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4]

Original Article

Evaluation of serum lactate dehydrogenase

in oral squamous cell carcinoma, oral leukoplakia
and oral submucous fibrosis
Atul Rathore, Anil Kumar Nagarajappa1, Sreedevi1
Department of Oral Medicine and Radiology, Index Institute of Dental Science, Indore, 1Department of Oral Medicine
and Radiology, Hitkarini Dental College and Hospital, Jabalpur, Madhya Pradesh, India

ABSTRACT

Introduction: Enzyme lactate dehydrogenase (LDH) is found in cells of almost all body tissues. Lactate dehydrogenase
activity in serum increases as a marker of cellular necrosis. Serum LDH levels have been used as an adjunct biochemical
marker in diagnosis in various pre-cancer and cancers. Aims and Objectives: To evaluate role of LDH as a biochemical
parameter in the diagnosis of oral squamous cell carcinoma (OSCC), oral leukoplakia (OL) and oral submucous fibrosis
(OSMF), to assess the levels of serum LDH in OSCC, OL and OSMF and to compare the same with normal individuals.
Materials and Methods: A total of 120 patients were recruited for the study including 30 patients of OSCC, 30 patients
of OL, 30 patients of OSMF and 30 normal controls. All were divided into age groups (20-60 years) irrespective of sex.
From five milliliters of blood drawn under aseptic conditions, the serum was separated. The sample was subjected to
biochemical analysis for quantitative estimation of serum LDH by a semi auto-analyzer. Results: It was observed that
serum LDH activity was significantly (P < 0.05) increased in patients with OSCC, OL and OSMF. Conclusion: Serum LDH
estimation can prove to be a valuable tool as a biochemical marker as it is a simple, non-invasive procedure and is easily
accepted by the patient.
Key words: Lactate dehydrogenase, leukoplakia, oral squamous cell carcinoma, oral sub-mucous fibrosis, serum

Introduction more common as compared to developed countries.

India tops in prevalence of oral cancer in the world

C
ancer is one of the leading causes of adult deaths and oral cancer remains the commonest cancer among
worldwide. Oral cancer is a serious problem male population. Oral cancer is the third-most common
in many countries. It accounts for significant
cancer in India after cervical and breast cancer among
mortality and is also responsible for extensive
women.[2]
disfigurement, loss of function, behavioral changes,
financial and sociologic hardship.[1] In India the
This is an open access article distributed under the terms of the
incidence of oral cancer is about three to seven times
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License, which allows others to remix, tweak, and build upon the
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How to cite this article: Rathore A, Nagarajappa AK, Sreedevi.

DOI: Evaluation of serum lactate dehydrogenase in oral squamous cell
10.4103/0972-1363.167071
carcinoma, oral leukoplakia and oral submucous fibrosis. J Indian
Acad Oral Med Radiol 2015;27:29-34.

Address for correspondence: Dr. Atul Rathore, Department of Oral Medicine and Radiology, Index Institute of Dental Science,
Indore - 452 009, Madhya Pradesh, India. E-mail: drrathore20@gmail.com
Received: 19-02-2015 Accepted: 03-07-2015 Published: 12-10-2015

