Evaluación de resultados anormales en enzimas hepaticas en pacientes asintomaticos

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The New England Journal of Medicine

E

VALUATION

OF

A

BNORMAL

L

IVER

-E

NZYME

R

ESULTS

IN

A

SYMPTOMATIC

P

ATIENTS

D

ANIEL

S. P

RATT

, M.D.,

AND

M

ARSHALL

M. K

APLAN

, M.D.

From New England Medical Center, Box 217, 750 Washington St., Bos-ton, MA 02111, where reprint requests should be addressed to Dr. Pratt.

©2000, Massachusetts Medical Society.

OW that routine laboratory testing is auto-mated and is frequently part of an annualcheckup, physicians are often faced with the

problem of a patient with one abnormal result onmeasurement of serum aminotransferases or alkalinephosphatase but no symptoms. Many batteries ofscreening tests now include measurement of serumalanine aminotransferase, aspartate aminotransferase,alkaline phosphatase, and

g

-glutamyltransferase. Al-though these enzymes are present in tissues through-out the body, they are most often elevated in pa-tients with liver disease and may reflect liver injury.

The first step in the evaluation of a patient withelevated liver-enzyme levels but no symptoms is torepeat the test to confirm the result. If the result isstill abnormal, the physician should evaluate the de-gree of the elevation. A minor elevation (less thantwice the normal value) may be of no clinical impor-tance if the disorders listed in Table 1 have beenruled out and, in fact, may not even be abnormal.The normal range for any laboratory test is the meanvalue in a group of healthy persons ±2 SD. Thus,5 percent of the results obtained from these normalpersons fall outside the defined normal range, 2.5percent of which may be above the upper limit ofnormal. There are also circumstances in which ele-vations in liver-enzyme levels are physiologic; for ex-ample, alkaline phosphatase levels are increased inhealthy women during the third trimester of preg-nancy. The evaluation of the patient with an isolatedelevation of an aminotransferase differs from that fora patient with an isolated elevation of alkaline phos-phatase or

g

-glutamyltransferase.

AMINOTRANSFERASE LEVELS

Aminotransferase levels are sensitive indicators ofliver-cell injury and are helpful in recognizing hepa-tocellular diseases such as hepatitis.

1

Both aminotrans-ferases are normally present in serum at low levels, usu-ally less than 30 to 40 U per liter. The normal rangevaries widely among laboratories. Some researchers

N

recommend adjusting aminotransferase values for sexand body-mass index,

2

but these adjustments are rare-ly made. Aspartate aminotransferase is found, in de-creasing order of concentration, in the liver, cardiacmuscle, skeletal muscle, kidneys, brain, pancreas, lungs,leukocytes, and erythrocytes. The highest level ofalanine aminotransferase is in the liver, and levels ofthis enzyme are accordingly more specific indicatorsof liver injury. Both enzymes are released into theblood in increasing amounts when the liver cell mem-brane is damaged. Necrosis of liver cells is not re-quired for the release of the aminotransferases. Infact, there is poor correlation between the degree ofliver-cell damage and the level of the aminotransfer-ases.

1

If the aminotransferase levels are normal on re-testing, no further evaluation is necessary. If the resultsof repeated tests remain abnormal, further evaluationis indicated.

The first step in the evaluation is to obtain a com-plete history in an effort to identify the most com-mon causes of elevated aminotransferase levels: alco-hol-related liver injury, chronic hepatitis B and C,autoimmune hepatitis, hepatic steatosis (fatty infiltra-tion of the liver), nonalcoholic steatohepatitis, hemo-chromatosis, Wilson’s disease, alpha

1

-antitrypsin de-ficiency, and a recently recognized cause, celiac sprue(Table 1). Table 2 lists the blood tests that can beused to identify many of these disorders. It is moreefficient to order all the blood tests in the first groupinitially, unless the history strongly suggests a defi-nite diagnosis, such as alcohol abuse. The cause ofthe aminotransferase elevation can usually be identi-fied on assessment of the pattern of the results of liv-er-enzyme tests and additional testing.

