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The clinical value of lactate dehydrogenase in serum: A quantitative review

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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 Chemie
2
Cardiologie
3
Interne Geneeskunde
4
Klinische Epidemiologie en Biostatistiek
Academisch 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 its
isoenzymes, 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 the
National Library of Medicine (Medline), concerning the clinical application (diagnosis, monitoring or treatment of
disease) of lactate dehydrogenase and lactate dehydrogenase isoenzyme measurements in serum in the following
main 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 diseases
expressed 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 a
disease lactate dehydrogenase is relevant in establishing the survival duration and rate in Hodgkin's disease and
non-Hodgkin's lymphoma, and in the follow-up of ovarian dysgerminoma. Rational use of lactate dehydrogenase
can be achieved when requests for its determination are limited to the above mentioned conditions. No rationale
could 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-
nostic laboratory tests is to identify those clinical situa-
tions in which the requested test provides critically use-
ful information. This can be achieved either by focusing
primarily on the differential diagnosis or on the labora-
tory test itself. The former approach is included in text-
books of medicine, in which several diseases are de-
scribed complete with the matching laboratory tests. We
have chosen the latter approach, i. e. we have evaluated
the usefulness of one laboratory test in different clin-
ical situations.
There are several publications on the guidelines for evalu-
ating diagnostic tests (1,2), but the use of the test as the
starting-point of the investigation is mentioned in only a
_ , . . . ,.„ A 1 0 . 1
few cases, each involving a different approach. Sox et al.
(3) screened the literature on erythrocyte sedimentation
rate, and their study resulted in guidelines for rational use.
,, , „ „ ^ , . ,.. _f j ,.·
Veldhuyzen van Zanten et al. (4) performed a prospective
study to test the clinical importance of routine measure-
ation in its
Diagnostic and Therapeutic Technology As-
se
ssment project started from the laboratory test itself, by
establishing the efficiency of maternal serum a-fetopro-
tein testin in
g detecting Down's Syndrome (5).
This article describes the results of a systematic review
of relevant literature on the clinical value of the determi-
nation of lactate dehydrogenase1) and its isoenzymes in
Semrrl5 and gives an indication of when and when not to
request this laboratory test,
') Enzymes mentioned in the text:
Lactate dehydrogenase:
^lactate : NAD+ oxidoreductase, EC 1.1.1.27.
Creatine kinase:
adenosine triphosphate creatine N-phosphotransferase,
EC 2.7.3.2.
Enolase:
phosphopyruvate hydratase, EC 4.2.1.11.
Mkaline phosphatase:
orthophosphoric-monoester phosphohydrolase, EC 3.1.3.1.
570
Searching Methods
According to six textbooks of medicine, there are four main clinical
fields in which serum lactate dehydrogenase is applicable to the
diagnosis and treatment of patients: cardiology, hepatology, haema-
tology and oncology (6—11). Lactate dehydrogenase was evaluated
by 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 papers
was 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 used
test criteria. Our goal was to look for English-language scientific
publications about the relation between lactate dehydrogenase and
lactate dehydrogenase isoenzyme measurements in human serum
and the four clinical specialities. The applied search strategies
were:
Cardiology
First, the titles of the manuscripts published in 1987-1996 had to
contain the terms "lactate dehydrogenase" and "myocardial". Se-
cond, "lactate dehydrogenase", "myocardial" and "creatine" had to
be defined as major or minor subject headings, used in the title or
used in the abstracts of manuscripts published in 1988—1996.
Hepatology
First, the title of the manuscript had to contain the terms "lactate
dehydrogenase" and "liver". Second, the major subject headings
"liver function tests" and "liver disease" were combined with the
