medical biochemistry - Lactic acidosis

1. Lactic Acidosis
Dr.M.Kotteswaran
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2. INTRODUCTION
• Lactic acid is the normal endpoint of the
anaerobic breakdown of glucose in the
tissues.
• Normal plasma lactate: 0.5 to 1.5 meq/L.
C3H6O3
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3. Lactic acidosis
Definition:
• Lactic acidosis is a pathological state diagnosed
when the serum concentration of lactate or lactic
acid is persistently 5mmol/L or greater and there is
significant acidemia and serum pH< 7.35.
• Associated with elevated anion gap.
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4. FORMATION OF LACTICACID
• RBCs, brain and skin are major sources of lactic acid
• During exercise skeletal muscles release significant amount of
lactic acid.
• Kidney and liver utilize lactic acid for biosynthesis of glucose.
• Lactic acid and pyruvic acid are interconvertible reaction
• It is catalyzed by the enzyme lactate dehydrogenase.
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5. Pyruvate to lactate
The reduction of pyruvate by NADH⁺ to form lactate is
catalyzed by lactate dehydrogenase
The reaction takes place in the cells when the amount of oxygen is
less, as in muscle during intense activity.
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6. • In the cells lacking
mitochondria and under
anaerobic conditions, the
NADH⁺ formed in the
oxidation of glyceraldehyde 3-
phosphate is consumed in the
hydrogenation of pyruvate.
• The regeneration of NAD + in
the hydrogenation of pyruvate
to lactate sustains the continued
operation of glycolysis under
anaerobic conditions.
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7. The Cori cycle
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8. PATHOPHYSIOLOGY
Lactic acidosis occurs whenever there is an imbalance between the
production and use of lactic acid.
• Types and Causes of Lactic acidosis
• Type A(hypoxic)
• Type B(metabolic)
• d-Lactic acidosis: Generated from glucose and carbohydrate
by bowel bacteria in short bowel syndromes
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9. Types and causes of lactic acidosis
Type A
• Due to hypoxia in tissues (most common)
• Hypoxia causes impaired oxidative phosphorylation and decreased
ATP synthesis
• To survive, the cells switch to anaerobic glycolysis for ATP
synthesis
• This produces lactate as a final product
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10. • Type A - is due to inadequate supply of oxygen in tissues
E.g.
• Myocardial infarction
• Pulmonary embolism
• Uncontrolled hemorrhage
• Tissue hypoperfusion (shock, cardiac arrest, acute heart failure,
etc.)
• Anaerobic muscular exercise
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11. Type B
• Due to disorders in carbohydrate metabolism
• It is speculated to be a primary defect in mitochondrial function
with impaired oxygen use.
• This leads to reduced stores of ATP and NAD⁺ with accumulation
of NADH⁺ and H⁺.
• In the presence of decreased liver perfusion or liver disease,
lactate removal from the blood is reduced, thereby aggravating
the lactic acidosis
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12. Type B associated with disease
• Liver disease and Liver failure
• Neoplasia,
• Drug intoxication (ethanol, methanol, salicylate)
• Inborn error of metabolism.
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14. • Alcohol taken in excess tends to
prevent the metabolism of
lactate in the liver, because
oxidation of ethanol to
acetaldehyde competes for the
NAD⁺ necessary for oxidation
of lactate to pyruvate.
Lactic acidosis in Alcoholism
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15. Metformin causes lactic acidosis
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• Mechanism via which metformin increases plasma lactate levels
relates to the inhibition of mitochondrial respiration.
• This results in both accelerated lactate production and reduced
lactate metabolism.
• In isolated hepatocytes, metformin inhibits complex 1 of the
mitochondrial respiratory chain in a concentration-dependent
manner and impairs gluconeogenesis.

16. Lactic acidosis caused by vitamin Deficiency
• Deficiency of vitamin B1 (thiamine) is
a very rare cause of type B lactic
acidosis.
• Thiamine is an essential co-factor for
the enzyme pyruvate dehydrogenase
that allows oxidation of pyruvate to
acetyl CoA.
• In the absence of thiamine this
reaction cannot proceed and instead,
pyruvate is converted to lactate. The
resulting accumulation of lactate
causes lactic acidosis. 16

