The Clinical Value of Lactate Dehydrogenase in Serum: A ... · The Clinical Value of Lactate Dehydrogenase in Serum: A Quantitative Review HenkJ. Huijgen1, Gerard T. B. Sanders1,

Eur J Clin Chem Clin Biochem 1997; 35(8):569-579 © 1997 by Walter de Gruyter · Berlin · New York

REVIEW

The Clinical Value of Lactate Dehydrogenase in Serum:A Quantitative Review

HenkJ. Huijgen1, Gerard T. B. Sanders1, Rudolph W. Koster2, Johan Vreeken" and Patrick M. M. Bossuyt4

1 Afdeling Klinische Chemie2 Cardiologie3 Interne Geneeskunde4 Klinische Epidemiologie en BiostatistiekAcademisch Medisch Centrum, Universiteit van Amsterdam, Amsterdam, The Netherlands

Summary: The aim of this article is to describe guidelines for rational use of lactate dehydrogenase and itsisoenzymes, in the diagnostic processes and during follow-up, based on a systematic review of relevant literature.Sources of data for this study were English-language scientific publications, obtained from the database of theNational Library of Medicine (Medline), concerning the clinical application (diagnosis, monitoring or treatment ofdisease) of lactate dehydrogenase and lactate dehydrogenase isoenzyme measurements in serum in the followingmain clinical fields: cardiology, hepatology, haematology and oncology. For acceptance in the present review,studies had to include: a proper definition of the tested patient population, diagnostic criteria, sampling time,sampling frequency, and test characteristics.Estimation of the relation between lactate dehydrogenase or lactate dehydrogenase isoenzymes and specific diseasesexpressed as sensitivity, specificity, survival or remission rate were extracted.The application of serum lactate dehydrogenase is relevant in the diagnosis of myocardial infarction (late detection),haemolytic anaemia, ovarian dysgerminoma and testicular germ cell tumour. For monitoring the progress of adisease lactate dehydrogenase is relevant in establishing the survival duration and rate in Hodgkin's disease andnon-Hodgkin's lymphoma, and in the follow-up of ovarian dysgerminoma. Rational use of lactate dehydrogenasecan be achieved when requests for its determination are limited to the above mentioned conditions. No rationalecould be found for measuring lactate dehydrogenase isoenzymes.

Introduction ment of liver enzymes, and the American Medical Associ-A proper way to reduce the number of requests for diag- ation in its Diagnostic and Therapeutic Technology As-nostic laboratory tests is to identify those clinical situa- sessment project started from the laboratory test itself, bytions in which the requested test provides critically use- establishing the efficiency of maternal serum a-fetopro-ful information. This can be achieved either by focusing tein testingin detecting Down's Syndrome (5).primarily on the differential diagnosis or on the labora- This article describes the results of a systematic reviewtory test itself. The former approach is included in text- of relevant literature on the clinical value of the determi-books of medicine, in which several diseases are de- nation of lactate dehydrogenase1) and its isoenzymes inscribed complete with the matching laboratory tests. We Semrrl5 and gives an indication of when and when not tohave chosen the latter approach, i. e. we have evaluated request this laboratory test,the usefulness of one laboratory test in different clin-ical situations.There are several publications on the guidelines for evalu- ') Enzymes mentioned in the text:ating diagnostic tests (1,2), but the use of the test as the Lactate dehydrogenase:starting-point of the investigation is mentioned in only a ^lactate : NAD+ oxidoreductase, EC 1.1.1.27._ , . . . ,.„ A 1 0 . 1 Creatine kinase:few cases, each involving a different approach. Sox et al. adenosine triphosphate creatine N-phosphotransferase,(3) screened the literature on erythrocyte sedimentation EC 2.7.3.2.rate, and their study resulted in guidelines for rational use. Enolase:,, , „ „ ^ , . ,.. _f j ,.· phosphopyruvate hydratase, EC 4.2.1.11.Veldhuyzen van Zanten et al. (4) performed a prospective Mkaline phosphatase:

study to test the clinical importance of routine measure- orthophosphoric-monoester phosphohydrolase, EC 3.1.3.1.

570 Huijgen et al.: Clinical value of lactate dehydrogenase in serum

Searching Methods

According to six textbooks of medicine, there are four main clinicalfields in which serum lactate dehydrogenase is applicable to thediagnosis and treatment of patients: cardiology, hepatology, haema-tology and oncology (6—11). Lactate dehydrogenase was evaluatedby reviewing relevant literature obtained with the aid of the compu-terized bibliographic search systems, Compact Search Cambridge(cardiology and hepatology) and Silver Platter (Spirs) version 3.1(haematology and oncology). The relevance of all selected paperswas judged by applying pre-defined criteria for inclusion. Effec-tiveness of lactate dehydrogenase was in most clinical fields ex-pressed by sensitivity and specificity. In haematology and oncol-ogy, however, remission and survival rate were frequently usedtest criteria. Our goal was to look for English-language scientificpublications about the relation between lactate dehydrogenase andlactate dehydrogenase isoenzyme measurements in human serumand the four clinical specialities. The applied search strategieswere:

Cardiology

First, the titles of the manuscripts published in 1987-1996 had tocontain the terms "lactate dehydrogenase" and "myocardial". Se-cond, "lactate dehydrogenase", "myocardial" and "creatine" had tobe defined as major or minor subject headings, used in the title orused in the abstracts of manuscripts published in 1988—1996.