major subject heading "lactate dehydrogenase". Both strategies
were 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 subject
heading 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 use
and therapy", the years 1985 — 1996 were searched. These MeSH
terms 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 the
subjects "analysis, blood, diagnostic use" and "therapy". In this
way the period 1985—1996 was searched.
The references mentioned in all selected publications were the next
source of information. Relevance of all papers was judged by ap-
plying inclusion criteria. We selected publications describing the
clinical 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 the
tested patient population, diagnostic criteria (gold standard), sam-
ple time, sample frequency, and test characteristics like sensitivity
and specificity of lactate dehydrogenase with regard to a specific
disease had to be described. However, handling of these inclusion
criteria depends on the clinical field for which lactate dehydroge-
nase was used. For cardiology (acute myocardial infarction) a
proper definition of the tested population, sampling moment and
frequency must be clarified, while in the case of tumour diagnosis
the precise time and frequency of sampling are less important. In
all studies confirmation of the disease (gold standard) without use
of lactate dehydrogenase should be properly defined, in oncology
for instance by use of histological investigation and in acute myo-
Huijgen et al.: Clinical value of lactate dehydrogenase in serum
cardial infarction patients by ECG and a typical creatine kinase
MB1) value or pattern.
Results
Cardiology
The applied search criteria resulted in 34 publications.
Ten publications plus 5 references (12—26), all about
acute myocardial infarction, were included. The tested
population of most studies consisted of consecutive pa-
tients admitted to a coronary care unit, but populations
of geriatric patients and patients selected by the labora-
tory computer were also described. Criteria used for di-
agnosing creatine kinase MB differed strongly between
the authors or were not even stated, as were sample time
and frequency. In most manuscripts test characteristics
like sensitivity and specificity were mentioned. In other
cases they could be calculated, using data from tables
and/or figures. Because the subject heading "creatine"
was used in the second search, studies on lactate dehy-
drogenase and creatine kinase isoenzyme MB could also
be included. After selection and combination of the most
appropriate studies, validation of the lactate dehydroge-
nase determination and comparison with creatine kinase
MB activity at different time intervals became possible
(17, 23-26).
Loughlin et al. (17) did not specify their gold standard
for acute myocardial infarction, but further information
showed that they had used the diagnostic criteria from a
perceding study, including positive creatine kinase MB
activity (29). Galbraith et al. (23) used receiver-operat-
ing characteristic (ROC) curves to assess the diagnostic
utility of lactate dehydrogenase, lactate dehydrogenase-
1 and several isoenzyme ratios at 6 hour intervals up to
95 hours after the onset of a myocardial infarction, as
did Jensen et al. for lactate dehydrogenase-1 on five
consecutive days (24). Levinson et al. (25) showed
ROC-curves for the lactate dehydrogenase-1 /lactate de-
ny drogenase-2 ratio, lactate dehydrogenase-1 (U/l) and
lactate dehydrogenase-1 (%) measured in samples ob-
tained within 24 hours after admission, and Painter et
al. (26) compared a new lactate dehydrogenase-1 assay
with existing lactate dehydrogenase-1 methods. Because
results 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 on
these measurements are not presented in this review. Af-
ter combining results of all authors, ROC curves could
be drawn for the first 24 hours after onset of complaints,
and also for the optimum time interval (see figs. 1 and
2). Serum lactate dehydrogenase and lactate dehydroge-
nase isoenzyme measurements at about 24 hours after
the first onset of pain resulted in sensitivities of about
95% and specificities of less than 90%, with the excep-
Huijgen et al.: Clinical value of lactate dehydrogenase in serum 571