The cause of an elevated alanine aminotransferaselevel varies greatly depending on the population stud-ied. Among 19,877 Air Force trainees who volun-teered to donate blood, 99 (0.5 percent) had elevat-ed alanine aminotransferase levels.

3

A cause for theelevation was found in only 12: 4 had hepatitis B,4 had hepatitis C, 2 had autoimmune hepatitis, 1 hadcholelithiasis, and 1 had acute appendicitis. In a groupof 100 consecutive blood donors with elevated ala-nine aminotransferase levels, 48 percent had changesrelated to alcohol use, 22 percent had fatty liver, 17percent had hepatitis C, 4 percent had another iden-tified problem, and in the remaining 9 percent, nospecific diagnosis was made.

4

In another study of149 asymptomatic patients with elevated alanine ami-notransferase levels who underwent liver biopsy, 56percent had fatty liver, 20 percent had non-A, non-B hepatitis, 11 percent had changes related to alco-hol use, 3 percent had hepatitis B, 8 percent hadother causes, and in 2 percent, no cause was identi-fied.

5

A recent study assessed 1124 consecutive pa-tients who were referred for chronic elevations in ami-notransferase levels.

6

Eighty-one of these patients hadno definable cause of the elevation and underwent a

Copyright © 2000 Massachusetts Medical Society. All rights reserved. Downloaded from www.nejm.org by VICTOR ARREDONDO MD on March 27, 2007 .

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liver biopsy. Of these 81 patients, 41 had steatosis,26 had steatohepatitis, 4 had fibrosis, 2 had cirrho-sis, and 8 had normal histologic findings. The pa-tients with histologic evidence of fibrosis and cirrho-sis also had evidence of fatty metamorphosis. Noneof the biopsies yielded a specific diagnosis except thoseshowing steatosis and steatohepatitis.

CAUSES OF ELEVATED

AMINOTRANSFERASE LEVELS

Alcohol Abuse

The diagnosis of alcohol abuse can be difficult be-cause many patients conceal information about theiralcohol use. The diagnosis is supported by the find-ing of a ratio of aspartate aminotransferase to alanineaminotransferase of at least 2:1. In a study of hun-dreds of patients who had histologically confirmedliver disorders, more than 90 percent of the patientswho had an aspartate aminotransferase:alanine ami-notransferase ratio of at least 2:1 had alcoholic liverdisease.

7

The percentage increased to more than 96percent when the ratio was greater than 3:1. The in-creased ratio reflects primarily the low serum activityof alanine aminotransferase in patients with alcohol-ic liver disease. This decrease is due to an alcohol-related deficiency of pyridoxal 5-phosphate.

8

Measurement of

g

-glutamyltransferase may also behelpful in diagnosing alcohol abuse. A

g

-glutamyl-transferase level that is twice the normal level in pa-tients with an aspartate aminotransferase:alanine ami-notransferase ratio of at least 2:1 strongly suggeststhe diagnosis of alcohol abuse. However, the lack ofspecificity of the

g

-glutamyltransferase level precludesits use as a single test to diagnose alcohol abuse.

The degree of elevation of aminotransferase levelsmay also be helpful in identifying alcohol abuse. Itis rare for the aspartate aminotransferase level to bemore than eight times the normal value in patientswith alcohol abuse, and it is even less common forthe alanine aminotransferase level to be more thanfive times the normal value in such patients.

7

In fact,the alanine aminotransferase level may be normal, evenin patients with severe alcoholic liver disease.

Medication

A careful history-taking and meticulous review oflaboratory data are critical for identifying a medica-tion as the cause of elevated aminotransferase levels.A drug effect is a possibility if the increase in liver-enzyme levels was associated with the initiation of amedication. Almost any medication can cause an el-evation in liver-enzyme levels. Common ones includenonsteroidal antiinflammatory drugs, antibiotics, an-tiepileptic drugs, inhibitors of hydroxymethylglutar-yl–coenzyme A reductase, and antituberculosis drugs(Table 3). In addition to medications, herbal prepa-rations and illicit drugs or substances may cause el-evations in liver-enzyme levels (Table 3).

