Review Article

Page 1 of 15

Investigative algorithms for disorders affecting plasma lactate

dehydrogenase: a narrative review
Alexa R. Shipman1, Sayna Bahrani1, Kate E. Shipman2,3
1
Department of Dermatology, Portsmouth Hospitals University NHS Trust, Portsmouth, UK; 2Department of Clinical Chemistry, University
Hospitals Sussex NHS Foundation Trust, Worthing, UK; 3Department of Medial Education, Brighton and Sussex Medical School, Brighton, UK
Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: AR
Shipman, KE Shipman; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: AR Shipman, KE Shipman; (VI)
Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Kate E. Shipman, BMBCh, MA (Hons Oxon), MRCP, FRCPath, EuSpLM. Department of Clinical Chemistry, University Hospitals
Sussex NHS Foundation Trust, Lyndhurst Road, Worthing BN11 2DH, UK; Department of Medial Education, Brighton and Sussex Medical School,
Brighton, UK. Email: kate.shipman@nhs.net.

Background and Objective: The following article is part of a special series to aid the reader in
diagnosing the cause of various plasma derangements in humans. By the end of the article, the reader will
be able to order and interpret appropriate investigations when faced with a patient with low or high lactate
dehydrogenase (LDH) activity in plasma.
Methods: A narrative, focused literature review was performed using Medline, OMIM and Google Scholar
from April 2023 to September 2023 to identify references published from database inception to September
2023; reference lists from these articles were also used. The language was restricted to English.
Key Content and Findings: LDH is produced by all cells and can be released into plasma in a vast
number of pathological processes. Liver and red blood cells are a common source as is skin, lung, muscle,
and the gastrointestinal tract. A laboratory approach to the investigation of elevated LDH is presented, no
algorithm was produced for low LDH activity as causes are too scarce and of unlikely clinical significance.
The clinical status and condition of the patient should be considered first in order to carry out a targeted
investigation however full blood count, liver and renal function tests may be used as first line tests.
Conclusions: Diagnostic flow charts have been created to help aid healthcare professionals to investigate
the cause of elevated LDH activity where the cause is not immediately apparent. These algorithms have been
presented and created within the limitations of the laboratory tests discussed within the paper, selected to be
widely available.

Keywords: Lactate dehydrogenase (LDH); diagnosis; measurement; investigation

Received: 21 September 2023; Accepted: 19 December 2023; Published online: 15 March 2024.
doi: 10.21037/jlpm-23-65
View this article at: https://dx.doi.org/10.21037/jlpm-23-65

Introduction clinician is faced with an unwell patient and is also part of

various staging and monitoring algorithms (3). As a wide
The measurement of plasma lactate dehydrogenase (LDH) range of normal tissues and tumors can produce LDH,
initially became widespread due to its role in detecting acute an isolated elevated LDH is not diagnostic of any single
myocardial infarction (1). However, LDH gained popularity condition, therefore clinical clues and other investigations
in a wide range of medical and surgical specialties due to its are required to elucidate the cause of an LDH elevation.
almost ubiquitous tissue location (2). Plasma LDH activity The following paper will discuss how to approach
therefore may be performed as part of screens when a deviations of LDH concentrations from the normal range

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 2 of 15 Journal of Laboratory and Precision Medicine, 2024

Table 1 The search strategy summary

Items Specification

Date of search April to September 2023

Databases and other sources searched Medline, Google Scholar, OMIM

Search terms used LDH, lactate dehydrogenase, Low, High, Raised, Tissue, Activity, Drugs, Investigations,
Algorithms, Guidelines, Diagnosis, Causes, Aetiology, Human

Timeframe From database inception to September 2023

Inclusion and exclusion criteria All papers and reviews were included but restricted to English. Animal data were
excluded

Selection process A.R.S. and S.B. conducted initial search, with refinement by all other authors to obtain
consensus and agreement

Any additional considerations, if applicable Seminal texts were also searched and the references of important articles and texts
were obtained and checked for relevance
OMIM, Online Mendelian Inheritance in Man.

and provide a systematic laboratory algorithm, which can be nicotinamide adenine dinucleotide (NADH) to
used to help the clinician account for plasma LDH activity nicotinamide adenine dinucleotide (NAD+), and generates
elevation when struggling to find the diagnosis. We will adenosine triphosphate (ATP) when oxygen supplies
not cover the investigation of LDH in bodily fluids. The dwindle (3,4). At the molecular level, LDH is a tetramer
algorithms are designed for all healthcare professionals comprising two common subunits, A and B, with subunit
irrespective of their expertise, or lack of expertise, with C predominating in sperm and testes. Chromosomes 11
diagnostics and are meant to provide an up-to-date and 12 host the genes encoding these subunits and various
suggestion to guide management steps that can be validated combinations—homo- or heterotetrameric—yield a diverse
in the future in a variety of healthcare settings and patient assortment of five LDH isoforms, called LDH1 to LDH5
populations. We present this article in accordance with the (3,4). Although all these isoenzymes facilitate the same
Narrative Review reporting checklist (available at https:// catalytic reaction, their structural composition, substrate
jlpm.amegroups.org/article/view/10.21037/jlpm-23-65/rc). affinity, temperature responsiveness, and tissue-specific
distributions diverge markedly (3,4). Distinguishing
between them however is not a test commonly available to
Methods
most clinicians.
The limited narrative literature review was created by
searching Medline, Google Scholar, OMIM and seminal
How is LDH measured?
texts over the period April 2023 to September 2023.
The diagnostic algorithms were then created based on LDH is quantified by measurement of the enzymatic
the literature review by the authors. The language was activity of the specimen rather than concentration of the
restricted to English and excluded if non-human studies. enzyme. When measuring the enzyme activity one can
For further information please see Table 1. either detect the formation of lactate from pyruvate, which
is the internationally recommended reference method
described as “forward” or “lactate pyruvate (LP)”, or vice
What is LDH?
versa [“backward” or “pyruvate lactate (PL)”] (5,6). This has
LDH is a universally expressed enzyme across all cells and allowed reference material to be produced and therefore an
conserved between organisms. LDH concentrations are ability to harmonize assays internationally making reference
highest in high energy consuming organs such as muscles, liver, intervals potentially comparable (7,8). However, there is a
kidneys, lungs, heart, and blood cells (4). LDH is involved variety of methods used internationally (6). In addition to
in the anaerobic metabolic pathway (Figure 1) (3,4). LDH the direction of the reaction, different reagents and buffers
reversibly converts pyruvate to lactate, and hydrogenated can be used resulting in very discrepant results between

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 3 of 15

Glucose
Gluconeogenesis The Cori cycle Glycolysis

Skeletal
Glucose Liver or muscle Glucose
kidney

Pyruvate + NADH + H+ Pyruvate + NADH + H+

LDH LDH

LDH is found Lactate + NAD+ Lactate + NAD+

in cytosol and
mitochondria in all
cells Skeletal muscle contributes
40% of circulating lactate,
depending on rate of exercise.
Lactate The rest predominantly comes
from skin, brain, red cells and
Lactate then circulates. On gastrointestinal tract
average 20 mmol/kg/day
is produced
Most tissues can use LDH is found in the
lactate as a substrate circulation as cells
lyse or leaks

Figure 1 Lactate production and the Cori cycle. Figure to show LDH activity in glycolysis and gluconeogenesis. LDH is involved in energy
production in muscle (and other tissues) and whilst lactate will be found in normal circulation (with levels increasing with exercise). LDH
should only be present in the circulation if cells are lysed. LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; NADH,
hydrogenated nicotinamide adenine dinucleotide.

assay manufacturers preventing harmonization (9). Causes of raised LDH activity

LDH isoenzymes can be separated and quantified by
Elevated LDH activity arises due to multiple aetiological
electrophoresis but other biomarkers have replaced this test
factors affecting almost every organ system (2). Commoner
and it is no longer routinely performed (10). Electrophoresis
organ system causes of LDH elevation are either because the
may also detect ‘macroLDH’, a spurious cause of increased
tissue has greater mass, more LDH expression or because
activity (11). In the “macro” condition antibody or cell wall
the diseases are the most common. For example, in one study
components bind LDH preventing clearance and hence
of 500 people with elevated LDH activity the pathology
causing accumulation that is not related to an increased rate identified, in descending order of frequency, was (21):
of release from the tissue of origin (12).  Cardiorespiratory diseases;
Although antibody binding can cause increased  Malignancy;
accumulation of LDH, and hence an increase in serum  Fracture;
activity which can be spuriously attributed to tissue  Central nervous system disease;
damage, it may also inhibit enzymatic activity analytically  Infection/inflammation;
causing a spuriously low measured level even in the face  Hepatic cirrhosis and/or alcoholism;
of an increased serum concentration (13,14). Other causes  Trauma without fracture;
of spurious results include in vitro haemolysis releasing  Infectious mononucleosis;
LDH into the tube and elevating LDH activity in the  Hypothyroidism;
specimen (15). Spuriously raised LDH activities have also  Uraemia;
been reported secondary to triamterene (16). Potentially  Necrosis;
spuriously low LDH activities have been reported secondary  Pseudo-mononucleosis;
to hyperlipidaemia, aspirin and vitamin C (17-19). Small  Viraemia;
elevations in activity of LDH in lymphoma may not always  Intestinal obstruction;
be indicative for change in tumour burden (20).  Idiopathic in 3%.

