic l iver disease w h e n a pa t ien t exhibi ts add ic t ive behav ior and w h e n the aspartate and a lanine aminot rans ferase levels are elevated, w i t h t he aspar tate aminot rans ferase level higher.

If med ica t ion or a lcohol is a suspected cause of e levated aminot rans ferase levels, retest the levels af ter 6 to 8 weeks of abst inence.

N S E E M I N G L Y H E A L T H Y P A T I E N T S , abnor-mal liver enzymes levels chal lenge

even experienced clinicians in deciding what further evaluation to pursue. Over the past decade, automated laboratory testing has made serum liver enzyme levels easy to obtain, and consequently, testing has increased—and so have incidental abnormal findings. A n estimated 1 % to 4 % of asymp-tomatic people have abnormal liver enzyme levels when screened using standard bio-chemistry panels.1

These findings can lead to extensive eval-uations that can be costly, anxiety-provoking, and risky, especially if they lead to unneces-sary invasive procedures such as a liver biopsy or endoscopic retrograde cholangiopancre-atography.

N o t all asymptomatic persons with a sin-gle, isolated mild elevation in a liver enzyme have underlying liver disease or require extensive evaluation. Factors to consider in evaluating these patients include:

• T h e patient's overall health. • T h e prevalence of different liver disor-

ders in the community. • T h e duration and pattern of enzyme

elevation. • Whether therapy is available. • T h e costs and risks associated with

additional evaluation. This review discusses the most likely caus-

es of elevated aminotransferase, alkaline phos-phatase, and gamma-glutamyl transferase lev-els. It also provides algorithms primary care providers can use to evaluate abnormal liver enzyme values in apparently healthy patients.

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PATTERMS OF LIVER ENZYME ELEVATION TABLE 1

Although the term "liver function test" is commonly used to describe liver enzyme eval-uations, the term should be reserved for bio-chemical tests that assess the functional hepatic reserve—traditionally, the albumin level and the prothrombin time.2 O n the other hand, elevated serum liver enzymes (aminotransferases, alkaline phosphatase, and gamma-glutamyl transferase) can reflect abnormalities in either liver cells or the bile duct. The emyme that is most elevated sug-gests different types of liver disease.

A m i n o t r a n s f e r a s e elevat ion suggests hepatocellular damage. Normal serum levels are < 40 U/L for aspartate aminotransferase ( A S T ) and < 50 U/L for alanine aminotrans-ferase (ALT).

Alkal ine phosphatase elevation (adult normal serum levels between 20 and 120 U/L) suggests biliary obstruction, injury to the bile duct epithelium, and cholestasis.

Gamma-glutamyl transferase elevation (normal range 0 to 50 U /L in men, 0 to 35 U/L in women) is a marker of either type of dis-ease, but the most sensitive marker of biliary tract disease.

• PREVALENCE OF LIVER DISEASES AND EVALUATION OF ELEVATED SERUM ENZYMES

Before starting an extensive evaluation of a patient with an elevated liver enzyme, one should consider the prevalence and the pre-disposing risks for different liver disorders ( T A B L E 1 ) . These epidemiologic data, plus other clinical data obtained from the history and physical examination, provide important clues to guide further investigation.

Chronic viral hepat i t i s Prevalence. Hepatitis C virus ( H C V )

infection affects an estimated 1.8% of the gen-eral population, and 14-4% of persons with ALT levels greater than 40 U /L, making it the most common cause of chronic liver disease, cirrhosis, and liver transplantation in the United States. Hepatitis B virus (HBV) infec-tion is somewhat less common: between 0.2% and 0.9% of the general population have posi-

Liver diseases: Frequency of occurrence Hepatocel lu lar diseases (aminot ransferase e levat ions p redomina te )

Common Chronic viral hepatitis Genetic hemochromatosis

(northern European descent) Alcoholic liver disease Nonalcoholic steatohepatit is Medicat ion toxicity (see T A B L E 2 )

Auto immune hepatitis Less common

Wilson's disease Alpha-1 -antitrypsin deficiency

Cho les ta t i c diseases (alkal ine phosphatase and gamma-g lu tamy l t ransferase elevat ions predominate)

Common Primary biliary cirrhosis Primary sclerosing cholangitis Neoplasms Biliary obstruction (gallstones, etc) Drug hepatotoxicity

Less common Auto immune cholangiopathy Sarcoidosis

tive reactions to H B V surface antigen. The prevalence of both viruses increases dramati-cally in the presence of risk factors (see below).