Hepatology

First, the title of the manuscript had to contain the terms "lactatedehydrogenase" and "liver". Second, the major subject headings"liver function tests" and "liver disease" were combined with themajor subject heading "lactate dehydrogenase". Both strategieswere used for searching the period 1983 — 1996.

Haematology

The medical subject heading (MeSH) term "lactate dehydrogenase"was combined with "leukaemia", "anaemia" and "neoplasm inva-siveness", respectively, all from the Thesaurus list. The subjectheading list contained the subjects "analysis, blood, diagnostic use"and "therapy". In this way the years 1985—1996 were searched.With the search strategy of combining "lactate dehydrogenase"with "anaemia, megaloblastic, Hodgkin and non-Hodgkin", respec-tively, and the subject headings "analysis, blood, diagnostic useand therapy", the years 1985 — 1996 were searched. These MeSHterms were obtained from the Thesaurus list as well.

Oncology

The MeSH term "lactate dehydrogenase" was combined with "tu-mour-marker-biology" and "neoplasm invasiveness", respectively,both from the Thesaurus list. The subject heading list contained thesubjects "analysis, blood, diagnostic use" and "therapy". In thisway the period 1985—1996 was searched.

The references mentioned in all selected publications were the nextsource of information. Relevance of all papers was judged by ap-plying inclusion criteria. We selected publications describing theclinical value (diagnosis, monitoring or treatment of the disease)of lactate dehydrogenase or lactate dehydrogenase isoenzyme mea-surements in serum. In these publications a proper definition of thetested patient population, diagnostic criteria (gold standard), sam-ple time, sample frequency, and test characteristics like sensitivityand specificity of lactate dehydrogenase with regard to a specificdisease had to be described. However, handling of these inclusioncriteria depends on the clinical field for which lactate dehydroge-nase was used. For cardiology (acute myocardial infarction) aproper definition of the tested population, sampling moment andfrequency must be clarified, while in the case of tumour diagnosisthe precise time and frequency of sampling are less important. Inall studies confirmation of the disease (gold standard) without useof lactate dehydrogenase should be properly defined, in oncologyfor instance by use of histological investigation and in acute myo-

cardial infarction patients by ECG and a typical creatine kinaseMB1) value or pattern.

Results

Cardiology

The applied search criteria resulted in 34 publications.Ten publications plus 5 references (12—26), all aboutacute myocardial infarction, were included. The testedpopulation of most studies consisted of consecutive pa-tients admitted to a coronary care unit, but populationsof geriatric patients and patients selected by the labora-tory computer were also described. Criteria used for di-agnosing creatine kinase MB differed strongly betweenthe authors or were not even stated, as were sample timeand frequency. In most manuscripts test characteristicslike sensitivity and specificity were mentioned. In othercases they could be calculated, using data from tablesand/or figures. Because the subject heading "creatine"was used in the second search, studies on lactate dehy-drogenase and creatine kinase isoenzyme MB could alsobe included. After selection and combination of the mostappropriate studies, validation of the lactate dehydroge-nase determination and comparison with creatine kinaseMB activity at different time intervals became possible(17, 23-26).

Loughlin et al. (17) did not specify their gold standardfor acute myocardial infarction, but further informationshowed that they had used the diagnostic criteria from aperceding study, including positive creatine kinase MBactivity (29). Galbraith et al. (23) used receiver-operat-ing characteristic (ROC) curves to assess the diagnosticutility of lactate dehydrogenase, lactate dehydrogenase-1 and several isoenzyme ratios at 6 hour intervals up to95 hours after the onset of a myocardial infarction, asdid Jensen et al. for lactate dehydrogenase-1 on fiveconsecutive days (24). Levinson et al. (25) showedROC-curves for the lactate dehydrogenase-1 /lactate de-ny drogenase-2 ratio, lactate dehydrogenase-1 (U/l) andlactate dehydrogenase-1 (%) measured in samples ob-tained within 24 hours after admission, and Painter etal. (26) compared a new lactate dehydrogenase-1 assaywith existing lactate dehydrogenase-1 methods. Becauseresults of the lactate dehydrogenase-1/lactate dehydro-genase-2 ratio (25) and the existing lactate dehydroge-nase-1 method (26) were used for diagnosing acute myo-cardial infarction, published characteristics based onthese measurements are not presented in this review. Af-ter combining results of all authors, ROC curves couldbe drawn for the first 24 hours after onset of complaints,and also for the optimum time interval (see figs. 1 and2). Serum lactate dehydrogenase and lactate dehydroge-nase isoenzyme measurements at about 24 hours afterthe first onset of pain resulted in sensitivities of about95% and specificities of less than 90%, with the excep-