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 4 of 15 Journal of Laboratory and Precision Medicine, 2024

Almost any pathology or organ can release LDH therefore thoroughly assess the patient clinically first in case the diagnosis
is apparent. LDH activity is used to monitor some disease activity. Organ atrophy affects biomarker performance

Raised LDH activity with no immediately obvious cause from clinical assessment

Full blood count, blood film, renal and liver function tests

Kidney Abnormal renal Abnormal liver Normal

Haematological abnormalities.
disease function function tests
Evidence of haemolysis?
Lab report ‘haemolysed’, Troponin,
anaemia, hyperbilirubinaemia, Urinalysis, BNP
raised AST, hyperkalaemia, ultrasound, Liver All Raised Raised
film, etc. autoantibodies abnormal AST ALP Abnormal
disease

Ultrasound, Creatinine Bone Cardiac

Yes No viral serology, kinase Fracture pathology
autoantibodies

See Abnormal Normal ECG and

Normal High
Figure 3 blood count or ECHO
blood film
Macro-lactate
Likely either Muscular dystrophy in dehydrogenase, drugs,
Haematological haematological, liver children, alcohol, very subtle pathology, e.g.,
malignancies, anaemia, or muscle. Consider exercise, drugs, occult cutaneous lymphoma, tumour
inflammation, infection no tissue left, e.g., seizures, trauma with possible metastases,
including viral cirrhosis or advanced idiopathic
muscle wasting, or
Consider inflammatory markers, stable chronic disease
autoantibodies, septic screen, viral Level of
Further investigation will depend on
serology, serum electrophoresis, suspicion will
Direction of investigation patient’s health and past medical
bone marrow examination, etc. dictate which
will again depend on past history, e.g., with a tumour history
depending on where suspicion investigations
medical, social, travel and a CT scan might be indicated. If
points clinically are required
drug history. well consider repeat in 3 months
or specialist
Extensiveness of investigation time to see if resolved with a
review
will depend on how well request for macroLDH studies. If
patient is persistent and of unknown origin
start algorithm again

Figure 2 Diagnostic algorithm for elevated LDH activity. LDH is produced in all tissue and so elevation of activity in human sera is
not, alone, a helpful diagnostic biochemical marker. The algorithm presented here is to help someone find a reason for LDH elevation
if the cause if not instantly obvious in the patient’s clinical presentation. It includes an approach to appropriate investigations that might
be required along with clues from history and examination. LDH, lactate dehydrogenase; AST, aspartate transaminase; ALP, alkaline
phosphatase; BNP, brain natriuretic peptide; ECG, electrocardiogram; ECHO, echocardiogram; CT, computed tomography.

One group tried to see if an elevated LDH activity tumors, liver metastases, and haematological malignancies
on admission to hospital could provide any diagnostic were more frequent in the case group and cardiovascular
or prognostic advantage (22). The cases were defined as disease more common in the controls. With 158 patients
those at hospital admission with LDH >800 IU/L [and in the case group and 188 in the control, and 14 main
aspartate transaminase/alanine transaminase (AST/ALT) diagnoses driving admission, power was limited but
<60 U/L] and the control group was those admitted with confirms the fact that LDH remains a non-specific marker
LDH <800 IU/L (and AST/ALT <60 U/L). Diagnoses were and other tests are required to reach a diagnosis. Therefore,
similar between the groups, the main notable exceptions whilst we present an algorithm (Figure 2) to help diagnose
were that infections (predominantly pulmonary), solid the cause of an elevated LDH if one is uncertain after

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 5 of 15

Suspicion of haemolysis, e.g., raised unconjugated bilirubin, LDH and reticulocytes, and low haemoglobin and haptoglobin

Urine dip

Haemoglobinuria on urine dip Urobilinogen on urine dip

Intravascular haemolysis Extravascular haemolysis

Direct Coombs Direct Coombs

Positive

Negative Positive Negative Non-immune

Immune, e.g., acute haemolytic transfusion reaction or
autoimmune haemolysis: 70% warm (IgG), 20% cold (IgM)
and 10% mixed (can be secondary to lymphoproliferative Immune, e.g., delayed Blood film
disease, infections, immunodeficiency, tumours and post Non-immune
haemolytic transfusion
stem cell transplant).
Blood film reaction, warm (IgG) or
cold (IgM) autoimmune
≥1% Schistocytes- Abnormal, e.g.,
haemolysis Normal
fragments of red cells spherocytes, elliptocytes, red cells
ovalocytes, stomatocytes
<0.5% schistocytes
Thrombotic microangiopathies,
e.g., DIC, HUS, malignant Membrane disorders, e.g., hereditary
hypertension, HELLP. Note spherocytosis and elliptocytosis; Splenomegaly due
intravascular haemolysis destroys Family history, haemoglobinopathies and congenital to any cause, e.g.,
Direct
RBCs at rate of 200 mL/hr dyserythropoietic anaemia, e.g., sickle myeloid malignancy,
Heinz bodies, damage,
cell and thalassaemia or portal hypertension;
elevated ferritin clues from
infection, e.g.,
history
malaria, clostridia,
‘flu, HIV, toxins, e.g.,
RBC enzymopathies, i.e., pentose phosphate Snake/insect venoms, infections, e.g., malaria, clostridia, snake and insect.
shunt (e.g., G6PD - cause an acute haemolysis) ‘flu, HIV, freshwater drowning, ECMO, dialysis, aortic Paroxysmal nocturnal
or glycolysis or nucleotide metabolism problems stenosis, prolonged marching, mechanical heart valves, haemoglobinuria
(e.g., pyruvate kinase deficiency - causes Wilson, drugs and toxins. Note extravascular haemolysis (very high LDH,
chronic haemolysis) destroys RBCs at rate of 20 mL/hr low platelets and
lymphocytes)

Figure 3 Investigative algorithm for determining the cause of haemolysis. Figure to show an algorithm of laboratory tests a clinician can
use to determine the cause of haemolysis if they are uncertain of the aetiology. LDH, lactate dehydrogenase; IgG, immunoglobulin G;
IgM, immunoglobulin M; DIC, disseminated intravascular coagulation; HUS, haemolytic uraemic syndrome; HELLP, haemolysis, elevated
liver enzymes and low platelets; RBC, red blood cells; G6PD, glucose 6-phosphate dehydrogenase; ECMO, extracorporeal membrane
oxygenation; ‘flu, influenza; HIV, human immunodeficiency virus.

clinical assessment, it is important to remember that LDH Elevated LDH was also shown by other groups in anorexia
in general is perhaps better employed as a marker of disease nervosa patients (compared to normal controls) but the
activity, rather than a specific diagnostic tool. LDH was also elevated, perhaps not unexpectedly, in a
comparator group of those who were anorectic due to bowel
surgery or malignancy (26,27). However, another study
Connective tissue
demonstrated lower LDH in anorexia nervosa compared
Adipocytes contain LDH however obesity alone does not to controls (28). Perhaps these contradictory results reflect
seem to cause an elevation in circulating LDH (23). In other tissue damage that can occur in anorexia nervosa
conditions of underweight patients, elevations to LDH are meaning low body weight alone is insufficient to cause a
due to a multitude of causes, e.g., in cancer cachexia the disturbance compared to, e.g., muscle breakdown, cardiac
tumor, tissue breaks down and drugs commonly elevate stress or liver damage (29).
LDH (24). In anorexia nervosa elevated LDH may be due All five LDH tetramers are expressed in skin but
to skeletal muscle breakdown, mediated by low T3 (25). LDH-5 is the most common form (30). Burns elevate