Risk factors . Risk factors include blood product transfusion, intravenous drug use, hemodialysis, and birth in an endemic region. Although both viruses can be transmitted sex-ually, H B V is more readily transmitted in this way than HCV. It should be noted that 30% to 40% of people infected with these viruses have no identifiable risk factors.

C o m m e n t s . Most patients with chronic viral hepatitis have no symptoms or only mild symptoms and minimally elevated amino-transferase levels (two to five times higher than the upper limit of normal). Given the relatively high prevalence of HCV, serologic testing for H C V should be done early in the course of evaluating a patient with chronical-ly elevated liver enzyme levels.^4

The most common chronic liver disease in the United States is chronic viral hepatitis

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L I V E R E N Z Y M E S Y O U N O S S I LJ

Medications with potential for hepatotoxicity H e p a t o c e l l u l a r a b n o r m a l i t i e s

Al lopurinol (granuloma) Azathioprine (veno-occlusive disease) Diclofenac and other nonsteroidal ant i - inf lammatory drugs Hydralazine (granuloma) Isoniazid Methotrexate (fibrosis) Methyldopa Nitrofurantoin (autoimmune-l ike) Quinidine (granuloma)

Cho les ta t i c a b n o r m a l i t i e s

Amoxic i l l in-davulanate and other penicill in derivatives Anabolic steroids Captopril Chlorpromazine Erythromycin estolate Estrogens Oral contraceptive Phenytoin (mononucleosis-like syndrome) Sulfa drugs

Fatty l iver ( w i t h or w i t h o u t hepa toce l l u l a r a b n o r m a l i t i e s )

Amiodarone (phospholipidosis) Corticosteroids Tetracycline Valproic acid

Genetic hemochromatos is Prevalence. The prevalence is 0.25% to

0.5% for people of northern European descent, of whom 1 in 10 is heterozygous and 1 in 200 to 400 is homozygous for the mutated gene.

Risk factors . Northern European ances-try is the primary risk factor. In men, the onset of disease is usually in the third and fourth decades of life, while menses protects women until menopause. Recently, mutations in a gene related to the major histocompatibility complex class I family (termed HFE) have been shown to be present in 83% to 85% of people homozygous for genetic hemochro-matosis. Although this test is currently con-sidered a research tool, it may become very useful in screening for and diagnosing this condition.

C o m m e n t s . Genetic hemochromatosis

should be considered early in the evaluation of male patients of northern European descent. Patients usually have no symptoms until iron overload causes significant end-organ damage. Phlebotomy is an extremely effective treatment for this potentially fatal disease.5

Alcohol ic l iver disease Preva lence . The prevalence varies,

depending on a variety of factors, including volume and duration of alcohol ingestion, type of liver disease, genetics, and coexistence of viral hepatitis.

Risk factors . Alcohol-related liver dis-ease can range from simple fatty liver to alco-holic hepatitis with or without cirrhosis. Cirrhosis develops in only 20% to 30% of patients who consume a substantial amount of alcohol, defined as more than a decade of 60 to 80 g/day of alcohol in men and as little as 20 to 40 g/day in women. (A standard drink contains 12 g of alcohol, equal to one 12-ounce beer, a 5-ounce glass of wine, or 1.5 ounces of distilled spirits.) Female gender, chronic viral hepatitis (especially H C V ) , genetic hemochromatosis, and certain med-ications (eg, methotrexate) potentiate the harmful effects of alcohol.

