1989 Rej Amintransferase in Disease

Diagnostic Enzymology 0272-2712/89 $0.00 + .20

Aminotransferases in Disease

Robert Rej, PhD*

The aminotransferases are a group of enzymes that catalyze thereversible transfer of the amino group from an a-amino-acid to an oxoacid. There are over 50 such enzymes characterized. Two of these,aspartate aminotransferase (AST, EC 2.6.1.1, formerly known as gluta-mate-oxalacetate transaminase or GOT) and alanine aminotransferase(ALT, EC 2.6.1.2, formerly known as glutamate-pyruvate transaminaseor GPT), entered the repertoire of the diagnostic laboratory in themid-1950s and have remained mainstays of diagnostic enzymology forthe subsequent three decades.

TISSUE DISTRIBUTION AND METABOLIC ROLES

These two enzymes are widely distributed among human organs, afact contributing to both their broad application to a variety of patho-logic conditions and to their reputation for lacking specificity. The reac-tions catalyzed by AST and ALT are

ASTL-aspartate -I- 2-oxoglutarate oxalacetate -f- L-glutamate

ALTL-alanine -f- 2-oxoglutarate pyruvate + L-glutamate

The three amino-acid substrates for the two aminotransferases,apart from their role as protein constituents, are focal points of interme-diary nitrogen metabolism while the three oxo acids are components ofthe tricarboxylic acid cycle or carbohydrate metabolism. The two ami-notransferases are key to shunting these substrates into several meta-bolic pathways. AST is particularly important in the transport of reduc-ing equivalents across the mitochondria) membrane via the malate-aspartate shuttle.

* Associate Professor, Department of Biomedical Sciences, School of Public Health, StateUniversity of New York at Albany; and Director, Clinical Chemistry, WadsworthCenter for Laboratories and Research, New York State Department of Health, Albany,New York

Clinics in Laboratory Medicine-Vol. 9, No. 4, December 1989 667

668 ROBERT REJ

Table 1. Distribution of Aminotransferases in Human Tissue Expressed as aRatio to That Found in Human Serum

TISSUE AST ALT

Liver 7000 2200Heart 7700 350Skeletal muscle 4800 250Kidney 4500 950Brain 2500 50Pancreas 1400 100Spleen 700 60Lung 500 35Erythrocytes 40 7Serum 1 1

Data from references 131,171,173, and 174.

As might be expected of enzymes with significant metabolic impor-tance, the tissue levels of the two aminotransferases are rather high andthey are sensitive indicators of necrosis in a number of tissues. Therelative activities of the two enzymes in a number of human tissues arepresented in Table 1. Isoenzymes and multiple forms exist for both en-zymes. 134,165 The mitochondrial form of AST (m-AST) is the predomi-nant form in human liver (80 per cent) although the amounts in serum areoften rather low even in acute liver damage.131 Mitochondrial ALT existsas a small portion of tissue activity and has not been demonstrated innormal human serum. Several other amino acids serve as substrates forAST135 and much, if not all, tyrosine aminotransferase (TAT) activity inmammalian brain is likely to be related to the presence of m-AST.116

It is generally accepted that the aminotransferases play no sig-nificant metabolic function in the peripheral circulation, and that theirpresence reflects normal cell turnover or release. It is uncertain ifmild hypoxia results in significant release of enzymes from tissue.Immunostaining studies with dog models suggest that in myocardium,necrosis rather than merely hypoxia is necessary for significant amino-transferase release. 15' Animal models also suggest that, in addition toincreased membrane permeability or cell death, increases in serumaminotransferases found in hepatotoxicity may be caused at least in partby increased enzyme synthesis.125 Aminotransferase activity in humanliver has been shown to be increased in individuals with alcoholic liverdisease.'°' Similarly in human heart following myocardial infarction,increased tissue and serum levels of ALT were found,54 suggesting in-creased enzyme synthesis upon tissue damage.

