Nicotinic Acid Deficiency

Warkany and E. Schraffenberger, Proc. Soc. Exptl. Biol. Med. 64, 92 (1943). 1 A. Giroud, XII Congr s international de zoologie, Paris, 1948. 

The small intestine in nicotinic acid deficiency becomes red, its walls become thickened, and it is covered by grey cyst-like structures which are produced by distension of the crypts of Lieberkiihn. The fluid content of these cysts is the normal secretion of the crypts (Hertzenberg ). The mucosa of the colon may also be infiltrated with various leucocytes, particularly lymphocytes, plasma cells, and eosinophiles (Denton ). 

The nerve plexuses associated with the colon show signs of degeneration, and other nervous changes occur, though they generally appear rather late in the deficiency. They are more usually central, as distinct from those of beriberi, which are more commonly peripheral. 

Pathological changes in pig pellagra and canine blacktongue are in general similar to those found in human pellagra. 

Although rats do not appear to develop characteristic skin lesions on a nicotinic acid-deficient diet. Bourne and Harris found that they suffered from a profound tubular degeneration of the kidneys. Other changes found were atrophy of pituitary adrenals and testes and a complete cessation of 

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Among mammals, symptoms of nicotinic acid deficiency have been... 

A deficiency syndrome is not well-defined in humans. Since pyridoxine deficiency often produces nicotinic acid deficiency, pellagra-like clinical manifestations may occur.29 The recommended daily allowance is 1.5 to 2 mg.112... 

It was furthermore reported (K20) that nicotinic acid-deficient animals would grow only if given tryptophan, thus suggesting the conversion of tryptophan to nicotinic acid. Not only is tryptophan converted to nicotinic acid but also kynurenine and 3-hydroxyanthranilic acid. The peculiar degradation of the latter to pyridine derivatives gave rise to many interesting investigations. 3-Hydroxyanthranilic acid is derived from 3-hydroxykynurenine, another important tryptophan metabolite, the his-... 

In 1945 Elvehjem and co-workers (518) reported that nicotinic acid-deficient rats would grow if given tryptophan, suggesting conversion of tryptophan to nicotinic acid. Hosen and co-workers (731) showed that administration of tryptophan to rats increased the urinary excretion of nicotinic acid derivatives, and numerous workers confirmed the conversion of tryptophan to nicotinic acid in man (399, 667, 755) and many other species (summary, 820). In the last ten years there has been intensive investigation of tryptophan metabolism. 

Pellagra and Nicotinic Acid Metabolism 271 Clinicopathology of Pellagra Nicotinic Acid Deficiency Nicotinic Acid Metabolism Pathogenesis of Pellagra... 

From the role of tryptophan in the biosynthesis of nicotinic acid, it is obvious that the nutritional studies on nicotinic acid deficiency must take tryptophan intake into account. Indeed, 60 mg of tryptophan in the diet is as effective as 1 mg of nicotinic acid. Since 70 g of protein yields 720 mg of tryptophan, the intake of such an amount of protein corresponds to 12 mg of nicotinic acid in preventing niacin deficiency. Since the requirements for niacin, like those of thiamine, depend essentially on the caloric intake, it is useful to express the requirements in niacin equivalents per 1000 calories. The optimum requirement is 4.4 mg niacin per 1000 calories. 

Only tryptophanuria due to (presumed) defects in tryptophan degradation via the kynurenine pathway is considered here. Tryptophan transport defects, renal and/or intestinal (Hartnup disorder, blue-diaper syndrome) are discussed in Sect. 13.4. The symptomatology of reported cases is caused by nicotinic acid deficiency, one of the products of the said pathway. The postulated enzymatic defects have not been confirmed by in vitro investigations [7-9]. 

The first enzyme in the kynurenine pathway of tryptophan degradation, liver tryptophan pyrrolase, is inducible by tryptophan and inhibited by reduced nicotinamide adenine dinucleotide. In the case of dietary nicotinic acid deficiency the kynurenine pathway becomes important for nicotinic acid synthesis. Nicotinic acid deficiency causes pellagra. Blocks in the kynurenine pathway because of cofactor deficiencies and/or enzymatic defects result quite often in pellagra-like symptoms. 

Nicotinic acid deficiency 278 Night vision, loss of 497 Night-blindness 644 Nocturnal myoclonus 114 Non-classical disease 552 Nostrils, anteverted 379 Nystagmus 124, 125, 130, 131, 172, 175, 223, 250, 251, 437, 439, 644... 

Pellagra is now recognized as a multifactorial disease and the vitamin status of nicotinic acid is questionable. The body is able to synthesize nicotinic acid from tryptophan so that nicotinic acid only becomes a dietary essential when the tryptophan content of the diet is low. The fact that maize proteins are relatively poor in tryptophan, and that the nicotinic acid it contains is in a form which is not readily available, would seem to explain the association of pellagra and the use of maize as a staple foodstuff. For nutritional purposes 60 mg tryptophan are believed to be equivalent to 1 mg of nicotinic acid and the recommended intake for an adult male is given as 18 mg of nicotinic acid or its equivalent. Primary nicotinic acid deficiency is unlikely to occur in this country where appreciable amounts of animal products are consumed and where flour must, by law, contain 1-6 mg nicotinamide per 100g. 

