Mechanisms of Lactic Acidosis PDF

Mechanisms of Lactic Acidosis Dr. Sameh Sarray, PhD Department of Medical Biochemistry  How lactate is produced? ❑ Hydrocarboxylic acid: 2 stereoisomers: L-lactate (predominant) and D-lactate ❑ The main sources of intracellular L-lacta...

Mechanisms of Lactic Acidosis Dr. Sameh Sarray, PhD Department of Medical Biochemistry  How lactate is produced? ❑ Hydrocarboxylic acid: 2 stereoisomers: L-lactate (predominant) and D-lactate ❑ The main sources of intracellular L-lactate are glucose and alanine (by transamination reaction catalyzed by ALT). The pyruvate produced will be reduced into lactate: ❑ in anaerobic conditions catalyzed by LDH when pyruvate oxidation in citric cycle is overwhelmed  What happens to the lactate? The lactate is metabolized predominantly in the liver and kidney: Liver: Lactate is converted to glucose by gluconeogenesis through Cori cycle. It uses 6 ATP molecules Kidneys: contribute to lactate removal approximately 10 to 20% of the total lactate metabolized. The kidneys dispose of lactate in three ways: excretion, gluconeogenesis, and oxidation Other tissues can use lactate as a substrate and oxidise it to CO2 and water; It is ONLY the liver and kidney have the enzymes that convert lactate to glucose  Lactic Acidosis Lactic acidosis occurs when lactic acid production exceeds lactic acid clearance. Lactic acidosis is a pathological state diagnosed when: Serum concentration of lactate above 4 mmol/L (RR 0.5 – 1.5 mmol/L) and Acidemia : serum pH < 7.35  Lactic Acidosis Consequence of inborn errors of metabolism: - glucose-6-phosphatase deficiency (von Gierke disease, GSD-I) - fructose-1,6-bisphosphatase deficiency - pyruvate carboxylase deficiency - pyruvate dehydrogenase deficiency - oxidative phosphorylation deficiency - methylmalonic aciduria - MELAS syndrome (Mitochondrial, Encephalopathy, Lactic acidosis, and Stroke) is a progressive neurodegenerative disorder caused by a point mutation in mitochondrial DNA. In association with an underlying disease: Diabete mellitus, alcoholic ketoacidosis, severe iron-deficiency anemia, liver diseases, renal failure, pancreatitis, short gut syndrome, infections (malaria, cholera), malignancy (e.g., leukaemia, Lymphoma, lung cancer), thiamine deficiency, carbohydrate malabsorption syndromes….. Types of lactic acidosis ❑ Type A ❑ Type B ❑ D-lactic acidosis  Type A lactic acidosis Type A lactic acidosis: common; due to: Hypoxia in tissues (tissue hypoperfusion: Inadequate supply of oxygen in tissues) E.g. Myocardial infarction, pulmonary embolism.. Dysoxia: A condition in which tissues cannot make full use of available oxygen Anemia alone is not common cause of lactic acidosis but a contributing factor only rare severe case of anemia will develop a potentially life- threatening lactic acidosis (e.g. PaO2 < 35mmHg; [Hb]