© 2015 Journal of Indian Academy of Oral Medicine and Radiology | Published by Wolters Kluwer - Medknow 29
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Rathore A et al.: Evaluation of serum lactate dehydrogenase
Classic features may include a white lesion, red lesion,
mixed red/white lesion, lump, ulcer with fissuring or
raised exophytic margins, pain or numbness, abnormal
blood vessels supplying a lump, loose tooth, unhealing
extraction socket, induration, fixation of a lesion to
deeper tissues, lymph node enlargement, dysphagia
and weight loss.[3] Premalignant lesions and conditions
such as leukoplakia, erythroplakia, oral sub-mucous
fibrosis (OSMF), and lichen planus are very common in
the general population. These lesions are precursors of
oral cancer. The role of dentist is very important in early
detection and management of precancer.
Recently, the role of tumor markers in management of
head and neck cancer has received increased attention.
Among all the body fluids, blood has been the media
of choice for the study of the biochemical markers.
Increased serum lactate dehydrogenase (LDH) activity
is considered as a marker of cellular necrosis and serum
LDH levels have been used as a biochemical marker in
diagnosis in various cancers such as oral, laryngeal and
breast cancer. Studies have also suggested that increased
levels of LDH in serum are seen in patients with oral
leukoplakia (OL), OSMF and oral squamous cell
carcinoma (OSCC).[4-6] Lactate dehydrogenase activity
is mainly due to genomic changes during malignant
transformation. Increased LDH levels are due to
increased mitotic index and more lactic acid production
by tumor cells due to breakdown of glycoprotein. Value
of LDH elevates in OSCC and potentially malignant
disorders; this finding can be used for benefit of the
patient in predicting prognosis.[4,7-13]
Materials and Methods
This study was approved by the ethical committee and
review board of the concerned institution. A total of 120
patients were recruited for the study viz, 30 patients of
OSCC, 30 patients of OL, 30 patients of OSMF and 30
normal subjects as controls. Thirty OSCC patients were
recruited from the Oncology Department of Netaji
Subhash Chandra Bose Medical College and Hospital,
Jabalpur, Madhya Pradesh (M.P.). All 30 patients
were histopathologically diagnosed as OSCC. Thirty
patients of OSMF, 30 patients of OL and 30 normal
subjects were recruited from the out patients attending
Hitkarini Dental College and Hospital, Jabalpur,
M.P. The 30 OSMF patients and 30 OL patients were
clinically examined and diagnosed. Later they were
confirmed histopathologically following punch biopsy
at the Department of Oral Medicine and Radiology
and Department of Oral Pathology, Hitkarini Dental
College and Hospital, Jabalpur, M.P. Duly signed
informed consent was obtained from every individual
participating in the study.
30 Journal of Indian Academy of Oral Medicine & Radiology | Jan-Mar 2015 | Vol 27 | Issue 1
Inclusion criteria
• Patient’s willingness to participate.
• Subjects in the age group of 20-60 years irrespective
of sex.
• Histopathologically diagnosed patients of OSCC,
OL and OSMF.
Exclusion criteria
• Patient not willing for participation in the study.
• Patients undergoing chemotherapy, radiotherapy
or any surgical procedure for OSCC.[8]
• Patients with a history of heart failure (myocardial
infarction) within past 2 weeks.[14]
• Patient taking procainamides and other drugs used
to treat arrhythmia, pulmonary infarction and
stroke.[15]
• Patients suffering from hepatitis, hypothyroidism,
anemia (hemolytic or pernicious anemia), lung
disease, liver disease, kidney disease, pancreatitis,
muscle trauma, and muscular dystrophy.[14,16,17]
• Patients with history of consumption of aspirin,
narcotics or alcohol, and recent anesthesia.[18]
Collection of blood sample
Collection of serum sample was done by the method
recommended by National Institute of Health (NIH
- Bethesda, MD, USA, 2009). Five milliliters of blood
was drawn from the peripheral veins (Brachial or Anti-
cubital Vein) under aseptic conditions. Collected blood
sample was kept in test tubes at room temperature for
30-60 minutes to allow sedimentation of cellular fraction
of blood. Later, the sedimented blood sample was
centrifuged at 3000 rpm for 10-15 minutes. Supernatant
serum was separated out with the help of a micro-pipette.
The quantification of LDH procedure was carried out at
the General Pathology Department, Jabalpur Hospital
and Research Centre, Jabalpur on the same day that the
blood was drawn.
Biochemical analysis
Biochemical analysis was carried out with a semi-
automated machine (Biochemistry Analyzer Prietest
EXP made by Rich Industry Limited, Kolkata, India)
and ENZOPAK (UV- Kinetic) reagent kit was used
which was manufactured by Reckon Diagnostic
Pvt. Ltd., Vadodara, India. The kit contained 1 LDH
(Coenzyme) and 2 LDH (Buffered substrate). One
tablet of 1 LDH with 1.1 ml of 2 LDH were mixed
gently to dissolve their contents. They were used after
5 minutes. It works on the principle that LDH catalyzes
the oxidation of lactate to pyruvate accompanied by
the simultaneous reduction of NAD to NADH. LDH
activity in serum is proportional to the increase in
absorbance due to the reduction of NAD.
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Rathore A et al.: Evaluation of serum lactate dehydrogenase

