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LABORATORY UPDATE
“Pathology that Adds Value”
THE PATHCARE NEWS
Lactic Acidosis
What is lactic acidosis?
Lactic acidosis is a high anion gap metabolic acidosis caused by the accumulation of lactic acid, either due to overproduction or
underutilization.
Lactate homeostasis
Lactate is constantly being produced and metabolised in the body. The brain, skin and red blood cells are major sources of lactic acid at rest,
whilst skeletal muscle releases significant amounts of lactic acid during exercise. Excess lactate can accumulate when there is increased lactate
production and/or diminished lactate utilization (Under 'normal' circumstances the lactate:pyruvate ratio ranges from 4:1 to 10:1). Three
mechanisms can underlie the accumulation of lactate:
1. Enhanced pyruvate production.
2. Reduced pyruvate conversion to CO2 and H2O.
3. An altered redox state within the cell during which pyruvate is preferentially converted to lactate.
To understand the metabolism of lactate, it is necessary to review the processes of anaerobic and aerobic respiration. The following figure
illustrates the basic process:
During aerobic respiration there are three steps involved in the oxidation of glucose to carbon dioxide and water:
1. Intracytoplasmic glycolysis, which is the metabolic pathway that converts glucose to pyruvate.
2. Oxygen dependent tricarboxylic acid (TCA) cycle in the mitochondria that converts NADH to NAD+ by means of electron
transport. This NAD+ production ceases under anaerobic conditions, resulting in the accumulation of pyruvate and NADH, conditions
that favour the production of lactate.
3. Oxygen dependent oxidative phosphorylation in the mitochondria which generates NAD+.
January 2013
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LABORATORY UPDATE
“Pathology that Adds Value”
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During anaerobic respiration lactate is derived from the metabolism of pyruvate. This reversible reaction is catalysed by lactate dehydrogenase
(LDH), and involves the conversion of NADH to NAD+. When oxygen supply to cells is reduced, NAD+ production by electron transport
ceases. This leads to a build-up of both pyruvate and NADH, conditions that favour the production of lactate.
What are the causes of lactic acidosis?
The causes of lactic acidosis can be divided into two groups: those associated with impaired tissue oxygenation (type A), and those in which
systemic impairment of oxygenation is not apparent (type B).
Classification
Classification
of causes
of causes
ofoflactic
lactic acidosis
acidosis (Cohen
(Cohen
& Woods,
& Woods,
1976)
1976)
Type A lactic acidosis: Clinical evidence of inadequate tissue oxygenation
Hypo-perfusion e.g. Cardiogenic-, hypovolemic-, septic-, or haemorrhagic shock or regional ischaemia
Tissue hypoxia
e.g. Carbon monoxide poisoning, severe asthma and severe anaemia
Mechanism:
Type A lactic acidosis refers to circumstances where tissue oxygen delivery is inadequate based on clinical assessment. With an adequate
supply of oxygen, aerobic tissues regenerate NAD+ via oxidative phosphorylation in the mitochondria. Under anaerobic conditions,
tissues regenerate NAD+ in the cytoplasm by converting pyruvate to lactate. NAD+ is essential for glycolysis to continue.
Type B lactic acidosis: No clinical evidence of inadequate tissue oxygen delivery
Type B1
Associated with acquired diseases e.g. diabetes mellitus (diabetic ketoacidosis - DKA), hepatic failure1, malignancies2,
septicaemia, phaeochromocytoma3, post-cardiopulmonary bypass, renal failure, thiamine deficiency4, thyroid storm etc.
Associated with metabolites, drugs and toxins e.g. paracetamol, biguanides, cocaine, epinephrine3, norepinephrine3,
Type B2 ethanol5, ethylene glycol, isoniazid, lactulose, metformin6, methanol, nalidixic acid, niacin, nitroprusside, nucleoside reverse
transcriptase inhibitors (NRTIs)7, paraldehyde, parenteral nutrition4, terbutaline, theophylline etc.
Due to inborn errors of metabolism e.g. Glucose-6-phosphate dehydrogenase deficiency, fructose-1,6-diphosphate
Type B3 deficiency, pyruvate carboxylase deficiency, organic aciduria, Leigh's disease, Alper's disease and mitochondrial
encephalopathies etc.