C o m m e n t s . Although cirrhosis affects less than a third of such long-term heavy drinkers, early detection and treatment can potentially reduce morbidity and early mortal-ity. Alcoholic liver disease should be suspect-ed in people whose behavior suggests an addictive personality and in those with ele-vated A L T and A S T levels in whom the A S T level is higher.6

Nonalcohol ic s teatohepat i t is ( fa t t y l iver) Prevalence. The prevalence is not well

defined, but populations at risk, such as patients with type 2 (formerly "adult-onset") diabetes, can have prevalence rates as high as 50%. It is perhaps the most common cause of mildly ele-vated liver enzymes in the United States.

Risk factors . Obesity, diabetes, hyperlipi-demia, medications ( T A B L E 2 ) , and jejunoileal bypass surgery are the major risk factors.

C o m m e n t s . Nonalcoholic steatohepatitis and steatonecrosis are terms recently coined to describe a form of fatty liver disease with a

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potentially progressive course. Although these disorders are histologically indistinguishable from alcohol-induced liver disease, their mechanism is not well understood: theories include abnormalities of lipid metabolism with increased hepatic lipid peroxidation, activated fibrocytes, and abnormal patterns of cytokine production. Data from a few limited natural history studies suggest that simple steatosis has a benign course, while nonalco-holic steatohepatitis or steatonecrosis can progress to cirrhosis in 1 0 % to 20% of patients.7 Treatment of obesity, hyperlipi-demia, and diabetes may have limited benefit but should be undertaken.

A u t o i m m u n e hepat i t i s Preva lence . T h e prevalence of autoim-

mune hepatitis depends on the geographic location and the extent of viral hepatitis in the community. In Hong Kong, only 1 % of all cases of chronic hepatitis are secondary to autoimmune hepatitis. By contrast, 3 4 % and 62% of patients with chronic hepatitis in Germany and Australia may have autoim-mune hepatitis.9 In North America , the prevalence of autoimmune hepatitis among patients with chronic liver disease is estimated to be 1 1 % to 23%. T h e incidence of autoim-mune hepatitis is about 0.69 per 100,000 indi-viduals each year in North America. In addi-tion to underlying genetic differences, selec-tion bias can explain the variability seen in these prevalence rates.

R i s k factors . Autoimmune hepatitis is predominantly seen in women.

C o m m e n t s . T h e diagnosis of autoimmune hepatitis is suspected by excluding viral causes of chronic hepatitis and by the presence of autoimmune markers such as antinuclear anti-body, smooth muscle antibody, and liver-kid-ney microsomal antibody. Treatment with immunosuppression is effective, and this diag-nosis should be considered in all individuals (especially in female patients) with chronic elevation of liver enzymes.

Pr imary b i l ia ry c i r rhosis P r e v a l e n c e . In one study of urban-

dwelling women in northeast England, the prevalence of primary biliary cirrhosis was estimated at 0.10%.8

Risk factors . Like autoimmune hepatitis, primary biliary cirrhosis is predominantly seen in women.

C o m m e n t s . Treatment of primary biliary cirrhosis with ursodeoxycholic acid improves liver enzyme levels, may lead to histological improvement and increased survival, and may also delay the need for liver transplantation.8'9

Wilson's disease Prevalence. T h e prevalence is estimated

at 1 in 30,000 in most populations. R i s k factors . A n y person younger than

age 40 with abnormal liver enzyme levels should be evaluated for Wilson's disease, even in the absence of neurologic or ocular find-ings. However, such routine screening is rarely fruitful in persons older than age 50.

C o m m e n t s . Effective therapy is available (eg, D-penicillamine, trientine, zinc). For Wilson's disease, alpha-1-antitrypsin deficien-cy, and genetic hemochromatosis, establishing the diagnosis is not only important to the indi-vidual patient, but may also be important in screening the asymptomatic members of the proband's family.10 '11

A lpha -1 -an t i t r yps in def ic iency Prevalence. Alpha-1-antitrypsin deficien-

cy occurs in 1 of every 1,600 to 1,800 live births.