Huijgen et al.: Clinical value of lactate dehydrogenase in serum 571

, ,

tν'Μ§

CO

100-,

95-

90-

85-

80-

75-

70-

65-

60-

55-

50-

^ Δ +

+ +

^Δ

° +

10 15100 - Specificity [%]

50

Fig. 1 Sensitivity and specificity of D lactate dehydrogenase(U/l), + lactate dehydrogenase-1 (U/l), O lactate dehydrogenase-1(%), Δ lactate dehydrogenase-1/lactate dehydrogenase-2 and Xlactate dehydrogenase-1/lactate dehydrogenase-4 determined about24 hours after the first onset of pain (17, 23-26).

100Ί

95-

90-

^ 85-

ί: 80-ί "-Φ 70-CO

65-

60-

55-

50.10 15 20 25 30 35 40

100-Specificity [%]45 50

Fig. 2 Sensitivity and specificity of lactate dehydrogenase andlactate dehydrogenase isoenzymes determined at their optimumtime interval. D lactate dehydrogenase (U/l), 19-24h; + lactatedehydrogenase-1 (UA), 19—24 h, 48 h; O lactate dehydrogenase-1(%), 67—72 h; Δ lactate dehydrogenase-1/lactate dehydrogenase-243—48 h, 55—60 h; X lactate dehydrogenase-1/lactate dehydroge-nase-4 31-60 h, 55-60 h (17, 23, 24).

tion of the lactate dehydrogenase-1 (U/l) (24, 25). Onthe other hand, creatine kinase MB measurements at thesame time interval resulted in sensitivity and specificityvalues which were comparable or even better (14, 26—28). When measurements were performed in blood ob-tained at the optimum time interval, both specificity andsensitivity of the lactate dehydrogenase determinationsincreased to above 90%. However, Galbraith et al. (23)did not register an improvement (increment of the areaunder the curve) when measuring lactate dehydrogenaseor lactate dehydrogenase-1 (expressed in U/l) at timeintervals other than at 19—24 hours. Best results wereobtained by measuring the ratio lactate dehydroge-nase-1/lactate dehydrogenase-4 and lactate dehydroge-nase-1/lactate dehydrogenase-2 in blood samples whichhad been drawn 31—60 hours after the onset of com-plaints.

Hepatology

The activity (U/g) of lactate dehydrogenase in liver cells(95% of which is lactate dehydrogenase-5) is about 1/3ofthat of myocardial cells, but 1800 times that in serum(30). For this reason Lott et al. (30) and Zimmerman (31)considered lactate dehydrogenase as a possible enzymetest for the diagnostic use in liver disease, although thelatter drew attention to the relatively moderate elevationof lactate dehydrogenase. Sherlock (32) pointed out thestrong rise in activity in neoplasmic liver disease andconsidered it to be a rather insensitive determination forother forms of liver disease. Johnson & McFarlain didnot even mention lactate dehydrogenase in their workon "The laboratory investigation of liver disease" (33).

The first screening in the search strategy resulted in 661articles published between 1983 and 1996. Only a fewof these indicated a close relation between lactate dehy-drogenase, its isoenzymes and the liver. In three of theselected articles an overview was given of laboratoryinvestigations in liver disease. Chopra et al. (34) consid-ered the lactate dehydrogenase determination to be non-specific; only a continuous elevation in combinationwith a high level of alkaline phosphatase1) could betaken as an indication of liver metastases. Reichling etal. (35) pointed out that lactate dehydrogenase is lessspecific than the transaminases and thus of smaller diag-nostic value. Other authors reviewing the relevance ofenzyme tests in liver disease never mentioned lactatedehydrogenase (36—38). Finally, an editorial in TheJournal of the American Medical Association com-mented on lactate dehydrogenase as the least specificenzyme test in liver disease (39).

The two fields in which lactate dehydrogenase (and itsisoenzymes) are claimed to contribute are tumour diag-nostics and liver transplantation. On suspicion of livermetastases the determination of lactate dehydrogenaseand lactate dehydrogenase isoenzymes was reported togive a valuable contribution to the final diagnosis (40).However, in the differentiation of a primary liver tumourfrom secondary metastases, the determination of a-feto-protein is more powerful (41). In orthotopic liver trans-plantation performed in paediatric patients, the lactatedehydrogenase-5/lactate dehydrogenase-2 ratio seems tobe a good indicator of early graft function and complica-tions (42).

