Lactic acidemia

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

Fatal infantile cytochrome c oxidase (CCO) deficiency is characterized by total absence of catalytic activity in skeletal muscle. This often occurs within the context of the Fanconi syndrome, or less commonly in association with a cardiomyopathy. Although the deficiency is global in skeletal muscle, with all fibers affected, only isolated scattered fibers show abnormal aggregations of mitochondria (ragged-red fibers). Multiple affected siblings within one family are frequently encountered and suggest autosomal recessive inheritance. The condition normally proves fatal before the age of six months and is characterized by worsening intractable lactic acidemia. 

Type 1 Von Gierke s disease Deficiency of glucose-6-phosphatase Liver cells and renal tubule cells loaded with glycogen. Hypoglycemia, lactic-acidemia, ketosis, hyperlipemia. 

Hyperventilation and vomiting result in early alkalosis, which changes to acidosis and lactic acidemia. 

Proline Prolinemia type 1 and 2 Lactic acidemias P-5-C synthase deficiency... 

Table 3.1.1 Disorders of organic acid metabolism (in alphabetical order). This table does not include disorders with primary accumulation of amino acids, disorders of mitochondrial fatty acid oxidation, or primary lactic acidemias. Co A Coenzyme A, FAD flavin adenine dinucleotide...

The GC-MS methods described here reflect the practice in the laboratory of the author. Organic acids are extracted from biological fluids by liquid-liquid extraction after mixing the specimen with an internal standard solution and a small amount of mineral acid (HC1) to bring the pH to < 2. Oximation of 2-keto acids with hy-droxylamine hydrochloride is not performed routinely, but only as a repeat analysis when the primary analysis reveals an abnormal excretion of 2-keto acids (e.g., lactic acidemia, ketonuria) and the potential presence of other compounds (e.g., glyoxylic acid, succinylacetone). 

Thus, physiological changes in blood flow through organs, such as shunting, may occur. Peripheral vasodilation due to hypoxia may exceed the cardiac output and hence fainting and unconsciousness can occur. Lactic acidemia will also result from impaired aerobic metabolism. 

BOX 17-F LACTIC ACIDEMIA AND OTHER DEFICIENCIES IN CARBOHYDRATE METABOLISM... 

Deficiency of pyruvate dehydrogenase is the most frequent cause of lactic acidemia ac Since this enzyme has several components (Fig. 15-15), a number of forms of the disease have been observed. Patients are benefitted somewhat by a high-fat, low-carbohydrate diet. Transient lactic acidemia may result from infections or from heart failure. One treatment is to administer dichloroacetate, which stimulates increased activity of pyruvate dehydrogenase, while action is also taken to correct the underlying illness.d Another problem arises if a lactate transporter is defective so that lactic acid accumulates in muscles.6... 

Khan JK, Pallaki M, Tolbert SR, Hornick TR. Lactic acidemia associated with metformin. Ann Pharmacother 2003 37 66-9. 

Cray SH, Robinson BH, Cox PN. Lactic acidemia and bradyarrhythmia in a child sedated with propofol. Crit Care Med 1998 26(12) 2087-92. 

C-IO) Fumarase deficiency. There is a deficit in the transformation of fumarate to malate. The infant has developmental retardation, with abnormal neuromuscular function, lactic acidemia, and fumarate aciduria. The lactic acidosis may result from a backup of Krebs cycle function, all the way to lactate. Lactic acidosis may also be present in rare disorders of cytochrome oxidase activity. Diagnostically, there is a deficit in fumarase activity in assay of liver and skeletal muscle mitochondria. 

Multisystem organ dysfunction and lactic acidemia occurred in two of 15 patients with HIV and hepatitis C infections who received interferon alfa, didanosine, and ribavirin (23). Co-administration of didanosine with ribavirin can lead to increased toxicity secondary to raised intracellular concentrations of phosphorylated didanosine (ddA-TP) (24,25). Thus, the evidence suggests that the combination of didanosine plus ribavirin increases the risk of lactic acidosis. 

Bicarbonate does not increase left ventricular contractility during L-lactic acidemia in pigs. American Review of Respiratory Disease 148 317-322 Cooper D J, Walley K R, Dodek P M et al 1992 Plasma ionized calcium and blood lactate concentrations are inversely associated in human lactic acidosis. Intensive Care M icine 18 286-289 Corley K T T 2002 Fluid therapy for horses with gastrointestinal diseeises. In Smith B P (ed) Large animal internal medicine, 3rd edn. Mosby, St Louis, MO, pp. 682-694... 

Robinson BH, Lactic acidemia (disorders of pyruvate carboxylase, pyruvate dehydrogenase). In Shriver CR, Beaudet WS, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th ed. New York McGraw-HiU, 1995 1479-99. 

Thiamine deficiency causes decreased pyruvate oxidation, leading to accumulation of pyruvate and lactate, particularly in the blood and brain, and is accompanied by impairment of the cardiovascular, nervous, and gastrointestinal systems (Chapter 38). Inherited deficiency of pyruvate dehydrogenase complex is accompanied by lactic acidemia and abnormalities of the nervous system (e.g., ataxia and psychomotor retardation). Pyruvate carboxylase deficiency causes similar abnormalities (Chapter 15). Both inherited disorders of pyruvate utilization are autosomal recessive. 

Excessive production of organic acids leads to elevated levels of uric acid. Lactate, acetoacetate, and /1-hydroxybutyrate (the latter two are known as ketone bodies) compete with uric acid for secretion by the kidney tubules. Lactic acidemia can occur in glucose-6-phosphatase deficiency and in alcohol ingestion. Ketonemia and ketonuria occur in untreated diabetes mel-litus, starvation, glucose-6-phosphatase deficiency, etc. (Figure 27-17). 

A 3-month-old boy presents with poor feeding and growth, low muscle tone (hypotonia), elevation of blood lactic acid (lactic acidemia), and mild acidosis (blood pH 7.3 to 7.35). The ratio of pyruvate to lactate in serum is elevated, and there is decreased conversion of pyruvate to acetyl coenzyme A in fibroblasts. Which of the following compounds might be considered for therapy ... 

Because persons may be bom with defects in almost any gene, a variety of other problems leading to accumulation of organic acids are also known. Methylmalonic aciduria and propionic acidemia are discussed in Box 17-B. Lactic acidemia (Box... 

Pyruvate carboxylase deficiency is one of the genetic diseases grouped together under the clinical manifestations of Leigh s disease (subacute necrotizing encephalopathy). In the mild form, the patient presents early in life with delayed development and a mild-to-moderate lactic acidemia. Patients who survive are severely mentally retarded, and there is a loss of cerebral neurons. In the brain, pyruvate carboxylase is present in the astrocytes, which use TCA cycle intermediates to synthesize glutamine. This pathway is essential for neuronal survival. The major cause of the lactic acidemia is that cells dependent on pyruvate carboxylase for an anaplerotic supply of oxaloacetate cannot oxidize pyruvate in the TCA cycle (because of low oxaloacetate levels), and the liver cannot convert pyruvate to glucose (because the pyruvate carboxylase reaction is required for this pathway to occur), so the excess pyruvate is converted to lactate. 

A number of other problems that interfere either with the electron transport chain or pyruvate oxidation in the TCA cycle result in lactic acidemia (see Fig.22.15). For example, OXPHOS diseases (inherited deficiencies in subunits of complexes in the electron transport chain, such as MERFF) increase the NADH/NAD ratio and... 

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