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 6 of 15 Journal of Laboratory and Precision Medicine, 2024

LDH and the deeper the burn the higher the LDH as the clinician needs to consider if there are other sources, e.g.,
the tissue anaerobically respires secondary to the tissue a cardiac event (52). LDH has also been shown to rise in
damage (31). However extensive and common skin diseases, rare sclerosing bone pathologies (53).
such as psoriasis and eczema, do not seem to cause a clinically
significant increase in LDH (32-34) However a correlation
Nervous and muscular systems
with LDH activity and the severity of eczema in children
has been noted and higher LDH activity predicting poorer Lactate metabolism increases in brain injury and multiple
response to treatment in these patients (35,36). pathologies have been related to elevated LDH in serum
LDH measurement has been recommended in including intracerebral haemorrhage, ischaemic or
various guidelines for skin malignancies, e.g., cutaneous haemorrhagic stroke, post-epileptic seizures (and indeed
lymphoma and melanoma (37). Elevated LDH levels have can be used as a biochemical marker to distinguish an
demonstrated a correlation with unfavourable prognosis epileptic versus non-epileptic seizure), infectious meningitis
with cutaneous lymphoma and LDH has also been and encephalitis, cerebral oedema, encephalopathy related
integrated into the tumor-node-metastasis (TNM) staging to pre-eclampsia, post brain surgery with complications and
system for melanoma (38-40). Insights gleaned from traumatic brain injuries (54-63).
cancer databases demonstrate the consistent elevation of Cardiac muscle is another common source of LDH
LDH expression in malignancies, thereby accentuating its elevation, with LDH once being used as a marker for
potential role in the meticulous monitoring of metastatic myocardial infarction before being replaced with troponin
cutaneous tumours (41). The interpretation of LDH T (64,65) and so will be elevated post cardiac arrest,
measurements within cutaneous malignancy warrants shock and hypoxia. Cardiomyopathies, heart failure, valve
thoughtful consideration and caution, given the absence of disease, QTc prolongation, pulmonary hypertension,
definitive trials to substantiate its specific role (3,41). arrhythmia such as atrial fibrillation, rheumatic heart
LDH is also elevated in connective tissue disease disease (66), prosthetic valves (particularly if leaking) and
conditions characterized by extensive tissue damage, trauma causing intravascular haemolysis and pre-eclampsia
including dermatomyositis, myositis, and panniculitides. can all cause LDH elevation and again LDH is often not
This connection means that LDH levels could potentially used diagnostically but as a marker of disease activity or
be used to track disease activity within these contexts (41). prognostication (67-74).
Other more traditional rheumatological disorders such as It should be noted that LDH is in smooth muscle too (75),
systemic sclerosis might elevate LDH, correlating with so whilst perhaps a rarer cause of serum LDH elevation
a more aggressive and multiorgan disease (42). However any damage to smooth muscle can contribute to LDH
cutaneous only sclerosis or lupus do not seem to be related elevation. Smooth muscle is present in blood vessels, uterus,
to an elevated LDH in the literature. A spectrum of ureteric tracts to name just a few systems. Smooth muscle
rheumatological diseases have not related to LDH elevation pathologies are unusual, but a few examples include:
in one small case series (43) however there are papers of  Autoimmune diseases, e.g., anti-smooth muscle
LDH being related to disease activity of Adult Still disease, antibodies often associated with autoimmune
rheumatoid arthritis and vasculitis for example (44-49). hepatitis;
Bone is another source of LDH and injuries, particularly  Tumours, e.g., leiomyomas and leiomyosarcomas, the
fractures, will lead to elevation. In athletes, a raised LDH latter often causing a greater elevation in LDH (76-78).
might point towards stress fractures for example with the Skeletal muscle breakdown will release LDH into the
correct history (50). Raised LDH is a poor prognostic serum. Any cause of muscle breakdown will trigger this, e.g.,
indicator in hip fracture patients, although whether the  Alcoholic myopathy (79);
LDH levels is related to the degree of bone injury or  Inflammatory myositis (80);
rather muscle death from ischaemia, haemorrhage, long  Muscular dystrophy (81);
lie, cardiac stress, etc. is not certain (51). Certainly, an early  Strenuous exercise (82);
study showed that operative repair of hip fractures did not  Drug induced, e.g., steroids, statins, quinines (83).
cause a significant change in LDH and therefore, whilst the As muscle is destroyed there is less tissue to release LDH
bone fracture and muscle damage can increase LDH serum and so if a disease has already caused significant muscle
activity levels, if there is a significant elevation of LDH then atrophy but is still active it may not produce high LDH

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 7 of 15

activity (unless for other reasons, e.g., increased cardiac infarction, the greater the elevation (103-109). LDH can be
stress due to failing skeletal muscles). used a poor prognostic marker in acute kidney injury and
renal cell carcinoma and also a marker of multiple organ
involvement in a particular illness (110,111).
Haematological
LDH can be used as a prognostic marker for the
Haemolysis is a common cause of LDH elevation. refractory nature of mycoplasma pneumonia, for example
Figure 3 shows a laboratory diagnostic algorithm approach in children a cut off 408 IU/L has an area under the
to haemolysis (from sister article in this series on bilirubin receiver operating characteristic curve (AUROC) of 0.812
investigation with identical methodology). Severe (sensitivity of 75% and specificity of 72.2%), i.e., LDH
pernicious anaemia can cause an LDH elevation (84) as can higher than 408 IU/L predicts the pneumonia will be
megaloblastic anaemia (85), sickle cell (86,87), Epstein- refractory to treatment (112). One group showed that
Barr virus (88), thrombocythaemia (89), haematological elevated LDH after subarachnoid haemorrhage statistically
malignancy (90), polycythaemia (91), splenic necrosis (92) significantly predicted post operative pneumonia (113)
and paroxysmal nocturnal haemoglobinuria (93). However, however their LDH values overlapped (pneumonia
a normal LDH does not preclude a haematological group 261.26±126.51 U/L vs. no pneumonia group
malignancy, for example, up to 80% of patients with 189.00±69.20 U/L) perhaps reflecting that the brain injury
myeloma will have normal LDH activity (94). The worse itself plus any seizures, surgery etc. might also be putting
the disease the more likely the elevation of LDH and the LDH up in this situation.
higher LDH is a clue to a worse prognosis. It should be Pulmonary embolus and infarction will elevate
noted that it also possible for inflammatory diseases with LDH (114) but not of a degree to help distinguish between
high lymphocyte activity to lead to a raised LDH, e.g., myocardial and pulmonary infarct in the setting of chest
T lymphocytes in psoriasis (32) or lymphadenopathy in pain and breathlessness (115). LDH elevation does seem
sarcoidosis (95). to distinguish between children with asthma, compared to
controls (116) and there may be a correlation of LDH with
prognosis in chronic obstructive pulmonary disease in adults
Other viscera
and interstitial lung disease (117,118). LDH elevation is
A study demonstrated elevated LDH in 204 newly perhaps more closely link to pneumonia compared to other
diagnosed cervical cancer patients but unfortunately, they causes of infection in acute hospital admissions but the
were compared to healthy controls rather than to those with actual difference between LDH levels does not render it a
cervical dysplasia or HPV infections, and whilst statistically useful clinical test in this setting (119).
significant the median LDH values were 194 U/L The gastrointestinal tract is another source of LDH in
[interquartile range (IQR), 65.25 U/L] in patients compared the serum. Pancreatitis, pancreatic necrosis or mesenteric
to 180 U/L (IQR, 40.75 U/L) in controls (96). However, ischaemia cause LDH elevation as does bowel gangrene
another study demonstrated a higher LDH pre-cervical (120-122). Any liver pathology can elevate LDH including
cancer treatment was associated with a worse prognosis (97). hepatitis, cholestasis, trauma and cirrhosis, and again higher
Ovarian tumors can elevate LDH, and in children point levels are more likely to be related to poor prognosis and
towards dysgerminomas in particular (98) but LDH is also mortality in both liver disease and peritonitis (123,124).
elevated in benign gynaecological disease (99). Whilst LDH Stomach pathologies do not seem to elevate LDH, whether
activity will be elevated more in malignant gynae pathology benign or malignant (125).
the degree of elevation is not great enough to allow for a Hypothyroidism can lead to an elevated LDH due
confident discrimination from benign disease using LDH to skeletal muscle breakdown and hyperthyroidism to a
activity alone (100). relative decrease (126,127). LDH is an important enzyme in
Renal transplant rejection has also been noted to cause phaeochromocytoma (128) and has also been shown to be
an elevation in LDH (101) and LDH has been noted to raised in diabetes mellitus and Cushing syndrome (129,130).
increase post dialysis although mechanical trauma might
be the reason for this elevation (102). Nephropathies and
Diseases
chronic kidney disease of any cause can also elevate LDH,
of course the more severe disease, especially if there is Tumours, particularly the malignant and metastatic, often