Now 1 ml of working reagent was mixed with 0.05 ml
of the serum sample. Reading of first absorbance of the
test was noted exactly at 1 minute and thereafter at 30,
60 and 90 seconds at 340 nm of light. Determination
of mean change in absorbance per minute and
calculation of test results in the semi-automated
biochemistry analyzer was done and the results were
obtained.
Results
The data obtained was analyzed using the SPSS software
18 for windows. Appropriate univariate and bivariate
analysis were carried out using the Student ‘t’ test for
the continuous variable (age) and two-tailed Fisher exact
test or chi-square (χ2) test for categorical variables. The
comparisons of mean LDH levels between four groups
were done using ANOVA followed by Bonferroni
post-hoc test for multiple comparisons.
Age and sex-wise distribution of study groups
and controls
In general, males were more commonly affected in all
three study groups when compared with controls. Oral
squamous cell carcinoma was most commonly seen
between 4 th and 6 th decades, OL between 3 rd and 5 th
decades and OSMF between 2nd and 4th decades.
247.57 ± 47.58 IU/L for males, 263.40 ± 10.74 IU/L for
females and total of 249.68 ± 44.65 IU/L [Table 1 and
Graph 1].
Inter-group comparison for mean value of LDH levels
for male subjects in OSCC was signifi cantly higher
than control, OL and OSMF groups (P < 0.0001). The
mean value of LDH levels in male subjects of OL and
OSMF were signifi cantly higher when compared to
mean LDH levels of control group subjects. When
value of LDH levels of male subjects of OL group were
compared with male subjects of OSMF group, mean
LDH levels of OL group was significantly increased
(P < 0.01). Similarly mean value of LDH levels for
female subjects between OSCC group subjects and
control and OSMF group subjects showed significantly
very high levels of LDH (P < 0.0001). Mean LDH levels
in OSMF subjects were also higher from control group
(P < 0.0001). The OL group did not have any female
subjects.
Overall comparison of mean LDH levels
Mean LDH level in control group, OSCC group, OL
group and OSMF group subjects was 161.39 ± 36.14 IU/L,
323.83 ± 46.80 IU/L, 277.91 ± 33.34 IU/L and 249.68 ± 44.65

Sex-wise comparison of LDH levels between study

population and controls
In the control group subjects, the mean value of LDH
was 162.44 IU/L ± 37.05 for males, 146.70 ± 18.80 IU/L
for females and total of 161.39 ± 36.14 IU/L. In the OSCC
subjects mean value of LDH was 323.18 IU/L ± 49.49 for
males, 327.04 ± 34.16 IU/L for females and total of 323.83
± 46.80 IU/L. In the OL subjects mean value of LDH was
277.91 ± 33.34 IU/L for males and total of 277.91 IU/L Graph 1: Sex-wise comparison of LDH levels between study population
± 33.34. In the OSMF subjects mean value of LDH was and controls

Table 1: Sex-wise comparison of LDH levels between study population and controls
Groups Male Female Total
Controls 162.44±37.05 146.70±18.80 161.39±36.14
(1) (n=28) (n=2) (n=30)
OSCC 323.18±49.49 327.04±34.16 323.83±46.80
(2) (n=25) (n=5) (n=30)
OL 277.91±33.34 277.91±33.34
(3) (n=30) (n=30)
OSMF 247.57±47.58 263.40±10.74 249.68±44.65
(4) (n=26) (n=4) (n=30)
Total 251.39±71.79 271.10±72.25 253.2±71.75
(n=109) (n=11) (n=120)
Significance t1/2=13.26; P<0.0001 t1/2=8.91; P<0.0001,
t1/3=12.45; P<0.0001 t1/3=NA,
t1/4 =7.30; P<0.0001 t1/4=8.14; P<0.0001
t2/3=3.90; P<0.0001, t2/3=NA,
t2/4=5.56; P<0.0001, t2/4=3.93; P<0.0001,
t3/4=2.72; P<0.01 t3/4=NA