Aminotransferases, and several other enzymes, are likely clearedfrom the peripheral circulation by endocytosis by macrophages in liver,spleen, and bone marrow. 71,161

PREANALYTIC VARIABLES

AST increases up to 25 per cent after exercise with the highest levelsobtained 8 to 24 hours after exercise; increases are less than those found

AMINOTRANSFERASES IN DISEASE 669

for creatine kinase (CK, EC 2.7.3.2), and such elevations are usually of nopathologic significance. 117, 145, 151, 169 Plasma levels are lower if blood iscollected from individuals in supine, compared to seated, positions.174 Ifmultiple specimen tubes are obtained, the order of filling after veni-puncture is unimportant for AST and ALT determinations.95 Artifac-tually increased AST has been reported with capillary serum that is notobserved with capillary plasma.62

Erythrocytes contain both enzymes at levels greater than thosefound in serum (see Table 1), but only gross hemolysis results in anunsatisfactory specimen; elevated AST levels were found only at serumhemoglobin levels at 1.5 g per L and elevated ALT activities were foundat 3.4 g of hemoglobin per liter of serum.163

There are conflicting reports on stability of the enzymes in serum. Arecent and comprehensive study of storage conditions found that AST inserum is rather stable refrigerated or frozen and that the stability isimproved with the addition of pyridoxal phosphate. 114 ALT is consider-ably less stable and refrigeration is usually preferable to freezing, inparticular, if storage at <- 60'C is not available.

ANALYTICAL VARIABLES AND MEASUREMENT OFAMINOTRANSFERASE ACTIVITY

A large number of analytical techniques have, over the years, beenutilized to determine the catalytic activity of both aminotransferases.The widespread diversity of techniques, each with its own interferences,biases, and inaccuracies, has tended to obscure subtle factors affectingenzyme activity and has led to significant variation among reports fromdifferent laboratories. Considerable care must be exercised in reviewingearlier literature, in particular for drug interferences, since this workmay be based on use of less specific assay procedures.

Highly specific analytical techniques are now in widespread use indeveloped countries. Today nearly all aminotransferase measurementsare based on the same principle, namely reduction of the oxo-acid-prod-uct (oxalacetate for AST and pyruvate for ALT) with a specific dehydro-genase (malate dehydrogenase [MDH, EC 1.1.1.37] for AST and lactatedehydrogenase [LDH, EC 1.1.1.27] for ALT) and oxidation of NADH,which can be followed spectrophotometrically. The methodology foraminotransferase measurements has been comprehensively reviewedearlier.136 Within-laboratory precision for aminotransferase measure-ments is usually excellent, the relative standard deviation typically beingless than 5 per cent.sa

One difference in methodology that significantly affects results ismeasurement temperature; over the past 25 years results have beencommonly reported at 25, 30, 32, and 37°C. Today, the temperature of37°C appears to be predominant in routine clinical applications, al-though 30'C is recommended for reference methods. 13,14 Conversion ofresults on the basis of temperature factors appears to introduce only asmall degree of error.141 The following multiplication factors may beuseful for comparison of results from different publications to equivalent

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enzyme activity at 37°C:

25°C 30°C

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AST 2.22 1.57ALT 1.80 1.38

Another analytical variable that affects clinical interpretation is themeasurement of enzyme activity in the presence or absence of pyridoxalphosphate . Both aminotransferases require pyridoxal phosphate as anessential cofactor while neither apoenzyme possesses enzyme activ-ity.130 Several national and international organizations have recom-mended supplementation of aminotransferase measurements with pyri-doxal phosphate13 , 14 but , unfortunately, this remains a practice that isnot standard . This variance in methodology has an effect on clinicalsensitivity and specificity for routine applications .56 It may be crucial forinterpretation in some cases . For example, there are different effects ofthe immunosuppressive agents cyclosporine and azathioprine on pyri-doxal phosphate stimulation ; assessing liver function in such cases re-quires careful interpretation in light of the analytical method used.80

REFERENCE VALUES

There is a demonstrable sex difference in reference values for theaminotransferases, with males exhibiting higher activities than women.For ALT the upper reference value is approximately 75 per cent that formales; the difference is less striking for AST. 10. 60 There is a progressivedecrease in AST activity in children from infancy to the age of 18years.88,126 Upper reference value limits (97.5 percentile) as a functionof age and sex are shown in Figure 1. These upper limits are based on anumber of reports4s, 57, 88, 127, 159, 173, 174 and expressed in numericalvalues equivalent to the IFCC method utilizing pyridoxal phosphate's, 14at 37°C.