17. • An uncommon and often undiagnosed cause of lactic acidosis is
d-lactic acidosis.
• It was thought that d-lactate was not produced in human
metabolism, but normal individuals have a large capacity to
metabolize d-lactate.
• Moreover, absorption and accumulation of d-lactate from
abnormal intestinal bacteria may cause systemic acidosis.
• This occurs after jejunoileal bypass surgery and manifests as
altered mental status (from mild drowsiness to coma) with
increased blood concentrations of d-lactate.
d- Lactic acidosis:
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18. Malignancy and Lactic acidosis:
• Warburg effect
• The Warburg effect is the phenomenon in which
cancer cells produce additional energy through
increased glycolysis followed by lactic acid
fermentation .
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19. Illustration of lactate as a key player in cancer.
• A number of oncogenes and
tumor suppressor genes are
involved in the metabolic
switch from oxidative
phosphorylation (OXPHOS)
toward an altered glycolysis of
tumor cells, such as myc, NF-kB
this is reason for increased
lactic acidosis in malignancy.
• Key for Cancer cell is Lactate
• Increase immune escape –
decrease cytokines
• Increase ROS Scavenging –
increase radio-resistance
• Play important role in cancer
cell motility, migration,&
distant metastasis
• Increase angiogenesis in cancer
cell.
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20. • Glucose 6-phosphatase deficiency
(type I G6PD)(von gierke disease)
• Fructose-1,6-biphosphatase
deficiency
• Pyruvate carboxylate deficiency
Inborn error of metabolism
causing lactic acidosis
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21. Pyruvate dehydrogenase deficiency
Inborn error of metabolism
causing lactic acidosis
Oxidative phosphorylation deficiencies
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22. SIGNS AND SYMPTOMS
• Shallow breathing
• Muscle pain that may later lead to cramping
• Loss of weight and loss of appetite
• Myalgia
• Weakness and fatigue
• Nausea, vomiting
• Abdominal pains
• Tachypnoea
• Tachycardia
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23. Diagnosis
• Determination of Lactate in Whole Blood
• Principle
• Lactate is oxidized to pyruvate by lactate dehydrogenase in the
presence of NAD⁺. The NADH⁺ formed in this reaction is measured by
a spectrophotometer at 340 nm and serves as a measure of the
lactate concentration.
• Because of its high specificity and simplicity, the enzymatic
method is the method of choice for measuring lactate, although
other methods may also be used (e.g., gas chromatography,
photometry).
Methods for Measuring Lactate and Pyruvate in Body Fluids
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24. • The Vitros Analyzer (Ortho-Clinical Diagnostics) uses an assay in
which lactic acid is oxidized to pyruvate by lactate oxidase.
• The H2O2 generated oxidizes a chromogen system, and absorbance
of the resulting dye complex, measured by a spectrophotometer at
540 nm, is directly proportional to the lactate concentration in the
specimen.
• Each mole of lactate oxidized produces 0.5 mole of dye complex.
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25. Diagnosis done by measuring blood lactate levels
Hyperlactemia: 2 – 5 mmols/L
Severe lactic acidosis: > 5 mmols/L
• All commonly used laboratory assays for lactate use l-lactate
dehydrogenase, which does not detect d-lactate.
• d-Lactate can be measured by gas-liquid chromatography or, more
easily, by using a specific d-lactate dehydrogenase (Sigma) from
Lactobacillus leishmanni.
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26. CSF lactate
• Lactate in CSF normally parallels blood concentrations in adults , but
not in children.
• CSF lactate values change independently of blood values.
• Increased CSF concentrations are noted in cerebrovascular accidents,
intracranial haemorrhage, bacterial meningitis, epilepsy, inborn errors
of the electron transport chain, and other CNS disorders.
• In aseptic (viral) meningitis, lactate concentrations in CSF are not
usually increased; hence, CSF lactate has been used to help
discriminate between viral and bacterial meningitis, but the clinical
utility has been questioned. In a few children with inherited metabolic
disease, increased.
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27. • Correcting the underlying conditions
• Restoring adequate tissue oxygen
• Avoiding sodium bicarbonate
• Haemodialysis
Treatment
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28. Potential harms of bicarbonate
Hydrogen ion stimulate
Chemoreceptors of respiratory centre
Hyperventilation
May worsen oxygen delivery to tissue
Increase lactate production
Increased arterial and tissue capillary PCO2
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Sodium bicarbonate

29. • Dialysis may be a useful mode of therapy when
severe lactic acidosis exists in conjunction with
renal failure or congestive heart failure.
• Dialysis would allow bicarbonate infusion
without precipitating or worsening fluid
overload. Therefore, dialysis would correct
acidosis by restoring the buffer pool.
Haemodialysis
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30. • Hemodialysis or continuous hemofiltration
used in conjunction with alkali infusion may
be tolerated in a patient with cardiovascular
instability.
• However, the overall benefit of such therapy
to a patient's outcome is not known.
Metformin-induced lactic acidosis has been
reported to improve after prolonged
hemodialysis.
Haemodialysis
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