Urine biotin excretion

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

Most patients with biotinidase deficiency excrete large quantities of biocytin in their urine, but there has been no evidence of accumulation of this metabolite in tissues. It remains to be determined whether biotin therapy is harmful because it may increase the concentration of biocytin in these children. 

The brush border of the kidney cortex has a sodium-biotin cotransport system similar to that in the intestinal mucosa, thus providing for reabsorption of free biotin filtered into the urine. It is only when this mechanism is saturated (it has a relatively low K n) that there will be a significant excretion of biotin. 

The affected infants have a normal plasma concentration of biotin and excrete normal amounts of biotin in the urine. Skin fibroblasts have extremely low activities of aU four biotin-dependent carboxylases when they are cultured in media containing approximately physiological concentrations of biotin. But, culture with considerably higher concentrations of biotin results in normal activity of aU four carboxylases. The defect is in the affinity of holocarboxylase synthetase for biotin (its is 20- to 70-fold higher than normal). 

Pantothenic acid is taken in as dietary CoA compounds and dCphosphopantetheine and hydrolyzed by pyrophosphatase and phosphatase in the intestinal lumen to dephospho-CoA, phosphopantetheine, and pantetheine. This is further hydrolyzed to pantethenic acid. The vitamin is primarily absorbed as pantothenic acid by a saturable process at low concentrations and by simple diffusion at higher ones. The saturable process is facilitated by a sodium-dependent multivitamin transporter, for which biotin and lipoate compete. After absorption, pantothenic acid enters the circulation and is taken up by cells in a manner similar to its intestinal adsorption. The synthesis of CoA from pantothenate is regulated by pantothenate kinase, which itself is subject to negative feedback from the products CoA and acyi-CoA. The steps involved were outlined above. Pantothenic acid is excreted in the urine after hydrolysis of CoA compounds by enzymes that cleave phosphate and the cys-teamine moieties. Only a small fraction of pantothenate is secreted into milk and even less into colostrum. 

Vitamins are a chemically and functionally inhomogeneous group of biomolecules. As a gross classification distinction is usually made between (1) fat-soluble and (2) water-soluble vitamins. Owing to their insolubility in water the fat-soluble vitamins A, D, E, and K can be accumulated in fat tissue and excessive intake causes hypervitaminoses. The water-soluble vitamins - vitamin Bj, vitamin B2, niacin, vitamin Bg, folic acid, pantothenic acid, biotin, vitamin B12, and ascorbic acid - can generally only be stored in a small amount and intake exceeding actual need is excreted in the urine. 

Reduced activities of carboxylase enzymes can cause a metabolic block of certain substrates and a use of alternative pathways for catabolism. Therefore, 3-hydroxyisovaleric acid and 3-methylcrotonyl glycine are formed consequently to a shunt of 3-methylcrotonyl carboxylase counterbalancing its activity decrease. Marginal biotin deficiency experimentally induced by 20 days of free biotin diets in human increased 3-hydroxyisovaleric acid excretion in urine above the upper limit of normal. The normal urinary excretion of 3-hydroxyisovaleric acid in healthy adults is 112 38 pmol per 24 hours (Mock et al. 1997). This suggests that 3-hydroxyisovaleric acid urinary excretion is a good indicator of marginal biotin deficiency. 

Biotin deficiency causes disturbances in a variety of carboxylase-mediated metabolic reactions. As a result, such a deficiency may induce ketolactic acidosis and organic aciduria (Zempleni et al. 2008). Organic acids such as 3-methylcrotonylglycine, 3-hydroxyvaleric acid or methylcitric acid are excreted in urine in case of biotin deficiency (Figure 43.2). 

The daily requirement is shown in Table 6.3. An indicator of sufficient biotin supply is the excretion level in the urine, which is normally SOSO pg/day. A deficiency is indicated by a drop to 5 pg/day. 

He was treated with 5 mg of biotin per day. After 3 days the various abnormal organic acids were no longer detectable in his urine, and his plasma lactate, pyruvate and ketones had returned to normal, although his excretion of biocytin and biocytin-containing peptides increased. At this stage he was discharged from hospital, with a supply of biotin tablets. After 3 weeks his skin rash began to clear and his hair loss ceased. 

Water soluble vitamins are generally not stored in the body, or are stored only for a limited time and the excess is excreted in the urine. Lipophilic vitamins are stored mainly in the Hver. The reserve capacity, defined as the time during which the need for the vitamin is covered by the organism reserves, is the longest for corrinoids (3-5 years) and vitamin A (1-2 years). The reserve capacity for folacin is 3-4 months, for vitamins C, D, E and K, riboflavin, pyridoxine and niacin it is 2-6 weeks, and for thiamine, pantothenic acid and biotin it is only 4-10 days. Reserve capacity is affected by the history of vitamin intake, the metabolic need for the vitamin and the health status of the individual. 

A considerable amount of biotin is synthesized by human intestinal bacteria, as evidenced by the fact that 3 to 6 times more biotin is excreted in the urine and feces than is ingested. But synthesis in the gut may occur too late in the intestinal passage to be absorbed well and play much of a direct role as a biotin source. Also, several variables affect the microbial synthesis in the intestines, including the carbohydrate source of the diet (starch, glucose, sucrose, etc.), the presence of other B vitamins, and the presence or absence of antimicrobial drugs and antibiotics. 

Excretion is mainly in the urine. Only traces of biotin are secreted in milk. 

RECOMMENDED DAILY ALLOWANCE OF BIOTIN. It is difficult to obtain a quantitative requirement for biotin, for the reason that intestinal microflora make a significant contribution to the body pool of available biotin often humans excrete via the feces and urine considerably more biotin than they have ingested. However, the estimated safe and adequate intakes of biotin are given in the section on VITAMIN(S), Table V-5, Vitamin Table. 

Also, considerable biotin is synthesized by the microorganisms in the intestinal tract, as evidenced by the fact that 3 to 6 times more biotin is excreted in the urine and feces than is ingested. 

As a component of biotin, sulfur is important in fat metabolism as a component of thiamin and insulin, it is important in carbohydrate metabolism as a component of coenzyme A, it is important in energy metabolism as a component of certain complex carbohydrates, it is important in various connective tissues. Insulin and glutathione, regulators of energy metabolism, contain sulfur. Also, sulfur compounds combine with toxic substances such as phenols and cresols and convert them to a nontoxic form, following which they are excreted in the urine. 

Oppel (148) produced quantitative evidence in respect to biotin. Human. subjects were found to excrete in the urine more biotin than they ingested in the diet. The stool output of biotin also was more than the amount ingested. Both urine and stools contained three to six times the biotin content of the diet. The conclusion was therefore drawn that bacterial synthesis was responsible. The results of Najjar and Holt (143) contain... 

Further enzymological studies on the condition have been provided by Bartlett et al. (1980), who described a 4-year-old girl with mild metabolic acidosis and who excreted grossly increased concentrations of 3-hydroxy-isovaleric acid and 3-methylcrotonylglycine in her urine. She was responsive to biotin therapy (oral, 5 mg day ) and studies on her cultured skin fibroblasts showed deficient activities of propionyl-CoA carboxylase and of 3-methyl-crotonyl-CoA carboxylase. Studies in vivo showed that the latter enzyme was stimulated by biotin supplementation of the medium to a much greater degree than the other mitochondrial carboxylase enzymes. 

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