Increased levels of ALT, and not AST, are found with obe-sity.68, 159, 166 There is no statistically significant difference in pregnancyfor serum activities of AST or ALT.12 However, vitamin B6 status is oftenaltered in pregnancy so that lower activities may be obtained with analyt-ical techniques not including exogenous pyridoxal phosphate.

Seasonal variations have been observed for both AST and ALT levelswith highest activities found in winter.' Studies of twins have demon-strated a genetic factor that affects reference values of both AST andALT. 17' In a study considering both analytical and intraindividual varia-tion, consecutive differences of about 30 per cent for either aminotrans-ferase were found to be highly significant in patients with liver diseases,that is, outside combined normal biologic and analytical variation.69

DRUG EFFECTS

AST is an excellent marker for hepatotoxicity caused by drugs suchas acetaminophen and iproniazid. 65,160,182 Drug-related hepatotoxicity

AMINOTRANSFERASES IN DISEASE

90

80

30

20

A010 20 30 40

Age (Years)

90

80

50

671

60

Males

40

30

200

F10 20 30 40

Age (Years)

50 60

Figure 1. Upper reference values (97.5% percentile) for AST (A) and ALT (B) as afunction of age and sex. Values are expressed in U/L at 37 °C and determined with additionof pyridoxal phosphate.

672 ROBERT REJ

often results in both a very high AST activity and an elevated AST/ALTratio and should be considered in nonalcoholic causes of hepatocellularnecrosis.65 Salicylate therapy may increase aminotransferase activity,particularly in children, with no other evidence of liver dysfunction. 147

Significant elevations in aminotransferase activity have been re-ported with anticonvulsant treatment .2, 37 Increases in ALT were ob-served in 28 per cent of patients using diphenylhydantoin while an in-crease in AST was observed in 11 per cent of such patients. A smallernumber of elevations were found with carbamazepine and increases inserum activity did not appear to be related to drug dose.2 While primi-done and valproic acid usually have no effect on ALT or AST activities,93there are reports that one in 10 children on valproate therapy had in-creased AST activities.41 The neuroleptics have no significant effect onserum AST activity.97 Sulfasalazine increases serum AST in rare compli-cations47; increases have also been observed with use of ritodrine,98phenothiazines,24 and isoniazid.7, 181 In many cases of drug-related in-

creases in aminotransferase activity, elevations may be transitory, withvalues returning to within normal reference limits within a few weeks.

Drugs affecting vitamin B6 status or that react with pyridoxal phos-phate often reduce aminotransferase activity. Azathioprine has beendemonstrated to cause a rise in a large fraction of apo-ALT, a responsenot observed with cyclosporine. 61, 8° The effect of cefazolin decreasingserum AST and ALT in experimental animals may be caused by reactionof the drug with pyridoxal phosphate . 311.4' Reported effects of drugs suchas metronidazole (Flagyl) are likely the consequence of interference onolder analytical methods for measuring AST.36, 143

Aminotransferases are useful as markers of chemotherapy-inducedhepatotoxicity; however, this application, as well as others, may beclouded by prior blood transfusions. Elevations in ALT have been foundto correlate with the number of prior transfusions in patients and mayreflect viral disease rather than a drug-related effect.64

Both aminotransferases have been observed to increase in heparintherapy, a phenomenon more frequently observed in males; more promi-nent elevations being found for ALT.44, 73,'05, us The exact mechanismfor this increase is unknown but may involve induction of enzyme andmay be a potentially significant factor in the differential diagnosis ofpulmonary embolism and acute myocardial infarction .44,73