The easiest way to determine whether a medica-tion is responsible for the elevation is to stop treat-ment and see whether the test results return to nor-mal. If the identified medication is essential to thepatient’s well-being and no suitable substitute is avail-able, the physician needs to make a risk–benefit analy-sis to determine whether the drug should be contin-

T

ABLE

1.

C

AUSES

OF

C

HRONICALLY

E

LEVATED

A

MINOTRANSFERASE

L

EVELS

.

Hepatic causes

Alcohol abuseMedicationChronic hepatitis B and CSteatosis and nonalcoholic steatohepatitisAutoimmune hepatitisHemochromatosisWilson’s disease (in patients «40 years old)Alpha

1

-antitrypsin deficiency

Nonhepatic causes

Celiac sprueInherited disorders of muscle metabolismAcquired muscle diseasesStrenuous exercise

*If the results of the initial set of tests are normal, these additional testsmay pinpoint the cause.

T

ABLE

2.

L

ABORATORY

T

ESTS

T

HAT

M

AY

I

DENTIFY

THE

C

AUSE

OF

E

LEVATED

A

MINOTRANSFERASE

L

EVELS

IN

A

P

ATIENT

WITH

N

O

S

YMPTOMS

.

T

EST

D

IAGNOSIS

Initial tests

Test for hepatitis C antibody in serum

Presence of hepatitis C antibody indi-cates chronic hepatitis C

Test for hepatitis B surface anti-gen, surface antibody, and core antibody in serum

Presence of hepatitis B surface antigen and core antibody indicates chronic hepatitis B

Measurement of serum iron and total iron-binding capacity

Iron overload suggests hemochroma-tosis

Measurement of serum cerulo-plasmin

Decreased ceruloplasmin levels suggest Wilson’s disease (if patient is «40 years old)

Serum protein electrophoresis Increase in polyclonal immunoglobu-lins suggests autoimmune hepatitis

Serum protein electrophoresis Marked decrease in

a

-globulin bands suggests alpha

1

-antitrypsin deficiency

Additional tests*

Reverse-transcriptase polymer-ase chain reaction for hepati-tis C virus RNA

Presence of viral RNA indicates chronic hepatitis C

Alpha

1

-antitrypsin phenotyping Presence of the ZZ phenotype indicates alpha

1

-antitrypsin deficiencyTests for antiendomysial and an-

tigliadin antibodies in serumPresence of antibodies indicates celiac

sprueMeasurement of creatine kinase

and aldolaseElevated enzyme levels indicate dis-

orders of striated muscle


1268

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Apr i l 27, 2000


ued despite the elevation in aminotransferase levels.Often, consultation with a hepatologist is necessary.Occasionally, a liver biopsy is necessary to determinethe nature and severity of liver injury.

Chronic Hepatitis

Chronic hepatitis C is very common in the UnitedStates. Approximately 3.9 million Americans are pos-itive for antibodies against hepatitis C, and an estimat-ed 2.7 million people are considered to be chronical-ly infected on the basis of the presence of hepatitisC virus RNA in serum.

9

The risk of chronic infec-tion is highest in patients with a history of parenteralexposure to the virus (e.g., because of blood trans-fusions, intravenous drug use, or work-related duties),cocaine use, tattoos, body piercing, and high-risk sex-ual behavior.

The initial test for hepatitis C infection is serolog-ic testing for the hepatitis C antibody. The testinghas a sensitivity of 92 to 97 percent, depending onthe assay.

10

A positive test in a patient with risk fac-

tors for infection is sufficient to make the diagnosis,but the diagnosis is usually confirmed by measure-ment of serum levels of hepatitis C virus RNA withuse of the reverse-transcriptase polymerase chain re-action. This approach is currently the gold standardfor detecting hepatitis C infection.

10

A positive testshould prompt consideration of a liver biopsy to as-sess the severity of damage. Patients with chronichepatitis C and evidence of fibrosis are usually treated.

