Clinical Aspects

Impaired Oxidation of Fatty Acids Gives Rise to Diseases Often Associated With Hypoglycemia

Carnitine deficiency can occur particularly in the new-born—and especially in preterm infants—owing to inadequate biosynthesis or renal leakage. Losses can also occur in hemodialysis. This suggests a vitamin-like dietary requirement for carnitine in some individuals. Symptoms of deficiency include hypoglycemia, which is a consequence of impaired fatty acid oxidation and lipid accumulation with muscular weakness. Treatment is by oral supplementation with carnitine.

Inherited CPT-I deficiency affects only the liver, resulting in reduced fatty acid oxidation and ketogene-sis, with hypoglycemia. CPT-II deficiency affects pri-

Acetyl-CoA

Ketone bodies

Figure 22-10. Regulation of long-chain fatty acid oxidation in the liver. (FFA, free fatty acids; VLDL, very low density lipoprotein.) Positive ((+)) and negative (©) regulatory effects are represented by broken arrows and substrate flow by solid arrows.

marily skeletal muscle and, when severe, the liver. The sulfonylurea drugs (glyburide [glibenclamide] and tolbutamide), used in the treatment of type 2 diabetes mellitus, reduce fatty acid oxidation and, therefore, hyperglycemia by inhibiting CPT-I.

Inherited defects in the enzymes of P-oxidation and ketogenesis also lead to nonketotic hypoglycemia, coma, and fatty liver. Defects are known in long- and short-chain 3-hydroxyacyl-CoA dehydrogenase (deficiency of the long-chain enzyme may be a cause of acute fatty liver of pregnancy). 3-Ketoacyl-CoA thiolase and HMG-CoA lyase deficiency also affect the degradation of leucine, a ketogenic amino acid (Chapter 30).

Jamaican vomiting sickness is caused by eating the unripe fruit of the akee tree, which contains a toxin, hypoglycin, that inactivates medium- and short-chain acyl-CoA dehydrogenase, inhibiting P-oxidation and causing hypoglycemia. Dicarboxylic aciduria is characterized by the excretion of Cg-C10 O-dicarboxylic acids and by nonketotic hypoglycemia. It is caused by a lack of mitochondrial medium-chain acyl-CoA dehydrogenase. Refsum's disease is a rare neurologic disorder due to a defect that causes the accumulation of phy-tanic acid, which is found in plant foodstuffs and blocks P-oxidation. Zellweger's (cerebrohepatorenal)

syndrome occurs in individuals with a rare inherited absence of peroxisomes in all tissues. They accumulate C26-C38 polyenoic acids in brain tissue and also exhibit a generalized loss of peroxisomal functions, eg, impaired bile acid and ether lipid synthesis.

Ketoacidosis Results From Prolonged Ketosis

Higher than normal quantities of ketone bodies present in the blood or urine constitute ketonemia (hyperke-tonemia) or ketonuria, respectively. The overall condition is called ketosis. Acetoacetic and 3-hydroxybutyric acids are both moderately strong acids and are buffered when present in blood or other tissues. However, their continual excretion in quantity progressively depletes the alkali reserve, causing ketoacidosis. This may be fatal in uncontrolled diabetes mellitus.

The basic form of ketosis occurs in starvation and involves depletion of available carbohydrate coupled with mobilization of free fatty acids. This general pattern of metabolism is exaggerated to produce the pathologic states found in diabetes mellitus, twin lamb disease, and ketosis in lactating cattle. Nonpathologic forms of ketosis are found under conditions of high-fat feeding and after severe exercise in the postabsorptive state.

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