APPLICATION TO LIVER DISEASES

Although AST measurements in serum were initially applied to thedifferential diagnosis of myocardial infarction,84 the same research teamquickly extended its use to liver diseases.180 Upon hepatocellular injuryof any type, increases in serum aminotransferase activity are observed,and it is generally accepted that serum levels reflect the severity ofinjury. Extremely high levels typically suggest acute hepatocellular ne-crosis. The greatest increases are observed in acute viral hepatitis inwhich serum concentrations of aminotransferases exceed 20-fold theupper reference limit and increases of up to 100-fold have been ob-


served. In a study of 15 laboratory tests, an AST activity greater than200 U per L and an ALT activity greater than 300 U per L were the mostpowerful discriminators of acute viral hepatitis.23 The increase in amino-transferase activity generally precedes jaundice, and maximum levelsare observed within 2 weeks of onset. Increases in ALT usually exceedthose of AST, and the AST/ALT ratio (see farther on) usually falls to^ 0.65 in such cases. This ratio is a good prognostic index of outcome incases of severe acute viral hepatitis; a low AST/ALT ratio (0.3 to 0.6) wasfound in survivors while a higher ratio (1.2 to 2.6) was found in nonsurvi-vors.55 Failure of AST and ALT to return to normal activities is a sugges-tion of progression to chronic hepatitis. In one study, about 16 per cent of160 patients with chronic active hepatitis had AST activities exceeding1000 U per L.33

An AST/ALT ratio greater than 1.5 may suggest cholestasis due toparenchymal liver disease.23 Since it is a sensitive indicator of hepatocytedisruption, an early and transient rise in serum AST is consistent withtransient ampullary obstruction in gallstone pancreatitis and may beuseful in identifying patients who require urgent surgical or endoscopicdisimpaction.102 A rapid rise and decline in AST suggests extrahepaticbiliary disease; a decrease in serum AST does not necessarily indicatethat the stone has passed.52

The two aminotransferases are often differentially elevated in liverdiseases and the relative elevation of each provides clinical informationthat is useful in identification of disease etiology. The use of the ratio ofAST/ALT was first suggested in 1955 by de Ritis,34, 35 who found that theratio was decreased in acute viral hepatitis and increased in cirrhosis.This introduced the concept of enzyme patterns in diagnostic enzymol-ogy. The use of this ratio has been expanded by others and has beenuseful in the differential diagnosis or classification of hepatic disorders.This ratio is particularly useful to differentiate intrahepatic (ratio >1.5) and extrahepatic cholestasis (ratio < 1.4) in alcoholic chronic pan-creatitis.2' The deRitis ratio is elevated in alcoholic or toxic hepatitis,intrahepatic cholestasis, hepatocellular carcinoma, and cirrhosis;slightly elevated in chronic hepatitis; normal or slightly depressed inextrahepatic cholestasis; and usually depressed in obstructive jaundiceand acute viral hepatitis. A summary of the AST/ALT ratio in a number ofconditions is given in Table 2.

The original proposers of the AST/ALT ratio cautioned that differ-ent analytical techniques result in considerable differences in the quan-titative and qualitative results.35 Depending on methods used, thedeRitis ratio found for normal individuals may vary from 0.7 to 1.4.35, 167Care should be taken in using published discriminating values of thedeRitis ratio to individual clinical cases. Clinical studies utilizing theAST/ALT ratio should clearly state the expected value for normal indi-viduals to aid comparison. On a relative basis, the differences in the ratiodue to disease (Table 2) should be valid with most analytical techniquesin current use.