Initial tests for hepatitis B infection include sero-logic tests for hepatitis B surface antigen, hepatitis Bsurface antibody, and hepatitis B core antibody. A pos-itive test for hepatitis B surface antibody and coreantibody indicates the presence of immunity to hep-atitis B, and another cause for the elevated amino-transferase levels should be sought. A positive test forhepatitis B surface antigen and core antibody indicatesthe presence of infection. Tests to determine wheth-er there is viral replication, including serologic testsfor hepatitis B e antigen, hepatitis B e antibody, andhepatitis B virus DNA, should be undertaken. In pa-tients with positive tests for hepatitis B virus DNAand hepatitis B e antigen, liver biopsy and treatmentshould be considered.

Autoimmune Hepatitis

Autoimmune hepatitis occurs primarily in young-to-middle-aged women.

11

The ratio of female pa-tients to male patients is 4:1.

12

The diagnosis is basedon the presence of elevated aminotransferase levels,the absence of other causes of chronic hepatitis, andserologic and pathological features suggestive of thedisease.

12

A useful screening test is serum protein elec-trophoresis. More than 80 percent of patients withautoimmune hepatitis have hypergammaglobuline-mia.

13

However, a finding of more than twice thenormal level of polyclonal immunoglobulins is mostsuggestive of the diagnosis. Additional tests that arecommonly ordered include serologic tests for anti-nuclear antibodies, antibodies against smooth mus-cle, and liver–kidney microsomal antibodies. The firsttwo tests have reported sensitivities of 28 percentand 40 percent, respectively.

13

The third test is rarelypositive among patients in the United States, Austral-ia, and Japan.

12

We do not recommend the routineuse of these three tests for the diagnosis of autoim-mune hepatitis. A liver biopsy is essential to confirmthe diagnosis.

Hepatic Steatosis and Nonalcoholic Steatohepatitis

The only clinical evidence of hepatic steatosis anda condition that may be associated with it, nonalco-holic steatohepatitis, may be mild elevations in ami-notransferase levels. The levels are usually less thanfour times the normal value.

14,15

In contrast to pa-tients with alcohol-related liver disease, patients withnonalcoholic steatohepatitis usually have an aspartateaminotransferase:alanine aminotransferase ratio that

T

ABLE

3.

M

EDICATIONS

, H

ERBS

,

AND

D

RUGS

OR

S

UBSTANCES

OF

A

BUSE

R

EPORTED

TO

C

AUSE

E

LEVATIONS

IN

L

IVER

-E

NZYME

L

EVELS

.

Medications

AntibioticsSynthetic penicillinsCiprofloxacinNitrofurantoinKetoconazole and fluconazoleIsoniazid

Antiepileptic drugsPhenytoinCarbamazepine

Inhibitors of hydroxymethylglutaryl–coenzyme A reductaseSimvastatinPravastatinLovastatinAtorvastatin

Nonsteroidal antiinflammatory drugsSulfonylureas for hyperglycemia

Glipizide

Herbs and homeopathic treatments

ChaparralChinese herbs

Ji bu huanEphedra (mahuang)

GentianGermanderAlchemilla (lady’s mantle)SennaShark cartilageScutellaria (skullcap)

Drugs and substances of abuse

Anabolic steroidsCocaine5-Methoxy-3,4-methylenedioxymethamphetamine

(MDMA, “ecstasy”)Phencyclidine (“angel dust”)Glues and solvents

Glues containing tolueneTrichloroethylene, chloroform


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is less than 1:1.

15,16

Fatty infiltration of the liver canbe identified by ultrasonography or computed to-mography. Ultrasonography should be part of theevaluation of patients with chronically elevated ami-notransferase levels. The diagnosis of nonalcoholicsteatohepatitis requires a liver biopsy. In addition tofatty infiltration, the histologic findings in patientswith nonalcoholic steatohepatitis include pericentralfibrosis, inflammation, liver-cell necrosis, and hyalinecytoplasmic inclusions in hepatocytes that are iden-tical to Mallory’s bodies, which are characteristic ofalcoholic liver disease.