Haematology

The search strategy resulted in 93 publications on themeasurement of the activities of lactate dehydrogenaseand lactate dehydrogenase isoenzymes in serum and alltypes of blood cells. Studies on serum lactate dehydro-genase measurements in four frequently reported leukae-mias were included (acute- and chronic lymphatic leu-kaemia, and acute and chronic myeloid leukaemia), as


well as studies on anaemia (megaloblastic, haemolyticand iron deficiency), Hodgkin's disease and non-Hodg-kin's lymphoma. These criteria resulted in 24 publica-tions (43—64, 65, 68). Patients in whom non-Hodgkin'slymphoma was diagnosed, were mostly classified ac-cording to the histopathological classification scheme ofKiel. Classifications according to Rappaport or Lennert(low-, intermediate- and high grade) were used too. AnnArbor criteria, used for clinical staging (stage I—IV),were applied in 6 of the 10 selected manuscripts. Testcharacteristics used were mean serum lactate dehydro-genase activity, sensitivity, specificity, remission dura-tion and rate, and survival duration and rate. Most au-thors divided the tested population into different groupsbased on the measured lactate dehydrogenase activity,the grade of malignancy or stage of disease, and estab-lished the remission- or survival rate subsequently. Forcomparison, we processed the data from these studies inthe following way. First, the mean lactate dehydrogenaseactivity of the patient populations tested was divided bythe upper reference limit. Higs nmez et al. (45) did notgive their reference interval; therefore we chose an arbi-trary upper reference limit of 450 U/l. Second, the re-mission- and survival duration and rate of the patientpopulation with a normal lactate dehydrogenase activitywas divided by the duration and rate of the patients withan elevated lactate dehydrogenase activity. In this waydifferent remission and survival intervals could be com-bined in one table.

Leukaemia

The highest lactate dehydrogenase activity and sensitiv-ity was measured in acute lymphatic leukaemia. Inchronic myeloid leukaemia, the activity and sensitivityof lactate dehydrogenase varied strongly: 1.9—3.9 timesthe upper limit of normal, and 33%—100%, respectively(tab. 1). Flanagan et al. (49) measured increased valuesin all their chronic myeloid leukaemia patients, butKornberg et al. (43) only detected high values in sam-ples of chronic myeloid leukaemia patients sufferingfrom a blastic crisis; whether Flanagan's populationconsists of patients with blastic crises is unknown. Patelet al. (50) measured in their chronic myeloid leukaemiapopulation a mean lactate dehydrogenase value of 575U/l which is 3 times the upper reference limit, and theycalculated the sensitivity and specificity for leukaemiain general. The chronic myeloid leukaemia patientstested by Buchsbaum et al. (51) were divided into twogroups, remission or not; sensitivity and specificity forlactate dehydrogenase-3 were 90% and 72%, respec-tively. In both acute myeloid- and chronic lymphatic leu-kaemia, lactate dehydrogenase activity was hardly ele-vated and a low sensitivity was found. A negative corre-lation between the duration of the remission and serumlactate dehydrogenase activity was demonstrated in

acute lymphatic- and acute myeloid leukaemia patients(44, 47, 48).

Anaemia

In almost all megaloblastic and haemolytic anaemia pa-tients a high serum lactate dehydrogenase activity wasdetected (52, 53). The highest values measured in mega-loblastic anaemia were up to 29 times the upper refer-ence limit. Carmel et al. (54) reported a study on serumtransferrin receptor in megaloblastic anaemia due to co-balamin deficiency. Only 19 of their 32 patients had apathological lactate dehydrogenase value. However, notall patients had megaloblastic anaemia as suggested inthe title of their manuscript, and diagnostic criteria werenot clearly defined. In iron-deficiency anaemia, the se-rum lactate dehydrogenase remained normal. Because ofthe high concentration in erythrocytes, lactate dehydro-genase is a good marker for haemolysis. A free haemo-globin concentration in serum of 6—12 μηιοΐ/ΐ causedby disrupted erythrocytes, results in an increased lactatedehydrogenase activity of 10-20 U/l (55, 56).

Hodgkin s disease

Two of the selected studies concerned Hodgkin 's disease(49, 59). Sensitivity was very low, and increased serumlactate dehydrogenase values were found only in very illpatients. Schilling et al. (59) demonstrated a significantreduction of survival with increasing serum lactate de-hydrogenase activity. The median survival of Hodgkinpatients with lactate dehydrogenase below the upper ref-erence limit was 129 months, and above the upper refer-ence limit the median survival was 39 months.