While y-glutamyltransferase (GGT, EC 2.3.2.2) is a sensitive test fordetecting alcohol consumption, it lacks specificity; therefore, as an indi-cator in patients with liver disease, AST is often superior to GGT.46 AST

674 ROBERT REJ

Table 2 . AST/ALT Ratio (de Ritis Ratio) in Liver Diseases

CONDITION AST/ALT RATIO

Alcoholic liver disease 2.0-> 6.0Organic toxic hepatitis > 2.0Cirrhosis 1.4-2.0Intrahepatic cholestasis > 1.5Extrahepatic cholestasis < 1.4Normal individuals 1.15Chronic active hepatitis 1.3Extrahepatic biliary obstruction 0.8Acute viral hepatitis 0.5-0.8

Data from references 3,21,28-30,34,35, and 149.

in serum is significantly increased at 24 hours after alcohol ingestion at1 g per kg."3 Elevated AST and ALT levels in an alcoholic or heavydrinker usually indicate alcohol-induced organ damage; an AST/ALTgreater than 1.5 is highly suggestive of alcoholic cause of liver damage.3'149,167, 179 The AST/ALT ratio may also be a marker of alcohol consump-tion.166

In addition to toxic liver damage caused by therapeutic drugs, ami-notransferases are elevated on exposure to various organic compounds.AST is increased in occupational exposure to organic compounds, and anAST determination is often used to assess the degree of exposure. Expo-sure to toluene, furan, methylene chloride, and acetyl furan leads toincreases in serum activity. 30,59,156 The ratio of AST to ALT is also oftenincreased in such subjects.

Since serum AST and ALT activities are elevated in viral hepatitis,and in the absence of more specific markers, their use as tests for screen-ing of blood donors had been proposed as early as the late 1950s. Thisapplication has a history of controversy that is nearly equally long.20

Currently, serum ALT measurement is considered the best availablemarker for acute or chronic non-A, non-B hepatitis.' ALT is now inwidespread use as an indicator of non-A , non-B hepatitis and nearly alldonor blood is so tested, even though such testing is not required by theU.S. Food and Drug Administration (FDA). 15 Although this application isrelatively new in the United States, both aminotransferases have beenused for such screening in other countries (for example, the FederalRepublic of Germany) for several years.

APPLICATION TO MYOCARDIAL INFARCTION

Myocardial muscle is the richest tissue source of AST; detecting itspresence in serum after acute myocardial infarction represented a mile-stone in the development of modern clinical enzymology.84 AST beginsto increase in serum about 5 hours after myocardial infarction andreaches maximum levels 24 to 48 hours post-infarct."' Appearance of theisoenzymes of AST are shown in Figure 2. Since other tissues contain


40

Time (Hours)Figure 2. Time course of serum AST (t-AST) and mitochondrial AST (m-AST) follow-

ing acute myocardial infarction. (Data from Rej R, Herder M, Hyltoft-Petersen P, et al:lsoenzymes of aspartate aminotransferase and creatine kinase in acute myocardial infarc-tion. Clin Chem 29:1233, 1983.)

AST at significant levels (see Table 1), this enzyme cannot be considereda specific marker for myocardial damage.

However, AST is still widely used in confirming this diagnosis,and some workers regard it as the best marker for early diagnosis ofmyocardial infarction, perhaps because of a larger analytic variationsometimes associated with determination of the MB isoenzyme of CK(CK-MB or CK-2).32 An examination of 27 laboratory tests by discrimi-nant analysis classified AST as the best single discriminating test forcorrectly classifying patients with (N = 64) and without (N = 70) myo-cardial infarction admitted to a coronary care unit."' Recent studieS146have confirmed the high diagnostic efficiency of AST in such cases. Itmay be particularly valuable in patients with suspected myocardial in-farction who are admitted later than 48 hours after onset of symptomswhen CK declines to near-normal levels. AST is also useful in cases inwhich CK increases may result from other causes. Since serum activitiesof CK increase after laparotomy,78 AST is a suitable marker for postoper-ative patients suspected of having myocardial infarct.