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 8 of 15 Journal of Laboratory and Precision Medicine, 2024

Table 2 Current known genetic conditions which result in low lactate dehydrogenase concentrations in serum
Genotype Title Phenotype

LDHA, autosomal recessive, Glycogen storage disease XI or Exertional myoglobinuria, easy fatigue, exercise-induced elevation of
chromosome 11 lactate dehydrogenase A deficiency lactate, pyruvate, creatine kinase with myoglobinuria. Can develop
renal failure. Skin rash—non-pruritic erythemato-squamous patches

LDHB, chromosome 12 Lactate dehydrogenase B deficiency Does not seem to cause a disease, just a low reading of lactate
dehydrogenase activity than normal values

LDHC, chromosome 11 Lactate dehydrogenase C deficiency Impaired sperm motility

(testicular form)

LDHD, chromosome 16, D-lactic aciduria with gout Elevated D-lactate in plasma and urine, elevated serum uric acid, low
autosomal recessive urinary uric acid levels, reduced renal clearance of uric acid and gouty
arthropathy
LDHA, lactate dehydrogenase A gene; LDHB, lactate dehydrogenase B gene; LDHC, lactate dehydrogenase C gene; LDHD, lactate
dehydrogenase D gene.

have a higher metabolism so take up more glucose [hence LDH activity than expected on laboratory testing (Table 2)
the rationale of positron emission tomography (PET) (139,140). However, the lack of LDH, as could be expected,
imaging] and produce more lactate, via LDH activity. The can impair the person’s ability to perform physical activity
higher the LDH the more active the cells metabolically and progress in labour (141). Clinically low LDH is not
but also the LDH activity seems to suppress immune something that is ever a cause for clinical concern.
surveillance and therefore helps the tumour survive (131).
This review will not tackle the prognostic indication that
Special circumstances
LDH might provide with cancer monitoring but it is widely
used in the oncology setting, partly as a marker of tumour Pregnancy
burden and monitoring changes to the levels indicating
treatment success or relapse. LDH activity has been shown A normal pregnancy does not increase LDH and if LDH
to be elevated in many tumours, particularly metastatic activity increases then one needs to consider disease like
breast, colorectal, germinal testicular, gastric, hepatoma, pre-eclampsia, pregnancy induced hypertension and
lung, ovarian, pancreatic, melanoma, prostatic, renal, cholestasis of pregnancy (142-144).
sarcoma, seminoma and thyroid (132,133). Chemotherapy
can lead to LDH rises initially, as expected, due to tumor Childhood
breakdown (134).
Infection can cause LDH elevation, e.g., human LDH activity is higher in children, dropping as they age and
immunodeficiency virus (HIV), usually in acquired reaching adult levels by the age of 22 (145). An idea of the
immunodeficiency syndrome (AIDS)-defining infections or range in paediatric population is therefore helpful to guide if
coronavirus disease 2019 (COVID-19) (135,136). There is a child needs further investigation or not (Table 3) (146).
an unusual LDH elevating virus, although this seems to be
specific to mice (137). Malaria is a cause of LDH elevation, Conclusions
partly due to its effects on red cells (138). Again, the worse
the infection the more likely one will detect an LDH Elevated LDH activity is a common finding and is not
elevation. diagnostic for any single disease process in isolation. The
most common causes included cardiorespiratory diseases,
any malignancy, fracture or trauma, infection, inflammation
Low LDH
and any cause of hepatitis. Low LDH activity is rare and
There are multiple different genetic conditions described genetic causes might be considered if testing is available.
as causing an LDH deficiency. In most, there is no disease If a thorough clinical assessment does not reveal a cause of
and instead what happens is that there is an unusually low LDH elevation then the included algorithm is presented to

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 9 of 15

Table 3 Lactate dehydrogenase concentration (IU/L) depending on age and sex in children
Lower limit Upper limit Sample size Lower confidence limit Upper confidence limit
Age
Female Male Female Male Female Male Female Male Female Male

0–14 days 309 309 1,222 1,222 197 197 267, 360 267, 360 1,116, 1,257 1,116, 1,257

15 days to <1 year 163 163 452 452 145 145 94, 173 94, 173 428, 483 428, 483

1 to <10 years 192 192 321 321 370 370 189, 199 189, 199 314, 333 314, 333

10 to <15 years 157 170 272 283 141 141 130, 162 138, 175 258, 308 277, 286

15 to 19 years 130 130 250 250 227 227 124, 142 124, 142 239, 257 239, 257

help support a systematic approach to determine possible K.E.S. served as the unpaid Guest Editor of the series and
reasons. There may be no single cause, or rather multiple serves as an unpaid editorial board member of the Journal
tissue sources of the LDH, and in the setting of a well of Laboratory and Precision Medicine from September 2022 to
person the result may be spurious. Specialist knowledge, August 2024. The authors have no other conflicts of interest
experience and local guidelines all remain vital in to declare.
elucidating the cause. It is recommended that LDH is not
measured unless the clinician has a very specific question in Ethical Statement: The authors are accountable for all
mind due to the non-specificity of serum LDH activity. aspects of the work in ensuring that questions related
to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.
Acknowledgments

All figures were created by the authors with BioRender.com Open Access Statement: This is an Open Access article
and are original. distributed in accordance with the Creative Commons
Funding: None. Attribution-NonCommercial-NoDerivs 4.0 International
License (CC BY-NC-ND 4.0), which permits the non-
commercial replication and distribution of the article with
Footnote
the strict proviso that no changes or edits are made and the
Provenance and Peer Review: This article was commissioned original work is properly cited (including links to both the
by the editorial office, Journal of Laboratory and Precision formal publication through the relevant DOI and the license).
Medicine for the series “Investigative Algorithms in See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
Laboratory Medicine II: Focus on Bone and Liver”. The
article has undergone external peer review.
References

Reporting Checklist: The authors have completed the 1. Vasudevan G, Mercer DW, Varat MA. Lactic dehydrogenase
Narrative Review reporting checklist. Available at https:// isoenzyme determination in the diagnosis of acute
jlpm.amegroups.org/article/view/10.21037/jlpm-23-65/rc myocardial infarction. Circulation 1978;57:1055-7.
2. Markert CL. Lactate dehydrogenase. Biochemistry and
Peer Review File: Available at https://jlpm.amegroups.org/ function of lactate dehydrogenase. Cell Biochem Funct
article/view/10.21037/jlpm-23-65/prf 1984;2:131-4.
3. Forkasiewicz A, Dorociak M, Stach K, et al. The usefulness
Conflicts of Interest: All authors have completed the of lactate dehydrogenase measurements in current
ICMJE uniform disclosure form (available at https:// oncological practice. Cell Mol Biol Lett 2020;25:35.
jlpm.amegroups.org/article/view/10.21037/jlpm-23-65/ 4. Wu Y, Lu C, Pan N, et al. Serum lactate dehydrogenase
coif). The series “Investigative Algorithms in Laboratory activities as systems biomarkers for 48 types of human
Medicine II: Focus on Bone and Liver” was commissioned diseases. Sci Rep 2021;11:12997.
by the editorial office without any funding or sponsorship. 5. Schumann G, Bonora R, Ceriotti F, et al. IFCC primary