14

The two conditions have different natural histories:steatosis appears to have a benign course, whereasnonalcoholic steatohepatitis can progress to cirrhosis.

17

Liver failure as a result of nonalcoholic steatohepati-tis is uncommon. Weight loss is the cornerstone oftreatment in patients who are obese.

18

Other treat-ments for nonalcoholic steatohepatitis that are beingstudied include vitamin E and ursodiol. Vitamin Ewas associated with decreases in alanine aminotrans-ferase and aspartate aminotransferase levels and inhistologic abnormalities in two pilot studies.

19,20

Ur-sodiol decreased alanine aminotransferase and aspar-tate aminotransferase levels but not the histologic ab-normalities in another pilot study.

21

Hemochromatosis

Hereditary hemochromatosis is a common genet-ic disorder.

22

Cost-effective screening starts with themeasurement of serum iron and total iron-bindingcapacity (Table 2). A transferrin-saturation value (ob-tained by dividing the serum iron level by the totaliron-binding capacity) of more than 45 percent issuggestive of hemochromatosis.

22

Measurement of se-rum ferritin provides less specific information, becauseit is an acute-phase reactant.

If screening tests suggest the presence of iron over-load, a liver biopsy should be performed to assesshepatic iron levels and the severity of liver damage.A hepatic iron index (the hepatic iron level in micro-moles per gram of dry weight divided by the pa-tient’s age) of more than 1.9 is consistent with thepresence of homozygous hereditary hemochromato-sis.

22

Genetic testing is now available to identify themutation in the hemochromatosis (

HFE

) gene thatcauses the majority of cases. A liver biopsy is notnecessary for patients with hereditary hemochroma-tosis who are younger than 40 years of age and whohave normal liver function.

Wilson’s Disease

Wilson’s disease, a genetic disorder of biliary cop-per excretion, may cause elevated aminotransferaselevels in patients with no other symptoms of the dis-ease. The clinical onset is usually between the agesof 5 and 25 years, but the diagnosis should be con-sidered in patients up to the age of 40 years. The ini-

tial screening test for Wilson’s disease is measurementof serum ceruloplasmin (Table 2). The levels will bereduced in approximately 85 percent of affected pa-tients. Patients should also be examined by an oph-thalmologist for Kayser–Fleischer rings.

If the ceruloplasmin level is normal and Kayser–Fleischer rings are absent, but the physician still sus-pects that Wilson’s disease may be present, the nexttest is a 24-hour urine collection for a quantitativeassessment of copper excretion. Excretion of morethan 100 µg of copper per day is suggestive of Wil-son’s disease. The diagnosis is usually confirmed byliver biopsy to measure hepatic copper levels. Patientswith Wilson’s disease have hepatic copper levels ofmore than 250 µg per gram of liver, dry weight. Al-though the gene responsible for Wilson’s disease hasbeen identified, the number of disease-specific mu-tations is so great that molecular diagnosis is not yetfeasible.

Alpha

1

-Antitrypsin Deficiency

Alpha1-antitrypsin deficiency is an uncommon causeof chronic liver disease in adults. Decreased levels ofalpha1-antitrypsin can be detected either by directmeasurement of serum levels or by the lack of a peakin a-globulin bands on serum protein electrophoresis.In affected patients, however, serum levels of alpha1-antitrypsin may be increased in response to inflam-mation, causing a false negative result. The diagnosisis best established by phenotype determination.

Nonhepatic Causes

In a recent study, occult celiac sprue was the causeof chronically elevated aminotransferase levels in 13of 140 asymptomatic patients who were referred forthis reason to a liver clinic.23 The diagnosis was madeby measuring serum levels of antigliadin and antien-domysial antibodies. None of these patients had pri-mary biliary cirrhosis, a liver disease that is occasion-ally found in patients with celiac sprue. On the basisof this study, we recommend testing for occult celiacsprue if other, more common causes of elevated ami-notransferase levels have been ruled out (Table 2).