The increase in serum AST activity reflects the magnitude of thelesion and appears to be as reliable as CK-MB for estimating myocardialinfarction size.63 It has been reported that the best indicators for survivalafter myocardial infarction are duration of pain and the peak AST level.94

676 ROBERT REJ

Increases in serum levels of AST and ALT in myocardial infarctionare often not solely of cardiac origin. Some liver damage commonlyoccurs in patients after acute myocardial infarct due to portal hypoten-sion and subsequent hepatic necrosis.16 Up to 48 hours after infarction,increases in serum ALT are of myocardial origin; thereafter additionalrelease is likely to be due to hepatic ALT.120 There is some evidence thatin infarction some newly synthesized ALT in the myocardium itself mayalso leak into the peripheral circulation.54

In streptokinase treatment subsequent to myocardial infarction,AST peaks earlier and higher in patients who have been successfullytreated.90 The initial kinetics of CK release and time to peak AST may beuseful in assessing reperfusion status in those patients receiving throm-bolytic therapy.175

In order to improve the diagnostic power of AST in cases of myocar-dial infarction, the enzyme ratio CK/AST was proposed in the early1970s by Szasz (see Schmidt et al'53 for a review of this and other enzymeratios). The CK/AST ratio has recently been rediscovered and found53 tohave a diagnostic efficiency equal to CK-MB, and it may be helpful ifCK-MB measurements are unavailable. This application has been con-firmed ,42, 43 but the ratio appears not helpful in alcoholics or in cases ofovert liver disease.

DIAGNOSTIC APPLICATIONS OF MITOCHONDRIAL AST

The first report that two isoenzymes of AST are present in serum wasmade by Fleisher and Wakim49 in studies of experimental liver damage indogs. Early applications of the diagnostic potential of serum m-AST mea-surements were made in the late 1960s by Boyde18 and Ideo.74, 75 De-spite this relatively long history, this marker remains at the researchlevel. Analytical techniques for the accurate measurement of m-AST arepresently available, and techniques based on immunochemical separa-tion appear most suited for clinical applications. 137

Although the major portion of AST activity in liver and muscle is themitochondrial form, m-AST is present in serum only at low catalyticactivities. Reference values are 0 to 4 U per L124,

132,133 ; there are onlyslight differences in normal values of m-AST between males and fe-males.82,15° Even with serious tissue damage, the relative amounts ofm-AST in serum remain low, seldom increasing to over 25 per cent oftotal AST activity in serum . These data do not support the commonlyaccepted (and intuitively appealing) explanation that upon severe tissuedamage more m-AST is released, resulting in an increase in the AST/ALTratio, since ALT is virtually absent from mitochondria. Although both anincrease in the de Ritis ratio and an increase in m-AST do indeed occur,the proportion of m-AST is often insufficient to account for the change inthe ratio. Calculation of the AST/ALT ratio using only the cytoplasmicisoenzyme of AST (c-AST) would provide results differing slightly fromthose given in Table 2. Although catalytic activity of m-AST is low, alarger amount of an immunologically active form of this protein can bedetected in serum . 66, 139


The most promising application of m-AST measurements is in thediagnosis of chronic alcoholism. 99, 116, 149 It has been found that m-AST isa better test than GGT or mean corpuscular volume for discriminatingbetween drinkers and nondrinkers in cirrhotic patients. Nearly all ab-stainers (96 per cent) have normal serum m-AST levels, whereas 89 percent of drinkers had high activity levels.76 Levels of m-AST were found tobe elevated in alcoholics both with and without overt liver damage, and adecrease in serum m-AST activity was found to be a reliable indicator ofabstinence. 110, III In these studies the ratio of m-AST to total AST (t-AST)was found to be the best discriminator between alcoholics and normalindividuals or individuals with other types of liver disease.

Screening of a large population found that m-AST is elevated inheavy drinkers but that this test is not particularly useful for widespreadapplication to an unselected population.150 Young alcoholics, who onaverage abstained from alcohol for 6 days, also demonstrate elevatedm-AST activity in serum; however, the ratio of m-AST/t-AST was notsignificantly increased in this population, which may be a function ofage.26

