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Lactic Acidosis Group Members • • • • • • Azam Muzafar Bin Ahmad Mokhtar (D20141066917) Nur Hasyimah Binti Ruslan (D20141066899) Nurhani Binti Nor Azwan (D20141066899) Balqis Aqilah Binti Alue (D201410 Muhammad Noor Bin Khozari (D20141066906) Huang Zheng Xian (D201410 PROBLEM STATEMENT Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood (acidosis) accompanied by the buildup of lactate, especially Llactate, and is considered a distinct form of metabolic acidosis. Lactic acidosis is characterized by lactate levels >5 mmol/L and serum pH <7.35. In a Young Biochemist Association Forum, you are invited to explain about the condition and how DCA could treat it. What is Lactic Acidosis? • Lactic acidosis is a physiological condition characterized by low pH in body tissues and blood (acidosis) accompanied by the buildup of lactate, especially L-lactate, and is considered a distinct form of metabolic acidosis. • The condition typically occurs when cells receive too little oxygen (hypoxia), for example, during vigorous exercise. In this situation, impaired cellular respiration leads to lower pH levels. • Simultaneously, cells are forced to metabolize glucose anaerobically, which leads to lactate formation. Therefore, elevated lactate is indicative of tissue hypoxia, hypoperfusion, and possible damage. Lactic Acidosis • Occur when execessive accumulation of lactic acid in bloodstream. • Decrease activity pyruvate Dehydrogenase CAUSES • It can be divided by 2: • 1. Can be prove clinically eg: left ventricular failure • 2. Cannot be prove clinically Underlying diseases - eg: chronic kidney diseases, diabetes, cancer Drug - alcohol, aspirin Inborn errors of metabolism - metabolism errors Causes of Lactic Acidosis • Genetic conditions ● Biotinidase deficiency, Multiple carboxylase deficiency, or non-genetic deficiencies of biotin ● Diabetes mellitus and deafness ● Fructose 1,6-diphosphatase deficiency ● Glucose-6-phosphatase deficiency ● GRACILE syndrome ● Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) ● Pyruvate dehydrogenase deficiency ● Pyruvate carboxylase deficiency How low oxygen level affect PDC? • mitochondria oxidation in PDC of pyruvate cannot proceed Dichloroacetate Acid (DCA) What is DCA? • It’s molecular formula is CHCL2COOH • DCA has been studied as potential drugs • Inhibits pyruvate dehydrogenase kinase that is responsible in inactivate the mitochondrial pyruvate dehydrogenase. How the activity of PDC affected by Dichloroacetate? • DCA ( an inhibitor of pyruvate dehydrogenase kinase) is a useful tool on regulation of PDC. • DCA indirectly activate the PDC by inhibit PD kinase as pyruvate • DCA stimulates the metabolic process (pyruvate oxidation) • DCA only effective when blood glucose maintained by gluconeogenesis. How DCA works? Glycolysis ends with the synthesis of pyruvate. But to be self-functioning it must end with lactate. ( low oxygen) Which mean accumalation of pyruvate lead to excess lactate production. DCA active pyruvate dehydrogenase (PDH) which will stimulate the oxidation of lactate to acetyl-coenzyme A and carbon dioxide. Extra Info • This New Drug(DCA) Appears to Cause Cancer Cells to Self-Destruct, however, whether it can reverse tumor growth without harming you in other ways remains to be seen. • In a test of using DCA in the treatment of lactic acidosis patient, it is observed that dichloroacetate decreased the lactate concentrations in the treated patients but had no beneficial effects on outcomes. The authors concluded that dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial blood lactate concentrations and pH and fails to alter either hemodynamics or survival rates.