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 10 of 15 Journal of Laboratory and Precision Medicine, 2024

reference procedures for the measurement of catalytic Lab Med 2006;44:311-6.

activity concentrations of enzymes at 37 degrees C. Part 16. Chainuvati T, Harinasuta U, Zimmerman HJ. Spurious
3. Reference procedure for the measurement of catalytic elevation of apparent lactate dehydrogenase activity caused
concentration of lactate dehydrogenase. Clin Chem Lab by triamterene. Clin Chem 1973;19:1202-4.
Med 2002;40:643-8. 17. Boice J, Prodanovich M, Howell J, et al. Spurious Decrease
6. Cattozzo G, Guerra E, Ceriotti F, et al. Commutable in Lactate Dehydrogenase Due to Hyperlipidemia. Lab
calibrator with value assigned by the IFCC reference Med 1978;9:28.
procedure to harmonize serum lactate dehydrogenase 18. Lee SH, Pekas EJ, Lee S, et al. The Impact of Aspirin
activity results measured by 2 different methods. Clin Intake on Lactate Dehydrogenase, Arterial Stiffness, and
Chem 2008;54:1349-55. Oxidative Stress During High-Intensity Exercise: A Pilot
7. Siekmann L, Bonora R, Burtis CA, et al. IFCC primary Study. J Hum Kinet 2020;72:101-13.
reference procedures for the measurement of catalytic 19. Taghiyar M, Darvishi L, Askari G, et al. The effect of
activity concentrations of enzymes at 37 degrees C. vitamin C and e supplementation on muscle damage and
International Federation of Clinical Chemistry and oxidative stress in female athletes: a clinical trial. Int J Prev
Laboratory Medicine. Part 7. Certification of four Med 2013;4:S16-23.
reference materials for the determination of enzymatic 20. William BM, Bongu NR, Bast M, et al. The utility
activity of gamma-glutamyltransferase, lactate of lactate dehydrogenase in the follow up of patients
dehydrogenase, alanine aminotransferase and creatine with diffuse large B-cell lymphoma. Rev Bras Hematol
kinase accord. Clin Chem Lab Med 2002;40:739-45. Hemoter 2013;35:189-91.
8. Schumann G, Klauke R. New IFCC reference procedures 21. Jacobs DS, Robinson RA, Clark GM, et al. Clinical
for the determination of catalytic activity concentrations significance of the isomorphic pattern of the isoenzymes
of five enzymes in serum: preliminary upper reference of serum lactate dehydrogenase. Ann Clin Lab Sci
limits obtained in hospitalized subjects. Clin Chim Acta 1977;7:411-21.
2003;327:69-79. 22. Erez A, Shental O, Tchebiner JZ, et al. Diagnostic
9. Jansen R, Schumann G, Baadenhuijsen H, et al. Trueness and prognostic value of very high serum lactate
verification and traceability assessment of results from dehydrogenase in admitted medical patients. Isr Med
commercial systems for measurement of six enzyme Assoc J 2014;16:439-43.
activities in serum: an international study in the EC4 23. Johansen MJ, Gade J, Stender S, et al. The Effect of
framework of the Calibration 2000 project. Clin Chim Overweight and Obesity on Liver Biochemical Markers
Acta 2006;368:160-7. in Children and Adolescents. J Clin Endocrinol Metab
10. Louderback AL, Shanbrom E. Lactic dehydrogenase 2020;105:dgz010.
isoenzyme electrophoresis. JAMA 1968;205:294-5. 24. McGovern J, Dolan RD, Simmons CPL, et al. Lactate
11. Gemma R, Suzuki Y, Tanaka I, et al. Lactate dehydrogenase: relationship with the diagnostic GLIM
dehydrogenase (LDH)-linked immunoglobulin in a patient criterion for cachexia in patients with advanced cancer. Br
with Graves' disease treated with methimazole. Intern J Cancer 2023;128:760-5.
Med 1992;31:377-9. 25. Kumano H, Kuboki T, Tawara R, et al. Interrelationship
12. Sturk A, Sanders GT. Macro enzymes: prevalence, between serum muscle enzymes and a low T3 in anorexia
composition, detection and clinical relevance. J Clin Chem nervosa. Endocrinol Jpn 1990;37:583-9.
Clin Biochem 1990;28:65-81. 26. Umeki S. Biochemical abnormalities of the serum in
13. Fujita K, Takeya C, Saito T, et al. Macro lactate anorexia nervosa. J Nerv Ment Dis 1988;176:503-6.
dehydrogenase: an LDH-immunoglobulin M complex that 27. Montagnese C, Scalfi L, Signorini A, et al. Cholinesterase
inhibits lactate dehydrogenase activity in a patient's serum. and other serum liver enzymes in underweight outpatients
Clin Chim Acta 1984;140:183-95. with eating disorders. Int J Eat Disord 2007;40:746-50.
14. Hirano T, Matsuzaki H, Miura M, et al. An 28. Nova E, Lopez-Vidriero I, Varela P, et al. Evolution of
immunoglobulin G inhibiting lactate dehydrogenase serum biochemical indicators in anorexia nervosa patients:
activity. Clin Chim Acta 1986;159:17-25. a 1-year follow-up study. J Hum Nutr Diet 2008;21:23-30.
15. Lippi G, Salvagno GL, Montagnana M, et al. Influence of 29. Di Pascoli L, Lion A, Milazzo D, et al. Acute liver damage
hemolysis on routine clinical chemistry testing. Clin Chem in anorexia nervosa. Int J Eat Disord 2004;36:114-7.