Risk factors . A patient with emphysema or who has a young sibling with liver failure should undergo an investigation for alpha-1-antitrypsin deficiency, consisting of a measure-ment of the alpha-1-antitrypsin level and a genetic study to look for phenotype PiZZ.

C o m m e n t s . Liver transplantation is the only effective therapy available for the treat-ment of liver disease associated with alpha-1-antitrypsin deficiency.

Med ica t i on - re l a ted and tox in - re la ted l iver diseases Nonsteroidal anti-inflammatory drugs (NSAIDs) and penicillin-derived antibiotics are the drugs that most commonly cause abnormal serum liver enzyme levels. T h e mechanism of drug-induced liver disease ranges from induction of hepatic enzymes (caused by anticonvulsants) to allergic reac-tion, autoimmunity (nitrofurantoin), idiosyn-

NSAIDs and penicillin-derived antibiotics can cause abnormal liver enzyme levels

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LIVER E N Z Y M E S Y O U N O S S I LJ

An AST level more than twice that of the ALT suggests alcohol-induced liver damage

cratic reaction, and veno-occlusive injury. Some medications with potential for hepato-toxicity are listed in T A B L E 2 .

A variety of environmental agents can injure the liver, including vinyl chloride (fibrosis, portal hypertension, angiosarcoma), carbon tetrachloride (acute hepatocyte necro-sis), aflatoxin, and Amanita types of mush-rooms (hepatocyte necrosis).

Given the availability of over-the-counter and prescribed medications and the potential for exposure to toxins, a thorough history of exposure to such agents is crucial.12

• MILD ENZYME ELEVATIONS AS INDICATORS OF SPECIFIC DISEASES

Despite the potential importance—and the frequency—of discovering an abnormal liver enzyme level, very few well-designed prospec-tive studies have addressed this issue. Most of the information presented here comes from small retrospective studies that lack accurate information on the important causes of liver disease such as H C V infection and nonalco-holic steatohepatitis. Despite these shortcom-ings, the literature delineates three patterns of mild liver enzyme elevations, depending on which enzyme is predominantly elevated: aminotransferase, alkaline phosphatase, or gamma-glutamyl transferase.

Amino t rans fe rase e leva t i on Causes of aminotransferase elevation.

Aminotransferases are commonly used mark-ers of hepatocyte injury. A S T is found in blood cells and many tissues, including liver, muscle, brain, pancreas, and lung. A L T is a cytosolic enzyme found primarily in hepato-cytes, making it a more specific indicator of liver disease.

Acute viral hepatitis, toxins, and liver ischemia can markedly elevate serum amino-transferase levels (into the thousands). O n the other hand, these enzymes are mildly ele-vated (< 300 U/L) in nonalcoholic steatohep-atitis, chronic hepatitis, cholestatic liver con-ditions, drug-induced hepatotoxicity, and liver tumors. Because A S T is a mitochondrial enzyme and is affected by alcohol ingestion, an A S T level more than twice that of the A L T suggests hepatic damage due to alcohol.

O f note, aminotransferase elevation can also be due to nonhepatic causes; for example, muscle necrosis can result in mild elevation of these enzymes, especially A S T .

Only a few studies have documented the results of a thorough evaluation of patients with mildly elevated aminotransferase levels. Hultcrantz1 studied 149 consecutive patients with chronic, asymptomatic, mild elevations of A S T or A L T who underwent a full evalua-tion, including liver biopsy. O f these patients, 63% had "fatty liver," 20% had "chronic hepatitis," and 1 7 % had miscellaneous diag-noses. W h e t h e r patients in the "chronic hepatitis" group had H C V was not deter-mined because serologic testing was not avail-able at the time.

Friedman et al1 3 studied 100 healthy blood donors with an elevated A L T level and found that in 33% of patients the elevation occurred once, in 36% it was intermittent, and in 28% it was persistent. In this series, 4 5 % of patients had no diagnosis, 22% were obese (presumed to have nonalcoholic steato-hepatitis), 5% had alcoholic liver disease, 3% had "resolving hepatitis," 1 % had hemochro-matosis, and 1 % had "cytomegalovirus hepati-tis." Although these patients underwent a complete history, physical, and serologic test-ing, liver biopsies were not done to confirm the clinical diagnosis.