100-, Hepatology
95- ^ Δ +
+
The activity (U/g) of lactate dehydrogenase in liver cells
90- +
(95% of which is lactate dehydrogenase-5) is about 1/3
, , 85-
^ ofthat of myocardial cells, but 1800 times that in serum
t
ν
'Μ
80-
75- Δ
(30). For this reason Lott et al. (30) and Zimmerman (31)
considered lactate dehydrogenase as a possible enzyme
§
CO
70- ° + test for the diagnostic use in liver disease, although the
65- latter drew attention to the relatively moderate elevation
60- of lactate dehydrogenase. Sherlock (32) pointed out the
55- strong rise in activity in neoplasmic liver disease and
50-
10 15 50
considered it to be a rather insensitive determination for
100 - Specificity [%] other forms of liver disease. Johnson & McFarlain did
not even mention lactate dehydrogenase in their work
Fig. 1 Sensitivity and specificity of D lactate dehydrogenase on "The laboratory investigation of liver disease" (33).
(U/l), + lactate dehydrogenase-1 (U/l), O lactate dehydrogenase-1
(%), Δ lactate dehydrogenase-1/lactate dehydrogenase-2 and X The first screening in the search strategy resulted in 661
lactate dehydrogenase-1/lactate dehydrogenase-4 determined about
24 hours after the first onset of pain (17, 23-26). articles published between 1983 and 1996. Only a few
of these indicated a close relation between lactate dehy-
drogenase, its isoenzymes and the liver. In three of the
100Ί
selected articles an overview was given of laboratory
95-
investigations in liver disease. Chopra et al. (34) consid-
90-
ered the lactate dehydrogenase determination to be non-
^ 85-
specific; only a continuous elevation in combination
ί: 80- with a high level of alkaline phosphatase1) could be
ί "- taken as an indication of liver metastases. Reichling et
Φ
CO
70- al. (35) pointed out that lactate dehydrogenase is less
65- specific than the transaminases and thus of smaller diag-
60- nostic value. Other authors reviewing the relevance of
55- enzyme tests in liver disease never mentioned lactate
50. dehydrogenase (36—38). Finally, an editorial in The
10 15 20 25 30 35 40 45 50
Journal of the American Medical Association com-
100-Specificity [%]
mented on lactate dehydrogenase as the least specific
Fig. 2 Sensitivity and specificity of lactate dehydrogenase and enzyme test in liver disease (39).
lactate dehydrogenase isoenzymes determined at their optimum
time interval. D lactate dehydrogenase (U/l), 19-24h; + lactate
The two fields in which lactate dehydrogenase (and its
dehydrogenase-1 (UA), 19—24 h, 48 h; O lactate dehydrogenase-1
isoenzymes) are claimed to contribute are tumour diag-
(%), 67—72 h; Δ lactate dehydrogenase-1/lactate dehydrogenase-2
nostics and liver transplantation. On suspicion of liver
43—48 h, 55—60 h; X lactate dehydrogenase-1/lactate dehydroge-
nase-4 31-60 h, 55-60 h (17, 23, 24). metastases the determination of lactate dehydrogenase
and lactate dehydrogenase isoenzymes was reported to
tion of the lactate dehydrogenase-1 (U/l) (24, 25). On give a valuable contribution to the final diagnosis (40).
the other hand, creatine kinase MB measurements at the However, in the differentiation of a primary liver tumour
same time interval resulted in sensitivity and specificity from secondary metastases, the determination of a-feto-
values which were comparable or even better (14, 26— protein is more powerful (41). In orthotopic liver trans-
28). When measurements were performed in blood ob- plantation performed in paediatric patients, the lactate
tained at the optimum time interval, both specificity and dehydrogenase-5/lactate dehydrogenase-2 ratio seems to
sensitivity of the lactate dehydrogenase determinations be a good indicator of early graft function and complica-
increased to above 90%. However, Galbraith et al. (23) tions (42).
did not register an improvement (increment of the area
under the curve) when measuring lactate dehydrogenase Haematology
or lactate dehydrogenase-1 (expressed in U/l) at time The search strategy resulted in 93 publications on the
intervals other than at 19—24 hours. Best results were measurement of the activities of lactate dehydrogenase
obtained by measuring the ratio lactate dehydroge- and lactate dehydrogenase isoenzymes in serum and all
nase-1/lactate dehydrogenase-4 and lactate dehydroge- types of blood cells. Studies on serum lactate dehydro-
nase-1/lactate dehydrogenase-2 in blood samples which genase measurements in four frequently reported leukae-