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 11 of 15

30. Bauhammer I, Sacha M, Haltner E. Validation and stability disease flare in patients with adult-onset Still's disease
analysis of a modified lactate dehydrogenase (LDH) test undergoing treatment with tocilizumab. Rheumatology
method to be employed for an in vitro viable skin model. (Oxford) 2020;59:440-2.
Heliyon 2019;5:e01618. 45. Pejovic M, Stankovic A, Mitrovic DR. Lactate
31. Cuddihy J, Wu G, Ho L, et al. Lactate dehydrogenase dehydrogenase activity and its isoenzymes in serum and
activity staining demonstrates time-dependent immune synovial fluid of patients with rheumatoid arthritis and
cell infiltration in human ex-vivo burn-injured skin. Sci osteoarthritis. J Rheumatol 1992;19:529-33.
Rep 2021;11:21249. 46. Wang W, Gong F, Zhu W, et al. Macrophage activation
32. Koguchi-Yoshioka H, Watanabe R, Matsumura Y, et al. syndrome in Kawasaki disease: more common than we
Serum lactate dehydrogenase level as a possible predictor thought? Semin Arthritis Rheum 2015;44:405-10.
of treatment preference in psoriasis. J Dermatol Sci 47. Chen Z, Lin L, Yang W, et al. Clinical characteristics
2021;103:109-15. and prognostic risk factors of anti-neutrophil cytoplasmic
33. Hisamoto T, Suga H, Yoshizaki-Ogawa A, et al. Increased antibody (ANCA)-associated vasculitides (AAV). Int
Serum Levels of Tumor Necrosis Factor-like Ligand 1A in Immunopharmacol 2020;87:106819.
Atopic Dermatitis. Int J Mol Sci 2023;24:1813. 48. Matsushita S, Sada K, Manabe A, et al. Elevated White
34. Yu L, Li L. Potential biomarkers of atopic dermatitis. Blood Cell Count and Lactate Dehydrogenase Levels
Front Med (Lausanne) 2022;9:1028694. Are Important Markers for Diagnosing Relapse of Adult-
35. Morishima Y, Kawashima H, Takekuma K, et al. Changes onset Still's Disease under Tocilizumab Use. Intern Med
in serum lactate dehydrogenase activity in children with 2022;61:3743-7.
atopic dermatitis. Pediatr Int 2010;52:171-4. 49. Ayano M, Arinobu Y, Tsukamoto H, et al. Shoulder
36. Kato A, Kamata M, Ito M, et al. Higher baseline serum ultrasound and serum lactate dehydrogenase predict
lactate dehydrogenase level is associated with poor inadequate response to glucocorticoid treatment in
effectiveness of dupilumab in the long term in patients patients with polymyalgia rheumatica. Rheumatol Int
with atopic dermatitis. J Dermatol 2020;47:1013-9. 2020;40:1101-9.
37. Tas F, Oguz H, Argon A, et al. The value of serum levels 50. Miyamoto T, Oguma Y, Sato Y, et al. Elevated Creatine
of IL-6, TNF-alpha, and erythropoietin in metastatic Kinase and Lactic Acid Dehydrogenase and Decreased
malignant melanoma: serum IL-6 level is a valuable Osteocalcin and Uncarboxylated Osteocalcin are
prognostic factor at least as serum LDH in advanced Associated with Bone Stress Injuries in Young Female
melanoma. Med Oncol 2005;22:241-6. Athletes. Sci Rep 2018;8:18019.
38. Marsden JR, Newton-Bishop JA, Burrows L, et al. 51. Demirel E, Şahin A. Predictive Value of Blood Parameters
Revised U.K. guidelines for the management of cutaneous and Comorbidities on Three-Month Mortality in Elderly
melanoma 2010. Br J Dermatol 2010;163:238-56. Patients With Hip Fracture. Cureus 2021;13:e18634.
39. Scarisbrick JJ. Staging and management of cutaneous T-cell 52. Wukich DK, Callaghan JJ, Graeber GM, et al.
lymphoma. Clin Exp Dermatol 2006;31:181-6. Operative treatment of acute hip fractures: its effect on
40. Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma serum creatine kinase, lactate dehydrogenase and their
staging: Evidence-based changes in the American Joint isoenzymes. J Trauma 1989;29:375-9.
Committee on Cancer eighth edition cancer staging 53. Whyte MP, Kempa LG, McAlister WH, et al. Elevated
manual. CA Cancer J Clin 2017;67:472-92. serum lactate dehydrogenase isoenzymes and aspartate
41. Livesey A, Garty F, Shipman AR, et al. Lactate transaminase distinguish Albers-Schönberg disease
dehydrogenase in dermatology practice. Clin Exp (Chloride Channel 7 Deficiency Osteopetrosis) among
Dermatol 2020;45:539-43. the sclerosing bone disorders. J Bone Miner Res
42. Jiang Y, Li X, Zhou W, et al. Clinical significance of serum 2010;25:2515-26.
ferritin in patients with systemic sclerosis. J Clin Lab Anal 54. Chu H, Huang C, Dong J, et al. Lactate Dehydrogenase
2022;36:e24597. Predicts Early Hematoma Expansion and Poor Outcomes
43. Erlij D, Cuellar MC, Badilla N, et al. Lymphadenopathies in Intracerebral Hemorrhage Patients. Transl Stroke Res
in patients with rheumatic diseases. Review of 19 cases. 2019;10:620-9.
Rev Med Chil 2020;148:320-6. 55. Parakh N, Gupta HL, Jain A. Evaluation of enzymes in
44. Yamada H, Kaneko Y, Tamai H, et al. Biomarkers for serum and cerebrospinal fluid in cases of stroke. Neurol

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 12 of 15 Journal of Laboratory and Precision Medicine, 2024

India 2002;50:518-9. maintenance hemodialysis patients: a cross-sectional study.

56. Jin XX, Fang MD, Hu LL, et al. Elevated lactate Ann Palliat Med 2022;11:3444-54.
dehydrogenase predicts poor prognosis of acute ischemic 69. Li M, Tang M, Zhao C, et al. Prognostic Potential of
stroke. PLoS One 2022;17:e0275651. Pulmonary Hypertension in Patients with Hematologic
57. Yilmaz M, Tekten BO. Serum prolactin level and lactate Malignancy. Adv Ther 2023;40:4792-804.
dehydrogenase activity in patients with epileptic and 70. Hu HJ, Zhang C, Tang ZH, et al. Regulating the
nonepileptic seizures: A cross-sectional study. Medicine Warburg effect on metabolic stress and myocardial fibrosis
(Baltimore) 2021;100:e27329. remodeling and atrial intracardiac waveform activity
58. Nand N, Sharma M, Saini DS. Evaluation of lactic induced by atrial fibrillation. Biochem Biophys Res
dehydrogenase in cases of meningitis. Indian J Med Sci Commun 2019;516:653-60.
1993;47:96-100. 71. Binder J, Palmrich P, Kalafat E, et al. Longitudinal
59. Zhang L, Liu K, Su Q, et al. Clinical features of the assessment of angiogenic markers in prediction of adverse
first critical case of acute encephalitis caused by the outcome in women with confirmed pre-eclampsia.
avian influenza A (H5N6) virus. Emerg Microbes Infect Ultrasound Obstet Gynecol 2023;62:843-51.
2022;11:2437-46. 72. Širáková A, Toušek P, Bednář F, et al. Intravascular
60. Gao B, Liu FL, Zhao B. Association of degree and type of haemolysis after transcatheter aortic valve implantation
edema in posterior reversible encephalopathy syndrome with self-expandable prosthesis: incidence, severity,
with serum lactate dehydrogenase level: initial experience. and impact on long-term mortality. Eur Heart J Suppl
Eur J Radiol 2012;81:2844-7. 2020;22:F44-50.
61. Vargas M, Servillo G, Striano P. Serum lactate 73. Wang X, Zhang J, Qian J, et al. The Regulatory
dehydrogenase as early marker of posterior reversible Mechanism and Effect of Receptor-Interacting Protein
encephalopathy syndrome: keep your eyes open. Anaesth Kinase 3 on Phenylephrine-Induced Cardiomyocyte
Intensive Care 2012;40:570-1. Hypertrophy. J Cardiovasc Pharmacol 2022;80:236-50.
62. Rabow L, Tibbling G. Serum enzyme activity of 74. Casós K, Ferrer-Curriu G, Soler-Ferrer P, et al.
hydroxybutyric dehydrogenase (HBD) and heat inactivated Response of the human myocardium to ischemic injury
lactate dehydrogenase (LD) after operations on intracranial and preconditioning: The role of cardiac and comorbid
aneurysms. Acta Neurochir (Wien) 1975;32:199-207. conditions, medical treatment, and basal redox status.
63. Rabow L, Tibbling G. Serum activities of hydroxybutyrate PLoS One 2017;12:e0174588.
dehydrogenase (HBD) and the isoenzymes of lactate 75. Wachsmuth ED. Localization of lactate dehydrogenase
dehydrogenase (LD) as an index of traumatic brain injury. isozymes in human muscle tissues by the mixed aggregation
Acta Neurochir (Wien) 1977;37:245-61. immunocytochemical technique. Histochemistry
64. Bodor GS. Biochemical Markers of Myocardial Damage. 1979;60:249-54.
EJIFCC 2016;27:95-111. 76. Suh DS, Song YJ, Roh HJ, et al. Preoperative Blood
65. Panteghini M. IFCC Committee on Standardization Inflammatory Markers for the Differentiation of Uterine
of Markers of Cardiac Damage: premises and project Leiomyosarcoma from Leiomyoma. Cancer Manag Res
presentation. International Federation of Clinical 2021;13:5001-11.
Chemistry and Laboratory Medicine. Clin Chem Lab Med 77. Glorie N, Baert T, VAN DEN Bosch T, et al. Circulating
1998;36:887-93. Protein Biomarkers to Differentiate Uterine Sarcomas
66. Caldara G. Lactic acid dehydrogenase in the diagnosis from Leiomyomas. Anticancer Res 2019;39:3981-9.
of rheumatic carditis. Arch Sci Med (Torino) 78. Köhler G, Vollmer M, Nath N, et al. Benign uterine mass-
1969;126:659-62. discrimination from leiomyosarcoma by a preoperative risk
67. Akhtar MS, Hassan Q, Afzal O, et al. Comparative score: a multicenter cohort study. Arch Gynecol Obstet
Efficacy of Levosimendan, Ramipril, and Sacubitril/ 2019;300:1719-27.
Valsartan in Isoproterenol-induced Experimental Heart 79. Sakamoto K, Ohata M, Hashimoto K, et al. Two cases
Failure: A Hemodynamic and Molecular Approach. Curr of alcoholics associated with rhabdomyolysis and acute
Mol Pharmacol 2023;16:629-39. renal failure. Nihon Arukoru Yakubutsu Igakkai Zasshi
68. Fang XX, Shen LL, Yao WB, et al. Correlation between 2002;37:505-12.
lactate dehydrogenase and QTc interval prolongation in 80. Gofshteyn JS, Mansfield L, Spitznagle J, et al. Association