Non-Hodgkin lymphoma

In serum of low grade, stage I—II non-Hodgkin pa-tients, both the mean serum lactate dehydrogenase ac-tivity and sensitivity were low. Increased activitieswere found in stage IV patients and high grade lym-phoma (49, 60-62, 64, 65). However, Lindh et al.(64) measured a low lactate dehydrogenase activity innearly all low grade non-Hodgkin patients whetherthey were classified stage I, II, III or IV. The correla-tion of an unfavourable histopathological classificationwith high serum lactate dehydrogenase activities hasalready been reported by Erickson & Morales in 1961(66, 67). In all clinical situations, the sensitivity wasless than 61%. Two authors determined lactate dehy-drogenase isoenzymes in the serum of non-Hodgkinpatients. Ricerra et al. (62) measured a disturbed ratio,namely decreased lactate dehydrogenase-1 andincreased lactate dehydrogenase-3 fractions, which oc-curred in all stages and classifications of the disease,while Ferraris et al. (57) could not find any significantmodification of the isoenzyme pattern.


Tab. 1 Clinical value of lactate dehydrogenase in haematology

Disease(References)

ActivityMultiple of upperlimit of normal

Sensitivity Remission

Duration Rate

Acute lymphatic leukaemia (43, 44-46, 48, 50)Acute myeloid leukaemia (43, 47, 50)Chronic lymphatic leukaemia (43, 49)

Chronic myeloid leukaemia (43, 49, 50)lactate dehydrogenase-3 (51)

Anaemia: (52, 53)megaloblasticiron deficiencyhaemolytic

3.3-3.91.0-2.51.0

1.9-3.9

6.41.02.4

7926-680.29

33-10090

88-1000100

2-32

Specificity

nsns

72 72

Hodgkin's disease (49, 59)

non-Hodgkin's disease (49, 57—64)low gradeb

high grade

1.0

1.0-1.53.0-3.3°

31-38

11-3842-60

Survival

Duration

3

3-16

Rate

2.3-3.53.32.2-5.5

Activity is defined as measured activity divided by the upper limitof normal; remission- and survival duration or rate are defined asthe duration or rate in the patient population with a normal lactatedehydrogenase activity divided by the duration or rate in the patientpopulation with an elevated lactate dehydrogenase activity; rate:the percentage of patients who survived or attained remission; ns:the difference between the remission rate in patients with a normallactate dehydrogenase and patients with an elevated lactate dehy-drogenase was not significant;

a in one publication only the activity interval was published; thisis indicated by —»;b grade of malignancy according to Kiel histopathological classifi-cation;c In the study of Lindh et al. four patients had extremely highlactate dehydrogenase values (9—19 times the reference value), allwith evidence of liver dysfunction (64).

The prognostic value of serum lactate dehydrogenase (innon-Hodgkin's lymphoma was determined in two dif-ferent ways: survival duration and survival rate (prob-ability of survival). Ferraris et al. (57) divided their non-Hodgkin population into three groups with a low, me-dian and high lactate dehydrogenase activity. The me-dian survival of these groups was 72.5, 31.1 and 4.6months, respectively. The survival rate was measured bysix different authors after 2, 3 and 5 years. All demon-strated a negative correlation between the pretreatmentserum lactate dehydrogenase activity and the probabilityof survival (58, 60, 51, 63—65). After autologous bonemarrow transplantation lactate dehydrogenase was oneof the main prognostic markers associated with a shortdisease-free survival. In transplanted patients, a high lac-tate dehydrogenase level was associated with a 2.5 timesincrease in relapse rate (68).

Oncology

The search criteria resulted in 208 articles covering awide field and a variety of different diseases. From therelevant publications those neoplasms which were en-countered twice or more were included. In this way 16publications about ovarian dysgerminoma, small celllung cancer and testicular germ cell tumour (seminoma

and non-seminoma) were selected (69-73, 76—78, 80-83, 85-88).

Ovarian dysgerminoma

Four of the five publications on this rare disease werecase reports; the remaining one was a small review (69—73). Because two of the selected publications containedresults about α-fetoprotein, carcinoembryonic antigenand human chorionic gonadotropin measurements indysgerminoma and primary carcinoma of the ovary,comparison of lactate dehydrogenase with these markerswas possible (tab. 2). To assess diagnostic strength, twoother studies about lactate dehydrogenase and lactate de-hydrogenase isoenzymes in patients with primary carci-noma of the ovary have been included for comparison(74, 75). Sensitivity and specificity of lactate dehydro-genase was calculated by comparing 5 patients positivefor ovarian dysgerminoma with 69 patients sufferingfrom all other kinds of malignant and benign ovariantumours (70). Kikuchi et al. (75) determined sensitivityand specificity hi 57 patients with primary carcinoma ofthe ovary, and compared the obtained results with thosefrom 220 patients with benign ovarian tumours. Othertest characteristics used were median activity and re-sponse to therapy (tab. 2).