had been drawn 31—60 hours after the onset of com- mias were included (acute- and chronic lymphatic leu-
plaints. kaemia, and acute and chronic myeloid leukaemia), as
572
well as studies on anaemia (megaloblastic, haemolytic
and 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's
lymphoma was diagnosed, were mostly classified ac-
cording to the histopathological classification scheme of
Kiel. Classifications according to Rappaport or Lennert
(low-, intermediate- and high grade) were used too. Ann
Arbor criteria, used for clinical staging (stage I—IV),
were applied in 6 of the 10 selected manuscripts. Test
characteristics 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 groups
based on the measured lactate dehydrogenase activity,
the grade of malignancy or stage of disease, and estab-
lished the remission- or survival rate subsequently. For
comparison, we processed the data from these studies in
the following way. First, the mean lactate dehydrogenase
activity of the patient populations tested was divided by
the upper reference limit. Higs nmez et al. (45) did not
give 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 patient
population with a normal lactate dehydrogenase activity
was divided by the duration and rate of the patients with
an elevated lactate dehydrogenase activity. In this way
different 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. In
chronic myeloid leukaemia, the activity and sensitivity
of lactate dehydrogenase varied strongly: 1.9—3.9 times
the upper limit of normal, and 33%—100%, respectively
(tab. 1). Flanagan et al. (49) measured increased values
in all their chronic myeloid leukaemia patients, but
Kornberg et al. (43) only detected high values in sam-
ples of chronic myeloid leukaemia patients suffering
from a blastic crisis; whether Flanagan's population
consists of patients with blastic crises is unknown. Patel
et al. (50) measured in their chronic myeloid leukaemia
population a mean lactate dehydrogenase value of 575
U/l which is 3 times the upper reference limit, and they
calculated the sensitivity and specificity for leukaemia
in general. The chronic myeloid leukaemia patients
tested by Buchsbaum et al. (51) were divided into two
groups, remission or not; sensitivity and specificity for
lactate 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 serum
lactate dehydrogenase activity was demonstrated in
Huijgen et al.: Clinical value of lactate dehydrogenase in serum
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 was
detected (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 serum
transferrin receptor in megaloblastic anaemia due to co-
balamin deficiency. Only 19 of their 32 patients had a
pathological lactate dehydrogenase value. However, not
all patients had megaloblastic anaemia as suggested in
the title of their manuscript, and diagnostic criteria were
not clearly defined. In iron-deficiency anaemia, the se-
rum lactate dehydrogenase remained normal. Because of
the 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 caused
by disrupted erythrocytes, results in an increased lactate
dehydrogenase 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 serum
lactate dehydrogenase values were found only in very ill
patients. Schilling et al. (59) demonstrated a significant
reduction of survival with increasing serum lactate de-
hydrogenase activity. The median survival of Hodgkin
patients 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 activities
were 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 in
nearly all low grade non-Hodgkin patients whether
they were classified stage I, II, III or IV. The correla-
tion of an unfavourable histopathological classification
with high serum lactate dehydrogenase activities has
already been reported by Erickson & Morales in 1961
(66, 67). In all clinical situations, the sensitivity was
less than 61%. Two authors determined lactate dehy-
drogenase isoenzymes in the serum of non-Hodgkin
patients. Ricerra et al. (62) measured a disturbed ratio,
namely decreased lactate dehydrogenase-1 and
increased lactate dehydrogenase-3 fractions, which oc-
curred in all stages and classifications of the disease,
while Ferraris et al. (57) could not find any significant
modification of the isoenzyme pattern.
Huijgen et al.: Clinical value of lactate dehydrogenase in serum 573