Hay et al14 described 47 patients with chronically elevated aminotransferases (threefold to eightfold) who underwent full evaluation and liver biopsy and who had no clinical symptoms of alcoholic, viral, or drug-induced liver disease. A diagnosis of steato-hepatitis was given in 10 patients, another 34 were diagnosed with "chronic hepatitis," and 3 had miscellaneous diagnoses. O f patients with chronic hepatitis, 16 had evidence of cir-rhosis on biopsy, and 18 tested positive for at least one autoimmune marker (antinuclear antibody or smooth muscle antibody).

T h e above studies suggest that fatty liver caused by either alcohol or nonalcoholic steatohepatitis is the major cause of mildly elevated aminotransferases. Chronic hepatitis is the other common diagnosis associated with mild elevation of aminotransferases. Two major drawbacks of these studies include lack of data on H C V serology in patients with the




Evaluating an isolated, mildly elevated aminotransferase level

Eleva ted a l a n i n e a m i n o t r a n s f e r a s e o r a s p a r t a t e a m i n o t r a n s f e r a s e

I His tory a n d physical e x a m

+

Repeat a n d c o n f i r m e l e v a t i o n t

- > - Establ ish d iagnos is

Establ ish s t a g i n g

No rma l

Test f o r hepa t i t i s C v i rus

v

Chronic hepatit is C

Aminotransferase levels still elevated

at 6 months

Disease-specif ic m a r k e r

A b n o r m a l I

Disease suspec ted (risk f a c t o r s p resen t )

f Nonalcoholic

steatohepati t is I

Ultrasound or computed tomography

Au to immune

Test fo r an t inudear ant ibody,

smooth muscle ant ibody

Wilson's disease

I Ceruloplasmin

and slit lamp exam

Hemochromatosis

Ferritins, % Iron

saturat ion

1 Viral

hepati t is I

Test f o r hepatit is C virus,

hepatit is B surface ant igen

Alcohol- or drug-related

I Recheck af ter 6-8 weeks of abstinence

L iver b i opsy Abnorma l Normal

Fol low-up

FIGURE 1.

diagnosis of "chronic hepatitis" and a lack of uniform approach to the pathologic diagnosis of nonalcoholic steatohepatitis. With serolog-ic testing for H C V now widely available, it is possible that a substantial portion of persons with "chronic hepatitis" can further be classi-fied as having chronic hepatitis C .

Clinical workup, F I G U R E 1 shows an algo-rithm for evaluating patients with elevated aminotransferase levels on an initial examina-tion. T h e first step is to confirm the abnor-mality by repeating the blood test. It an enzyme elevation is confirmed, further inves-tigation is warranted.

A directed history and physical exami-nation can give crucial clues in the prelimi-nary workup. T h e history may disclose risk factors for:

• Viral hepatitis (intravenous drug use, natives of endemic areas of the world, blood product transfusions, etc).

• Alcohol ic liver disease. • Medication exposure. • Genetic liver disorders (family history

of liver disease). • Possible coexisting diseases (diabetes

and obesity in nonalcoholic steatohepatitis, neurologic disorders in Wilson's disease, emphysema in alpha-1-antitrypsin deficiency, thyroid disease in autoimmune hepatitis and primary biliary cirrhosis, and diabetes and impotence in generic hemochromatosis).