Elevated serum aminotransferase levels, especiallyaspartate aminotransferase levels, may be caused bydisorders that affect organs or tissues other than theliver, with the most common being striated muscle.Conditions or activities that can cause such elevationsinclude subclinical inborn errors of muscle metabo-lism; acquired muscle disorders, such as polymyosi-tis; and strenuous exercise, such as long-distance run-ning. If striated muscle is the source of increasedaminotransferase levels, serum levels of creatine ki-nase and aldolase will be elevated to the same degreeor to an even higher degree. Creatine kinase or aldo-lase levels should be measured if other, more commonhepatic conditions have been ruled out (Table 2).

If, despite comprehensive testing as outlined in Ta-


1270 · Apr i l 27, 2000


ble 2, the cause of the elevation in aminotransferaselevels remains unidentified, then a percutaneous liverbiopsy may be indicated. If the alanine aminotrans-ferase and aspartate aminotransferase levels are lessthan twice the normal value and no chronic liver con-dition has been identified, we recommend observa-tion alone. Supporting this position are the resultsof two recent studies. The first study suggested thatclose clinical follow-up is the most cost-effective strat-egy for asymptomatic patients with negative tests forviral, metabolic, and autoimmune markers of liver dis-ease and chronically elevated aminotransferase lev-els.24 The second study examined 36 patients witha chronic elevation (at least 50 percent above nor-mal) of alanine aminotransferase, aspartate aminotrans-ferase, or alkaline phosphatase levels.25 Patients withstrong evidence of a particular liver disease were ex-cluded. All patients underwent liver biopsy. The re-sults of liver biopsy led to a change in the diagnosisin only five patients and to a change in treatment intwo patients.

If the alanine aminotransferase and aspartate ami-notransferase levels are persistently more than twicethe normal value, we recommend a biopsy. Althoughthe results of the biopsy are unlikely to lead to a di-agnosis or to changes in management, they oftenprovide reassurance to the patient and the physicianthat no serious disorder is present.

CAUSES OF ELEVATED ALKALINE

PHOSPHATASE LEVELS

Elevations in serum alkaline phosphatase levels orig-inate predominantly from two sources, liver and bone.1

Women in the third trimester of pregnancy have el-evated serum alkaline phosphatase levels because ofan influx of placental alkaline phosphatase into theirblood. In persons with blood type O or B, serumalkaline phosphatase levels may increase after the in-gestion of a fatty meal, because of an influx of intes-tinal alkaline phosphatase. There are also reports ofa benign familial elevation in serum alkaline phos-phatase levels because of increased levels of intestinalalkaline phosphatase. Alkaline phosphatase levels alsovary with age. Rapidly growing adolescents can haveserum alkaline phosphatase levels that are twice thoseof healthy adults as a result of the leakage of bonealkaline phosphatase into blood. Also, serum alka-line phosphatase levels normally increase graduallybetween the ages of 40 and 65 years, particularly inwomen. The normal alkaline phosphatase level in anotherwise healthy 65-year-old woman is more than50 percent higher than the level in a healthy 30-year-old woman.26

The first step in the evaluation of an elevated al-kaline phosphatase level in a patient with no othersymptoms is to identify the source of the elevation.Although electrophoretic separation on either poly-acrylamide gel or Sepharose columns is the most sen-

sitive and specific way of doing this, neither methodis widely available.1 If gel electrophoresis is not avail-able, measurement of either serum 5'-nucleotidaseor g-glutamyltransferase should be performed. Lev-els of these enzymes are usually elevated in parallelwith the elevation in the alkaline phosphatase levelin patients with liver disorders, but they are not in-creased in patients with bone disorders. The findingof an elevated serum alkaline phosphatase level but anormal 5'-nucleotidase or g-glutamyltransferase lev-el should prompt an evaluation for bone diseases. Testsinvolving heat and urea denaturation of serum alka-line phosphatase are still used by many laboratoriesbut are neither sensitive nor specific.