Tab. 1 Clinical value of lactate dehydrogenase in haematology

Disease Activity Sensitivity Remission

(References) Multiple of upper
limit of normal Duration Rate

Acute lymphatic leukaemia (43, 44-46, 48, 50) 3.3-3.9 79 2-3 ns

Acute myeloid leukaemia (43, 47, 50) 1.0-2.5 26-68 2 ns
Chronic lymphatic leukaemia (43, 49) 1.0 0.29
Specificity

Chronic myeloid leukaemia (43, 49, 50) 1.9-3.9 33-100

lactate dehydrogenase-3 (51) 90 72 72

Anaemia: (52, 53)

megaloblastic 6.4 88-100
iron deficiency 1.0 0
haemolytic 2.4 100
Survival

Duration Rate

Hodgkin's disease (49, 59) 1.0 31-38 3

non-Hodgkin's disease (49, 57—64) 3-16 2.3-3.5
low gradeb 1.0-1.5 11-38 3.3
high grade 3.0-3.3° 42-60 2.2-5.5
a
Activity is defined as measured activity divided by the upper limit in one publication only the activity interval was published; this
of normal; remission- and survival duration or rate are defined as is indicated by —»;
b
the duration or rate in the patient population with a normal lactate grade of malignancy according to Kiel histopathological classifi-
dehydrogenase activity divided by the duration or rate in the patient cation;
c
population with an elevated lactate dehydrogenase activity; rate: In the study of Lindh et al. four patients had extremely high
the percentage of patients who survived or attained remission; ns: lactate dehydrogenase values (9—19 times the reference value), all
the difference between the remission rate in patients with a normal with evidence of liver dysfunction (64).
lactate dehydrogenase and patients with an elevated lactate dehy-
drogenase was not significant;