Although the m-AST/t-AST ratio appears highest in alcoholic liverdamage, it is also raised in other acute liver diseases.123 The clearancerate of m-AST from serum may provide useful information on hepaticdamage.79 The half-life of m-AST in serum is shorter than that of c-AST sothat high levels indicate continued hepatic injury, disease chronicity,and likely are associated with chronic hepatitis.104 Increased m-AST hasbeen found in primary hepatoma and malignant-but not benign-ex-trahepatic biliary obstruction. 104 It has been reported,168 and oftenstated, that the proportion of m-AST is extraordinarily high in serumduring the active stages of Reye's syndrome. Since mitochondrial mem-brane abnormalities in hepatocytes are associated with this condition,this is also intuitively appealing; however, this hypothesis could not beconfirmed using refined analytical techniques.106

Measurement of m-AST may also prove to be a useful index to evalu-ate the degree of myocardial injury.4 The m-AST/t-AST ratio reflectsseverity of myocardial cellular damage,77 and m-AST is a better index ofthe likelihood of fatal outcome than any cytosolic enzyme.5,162 Use of aratio of m-AST/t-AST with a threshold of 0.10 had the highest diagnosticefficiency. In myocardial infarction, the peak of serum m-AST is reachedafter that of cytoplasmic enzymes.70

AMINOTRANSFERASES AND VITAMIN B6 STATUS

As noted earlier, some analytical procedures fail to include exoge-nous pyridoxal phosphate. As a consequence, these techniques to deter-mine aminotransferase activity measure two variables: an activity that isdirectly proportional to the enzyme itself and also directly related to thepyridoxal phosphate concentration. Therefore, factors leading to poorvitamin B6 status often result in a low aminotransferase activity in suchassays. Since the apo-aminotransferases are less stable and more easilyirreversibly denatured than the bolo- forms, addition of exogenous pyri-

678 ROBERT REJ

doxal phosphate may not fully compensate for poor vitamin B6 status. Ithas been suggested that carbamylation of apo-AST may be a mechanismfor its inactivation in uremic patients.172

It is now generally recognized that the pyridoxal phosphate status ofpatients undergoing renal dialysis is poor and artifactually low amino-transferase activities are often observed in these cases. 8,19, so, 81, s2 Apo-

enzyme may represent half of the aminotransferase in serum. It hasbeen recommended that assays with exogenous pyridoxal phosphate berequired for dialysis patients in order to diagnose liver disease in thesepatients.81 Earlier reports that renal dialysis leads to increases in serumAST activity31 are likely to be due to the use of less-specific methods inwhich dialysis removes interferences of colorimetric methods. Pyridoxalphosphate depletion and differing affinities of the two aminotransferasesfor the coenzyme may be partially responsible for increased AST/ALTratio in alcoholic hepatitis.40

Other factors affecting vitamin B6 status, and consequently amino-transferase activity, include use of oral contraceptives'', 86 and cefazo-lin,48 and the presence of carpal tunnel syndrome.50' 157 Vitamin B6 statusis often poor in elderly institutionalized individuals.58 Increased serumalkaline phosphatase (EC 3.1.3.1) may also result in lower serum pyri-doxal phosphate levels (pyridoxal phosphate is a substrate for phospha-tases) and lower aminotransferase activities.'°°

OTHER CAUSES OF AMINOTRANSFERASE ELEVATION ANDMISCELLANEOUS APPLICATIONS

Elevations of aminotransferases (in particular mild elevations) with-out other laboratory test abnormalities in asymptomatic individuals areoften classified as uninterpretable. Such cases may be depreciatinglytermed "transaminitis" and frequently ignored.68 Elevated aminotrans-ferase levels discovered incidentally by screening of nonacutely ill per-sons may be caused by chronic alcoholism, chronic hepatitis, use ofhepatotoxic drugs, or other conditions. In a study of 149 asymptomaticpatients with persistent aminotransferase elevations, only two (1.3 percent) were found to be without disease, whereas 64 per cent demon-strated fatty liver and 20 per cent were found to have chronic or persist-ent hepatitis.72

Unexplained elevations in AST and ALT may indicate precirrhotichemochromatosis.87 It has been suggested that hemochromatosis be keptin mind in the evaluation of patients with "transaminitis," as this diseaseis more common than once thought and early diagnosis and treatmentcan prevent organ damage."'