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Rathore A et al.: Evaluation of serum lactate dehydrogenase

Table 2: LDH level ANOVA descriptive body fluids during neoplastic process are of clinical
Groups N Mean Standard Minimum Maximum value in the management of patients with various
deviation body cancers.[4] One of the key enzymes involved in
Controls 30 161.393 36.1497 110.3 231.2 glycolysis, the muscle isoform of lactate dehydrogenase
OSCC 30 323.830 46.8075 229.5 447.0 is overexpressed by metastatic cancer cells and is linked
OL 30 277.913 33.3457 224.2 356.8 to the vitality of tumors in hypoxia.
OSMF 30 249.688 44.6526 143.2 341.0
Total 120 253.206 71.7551 110.3 447.0 Lactate dehydrogenase is a hydrogen transfer enzyme
One way ANOVA 85.046, P-value 0.000
and is involved in the final step in the metabolic chain
of anerobic glycolysis. Lactate dehydrogenase catalyzes
Table 3: Post-hoc tests (Bonferroni multiple comparisons) the oxidation of L-lactate to pyruvate with Nicotinamide-
Comparison of groups Mean difference P-value (significance) Adenine Dinucleotide (NAD+) as the hydrogen acceptor.
OSCC and controls 162.4367* 0.0001 The enzyme is composed of four peptide chains of two
OL and controls 116.5200* 0.0001 types: M (Muscle) and H (Heart), each under separate
OSMF and controls 88.2947* 0.000
genetic control. Lactate dehydrogenase, a cytoplasmic
OSCC and OL 45.9167* 0.0001
enzyme is present essentially in all major organ systems.
OSCC and OSMF 74.1420* 0.0001
The extracellular appearance of LDH is used to detect
OL and OSMF 28.2253* 0.049
The mean difference is significant at the 0.05 level, *Significance
cell damage or cell death.

Results of our study suggested that males were more

Graph 2: Comparison of mean LDH levels in study groups and controls,
*Significance
IU/L, respectively [Tables 2 and 3, and Graph 2]. ANOVA
results showed a significant F ratio (F = 85.046; P < 0.0001)
and individual group comparison using Bonferroni post
hoc tests showed a significantly very high mean LDH
levels with OSCC subjects and very low levels in controls.
Mean LDH levels of OSCC subjects were significantly
higher than OL and OSMF group subjects. Mean levels
of LDH of OL and OSMF group subjects were also found
significantly different. Results clearly suggest that mean
levels of LDH were significantly higher in OL and OSMF
group subjects compared to the control subjects.
Discussion
Oral cancer often presents a clinical diagnostic challenge
to the dental practitioner, particularly in its early stage
of development. Typically, they tend to be preceded by
a premalignant state for a long time.[19,20] It is believed
that the etiology is multi-factorial and the process is
multiple stepwise one. The role of carcinogens such
as tobacco and alcohol has been well established. [1]
Tumor markers present in serum, tissue and other
commonly affected than females in all groups. Mean
age of occurrence in OSCC group was highest when
compared with OL, OSMF and control group. Mean
age in OL group was higher than OSMF and control.
Similar observations were made in studies conducted
by Cunmigaiper et al. (1998), Narang et al. (2001) and
Sciubba (1995).[5,21,22] Individual group comparison using
Bonferroni post-hoc tests showed a significantly very high
mean LDH levels with OSCC subjects and very low levels
in controls. Mean LDH levels of OSCC subjects were
significantly higher than OL and OSMF group subjects.
These findings are supported by the studies conducted
by other investigators.[9-11,23-25] Mean levels of LDH of OL
and OSMF group subjects were also found significantly
different. Results clearly suggest that mean levels of LDH
were significantly higher in OL and OSMF group subjects
compared to control subjects. Similar observations
were made in studies conducted by various other
investigators.[4-6,26] Significant elevated mean LDH levels
were found in serum of patients indulging in various
kinds of adverse habits i.e., betel nut[27,28] and smoking.[29]
Joshi et al. (2012) found increased serum and salivary
LDH levels in all cases in OL and OSCC groups in
comparison with the control group, but the increase in
LDH levels was less in saliva as compared to serum in
group II OL patients. The increase in LDH levels was
consistent in saliva and serum of OSCC patients.[4] Shklar
(1966) conducted a study on epidermoid carcinoma of
oral mucosa which showed a notable increase in LDH
activity.[9] Masahiro et al. (1971) correlated clinical and