Although there is little doubt that nicotinic acid synthesis takes place in the rat, sheep, cow, and other animals, the simple measurement of nicotinic acid excretion does not seem to be an adequate index. From ail available evidence the only index of nicotinic acid deficiency appears to be the urinary F2 fraction of Najjar and Wood (82-86). This was confirmed by workers using the Fj assay (87, 88) and the so-called trigonelline fraction (89, 90) which is mainly, if not all, F2 (91, 92). The F2 fraction, a derivative of V -methylnicotinamide (80, 91, 93-95) was found to be excreted in substantial quantities in rats and pigs while on a nicotinic-acid-deficient diet, a fact which indicates synthesis of the vitamin. 

Pella r, Nia.cin Deficiency. It was 220 years after the first description of pellagra that nicotinic acid was discovered to be the cure for black tongue in dogs (14), a condition suggested by a veterinarian in North Carolina to be similar to human pellagra (15). 

NADP can be converted to nicotinic acid adenine dinucleotide phosphate (NAADP), which has distinct functions in the regulation of intracellular calcium stores. The studies of these new roles of NAD(P) in metabolism are in their early stages, but they might soon help to better understand and explain the symptoms of niacin deficiency ( pellagra) [1]. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

Epileptiform fits associated with degenerative changes in the myelin sheath of peripheral nerves and spinal cord occur in B6-deficient animals. Lesions in the arteries, resembling those of human atherosclerosis, have been observed in Be-deficient monkeys. Recently, a state of Be deficiency in human infants, characterized by loss of ability to convert tryptophan to nicotinic acid, by impaired growth, convulsions, and hypochromic anemia, has been described, following omission of vitamin B6 from the diet. 

Nicotinic acid, when given at the rate of several hundred milligrams a day, has pharmacological effects of which cerebral vasodilation is one. Nicotinamide does not have this effect, and hence the pharmacological effects of nicotinic acid probably do not involve simple replacement of a deficiency in an enzyme system. The fact that nicotinic acid itself in pharmacological doses appears to be of Implications for Advance in Psychiatry... 

Niacin, which refers to nicotinic acid and nicotinamide, is the metabolic precursor to three nicotinamide coenzymes. These are essential for the activity of a large number of enzymes catalyzing redox reactions. Pellagra is a niacin deficiency disease. 

Oxidation of nicotine with chromic acid led to the isolation of pyridine-3-carboxylic acid, which was given the trivial name nicotinic acid. We now find that nicotinic acid derivatives, especially nicotinamide, are biochemically important. Nicotinic acid (niacin) is termed vitamin B3, though nicotinamide is also included under the umbrella term vitamin B3 and is the preferred material for dietary supplements. It is common practice to enrich many foodstuffs, including bread, flour, corn, and rice products. Deficiency in nicotinamide leads to pellagra, which manifests itself in diarrhoea, dermatitis, and dementia. 

Drug-induced niacin deficiency has resulted from the use of isonicotinic acid hydrazide, which interferes with the conversion of niacin from tryptophan. Administration of ethanol or the antimetabolites 6-mercaptop-urine and 5-fluorouracil also may lead to niacin deficiency. The uricosuric effects of sulfinpyrazone and probenecid may be inhibited by nicotinic acid. 

Nicotine forms a number of metabolites in the body, mainly in the liver. Approximate 75% of nicotine is oxidized to cotinine, which is the primary nicotine metabolite. Cotinine can be measured in the blood, urine, and saliva and this is used as a measure of nicotine exposure in tobacco users and in those exposed to secondhand smoke. The oxidation of nicotine also produces nicotinic acid. Nicotinic acid is vitamin B3 and has the common name niacin. Niacin deficiency results in a disease called pellagra, which is found in certain malnourished populations. Pellagras symptoms include dermatitis, diarrhea, sensitivity to light, and dementia. 

Niacin (nicotinic acid, nicotinamide) has the active forms NAD and NADPH. It functions in electron transfer. A deficiency of niacin causes pellagra, which is characterized by der matitis, diarrhea, and dementia. There is no known toxicity for this vitamin. High doses of niacin are used to treat hyperlipidemia. 

Two vitamins, nicotinamide and pyridoxine (vitamin B6), are pyridine derivatives. Nicotinamide participates in two coenzymes, coenzyme I (65 R = H) which is known variously as nicotinamide adenine dinucleotide (NAD) or diphosphopyridine nucleotide (DPN), and coenzyme II (65 R = P03H2) also called triphosphopyridine nucleotide (TPN) or nicotinamide adenine dinucleotide phosphate (NADP). These are involved in many oxidation-reduction processes, the quaternized pyridine system acting as a hydrogen acceptor and hydrogen donor. Deficiency of nicotinamide causes pellagra, a disease associated with an inadequately supplemented maize diet. Nicotinic acid (niacin) and its amide are... 

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