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 13 of 15

of Juvenile Dermatomyositis Disease Activity With the Hematologic Lab Measures Observed in Patients with
Expansion of Blood Memory B and T Cell Subsets Lacking Paroxysmal Nocturnal Hemoglobinuria Treated with C5
Follicular Markers. Arthritis Rheumatol 2023;75:1246-61. Inhibitors, Ravulizumab and Eculizumab: Real-World
81. Sadek AA, Mahmoud SM, El-Aal MA, et al. Evaluation Evidence from a US Based EMR Network. Hematol Rep
of cardiac functions in children with Duchenne Muscular 2023;15:266-82.
Dystrophy: A prospective case-control study. Electron 94. Tsuchiya J. Some problems in the laboratory findings
Physician 2017;9:5732-9. in multiple myeloma. Nihon Ketsueki Gakkai Zasshi
82. Mieszkowski J, Stankiewicz BE, Kochanowicz A, et al. 1989;52:1273-8.
Remote Ischemic Preconditioning Reduces Marathon- 95. Chen W, Zhang Q, Li M, et al. Clinical diagnostic value
Induced Oxidative Stress and Decreases Liver and of serum soluble IL-2 receptor for stage I sarcoidosis in
Heart Injury Markers in the Serum. Front Physiol benign isolated mediastinal and hilar lymphadenopathy.
2021;12:731889. Clin Chim Acta 2023;545:117372.
83. Biguetti CC, Junior JFS, Fiedler MW, et al. The toxic 96. Ye Y, Chen M, Chen X, et al. Clinical Significance and
effects of chloroquine and hydroxychloroquine on skeletal Prognostic Value of Lactate Dehydrogenase Expression
muscle: a systematic review and meta-analysis. Sci Rep in Cervical Cancer. Genet Test Mol Biomarkers
2021;11:6589. 2022;26:107-17.
84. Hassouneh R, Shen S, Lee O, et al. Severe Vitamin B12 97. Li J, Wu MF, Lu HW, et al. Pretreatment serum lactate
Deficiency Mimicking Microangiopathic Hemolytic dehydrogenase is an independent prognostic factor for
Anemia. J Hematol 2021;10:202-5. patients receiving neoadjuvant chemotherapy for locally
85. Jaswal TS, Mehta HC, Gupta V, et al. Serum lactate advanced cervical cancer. Cancer Med 2016;5:1863-72.
dehydrogenase in diagnosis of megaloblastic anaemia. 98. Birbas E, Kanavos T, Gkrozou F, et al. Ovarian Masses in
Indian J Pathol Microbiol 2000;43:325-9. Children and Adolescents: A Review of the Literature with
86. Najim OA, Hassan MK. Lactate dehydrogenase and Emphasis on the Diagnostic Approach. Children (Basel)
severity of pain in children with sickle cell disease. Acta 2023;10:1114.
Haematol 2011;126:157-62. 99. Karim SMH, Fattah CN. The correlation between
87. Stankovic Stojanovic K, Lionnet F. Lactate dehydrogenase women's various gynaecological diseases to ovarian
in sickle cell disease. Clin Chim Acta 2016;458:99-102. cancer in Sulaimaniyah City, Iraq. J Int Med Res
88. Ikeda S, Sugihara T, Kihara T, et al. Chronic Active 2023;51:3000605231158949.
Epstein-Barr Virus Infection Indistinguishable from 100. Shinmura H, Yoneyama K, Harigane E, et al. Use of tumor
Autoimmune Hepatitis: A Case Report. Yonago Acta Med markers to distinguish endometriosis-related ovarian
2022;65:160-5. neoplasms from ovarian endometrioma. Int J Gynecol
89. Kaya A, Kuku İ, Erkurt MA, et al. The effect of Cancer 2020;30:831-6.
thrombocytapheresis on hemogram and biochemistry 101. Khan TT, Mirza AB, Zahid R, et al. Antibody-mediated
parameters in patients with essential thrombocytemia. rejection: importance of lactate dehydrogenase and
Transfus Clin Biol 2023;30:421-5. neutrophilia in early diagnosis. Saudi J Kidney Dis Transpl
90. Miyashita N, Ohashi K, Fujita M, et al. Prognostic 2011;22:525-30.
factors in patients in the terminal phase of haematological 102. Sakhinia F, Ollerenshaw R, Wallace D. Mechanical stress-
malignancies who are receiving home medical care. Br J related haemolysis in a paediatric haemodialysis patient.
Haematol 2023;201:290-301. BMJ Case Rep 2022;15:e245248.
91. Lee AJ, Kim SG, Nam JY, et al. Clinical features and 103. Huang Z, Hu Y, Chen B, et al. Clinical significance of
outcomes of JAK2 V617F-positive polycythemia vera and intrarenal vascular lesions in non-hypertensive patients
essential thrombocythemia according to the JAK2 V617F with IgA nephropathy. J Nephrol 2023;36:429-40.
allele burden. Blood Res 2021;56:259-65. 104. Alkhatib MH, Kant S, Menez S, et al. Thrombotic
92. el Barzouhi A, van Buren M, van Nieuwkoop C. Renal microangiopathy versus class IV lupus nephritis in systemic
and Splenic Infarction in a Patient with Familial lupus erythematosus. J Nephrol 2021;34:1907-13.
Hypercholesterolemia and Previous Cerebral Infarction. 105. Lee DY, Kim JY, Ahn E, et al. Associations between local
Am J Case Rep 2018;19:1463-6. acidosis induced by renal LDHA and renal fibrosis and
93. Fishman J, Kuranz S, Yeh MM, et al. Changes in mitochondrial abnormalities in patients with diabetic

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Page 14 of 15 Journal of Laboratory and Precision Medicine, 2024