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Rathore A et al.: Evaluation of serum lactate dehydrogenase
experimental activity of serum LDH and its isoenzymes in
oral cancer and noted increased levels.[23] Ninomiya et al.
(1985) stated that neoplastic cells showed morphologic
and enzymatic changes indicating incomplete cellular
destruction; dilatation of capillary vessels was also
found. LDH isozyme pattern displayed a high level
of LDH 5 in the non-treated OSCC, and following
cryosurgery, it decreased and revealed an approximately
normal LDH 5 pattern.[24] Gorogh et al. (1990) studied
serum LDH isoenzymes in OSCC. They concluded that
the percentage distribution of serum LDH isoenzymes
may represent a useful parameter of disease activity
in patients with OSCC.[10] Dreyfuss et al. (1992) in their
study found that LDH and carcino-embryonic antigen
(CEA) elevations correlated primarily with the presence
of distant metastases.[11] Mody et al. (1994) found that
there was a significant correlation between the degree
of differentiation of OSCC and serum LDH.[25] Liaw et al.
(1997) estimated serum LDH values in patients with
nasopharyngeal carcinoma. The results showed higher
serum LDH values in patients with metastatic disease.
They concluded that serum LDH levels correlate with
the clinical responsiveness to systemic chemotherapy.[12]
Narang et al. (2001) found that of all the three parameters
they studied which were raised irrespective of the
site and the character of the tumor, only LDH was
significantly raised in the metastatic group compared to
the non-metastatic group.[21] Hong et al. (2010) in their
study observed reactivity of Hypoxia-induced Factor 1 a
(HIF-1a), PDK 1 (pyruvate dehydrogenase kinase 1) and
LDH 5 in 29, 32 and 54 patients, respectively, and found
that the expression levels of the three biomarkers were
significantly correlated.[13] Rajendran (1994) confirmed
a positive relation between OSMF and serum LDH
isoenzyme pattern.[30] Anuradha et al. (1998) in their
study found that the activity of LDH in the serum of
OSMF patients was significantly higher than the normal
patients.[5] Kamath et al. (2013) in their study found that
tissue breakdown releases LDH; and therefore, LDH can
be measured as a surrogate for tissue breakdown, e.g.,
hemolysis. Elevated levels were seen in OSMF patients
indicating evidence of tissue breakdown.[6] The results of
our study suggest that elevation of LDH above baseline
is a specific marker for OSCC, OL and OSMF.
Conclusion
Based on our study results it can be concluded that the
activities of LDH enzyme was significantly increased
in potentially malignant disorders (like OL, OSMF) and
OSCC patients. Therefore, quantification of serum LDH
can be used as a biochemical marker, as it is simple and
easily accepted by the patient. An attempt should be
made to integrate the simultaneous testing of different
serum molecular markers in order to raise the possibility
Journal of Indian Academy of Oral Medicine & Radiology | Jan-Mar 2015 | Vol 27 | Issue 1
of an accurate diagnosis by simply using micro- and
nano-electrical-mechanical systems biosensors.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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