Although the physical signs of chronic liver disease (eg, spider angiomata, palmar ery-thema, gynecomastia) are nonspecific, some physical findings (eg, Kayser-Fleischer rings




LIVER E N Z Y M E S Y O U N O S S I LJ

Evaluating an isolated, mildly elevated alkaline phosphatase level E l e v a t e d a l k a l i n e p h o s p h a t a s e

I H i s t o r y a n d phys ica l e x a m

I C o n f i r m a n d i d e n t i f y h e p a t o b i l i a r y sou rce ,

check g a m m a g l u t a m y l t r a n s f e r a s e

- > - Establ ish d i a g n o s i s

Establ ish s t a g i n g

I N o r m a l

A l k a l i n e p h o s p h a t a s e s t i l l e l e v a t e d a t 6 m o n t h s

- C o n s i d e r — ea r l y t e s t i n g

U l t r a s o u n d -o r c o m p u t e d t o m o g r a p h y

- Bi l iary — > • Endoscopic retrograde — d i l a t a t i on cholangiopancreatography

f Primary

sclerosing cholangi t is

I Endoscopic retrograde

cholangiopancreatography

Viral hepat i t i s

I Test for

hepatitis C virus, hepatitis B

surface antigen

1 A b n o r m a l

I Disease suspec ted

(r isk f a c t o r s p resen t ) I

O b s t r u c t i o n

I T r e a t

u n d e r l y i n g cause o f

o b s t r u c t i o n

Primary b i l iary cirrhosis

I Test for

antimitochondrial antibody

Liver biopsy

} Alcoho l - or

d rug- re la ted I

Recheck after 6-8 weeks of abstinence

I

Abnormal Normal

Follow-up

F I G U R E 2. * T h e decision is based o n clinical suspicion f o r bi l iary disease vs cholestat ic disease

on slit lamp examination for Wilson's disease, hypertrophy of the second and third metacar-pophalangeal joint for hemochromatosis) sug-gest potential causes. Iron studies for middle-aged men, autoimmune markers for women, and screening for Wilson's disease in young patients are helpful when the clinical infor-mation points to one of these entities as a potential diagnosis.

If medication or alcohol is a suspected cause, aminotransferase levels should be repeated after 6 to 8 weeks of abstinence. If nonalcoholic steatohepatitis is suspected, we recommend repeating tests after treating the potential risk factor (obesity, diabetes, hyper-lipidemia) for 8 to 12 weeks. A n imaging study (ultrasound or computed tomography scan) may show increased hepatic echogenic-

ity, suggesting increased fatty infiltration, in addition to excluding most hepatic tumors.

If the clinical data obtained from the his-tory and physical examination raise clinical suspicion for a particular disease, a disease-specific marker ( F I G U R E S 1 A N D 2 ) can further help in supporting the potential diagnosis. Remember: liver biopsy remains the gold stan-dard in establishing the diagnosis for most liver disorders and is the only method cur-rently available to establish cirrhosis with important prognostic implications.15

If the history and physical do not suggest any particular condition, serologic testing for H C V should be obtained. If negative, other selected testing can be helpful (iron studies in a male patient, autoimmune markers in women, ceruloplasmin and slit lamp examina-




tion in a young individual). If the preliminary workup remains negative and the aminotrans-ferase levels remain elevated for 6 months, a liver biopsy is indicated to establish the diag-nosis. Features in the liver biopsy specimens may provide further confirmation of the diag-nosis: eg, periodic acid-Schiff-positive glob-ules in alpha-1-antitrypsin deficiency, hepatic iron index for hemochromatosis, and hepatic copper content for Wilson's disease.

A lka l i ne phospha tase e leva t ion Causes of alkaline phosphatase eleva-

tion. Alkal ine phosphatase activity has been found in multiple organs, including the liver, bones, small bowel, kidneys, and placenta. Diseases of the hepatobiliary system can result in moderately to markedly elevated alkaline phosphatase levels. A n y conditions associated with bone involvement, such as Paget's dis-ease, sarcoma, metastatic disease, hyper-parathyroidism, and rickets, can elevate the alkaline phosphatase level. Elevated gamma-glutamyl transferase in conjunction with ele-vated alkaline phosphatase usually points to a hepatobiliary source. Now rarely done, isoen-zyme fractionation of alkaline phosphatase may help further distinguish the source of the elevation and identify the liver, bone, or other organ as the predominant origin of this abnor-mality.