kidney disease. Transl Res 2022;249:88-109. Between Serum Lactate Dehydrogenase with All-
106. Korzets Z, Plotkin E, Bernheim J, et al. The clinical Cause Mortality in Patients with Chronic Obstructive
spectrum of acute renal infarction. Isr Med Assoc J Pulmonary Disease. Int J Chron Obstruct Pulmon Dis
2002;4:781-4. 2023;18:305-16.
107. Kiker JD, Woodside JR, Reed WP, et al. Urinary lactic 118. Okamoto S, Tsuboi H, Noma H, et al. Predictive
dehydrogenase and serum C-reactive protein as means of Factors for Pneumomediastinum During Management
localizing the site of urinary tract infection in patients with of Connective Tissue Disease-related Interstitial
ileal conduits. J Urol 1982;128:749-51. Lung Disease: A Retrospective Study. Intern Med
108. Yang F, Li D, Di Y, et al. Pretreatment Serum Cystatin 2021;60:2887-97.
C Levels Predict Renal Function, but Not Tumor 119. Frenkel A, Shiloh A, Azulay B, et al. The role of lactate
Characteristics, in Patients with Prostate Neoplasia. dehydrogenase in hospitalized patients, comparing those
Biomed Res Int 2017;2017:7450459. with pulmonary versus non-pulmonary infections: A
109. Neĭmark AI, Fidirkin AV, Zviagintsev EN, et al. The nationwide study. PLoS One 2023;18:e0283380.
diagnostic significance of enzymuria in assessing kidney 120. Komolafe O, Pereira SP, Davidson BR, et al. Serum
function in patients with urolithiasis. Urol Nefrol (Mosk) C-reactive protein, procalcitonin, and lactate
1997;(1):5-7. dehydrogenase for the diagnosis of pancreatic necrosis.
110. Wei W, Cai Z, Chen L, et al. Short-term prognostic Cochrane Database Syst Rev 2017;4:CD012645.
models for severe acute kidney injury patients receiving 121. Sachs SM, Morton JH, Schwartz SI. Acute mesenteric
prolonged intermittent renal replacement therapy based ischemia. Surgery 1982;92:646-53.
on machine learning. BMC Med Inform Decis Mak 122. Ceylan C, Baran NT, Kocaaslan H, et al. A new model for
2023;23:133. prediction of bowel gangrene in sigmoid volvulus. Ulus
111. Chen J, Wu F, Cao Y, et al. The novel role of LDHA/ Travma Acil Cerrahi Derg 2023;29:471-6.
LDHB in the prognostic value and tumor-immune 123. Price JR, Hagrass H, Filip AB, et al. LDH and the
infiltration in clear cell renal cell carcinoma. PeerJ MELD-LDH in Severe Acute Liver Injury and Acute
2023;11:e15749. Liver Failure: Preliminary Confirmation of a Novel
112. Liu TY, Lee WJ, Tsai CM, et al. Serum lactate Prognostic Score for Risk Stratification. J Appl Lab Med
dehydrogenase isoenzymes 4 plus 5 is a better biomarker 2023;8:504-13.
than total lactate dehydrogenase for refractory 124. Ocak T, Gülten M. Retrospective Investigation of Factors
Mycoplasma pneumoniae pneumonia in children. Pediatr Affecting Mortality in Spontaneous Bacterial Peritonitis.
Neonatol 2018;59:501-6. Euroasian J Hepatogastroenterol 2023;13:5-9.
113. Ding CY, Peng L, Lin YX, et al. Elevated Lactate 125. Teniola D, Ayoola EA, Arigbabu AO. Lactic dehydrogenase
Dehydrogenase Level Predicts Postoperative Pneumonia levels in patients with duodenal ulcer, gastric ulcer, gastric
in Patients with Aneurysmal Subarachnoid Hemorrhage. polys and gastric carcinoma. Scand J Gastroenterol Suppl
World Neurosurg 2019;129:e821-30. 1986;124:169-78.
114. Kavvasoglu B, Kavvasoglu GH. Predictive value of clinical 126. McGrowder DA, Fraser YP, Gordon L, et al. Serum
and laboratory parameters in differentiating hypertensive creatine kinase and lactate dehydrogenase activities
pulmonary edema and acute pulmonary embolism. Eur in patients with thyroid disorders. Niger J Clin Pract
Rev Med Pharmacol Sci 2023;27:7255-63. 2011;14:454-9.
115. He Z, Bi W, Lang Z, et al. Comparative study on 127. Roti E, Bandini P, Robuschi G, et al. Serum concentrations
electrocardiograms and serological examinations of of myoglobin, creatine kinase, lactate dehydrogenase
acute pulmonary embolism and acute non-ST elevation and cardiac isoenzymes in euthyroid, hypothyroid and
myocardial infarction. Ann Noninvasive Electrocardiol hyperthyroid subjects. Ric Clin Lab 1980;10:609-17.
2022;27:e12920. 128. Zhong XH, Howard BD. Phosphotyrosine-containing
116. Pan R, Ren Y, Li Q, et al. Neutrophil-lymphocyte ratios lactate dehydrogenase is restricted to the nuclei of PC12
in blood to distinguish children with asthma exacerbation pheochromocytoma cells. Mol Cell Biol 1990;10:770-6.
from healthy subjects. Int J Immunopathol Pharmacol 129. Hsieh YS, Yeh MC, Lin YY, et al. Is the level of serum
2023;37:3946320221149849. lactate dehydrogenase a potential biomarker for glucose
117. Huang L, Lu Z, Zhou X, et al. U-Shaped Relationship monitoring with type 2 diabetes mellitus? Front

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65
Journal of Laboratory and Precision Medicine, 2024 Page 15 of 15

Endocrinol (Lausanne) 2022;13:1099805. RNA viruses. Adv Virus Res 1992;41:99-192.

130. Sato T, Hiramatsu R, Iwaoka T, et al. Changes 138. Nair RK, Rao KA, Mukherjee D, et al. Acute kidney injury
of platelets, serum lactic dehydrogenase, gamma- due to acute cortical necrosis following vivax malaria.
glutamyltranspeptidase, choline esterase and creatine Saudi J Kidney Dis Transpl 2019;30:960-3.
phosphokinase levels in patients with Cushing's syndrome. 139. Dodo M, Kitamura H, Shima H, et al. Lactate
Tohoku J Exp Med 1984;142:195-200. dehydrogenase C is required for the protein expression
131. Ding J, Karp JE, Emadi A. Elevated lactate dehydrogenase of a sperm-specific isoform of lactate dehydrogenase A. J
(LDH) can be a marker of immune suppression in cancer: Biochem 2019;165:323-34.
Interplay between hematologic and solid neoplastic 140. OMIM. Accessed 20.09.2023. Available online: https://
clones and their microenvironments. Cancer Biomark www.omim.org/search?index=entry&start=1&limit=10&so
2017;19:353-63. rt=score+desc%2C+prefix_sort+desc&search=%22lactate+
132. Bien E, Rapala M, Krawczyk M, et al. The serum levels dehydrogenase%22
of soluble interleukin-2 receptor alpha and lactate 141. Anai T, Urata K, Tanaka Y, et al. Pregnancy complicated
dehydrogenase but not of B2-microglobulin correlate with lactate dehydrogenase M-subunit deficiency: the first
with selected clinico-pathological prognostic factors and case report. J Obstet Gynaecol Res 2002;28:108-11.
response to therapy in childhood soft tissue sarcomas. J 142. He S, Bremme K, Kallner A, et al. Increased
Cancer Res Clin Oncol 2010;136:293-305. Erratum in: J concentrations of lactate dehydrogenase in pregnancy
Cancer Res Clin Oncol 2010;136:307. with preeclampsia: a predictor for the birth of small-
133. Boran N, Kayikçioğlu F, Yalvaç S, et al. Significance of for-gestational-age infants. Gynecol Obstet Invest
serum and peritoneal fluid lactate dehydrogenase levels in 1995;39:234-8.
ovarian cancer. Gynecol Obstet Invest 2000;49:272-4. 143. Bera S, Gupta S, Saha S, et al. Study of liver enzymes
134. Fitzgerald RT, Wright SM, Samant RS, et al. Elevation especially lactate dehydrogenase to predict foetal outcome
of serum lactate dehydrogenase at posterior reversible in pregnancy induced hypertension. Sch J App Med Sci
encephalopathy syndrome onset in chemotherapy-treated 2014;2:1569-72.
cancer patients. J Clin Neurosci 2014;21:1575-8. 144. Zhang X, Chen Y, Salerno S, et al. Prediction of
135. Shi M, Lin J, Wei W, et al. Machine learning-based in- intrahepatic cholestasis of pregnancy in the first 20
hospital mortality prediction of HIV/AIDS patients with weeks of pregnancy. J Matern Fetal Neonatal Med
Talaromyces marneffei infection in Guangxi, China. PLoS 2022;35:6329-35.
Negl Trop Dis 2022;16:e0010388. 145. van der Sluijs Veer G. Reference values for lactate
136. Nakakubo S, Unoki Y, Kitajima K, et al. Serum Lactate dehydrogenase in the serum during childhood and
Dehydrogenase Level One Week after Admission Is the puberty (author's transl). J Clin Chem Clin Biochem
Strongest Predictor of Prognosis of COVID-19: A Large 1980;18:305-6.
Observational Study Using the COVID-19 Registry Japan. 146. Colantonio DA, Kyriakopoulou L, Chan MK, et al.
Viruses 2023;15:671. Closing the gaps in pediatric laboratory reference
137. Plagemann PG, Moennig V. Lactate dehydrogenase- intervals: a CALIPER database of 40 biochemical markers
elevating virus, equine arteritis virus, and simian in a healthy and multiethnic population of children. Clin
hemorrhagic fever virus: a new group of positive-strand Chem 2012;58:854-68.

doi: 10.21037/jlpm-23-65
Cite this article as: Shipman AR, Bahrani S, Shipman KE.
Investigative algorithms for disorders affecting plasma lactate
dehydrogenase: a narrative review. J Lab Precis Med 2024;9:15.

© Journal of Laboratory and Precision Medicine. All rights reserved. J Lab Precis Med 2024;9:15 | https://dx.doi.org/10.21037/jlpm-23-65