Carnitine urinary

Quantitation of urinary carnitine esters in a patient with medium-chain acyl-coenzyme A dehydrogenase deficiency effect of metabolic state and L-camitine therapy. 

Chalmers RA, Roe CR, Stacey , Hoppel CL (1988) Urinary excretion of L-carnitine and acylcarnitines by patients with disorders of organic acid metabolism evidence for secondary insufficiency of L-carnitine. Pediatr Res 18 1325-1328... 

Although oral carnitine aided the elimination of the pivaloyl moiety, its simultaneous use did not fully compensate for the adverse metabolic effects of pivaloyl-con-taining beta-lactams (217,218). The consequences of pivaloyl-induced carnitine loss seem to be generally reversible. But as long as the risk of pivaloyl-induced urinary loss of carnitine and particular risk factors are not better defined, it is prudent to use pivaloyl-containing prodrugs only in short-term treatment. 

Valproate also causes urinary loss of carnitine (SEDA-12, 209), most probably by a different mechanism than pivalic acid (44). However, the combination can rapidly cause serious adverse effects (45). 

Nakashima M, Kosuge K, Ishii I, Ohtsubo M. [Influence of multiple-dose administration of cefetamet pivoxil on blood and urinary concentrations of carnitine and effects of simultaneous administration of carnitine with cefetamet pivoxil.]Jpn J Antibiot 1996 49(10) 966-79. 

Laboratory studies Serum transaminases, blood glucose, plasma and urine carnitine and acylcarnitines, urinary organic acids... 

After 3 months of therapy (Table 9-1), serum levels of carnitine, though still lower than the controls, had increased markedly from the pretherapy levels. Muscle carnitine levels also increased but remained well below normal. Despite this, clinical muscle strength and tone were remarkably improved. Carnitine levels in the liver (where carnitine transport is not dependent on OCTN-2) increased more dramatically than those in muscle. Despite the low serum carnitine concentration, urinary carnitine losses were dramatically increased in the patient while on therapy as compared with controls. This reflects the continued dysfunction of the renal OCTN-2 and thus the continued urinary wasting of carnitine. 

Carnitine deficiency complicates HMG-CoA lyase deficiency and other inborn errors of metabolism, which results in organic acidemia. L-Camitine or P-hydroxy-y-trimethylammonium butyrate is a carrier molecule that transports long-chain fatty acids across the inner mitochondrial membrane for subsequent P-oxi-dation. L-Carnitine also facilitates removal of toxic metabolic intermediates or xenobiotics via urinary excretion of their acyl carnitine derivatives. Indeed, individuals with HMG-CoA lyase deficiency have been shown to excrete 3-methylgluatarylcamitine (Roe et al., 1986). In the absence of ketogenesis, the formation of the acyl carnitine derivative of 3-hydroxy-3-methylglutarate from HMG-CoA also serves to regenerate free CoA in the mitochondria and permits continued P-oxidation of fatty acids. 

As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

Total urinary excretion of carnitine is between 300 to 530 /rmol (men) or 200 to 320 /rmol (women) 30% to 50% of this is free carnitine the remainder is a variety of acyl carnitine esters. Acyl carnitine esters are readily cleared in... 

Urinary excretion of acyl carnitine esters increases considerably in a variety of conditions involving organic aciduria carnitine acts to spare CoA and pantothenic acid (Section 12.2), by releasing the coenzyme from otherwise nonmetabolizable esters that would trap the coenzyme and cause functional pantothenic acid deficiency. 

The administration of pivaloyl-conjugated beta-lactam antibiotics to healthy volunteers for 54 days reduced mean serum carnitine 10-fold and muscle carnitine, as measured per non-collagen protein, more than 2-fold (62). Long-term treatment of children for 12-37 months to prevent urinary tract infection resulted in serum carnitine concentrations of 0.9-3.6 pmol/l (reference range 23-60 pmol/l). In four cases, muscle carnitine was 0.6-1.4 j,mol/g non-collagen protein (reference range 7.1-19) (63). 

Primary carnitine deficiency results from a defect in the carnitine transporter within the plasma membrane resulting in the inability to reabsorb carnitine and in significant loss of urinary carnitine. As a result, extremely low serum... 

Supplementation of carnitine (100-400 mg/ kg/day divided two to three times per day) is also an important aspect of the treatment of PROP and MMA [3,7,13,19,47,74]. Provision of oral carnitine is effective in preventing carnitine depletion, regenerating the intracellular pool of free coenzyme A (CoA), and allows urinary excretion of propionylcamitine, thereby reducing propionate toxicity [13, 75]. High doses of carnitine may cause a hshy odor due to overproduction of methylamines and may cause diarrhea [7, 74] but may be particularly helpful in PROP [47]. 

Isovaleryl-CoA dehydrogenase (EC 1.3.99.10). Defective conversion of isovaleryl-CoA to methylcro-tonyl-CoA (see Leudne). Elevated isovalerate in plasma and urine also increased urinary isovaleryl-glydne, isovalerylcamitine and sometimes 3-hydro-xyisovalerate. Ketoacidotic crises, sometimes with fatal coma. Slight mental retardation in survivors. Treated with low leucine diet and supplements of glycine and/or carnitine to increase excretion of isovaler-yl conjugates. Peritoneal dialysis in crises. 

Stratton, S.L., Horvath, T.D., Bogusiewicz, A., Matthews, N.I., Henrich, C.L., Spencer, H.J., Moran, J.H., and Mock, D.M., 2011. Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. The Journal of Nutrition. 141 353-358. 

Note that MS/MS is unable to distinguish between isomeric acylcarnitines. Therefore, elevations of C4 can be either from accumulation of butyr-yl or isobutyryl carnitine, C5 can be either isovaleryl or 2-methylbutyryl and so on. Some individual metabolites are characteristic of more that one disease. Propionylcarnitine is markedly elevated in both propionic and methylmalonic acidemia. 3-Hydroxyisovalerylcarnitine (OH-C5) is associated with both 3-MCC deficiency and HMG-CoA-lyase deficiency. Minor elevations in either or both of these metabolites are also consistent with ho-locarboxylase deficiency or with deficiency of the cofactor biotin (or bioti-nidase). The differential diagnosis of each of these conditions is generally made from a careful analysis of urinary organic acids, performed by capillary column GC/MS in a reputable facility. This is especially important in the follow-up of abnormal newborn screening acylcarnitine results. 

Plasma eamitine coneentrations in a normal U.S. population ean range from 37 to 89 ]aM, with approximate eoneentrations for males ranging from 59.3 +11.9 piM and females 51.5+11.6 piM. Studies have revealed that 54 to 87% of dietary carnitine is absorbed, which contributes to this plasma pool, and furthermore during its metabolism and excretion it is highly eonserved within the kidneys. Approximately 90 to 98% of ingested eamitine is reabsorbed in the renal tubules." That whieh is not reabsorbed can be exereted via the feees (about 1 to 2%) or its typieal elimination pathway through the urinary system (about 0.1 to 0.3%). ... 

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