If the excess alkaline phosphatase is determined tobe of liver origin and persists over time, the patientshould be evaluated for chronic cholestatic or infil-trative liver diseases. Cholestatic diseases or condi-tions include partial obstruction of bile ducts, pri-mary biliary cirrhosis, primary sclerosing cholangitis,adult bile ductopenia, and cholestasis induced by theuse of drugs such as anabolic steroids. Infiltrativediseases include sarcoidosis, other types of granulo-matous diseases, and less often, unsuspected metas-tasis of cancer to the liver. The appropriate initial testsare ultrasonography of the right upper quadrant toassess the hepatic parenchyma and bile ducts and se-rologic tests for antimitochondrial antibodies. Thepresence of antimitochondrial antibodies is highlysuggestive of the presence of primary biliary cirrho-sis. A finding of biliary dilatation suggests the pres-ence of obstruction of the biliary tree. This finding isunlikely in the absence of hyperbilirubinemia. Shouldbiliary dilatation or choledocholithiasis be present,endoscopic retrograde cholangiopancreatography isnecessary to identify the cause of obstruction andcan also be used to remove a stone or place a stentif required. Patients with serum antimitochondrial an-tibodies should undergo liver biopsy to confirm thediagnosis of primary biliary cirrhosis.

If the serologic test for antimitochondrial anti-bodies is negative and ultrasonography reveals no ab-normality, but the alkaline phosphatase level remainsmore than 50 percent above the normal level, we sug-gest a liver biopsy and either endoscopic retrogradecholangiopancreatography or magnetic resonance cho-langiopancreatography. If the increase in the alkalinephosphatase level is less than this, the results of allthe other liver-enzyme tests are normal, and the pa-tient has no symptoms, we suggest observation alone.This position is supported by the results of a recentstudy.25

CAUSES OF ELEVATED

g-GLUTAMYLTRANSFERASE LEVELS

g-Glutamyltransferase is found in hepatocytes andbiliary epithelial cells. Measurement of serum g-glu-tamyltransferase provides a very sensitive indicator of


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the presence or absence of hepatobiliary disease, butthe usefulness of this test is limited by its lack ofspecificity. Elevated levels of g-glutamyltransferasehave been reported in a wide variety of clinical con-ditions, including pancreatic disease, myocardial in-farction, renal failure, chronic obstructive pulmo-nary disease, diabetes, and alcoholism.27 High serumg-glutamyltransferase levels are also found in patientswho are taking medications such as phenytoin andbarbiturates.28

Some have advocated the use of serum g-glutamyl-transferase measurements to identify patients with un-reported alcohol use. The reported sensitivity of anelevated g-glutamyltransferase level for detecting al-cohol ingestion has ranged from 52 to 94 percent.29,30

Its lack of specificity makes the use of this test forthis purpose questionable. In our opinion, measure-ment of serum g-glutamyltransferase is best used asa way of evaluating the meaning of elevations in oth-er serum enzyme levels. For instance, it can be usedto confirm the hepatic origin of elevated alkaline phos-phatase levels or to support the diagnosis of alcoholabuse in a patient with an elevated aspartate amino-transferase level and an aspartate aminotransferase:ala-nine aminotransferase ratio of at least 2:1.

REFERENCES

1. Pratt DS, Kaplan MM. Laboratory tests. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff ’s diseases of the liver. 8th ed. Vol. 1. Philadelphia: Lippincott–Raven, 1999:205-44.2. Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with se-rum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. Hepatology 1998;27:1213-9.3. Kundrotas LW, Clement DJ. Serum alanine aminotransferase (ALT) el-evation in asymptomatic US Air Force basic trainee blood donors. Dig Dis Sci 1993;38:2145-50.4. Katkov WN, Friedman LS, Cody H, et al. Elevated serum alanine ami-notransferase levels in blood donors: the contribution of hepatitis C virus. Ann Intern Med 1991;115:882-4.5. Hultcrantz R, Glaumann H, Lindberg G, Nilsson LH. Liver investiga-tion in 149 asymptomatic patients with moderately elevated activities of se-rum aminotransferases. Scand J Gastroenterol 1986;21:109-13.6. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormal-ities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999;94:3010-4.7. Cohen JA, Kaplan MM. The SGOT/SGPT ratio — an indicator of al-coholic liver disease. Dig Dis Sci 1979;24:835-8.8. Diehl AM, Potter J, Boitnott J, Van Duyn MA, Herlong HF, Mezey E.