Hepatobiliary causes of alkaline phos-phatase elevation can be divided into four cat-egories: chronic inflammation involving the bile ducts (eg, as in primary biliary cirrhosis and primary sclerosing cholangitis), infiltra-tive process (eg, neoplasm, tuberculosis), cholestatic disease (eg, drug hepatotoxicity), or biliary obstruction (eg, due to neoplasia or cholelithiasis).

Only a few studies have investigated the significance of a mild, isolated alkaline phos-phatase elevation. Lieberman et al16 evaluated 87 patients, finding that the abnormality resolved completely in less than 3 months in 28 patients, while in another 17 patients it had resolved in 3 to 12 months. O f the remaining 42 patients, 24 did not undergo further evalu-ation due to significant coexisting disease. O f the remaining 18 patients, 5 had phenytoin-related hepatotoxicity, .3 had congestive heart failure, 3 had metabolic bone disease, 2 had

hepatobiliary disease, 1 had metastatic bone disease, and in 4 no explanation was found. Follow-up was 1.5 to 3 years.

Clinical workup . A n isolated elevated alkaline phosphatase level should always be confirmed and a hepatic origin suspected if the gamma-glutamyl transferase level is also ele-vated ( F I G U R E 2 ) . History of recent drug or med-ication exposure usually points to drug hepato-toxicity as the source of this abnormality.

Similarly, other historical data can point to the potential underlying pathologic process responsible for this rise in alkaline phos-phatase. For example, a history of ulcerative colitis suggests primary sclerosing cholangitis, and history of previous cancer or sarcoidosis can suggest liver involvement. A s a part of the initial evaluation, an imaging study (such as ultrasound) will exclude biliary obstruction or an infiltrative process.

If alcohol or medication is suspected, the alkaline phosphatase level should he deter-mined again after the patient has abstained from these agents for approximately 6 to 8 weeks. If the initial examination suggests a specific disease, disease-specific markers (antimitochondrial antibody for primary bil-iary cirrhosis and viral serology) can confirm the suspected diagnosis. If the disease-specific markers are negative and the alkaline phos-phatase level does not return to normal, fur-ther studies, including a liver biopsy and endoscopic retrograde cholangiopancreatog-raphy, should be considered.

G a m m a - g l u t a m y l t ransferase e leva t i on Causes of gamma-glutamyl transferase

elavat ion. Gamma-glutamyl transferase is a membrane enzyme that is a marker of hepato-biliary disease. Increases in gamma-glutamyl transferase usually parallel the elevation of alkaline phosphatase, confirming the hepatic source of the latter. Although gamma-glu-tamyl transferase is the most sensitive marker of biliary tract disease, it lacks specificity. A l c o h o l and a variety of drugs, such as pheny-toin and phenobarbital, induce gamma-glu-tamyl transferase. In one study of patients with alcoholic liver disease, it was elevated in 5 2 % of patients without known liver disease. T h e gamma-glutamyl transferase level can be used to monitor abstinence from alcohol in

Hepatobiliary diseases can cause moderate to marked rises in alkaline phosphatase levels




LIVER E N Z Y M E S Y O U N O S S I L J

patients with alcoholic liver disease.17

Clinical w o r k u p . Due to the lack of speci-ficity and the highly inducible property of this enzyme, an extensive evaluation of an isolated gamma-glutamyl transferase elevation in an otherwise asymptomatic individual is not war-ranted.

• CONCLUSION

A great deal of the evaluations discussed in this paper and other similar papers18"21 can be carried out by the primary care provider fol-lowing a systematic approach. A gastroen-terologist's input can be valuable in patients in whom the initial workup fails to establish the diagnosis, as well as in assuring that the most effective therapy for a specific disease is insti-tuted. Reassurance, patient education, and a systematic approach for evaluating these abnormalities will identify most treatable causes of liver disease in the most cost-effec-tive and efficient manner. E j

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ADDRESS: Zobair M. Younossi, MD, MPH, Department of Gastroenterology, S40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

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Evaluating asymptomatic patients with mildly elevated