Hyperlactatemia and Lactic Acidosis
Hyperlactatemia and Lactic Acidosis
Lactic acidosis represents an infrequent complication of antiretroviral therapy but a common challenge in critical care medicine. Lactic acidosis with or without hepatic steatosis is the most serious presentation of nucleoside reverse transcriptase inhibitor (NRTI) toxicity and the one that clearly indicates that mitochondrial dysfunction can occur in persons using these agents. It has been reported during therapy with all NRTIs.
Lactic acidosis can be classified into types A and B. Type A occurs when the cells must generate adenosine triphosphate (ATP) without oxygen, a situation usually related to poor tissue oxygenation accompanying, for example, hypovolemic shock, hemorrhage, circulatory and pulmonary disease, and hemoglobin disorders. Type B is secondary to drugs, toxins, or diseases that do not cause poor tissue oxygenation.
The Figure shows the formation and elimination paths of lactate. In normal conditions, the majority of cellular energy needs are satisfied via the tricarboxylic acid cycle, also known as the Krebs cycle, and subsequent oxidative phosphorylation in the mitochondria. This process requires oxygen and produces as by-products carbon dioxide and water. ATP may also be derived by the cytosolic (or anaerobic) metabolism of pyruvate, producing lactate and water as by-products. Erythrocytes, which have no mitochondria, derive all their energy needs in this way. Approximately 1400 mmol of lactate is produced daily. Hyperlactatemia occurs when increased production, increased cellular release, or decreased utilization of lactate occurs; it is not, therefore, always accompanied by or a prelude to acidosis.
As the Figure indicates, there is no net production of hydrogen ions (H) in this process, no production of "acid." The source of H key to the development of acidosis is the hydrolysis of ATP to adenosine diphosphate. In normal circumstances, H is rapidly reutilized in the oxidative phosphorylation system. Thus, for acidosis to occur, oxidative metabolism must be impaired. Hyperlactatemia is a readily understood accompaniment, first, because impaired oxidative metabolism would mean more cellular energy requirements would need to be met by the cytosolic metabolism of glucose, hence more lactate would be produced, and second, because the clearance of lactate in the Cori cycle is ATP-dependent. If the cell is energy-deficient, this conversion cannot occur.
(Enlarge Image)
The production and utilization of lactate and the fates of pyruvate. (NADH, nicotinamide-adenine dinucleotide, reduced; NAD+, nicotinamide-adenine dinucleotide, oxidized; acetyl CoA, acetyl coenzyme A.) (Adapted from Mizock BA. JAMA. 1987.[2])
The primary site of lactate clearance and gluconeogenesis is the liver. Liver disease or dysfunction is commonly present in persons in whom lactic acidosis develops. In both type A and type B lactic acidosis, it is thought that both overproduction and underutilization of lactate are present to varying degrees.
Lactic acidosis represents an infrequent complication of antiretroviral therapy but a common challenge in critical care medicine. Lactic acidosis with or without hepatic steatosis is the most serious presentation of nucleoside reverse transcriptase inhibitor (NRTI) toxicity and the one that clearly indicates that mitochondrial dysfunction can occur in persons using these agents. It has been reported during therapy with all NRTIs.
Lactic acidosis can be classified into types A and B. Type A occurs when the cells must generate adenosine triphosphate (ATP) without oxygen, a situation usually related to poor tissue oxygenation accompanying, for example, hypovolemic shock, hemorrhage, circulatory and pulmonary disease, and hemoglobin disorders. Type B is secondary to drugs, toxins, or diseases that do not cause poor tissue oxygenation.
The Figure shows the formation and elimination paths of lactate. In normal conditions, the majority of cellular energy needs are satisfied via the tricarboxylic acid cycle, also known as the Krebs cycle, and subsequent oxidative phosphorylation in the mitochondria. This process requires oxygen and produces as by-products carbon dioxide and water. ATP may also be derived by the cytosolic (or anaerobic) metabolism of pyruvate, producing lactate and water as by-products. Erythrocytes, which have no mitochondria, derive all their energy needs in this way. Approximately 1400 mmol of lactate is produced daily. Hyperlactatemia occurs when increased production, increased cellular release, or decreased utilization of lactate occurs; it is not, therefore, always accompanied by or a prelude to acidosis.
As the Figure indicates, there is no net production of hydrogen ions (H) in this process, no production of "acid." The source of H key to the development of acidosis is the hydrolysis of ATP to adenosine diphosphate. In normal circumstances, H is rapidly reutilized in the oxidative phosphorylation system. Thus, for acidosis to occur, oxidative metabolism must be impaired. Hyperlactatemia is a readily understood accompaniment, first, because impaired oxidative metabolism would mean more cellular energy requirements would need to be met by the cytosolic metabolism of glucose, hence more lactate would be produced, and second, because the clearance of lactate in the Cori cycle is ATP-dependent. If the cell is energy-deficient, this conversion cannot occur.
(Enlarge Image)
The production and utilization of lactate and the fates of pyruvate. (NADH, nicotinamide-adenine dinucleotide, reduced; NAD+, nicotinamide-adenine dinucleotide, oxidized; acetyl CoA, acetyl coenzyme A.) (Adapted from Mizock BA. JAMA. 1987.[2])
The primary site of lactate clearance and gluconeogenesis is the liver. Liver disease or dysfunction is commonly present in persons in whom lactic acidosis develops. In both type A and type B lactic acidosis, it is thought that both overproduction and underutilization of lactate are present to varying degrees.
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