Tab. 2 Clinical value of lactate dehydrogenase in oncology: Ovarian dysgerminoma

Laboratory test(References)

ActivityMultiple of upperlimit of normal

Sensitivity Specificity Responseto therapy

Ovarian dysgerminomaLactate dehydrogenase (69—73)Lactate dehydrogenase-1—3 (69, 70)a-Fetoprotein (69, 71)Carcinoembryonin antigen (69, 71)Human chorionic β gonadotropin (69, 72)

Other ovarian tumours0

Lactate dehydrogenase (70, 74, 75)Lactate dehydrogenase-1 (74)Lactate dehydrogenase-4 (75)

4.5(1.1-109)elevated111-18.6

1.41.12.2

92-100 66a 100

42-717142

87b

93b66

Specificity based on:a 74 ovarian tumours (different types) including 5 dysgerminoma;b 57 primary carcinoma and 220 benign tumours of the ovary;c serous cystadeno-, mucious cystadeno-, endometroid-, meso-nephroid- and clear cell carcinom;

In all the reported cases of ovarian dysgerminomaonly one patient had a normal serum lactate dehydro-genase while the others showed elevated values up to109 times the upper reference limit. Thus, sensitivityis nearly 100%, but specificity only 66% (70). Afterremoval of the tumour, serum lactate dehydrogenasedecreased, and recurrence of the disease was accompa-nied by re-elevation of lactate dehydrogenase (72, 73).Measurement of the isoenzymes showed an elevatedlactate dehydrogenase-1 to lactate dehydrogenase-3, orchanging fractions, depending on the progress of thedisease (69, 73). In one case, an elevated β humanchorionic gonadotropin was reported (69), while inthat of Pressley et al. both β human chorionic gonado-tropin and α-fetoprotein were negative (72). Sensitivityof lactate dehydrogenase and lactate dehydrogenaseisoenzymes for other ovarian tumours was less, but aspecificity of nearly 90% or even 93% was found forlactate dehydrogenase-4.

Small cell lung cancer

Seven of the eight manuscripts were included. In thesestudies small cell lung cancer was histologically proven.In the remaining one the authors mentioned only thatthey had reviewed the cases of 103 small cell lung can-cer patients (79). In five studies the change of lactatedehydrogenase as an indicator of response to therapywas determined. One author calculated the relation be-tween the response to therapy and the lactate dehydroge-nase level at presentation (81). Other test characteristicsused were median activity, sensitivity, specificity andsurvival rate. In several studies the patient populationwas divided into two groups, depending on the spread ofthe tumour: limited (local) disease and extended disease.Starting from these groups, test characteristics were de-termined. Four authors also measured neuron-specific

activity is defined as measured activity divided by the upper limitof normal

enolase1) in addition to serum lactate dehydrogenase ac-tivity (78, 80-82). Compilation of these results in ta-ble 3 enables a comparison between the two potentialtumour markers.An elevated mean lactate dehydrogenase activity wasfound only in the serum of small cell lung cancer pa-tients with extended disease (results not shown). Thesensitivity is therefore low (78, 80, 82). Cerny et al. (77)and Lassen et al. (83) reported a survival rate of patientswith an elevated lactate dehydrogenase which was abouthalf that of the group with a normal lactate dehydroge-nase. In the population of Johnson et al. (81), all patientswith an elevated lactate dehydrogenase died within twoyears, while 23% of the group with a low lactate dehy-drogenase survived. Progression of the disease was asso-ciated with an increase in lactate dehydrogenase in only56% of the patients. In 93% of the patients progressionwas associated with an increase in neuron-specific eno-lase (82). The sensitivity and survival rate for neuron-specific enolase, like its ability to indicate the responseto therapy, exceed those of lactate dehydrogenase (78,82). On the other hand, lactate dehydrogenase levelsabove normal when measured at presentation were sig-nificantly associated with a low response to therapy,while neuron-specific enolase levels did not correlatewith the response to treatment.

Testicular germ cell tumour

Of the five selected manuscripts about testicular germcell tumour, three were published by von Eyben et al.(84, 85, 88). In two of these manuscripts the same pa-tient population was described, we therefore ruled outthe oldest one (84). The two remaining studies con-cerned testicular germ cell tumours (seminoma and non-seminomas). Munro et al. (87) and Foss et al. (86) se-lected patients suffering from pure seminomas. Except


Tab. 3 Clinical value of lactate dehydrogenase in oncology: Small cell lung cancer

Laboratory test Stage Sensitivity(References) of (%)

disease

Survival Response to therapy (%)rale)

Change inmarker level

Correlation with markerat presentation

Lactate dehydrogenase(76-83)

Id + ed 37-58 2-23 33-96 81 low lactate dehydrogenase55 high lactate dehydrogenase

Neuron specific enolase(78, 80-82)

