In carnitine deficiency, fatty acid oxidation is reduced, and fatty acids are diverted into triglyceride synthesis, particularly in the liver. Mitochondrial failure develops in carnitine deficiency when there is insufficient tissue carnitine available to buffer toxic acyl-coenzyme (CoA) metabolites. Toxic amounts of acyl-CoA impair the citrate cycle, gluconeogenesis, the urea cycle and fatty acid oxidation. Carnitine replacement treatment is safe and induces excretion of toxic acyl groups in the urine (Stumpf et al., 1985).
If carnitine deficiency involves the liver, the supply of ketones and the utilization of long-chain fatty acids during starvation are cut off; all tissues become glucose dependent. When liver carnitine is depleted, starvation tends to cause nonketotic, insulinopenic hypoglycemia. Because liver hepatocytes depend on fatty acids for their energy requirements during fasting, carnitine depletion may also cause clinical liver dysfunction, shown by hyperammonemia, encephalopathy and hyperbilirubinemia (Feller and Rudman, 1988). Skeletal muscles are generally involved, with weakness, lipid myopathy and myoglobinuria often aggravated or precipitated by fasting or exercise. The heart, like skeletal muscle, is dependent on fatty acids for energy during fasting, and heart failure and arrhythmias are frequent manifestations of systemic carnitine deficiency. The heart derives approximately 60% of its ATP supply from beta-oxidation of fatty acids. Carnitine concentrations in the heart are normally very high in many species (Rebouche and Paulson, 1986).
Carnitine deficiency is differentiated into three categories: excessive loss of free carnitine, excessive loss of acylcarnitine as a result of accumulation of acyl-CoA in tissues, and a combined type. The first condition is reported in humans as Fanconi syndrome and renal carnitine transport deficiency (primary carnitine deficiency), and the latter two types are found in various inborn errors of fatty acid metabolism (DiDonato et al., 1992).
Assessment of the carnitine status of a particular animal or human is difficult because plasma carnitine concentrations and urinary carnitine excretion are not good indicators of tissue carnitine status (Borum, 1991). Individuals with low carnitine concentrations in plasma may have normal carnitine concentrations in muscle or liver, and those with normal plasma carnitine concentrations may have low carnitine concentrations in muscle or liver.