Persistent aminotransferase elevations may be due to occult muscledisease148,154 and increases in both AST and ALT are associated withDuchenne's-type muscular dystrophy.'8, 96 Skeletal muscle trauma andsurgery elevate serum values." Increases have been observed in cases ofmalnutrition, 122 in favic and sickle cell subjects in crisis,103,121 in cyanideexposure,67 and in untreated T-cell variants of lymphoblastic leukemia.85Mild increases in serum AST are observed in children with rotovirus


gastroenteritis 57 in whom the tissue source may be damaged enterocytes.The higher reference values for children (see Fig. 1A) must be taken intoaccount in such infections. A dietary surplus of calories and high sucroselevels may play a role in elevation of aminotransferases. 128 Burned pa-tients demonstrate an increase that is not related to hemolytic phenom-ena occurring during burn or to early liver damage occurring at time ofburn and may be a marker of a repair process.27 Increased levels of ASTare found in heat exhaustion, and levels upon admission may be used topredict individuals who are prone to recurrence if returned to exer-cise.144 Mushroom poisoning results in large increases in serum amino-transferase activity.155

ALT exists in several phenotypes, and its genetic variants have beenused in paternity disputes.89,152 Increased ALT has been observed inrapidly progressing acute lymphoblastic leukemia.129 Both aminotrans-ferases serve as criteria for classification of severe preeclampsia, orHELLP syndrome, where elevated liver enzymes contribute to the ori-gin of the acronym.177 Lead poisoning increases both AST and ALT inserum of both humans and experimental animals but neither is an accept-able marker for routine screening. 311,170

There is a growing number of reports on complexes of both ASTisoenzymes with immunoglobulins, these are usually of the IgG class butIgA complexes have also been described .6

, 83, 109,176 Enzyme activity in

serum is usually elevated in such cases, and this phenomenon should beexamined as a source of an otherwise inexplicable increase in serum ASTactivity. Atypically migrating enzyme on electrophoresis is a facile man-ner to identify such

cases. 112,140

Measurement of aminotransferase activity in fluids other than serumprovides diagnostic information. AST levels in cerebrospinal fluid and, toa lesser extent, ALT levels, increase proportionately to the degree ofbrain injury.164 AST is a good marker for determination of the age oferythrocytes, with lower activities observed in old red blood cells.142 Inperiodontal disease high increases in AST are observed in crevicularfluid.25 Seminal AST and ALT activities correlate with sperm concentra-tion 22 ,22 ,108 and seminal AST is a reliable indicator of sperm density as wellas an indicator of cryodamage.107 AST is detectable in urine and has beenapplied to several kidney diseases but other enzymes are more useful inthis regard. AST has been used to assess viability of kidneys for transplan-tation.51

SUMMARY

Aspartate and alanine aminotransferases are two of the enzymesmost frequently measured by the clinical laboratory. They are mostcommonly used in the differential diagnosis of various liver diseaseswhere the ratio of the two enzymes provides additional clinical insight.AST is also useful in many cases for diagnosis, or estimating severity, ofmyocardial infarction. The mitochondrial isoenzyme of AST has a grow-ing significance in the diagnosis of alcoholism and other conditions.

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2. Aldenhbvel HG: The influence of long-term anticonvulsant therapy with diphenyl-hydantoin and carbamazepine on serum gamma -glutamyltransferase, aspartateaminotransferase , alanine aminotransferase and alkaline phosphatase . Eur ArchPsychiatry Neurol Sci 237:312, 1988

3. Alves PS, Camilo EA, Correia JP: The SGOT/SGPT ratio in alcoholic liver disease.Acta Med Port 3:255, 1981

4. Amano J, Sunamori M, Okumura T, et al : Studies on the significance of serum mito-chondrial aspartate aminotransferase activity following ischemic cardiac arrest.Jpn Circ J 46:1345, 1982

5. Annoni G , Chirillo R, Swannie D: Prognostic value of mitochondrial aspartate amino-transferase in acute myocardial infarction . Clin Biochem 19:235, 1986

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1989 Rej Amintransferase in Disease