Ided

Id + edIded

21-3842-68

77-85 2769-8783-86

98-100 no correlation

Id: limited disease; ed: extended disease; patient population with an elevated lactate dehydrogenase activity;survival rate is defined as the rate in the patient population with a rate is the percentage of patients who survived,normal lactate dehydrogenase activity divided by the rate in the

for the latter publication, diagnosis of testicular germcell tumour was histologically proven by all authors.Three authors included a reference population in theirstudy: patients with a benign testis disorder, and peoplewithout disease (85, 86, 87). In one study the patientpopulation was divided randomly into two groups: onegroup to obtain a data set for generating work hypothe-ses/strategies based on the performance of the measuredtumour markers, and the second one as a test set to in-vestigate the generated hypotheses. The results obtainedfrom the data generating set were given by ROC curvesfrom which the sensitivity and specificity of the tumourmarkers could be read (87). The test characteristics(likelihood ratio, true positive and false positive rate)obtained with the strategy which performed best (a com-bination of β human chorionic gonadotropin, placentalalkaline phosphatase and lactate dehydrogenase) wererecalculated to the matching sensitivity and specificity.Other test characteristics used were mean activity andsurvival rate.

Sensitivity of all tumour markers including lactate dehy-drogenase in testicular germ cell tumour is low (table 4).

The best results (71%) were obtained with lactate dehy-drogenase-1. The specificity of most markers was quitehigh, especially for lactate dehydrogenase-1 and β hu-man chorionic gonadotropin. A combination of β humanchorionic gonadotropin or lactate dehydrogenase andplacental alkaline phosphatase, did not result in muchextra information when compared with a single -hu-man chorionic gonadotropin measurement. When com-paring initially β human chorionic gonadotropin nega-tive patients with patients who have elevated pre-treat-ment β human chorionic gonadotropin, no significantdifference in survival was measured. Using lactate de-hydrogenase as a marker, patients with a low startingvalue seem to have a poorer prognosis than the patientpopulation with an elevated lactate dehydrogenase(86). However, in a study of von Eyben, lactate dehy-drogenase-1 was found to be a significant predictor ofsurvival. After 3 years, 100% survival was measuredin testicular germ cell tumour patients with pre-treat-ment normal lactate dehydrogenase-1 versus 60% sur-vival in the patient population with an elevated lactatedehydrogenase-1.

Tab. 4 Clinical value of lactate dehydrogenase in oncology: Testicular germ cell tumour

Laboratory test(References)

Lactate dehydrogenase (86—88)Lactate dehydrogenase- 1 (85, 88)a-Fetoprotein (85, 88)Human chorionic gonadotropin (85—88)Placental alkaline phosphatase (87)Human chorionic gonadotropin or lactate dehydrogenase

and placental alkaline phosphatased (87)

Activity SensitivityMultiple of upper (%)limit of normal

2.51.5

4.73.3

40-607129-4524-504554

Specificity(%)

93b-95c

100a

99-1008298

Survival rate

0.6 ρ = 0.081.7

1.4 ρ = 0.17

Activity is defined as measured activity divided by the upper limitof normal; survival rate are defined as the rate in the patient pop-ulation with a normal lactate dehydrogenase activity divided by therate in the patient population with an elevated lactate dehydroge-nase activity;rate: the percentage of patients who survived;specificity based on:

a 25 benign and 21 malignant tumours,b 22 patients suspected of testes cancer with benign histology and105 malignant tumours,c 1717 samples from patients known to be disease free;d human chorionic gonadotropin > 61 U/l or lactate dehydroge-nase > 400 U/l and placental alkaline phosphatase > 60 U/l.


Discussion

The enzyme lactate dehydrogenase is distributed widelyin the body. This fact, together with the general trendtowards rationalization of laboratory requests, raisesdoubts about the relevance of lactate dehydrogenase inmedicine. To identify clinical situations in which the de-termination of lactate dehydrogenase and its isoenzymesin serum are of real value, we reviewed relevant litera-ture obtained by a computerized bibliographic searchsystem. In trying to structure the evaluation process wedefined four main clinical fields: cardiology, hepatology,haematology and oncology. We realize that working inthis way probably excludes a few clinical applicationsof lactate dehydrogenase, but they concern only a veryminor fraction of all lactate dehydrogenases measuredin our laboratory.