The prognostic value of serum lactate dehydrogenase (in
non-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 4.6
months, respectively. The survival rate was measured by
six different authors after 2, 3 and 5 years. All demon-
strated a negative correlation between the pretreatment
serum lactate dehydrogenase activity and the probability
of survival (58, 60, 51, 63—65). After autologous bone
marrow transplantation lactate dehydrogenase was one
of the main prognostic markers associated with a short
disease-free survival. In transplanted patients, a high lac-
tate dehydrogenase level was associated with a 2.5 times
increase in relapse rate (68).
Oncology
The search criteria resulted in 208 articles covering a
wide field and a variety of different diseases. From the
relevant publications those neoplasms which were en-
countered twice or more were included. In this way 16
publications about ovarian dysgerminoma, small cell
lung 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 were
case reports; the remaining one was a small review (69—
73). Because two of the selected publications contained
results about α-fetoprotein, carcinoembryonic antigen
and human chorionic gonadotropin measurements in
dysgerminoma and primary carcinoma of the ovary,
comparison of lactate dehydrogenase with these markers
was possible (tab. 2). To assess diagnostic strength, two
other 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 positive
for ovarian dysgerminoma with 69 patients suffering
from all other kinds of malignant and benign ovarian
tumours (70). Kikuchi et al. (75) determined sensitivity
and specificity hi 57 patients with primary carcinoma of
the ovary, and compared the obtained results with those
from 220 patients with benign ovarian tumours. Other
test characteristics used were median activity and re-
sponse to therapy (tab. 2).
574
Tab. 2 Clinical value of lactate dehydrogenase in oncology: Ovarian dysgerminoma
Laboratory test Activity
(References) Multiple of upper
limit of normal
Ovarian dysgerminoma
Lactate dehydrogenase (69—73) 4.5(1.1-109)
Lactate dehydrogenase-1—3 (69, 70) elevated
a-Fetoprotein (69, 71) 1
Carcinoembryonin antigen (69, 71) 1
Human chorionic β gonadotropin (69, 72) 1-18.6
Other ovarian tumours0
Lactate dehydrogenase (70, 74, 75) 1.4
Lactate dehydrogenase-1 (74) 1.1
Lactate dehydrogenase-4 (75) 2.2
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 dysgerminoma
only one patient had a normal serum lactate dehydro-
genase while the others showed elevated values up to
109 times the upper reference limit. Thus, sensitivity
is nearly 100%, but specificity only 66% (70). After
removal of the tumour, serum lactate dehydrogenase
decreased, and recurrence of the disease was accompa-
nied by re-elevation of lactate dehydrogenase (72, 73).
Measurement of the isoenzymes showed an elevated
lactate dehydrogenase-1 to lactate dehydrogenase-3, or
changing fractions, depending on the progress of the
disease (69, 73). In one case, an elevated β human
chorionic gonadotropin was reported (69), while in
that of Pressley et al. both β human chorionic gonado-
tropin and α-fetoprotein were negative (72). Sensitivity
of lactate dehydrogenase and lactate dehydrogenase
isoenzymes for other ovarian tumours was less, but a
specificity of nearly 90% or even 93% was found for
lactate dehydrogenase-4.
Small cell lung cancer
Seven of the eight manuscripts were included. In these
studies small cell lung cancer was histologically proven.
In the remaining one the authors mentioned only that
they had reviewed the cases of 103 small cell lung can-
cer patients (79). In five studies the change of lactate
dehydrogenase as an indicator of response to therapy
was determined. One author calculated the relation be-
tween the response to therapy and the lactate dehydroge-
nase level at presentation (81). Other test characteristics
used were median activity, sensitivity, specificity and
survival rate. In several studies the patient population
was divided into two groups, depending on the spread of
the tumour: limited (local) disease and extended disease.
Starting from these groups, test characteristics were de-
termined. Four authors also measured neuron-specific
Huijgen et al.: Clinical value of lactate dehydrogenase in serum
Sensitivity Specificity Response
to therapy
92-100 66a 100
42-71 87b
71 66
42 93b
activity is defined as measured activity divided by the upper limit
of 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 potential
tumour markers.
An elevated mean lactate dehydrogenase activity was
found only in the serum of small cell lung cancer pa-
tients with extended disease (results not shown). The
sensitivity is therefore low (78, 80, 82). Cerny et al. (77)
and Lassen et al. (83) reported a survival rate of patients
with an elevated lactate dehydrogenase which was about
half that of the group with a normal lactate dehydroge-
nase. In the population of Johnson et al. (81), all patients
with an elevated lactate dehydrogenase died within two
years, 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 only
56% of the patients. In 93% of the patients progression
was 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 response
to therapy, exceed those of lactate dehydrogenase (78,
82). On the other hand, lactate dehydrogenase levels
above normal when measured at presentation were sig-
nificantly associated with a low response to therapy,
while neuron-specific enolase levels did not correlate
with the response to treatment.
Testicular germ cell tumour
Of the five selected manuscripts about testicular germ
cell 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 out
the 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
Huijgen et al.: Clinical value of lactate dehydrogenase in serum 575

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

Laboratory test Stage Sensitivity Survival Response to therapy (%)

(References) of (%) rale)
disease Change in Correlation with marker
marker level at presentation