Mechanism:
1. Hepatic Failure – Lactic acidosis due to poor utilization of lactate and altered metabolism;
2. Malignancies – Leukaemia, lymphoma, solid tumours predispose to lactic acidosis;
3. Epinephrine enhances hepatic glycogenolysis and glycolysis to lactate;
4. Fructose in IV fluids and parenteral nutrition leads to thiamine deficiency (co-factor for PDH) and accumulation of lactate;
5. Ethanol oxidation increases the conversion of pyruvate to lactate and decreases the clearance of lactate;
6. Metformin – increases glycolysis in peripheral tissues, decrease pyruvate oxidation and reduces hepatic lactate clearance;
7. NRTIs – drug induced mitochondrial dysfunction
Miscellaneous lactic acidosis
Spontaneous
lactic acidosis
Idiopathic lactic acidosis may be due to subclinical, regional hypoperfusion or coexistence of various predisposing
conditions or late manifesting enzymatic defect.
D-Lactic acidosis
Mammalian tissues produce the L-lactate isomer. D-lactate is a metabolic by-product of certain bacteria that may be
produced in excess if there is overgrowth of such organisms in the gut (e.g. after jejunal bypass surgery). Laboratory
tests will not detect D-lactate since L-LDH is used in the assays. An increased anion gap with normal serum lactate
and negative ketones in urine should raise suspicion of a possible D-lactic acidosis.
January 2013
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LABORATORY UPDATE
“Pathology that Adds Value”
THE PATHCARE NEWS
Clinical considerations and interpretation
With the availability of point-of-care lactate tests, there has been a renewed awareness of lactate as prognostic marker and as an indicator of
circulatory impairment in critical care patients. A recent systematic review by Borthwick et al concluded that no specific cut-off value for
predicting in-hospital mortality or sequential organ failure can be recommended, since there is a marked overlap between lactate levels of
survivors and non-survivors in studies. The most common recommendation across all studies was to use normalisation of blood lactate
concentration as a target during goal directed therapy.
What are the reference ranges for blood lactate?
Plasma Lactate
Whole Blood Lactate
Arterial reference range
0.5 – 1.6 mmol/L
Venous reference range
0.5 – 2.2 mmol/L
Specimen
Sodium fluoride (grey stopper) tube
Heparinised blood gas syringe
Note: Plasma and whole blood lactate levels analysed on different instruments in PathCare showed good correlation. It is strongly
recommended to use the same specimen type (e.g. arterial/venous) and the same method or instrument for serial lactate
measurements.
What are the specimen requirements for blood lactate?
Venous stasis should be avoided during specimen collection, and the specimen should be analysed without delay. If any delay occurs during
specimen collection prior to analysis, the specimen should be kept on ice during that time. Whole blood lactate is available at most
laboratories on the blood gas point-of-care analysers, offering a rapid whole blood lactate result. Plasma lactate is usually measured on a
central laboratory instrument, blood for plasma lactate should be collected in a sodium fluoride (grey stopper) tube, and transported on ice to
the laboratory, for separation of plasma from cells within 15 minutes to prevent false increases in lactate levels (glycolysis continues in vitro).
Conclusion:
Lactic acidosis is the most common cause of metabolic acidosis in hospitalized patients. Major clues suggesting a diagnosis of lactic acidosis
includes:
- Increased anion gap,
- Increased serum lactate levels, > 4.0 mmol/L (depending on the type of specimen),
- ± arterial pH < 7.35 (not always present, especially if a combined acid-base disorder is present).
Early identification of lactic acidosis and timely correction of lactic acidosis can improve patient care and outcome.
Compiled by: Dr. M. Lloyd, Chemical Pathologist, PathCare, Tel: 051 401 4600, [email protected].
References:
1. Borthwick H, Brunt LK, Mitchem KL, Chaloner C. Does lactate measurement performed on admission predict clinical outcome on the
intensive care unit? A concise systematic review. Ann Clin Biochem 2012; 49:391-394.
2. Wu AHB. Tietz clinical guide to laboratory tests 4th ed 2006; 650.
3. Nandwani S, Saluja M, Vats M, Mehta Y. Lactic acidosis in critically ill patients. People's Journal of Scientific Research 2010; 3(1): 43-47.
4. Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol 2001; 12:S15-S19.
5. Hancock MR. Mitochondrial dysfunction and the role of the non-specialist laboratory. Ann Clin Biochem 2002; 39:456-463.
January 2013
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