A systematic literature search like this presents the stateof the art over a short period of time. In all applicationsreported technical progress can lead to better diagnostictools. These may change the diagnostic efficiency of lac-tate dehydrogenase; the diagnosis of Pneumocystis cari-nii pneumonia serves as an example. Thus, in both "In-ternal medicine" by Stein et al. and the "Cecil textbookof medicine" (9, 11) lactate dehydrogenase is mentionedas a sensitive marker of Pneumocystis carinii pneumo-nia, based on a publication of Zaman et al. (89). Thisstudy appeared in 1988 which for Pneumocystis cariniipneumonia is a long time ago. In the early days of ac-quired immunodeficiency syndrome (AIDS), the diag-nosis of Pneumocystis carinii pneumonia was estab-lished in a late stage, since clinicians were at the timeunacquainted with this disease. Therefore, the lungswere already damaged, which resulted in high levels oflactate dehydrogenase. Nowadays, Pneumocystis cariniipneumonia is diagnosed in an early stage by detectingPneumocystis in bronchoalveolar lavage fluid. So, theincreased clinical experience resulted in a lower sensi-tivity of lactate dehydrogenase, which rendered lactatedehydrogenase obsolete as a diagnostic tool in Pneumo-cystis carinii pneumonia.

In cardiology the measurement of lactate dehydrogenaseand lactate dehydrogenase isoenzymes is a good methodfor the late detection (> 36—48 hours after the first on-set of complaints) of a myocardial infarction (see figures1 and 2). In particular, the lactate dehydrogenase-1 /lac-tate dehydrogenase-2 ratio with a diagnostic efficiencyof 93%—98% gives the best information. For an earlydiagnosis, the determination of creatine kinase MB issuperior, particularly in its specificity, to the lactate de-hydrogenase and lactate dehydrogenase isoenzyme de-termination.

To monitor non-cancer disease in the liver neither lactatedehydrogenase nor its isoenzymes make a real contribu-tion to the diagnostic process. Ample alternatives with

higher sensitivity and specificity exist. Although littlehas been published on the use of lactate dehydrogenaseand lactate dehydrogenase isoenzymes in liver malig-nancies, the enzyme does not emerge as the method ofchoice in this field of clinical enzymology at all.

In haematology lactate dehydrogenase is of little diag-nostic value. It makes a substantial contribution only inmegaloblastic- and haemolytic anaemia. However, lac-tate dehydrogenase-3 isoenzyme seems to be a usefulmarker for detecting chronic myeloid leukaemia andmonitoring changes of active disease into remission.Prognostic value could be attributed to lactate dehydro-genase for Hodgkin's disease and non-Hodgkin's lym-phoma survival; duration and rate decrease with a higherpre-treatment lactate dehydrogenase activity.

Presumably because dysgerminoma is a rare disease, noextensive studies on the diagnostic value of lactate dehy-drogenase were found during the literature search. How-ever, from the few case reports and the review it canbe concluded that lactate dehydrogenase is valuable indiagnosis and follow up of therapy control.

In cases of small cell lung cancer, lactate dehydrogenaseperforms less than neuron-specific enolase; both mark-ers have a prognostic value in survival and can be usedin monitoring the therapy. The only advantage of lactatedehydrogenase over neuron-specific enolase seems to bethe correlation between the marker level at presentationand the response to therapy.

In testicular germ cell tumour, lactate dehydrogenase-1isoenzyme shows the best sensitivity and specificity, aswell as prediction of survival. A good alternative is βhuman chorionic gonadotropin. Combination of β hu-man chorionic gonadotropin, lactate dehydrogenase andplacental alkaline phosphatase increases the low sensi-tivity (50%) by only 4%.

The final conclusions concerning relevant indicationsfor the determination of total serum lactate dehydroge-nase and in some cases its isoenzymes are: determina-tion of serum lactate dehydrogenase is significant in thelate detection of myocardial infarction, diagnosis ofmegaloblastic and haemolytic anaemia, establishing thesurvival duration and rate in Hodgkin's disease and non-Hodgkin's lymphoma, and diagnosis and follow up ofovarian dysgerminoma. Lactate dehydrogenase-1 isoen-zyme is a rather sensitive marker in the diagnosis oftesticular germ cell tumour. When the indications forlactate dehydrogenase are confined to the above clinicalsituations, lactate dehydrogenase will no longer be usedin a non-specific manner as the "erythrocyte sedimenta-tion rate of clinical enzymology".

In our opinion in clinical chemistry this kind of system-atic review should be performed for the top 50, and pos-sibly more, determinations. We realize this is a complex


task, especially when the test of choice, in this case lac-tate dehydrogenase, is used in nearly all medical disci-plines. On the other hand, we think that especially thesegenerally used laboratory tests need to be examined.

Only then will clinical chemistry be able to present itselfas a clinical discipline with clear indications of how touse the data it produces.

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Received February 14/May 16, 1997Corresponding author: Henk J. Huijgen, Academic MedicalCentre, University of Amsterdam, Department of ClinicalChemistry F1-217, PO Box 22700, NL-1100 DE Amsterdam, TheNetherlands

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The Clinical Value of Lactate Dehydrogenase in Serum: A ... · The Clinical Value of Lactate Dehydrogenase in Serum: A Quantitative Review HenkJ. Huijgen1, Gerard T. B. Sanders1,