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

(76-83) 55 high lactate dehydrogenase
Id 21-38
ed 42-68

Neuron specific enolase Id + ed 77-85 27 98-100 no correlation

(78, 80-82) Id 69-87
ed 83-86

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 germ
cell tumour was histologically proven by all authors.
Three authors included a reference population in their
study: patients with a benign testis disorder, and people
without disease (85, 86, 87). In one study the patient
population was divided randomly into two groups: one
group to obtain a data set for generating work hypothe-
ses/strategies based on the performance of the measured
tumour markers, and the second one as a test set to in-
vestigate the generated hypotheses. The results obtained
from the data generating set were given by ROC curves
from which the sensitivity and specificity of the tumour
markers 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, placental
alkaline phosphatase and lactate dehydrogenase) were
recalculated to the matching sensitivity and specificity.
Other test characteristics used were mean activity and
survival 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 quite
high, especially for lactate dehydrogenase-1 and β hu-
man chorionic gonadotropin. A combination of β human
chorionic gonadotropin or lactate dehydrogenase and
placental alkaline phosphatase, did not result in much
extra 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 significant
difference in survival was measured. Using lactate de-
hydrogenase as a marker, patients with a low starting
value seem to have a poorer prognosis than the patient
population with an elevated lactate dehydrogenase
(86). However, in a study of von Eyben, lactate dehy-
drogenase-1 was found to be a significant predictor of
survival. After 3 years, 100% survival was measured
in testicular germ cell tumour patients with pre-treat-
ment normal lactate dehydrogenase-1 versus 60% sur-
vival in the patient population with an elevated lactate
dehydrogenase-1.

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

Laboratory test Activity Sensitivity Specificity Survival rate

(References) Multiple of upper (%) (%)
limit of normal

Lactate dehydrogenase (86—88) 2.5 40-60 93b-95c 0.6 ρ = 0.08

Lactate dehydrogenase- 1 (85, 88) 1.5 71 100a 1.7
a-Fetoprotein (85, 88) 29-45
Human chorionic gonadotropin (85—88) 4.7 24-50 99-100 1.4 ρ = 0.17
Placental alkaline phosphatase (87) 3.3 45 82
Human chorionic gonadotropin or lactate dehydrogenase 54 98
and placental alkaline phosphatased (87)
a
Activity is defined as measured activity divided by the upper limit 25 benign and 21 malignant tumours,
b
of normal; survival rate are defined as the rate in the patient pop- 22 patients suspected of testes cancer with benign histology and
ulation with a normal lactate dehydrogenase activity divided by the 105 malignant tumours,
c
rate in the patient population with an elevated lactate dehydroge- 1717 samples from patients known to be disease free;
d
nase activity; human chorionic gonadotropin > 61 U/l or lactate dehydroge-
rate: the percentage of patients who survived; nase > 400 U/l and placental alkaline phosphatase > 60 U/l.
specificity based on:
576 Huijgen et al.: Clinical value of lactate dehydrogenase in serum