Relationship between pyridoxal 5'-phosphate deficiency and aminotransfer-ase levels in alcoholic hepatitis. Gastroenterology 1984;86:632-6.9. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hep-atitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-62.10. Schiff ER, de Medina M, Kahn RS. New perspectives in the diagnosis of hepatitis C. Semin Liver Dis 1999;19:Suppl 1:3-15.11. Krawitt EL. Autoimmune hepatitis. N Engl J Med 1996;334:897-903.12. Manns MP. Autoimmune hepatitis. In: Schiff ER, Sorrell MF, Mad-drey WC, eds. Schiff ’s diseases of the liver. 8th ed. Vol. 2. Philadelphia: Lippincott–Raven, 1999:919-35.13. Czaja AJ. Natural history, clinical features, and treatment of autoim-mune hepatitis. Semin Liver Dis 1984;4:1-12.14. Diehl AM, Goodman Z, Ishak KG. Alcohollike liver disease in nonal-coholics: a clinical and histologic comparison with alcohol-induced liver in-jury. Gastroenterology 1988;95:1056-62.15. Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Non-alcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994;107:1103-9.16. Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransfer-ase to alanine aminotransferase: potential value in differentiating nonalco-holic steatohepatitis from alcoholic liver disease. Am J Gastroenterol 1999;94:1018-22.17. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, Mc-Cullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-9.18. Eriksson S, Eriksson KF, Bondesson L. Nonalcoholic steatohepatitis in obesity: a reversible condition. Acta Med Scand 1986;220:83-8.19. Hasegawa T, Yoneda M, Nakamura K, et al. Diagnostic significance of measurement of serum transforming growth factor b1 (TGF-b1) level and effect of a-tocopherol in patients with nonalcoholic steatohepatitis (NASH). Gastroenterology 1997;112:Suppl 1:A1278. abstract.20. Lavine JE. Treatment of obesity-induced steatohepatitis with vitamin E. Gastroenterology 1998;114:A1284. abstract.21. Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofi-brate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464-7.22. Powell LW, George DK, McDonnell SM, Kowdley KV. Diagnosis of hemochromatosis. Ann Intern Med 1998;129:925-31.23. Bardella MT, Vecchi M, Conte D, et al. Chronic unexplained hyper-transaminasemia may be caused by occult celiac disease. Hepatology 1999;29:654-7.24. Das A, Post AB. Should liver biopsy be done in asymptomatic patients with chronically elevated transaminases: a cost-utility analysis. Gastroenter-ology 1998;114:A9. abstract.25. Sorbi D, McGill DB, Thistle JL, Henry JJ, Therneau TM, Lindor KD. An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Hepatology 1999;30:Suppl:477A. abstract.26. Wolf PL. Clinical significance of an increased or decreased serum al-kaline phosphatase level. Arch Pathol Lab Med 1978;102:497-501.27. Goldberg DM, Martin JV. Role of gamma-glutamyl transpeptidase ac-tivity in the diagnosis of hepatobiliary disease. Digestion 1975;12:232-46.28. Rosalki SB, Tarlow D, Rau D. Plasma gamma-glutamyl transpeptidase elevation in patients receiving enzyme-inducing drugs. Lancet 1971;2:376-7.29. Moussavian SN, Becker RC, Piepmeyer JL, Mezey E, Bozian RC. Se-rum gamma-glutamyl transpeptidase and chronic alcoholism: influence of alcohol ingestion and liver disease. Dig Dis Sci 1985;30:211-4.30. Orrego H, Blake JE, Israel Y. Relationship between gamma-glutamyl transpeptidase and mean urinary alcohol levels in alcoholics while drinking and after alcohol withdrawal. Alcohol Clin Exp Res 1985;9:10-3.


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