Discussion higher sensitivity and specificity exist. Although little

The enzyme lactate dehydrogenase is distributed widely has been published on the use of lactate dehydrogenase
in the body. This fact, together with the general trend and lactate dehydrogenase isoenzymes in liver malig-
towards rationalization of laboratory requests, raises nancies, the enzyme does not emerge as the method of
doubts about the relevance of lactate dehydrogenase in choice in this field of clinical enzymology at all.
medicine. To identify clinical situations in which the de- In haematology lactate dehydrogenase is of little diag-
termination of lactate dehydrogenase and its isoenzymes nostic value. It makes a substantial contribution only in
in serum are of real value, we reviewed relevant litera- megaloblastic- and haemolytic anaemia. However, lac-
ture obtained by a computerized bibliographic search tate dehydrogenase-3 isoenzyme seems to be a useful
system. In trying to structure the evaluation process we marker for detecting chronic myeloid leukaemia and
defined four main clinical fields: cardiology, hepatology, monitoring changes of active disease into remission.
haematology and oncology. We realize that working in Prognostic value could be attributed to lactate dehydro-
this way probably excludes a few clinical applications genase for Hodgkin's disease and non-Hodgkin's lym-
of lactate dehydrogenase, but they concern only a very phoma survival; duration and rate decrease with a higher
minor fraction of all lactate dehydrogenases measured pre-treatment lactate dehydrogenase activity.
in our laboratory.
Presumably because dysgerminoma is a rare disease, no
A systematic literature search like this presents the state extensive studies on the diagnostic value of lactate dehy-
of the art over a short period of time. In all applications drogenase were found during the literature search. How-
reported technical progress can lead to better diagnostic ever, from the few case reports and the review it can
tools. These may change the diagnostic efficiency of lac- be concluded that lactate dehydrogenase is valuable in
tate dehydrogenase; the diagnosis of Pneumocystis cari- diagnosis and follow up of therapy control.
nii pneumonia serves as an example. Thus, in both "In-
In cases of small cell lung cancer, lactate dehydrogenase
ternal medicine" by Stein et al. and the "Cecil textbook
performs less than neuron-specific enolase; both mark-
of medicine" (9, 11) lactate dehydrogenase is mentioned
ers have a prognostic value in survival and can be used
as a sensitive marker of Pneumocystis carinii pneumo-
in monitoring the therapy. The only advantage of lactate
nia, based on a publication of Zaman et al. (89). This
dehydrogenase over neuron-specific enolase seems to be
study appeared in 1988 which for Pneumocystis carinii
the correlation between the marker level at presentation
pneumonia is a long time ago. In the early days of ac-
and the response to therapy.
quired immunodeficiency syndrome (AIDS), the diag-
nosis of Pneumocystis carinii pneumonia was estab- In testicular germ cell tumour, lactate dehydrogenase-1
lished in a late stage, since clinicians were at the time isoenzyme shows the best sensitivity and specificity, as
unacquainted with this disease. Therefore, the lungs well as prediction of survival. A good alternative is β
were already damaged, which resulted in high levels of human chorionic gonadotropin. Combination of β hu-
lactate dehydrogenase. Nowadays, Pneumocystis carinii man chorionic gonadotropin, lactate dehydrogenase and
pneumonia is diagnosed in an early stage by detecting placental alkaline phosphatase increases the low sensi-
Pneumocystis in bronchoalveolar lavage fluid. So, the tivity (50%) by only 4%.
increased clinical experience resulted in a lower sensi- The final conclusions concerning relevant indications
tivity of lactate dehydrogenase, which rendered lactate for the determination of total serum lactate dehydroge-
dehydrogenase obsolete as a diagnostic tool in Pneumo- nase and in some cases its isoenzymes are: determina-
cystis carinii pneumonia. tion of serum lactate dehydrogenase is significant in the
In cardiology the measurement of lactate dehydrogenase late detection of myocardial infarction, diagnosis of
and lactate dehydrogenase isoenzymes is a good method megaloblastic and haemolytic anaemia, establishing the
for the late detection (> 36—48 hours after the first on- survival duration and rate in Hodgkin's disease and non-
set of complaints) of a myocardial infarction (see figures Hodgkin's lymphoma, and diagnosis and follow up of
1 and 2). In particular, the lactate dehydrogenase-1 /lac- ovarian dysgerminoma. Lactate dehydrogenase-1 isoen-
tate dehydrogenase-2 ratio with a diagnostic efficiency zyme is a rather sensitive marker in the diagnosis of
of 93%—98% gives the best information. For an early testicular germ cell tumour. When the indications for
diagnosis, the determination of creatine kinase MB is lactate dehydrogenase are confined to the above clinical
superior, particularly in its specificity, to the lactate de- situations, lactate dehydrogenase will no longer be used
hydrogenase and lactate dehydrogenase isoenzyme de- in a non-specific manner as the "erythrocyte sedimenta-
termination. tion rate of clinical enzymology".
To monitor non-cancer disease in the liver neither lactate In our opinion in clinical chemistry this kind of system-
dehydrogenase nor its isoenzymes make a real contribu- atic review should be performed for the top 50, and pos-
tion to the diagnostic process. Ample alternatives with sibly more, determinations. We realize this is a complex
Huijgen et al.: Clinical value of lactate dehydrogenase in serum
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 these
generally used laboratory tests need to be examined.
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Received February 14/May 16, 1997
Corresponding author: Henk J. Huijgen, Academic Medical
Centre, University of Amsterdam, Department of Clinical
Chemistry F1-217, PO Box 22700, NL-1100 DE Amsterdam, The
Netherlands
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