Pellagra-A Disease of Tryptophan and Niacin Deficiency

The role of cADP-ribose and NAADP in regulating cytosolic calcium may provide an alternative explanation to the serotonin hypothesis for the psychiatric and neurological signs of the niacin deficiency disease pellagra (Section 8.5 Petersen and Cancela, 1999). 

AU-trans-retinoic acid (Section 2.2.S.2) stimulates the synthesis of cADP-ribose in kidney cells in culture, apparendy as a result of the induction of CD38 (Beers et al., 1995 Takahashi et al., 1995) in ovariectomized rats, estradiol induces cytosolic ADP-ribosyl cyclase in the uterus, but not in estrogen unresponsive tissues (Chini et al., 1997). If this induction of ADP-ribose cyclase by estrogens leads to significant depletion of nicotinamide nucleotides, it may provide an additional explanation for the 2 1 excess of females to males in the incidence of pellagra (Section 8.5). 

Pellagra is characterized by a photosensitive dermatitis, like severe sunburn, typically with a butterfly-like pattern of distribution over the face, affecting aU parts of the skin that are exposed to sunlight. Similar skin lesions may also occur in areas not exposed to sunlight, but subject to pressure, such as the knees, elbows, wrists, and ankles. Advanced pellagra is also accompanied by a dementia or depressive psychosis, and there may be diarrhea. Untreated pellagra is fatal. 

The other characteristic feature of pellagra is the development of a depressive psychosis, superficially similar to schizophrenia and the organic psychoses, but clinically distinguishable by the sudden lucid phases that alternate with the most florid psychiatric signs. The mental symptoms may be the result of tryptophan depletion, and hence a lower availability of tryptophan for synthesis of the neurotransmitter serotonin (5-hydroxytryptophan). But the role of cADP-ribose and NAADP in controlling calcium release in response to neurotransmitters (Section 8.4.4) and impaired energy-yielding metabolism in the central nervous system as a result of depletion of NAD (P) may also be important. 

The diarrhea associated with pellagra is caused by rectal inflammation within 5 to 7 days of starting treatment with niacin, rectal histology is normalized and the diarrhea ceases (Segal et al., 1986). 

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Although pellagra is uncommon, it most frequently afflicts alcoholics and the elderly. Thyrotoxicosis and sepsis increase niacin requirements but rarely precipitate pellagra. Though the disease is produced by dietary insufficiency of tryptophan and niacin, the full deficiency syndrome can develop in patients who shunt tryptophan into other metabolic pathways despite a normal diet. Such is the case for patients with the carcinoid syndrome, in whom 60 times more tryptophan than normal is hydroxy-lated to serotonin (Melmon, 1981). 

Nicotinate (also called niacin or vitamin Bg) is derived from tryptophan. Human beings can synthesize the required amount of nicotinate if the supply of tryptophan in the diet is adequate. However, nicotinate must be obtained directly if the dietary intake of tryptophan is low. A dietary deficiency of tryptophan and nicotinate can lead to pellagra, a disease characterized by dermatitis, diarrhea, and dementia. An endocrine tumor that consumes large amounts of tryptophan in synthesizing the hormone and neurotransmitter serotonin (5-hydroxytryptamine) can lead to pellagralike symptoms. 

Our species has lost the ability to make vitamins. Thus, deficiency of niacin (nicotinamide), the N in NAD, leads to the disease pellagra, a collection of skin, intestinal, and neurological symptoms. (Niacin can be synthesized from the amino acid tryptophan, so pellagra results from a deficiency of both niacin and tryptophan in the diet.)... 

The classical niacin deficiency disease is pellagra, which is characterized by symptoms including diarrhoea, dermatitis, dementia and eventually death. High-protein diets are rarely deficient in niacin since, in addition to the preformed vitamin, such diets supply sufficient tryptophan to meet dietary requirements. Large doses of niacin can cause the dilation of capillaries, resulting in a painful tingling sensation. 

After it had been established that pellagra was a nutritional deficiency disease, the next problem was to discover the missing nutrient. Additional dietary protein was shown to be beneficial, thus it was concluded that pellagra was because of a protein deficiency. This view, and later that it was more specifically from a deficiency of tryptophan, was held for some time. In 1938, Spies and coworkers showed that nicotinic acid would cure pellagra thereafter it was gradually accepted that it was a niacin deficiency disease. 

A number of inborn errors of metabolism of the tryptophan oxidative pathway (see Figure 8.4) have been reported, aU of which result in the development of pellagra that responds to high doses of niacin. These conditions include vitamin Be-responsive xanthurenic aciduria, caused by a defect of kynureni-nase (Section 9.4.3) hydroxykynureninuria, apparentiy caused by a defect of kynureninase tryptophanuria, apparentiy caused by tryptophan dioxygenase deficiency a hereditary pellagra-like condition, apparentiy caused by an increase in activity of picoUnate carboxylase and Hartnup disease. 

Another disease of prominent dermatological interest is pellagra, in which pyridoxine deficiency seems to represent one of the pathogenetic factors even though of less importance than the fundamental niacin deficiency. For this reason Csermely and Zardi (G13) examined 12 patients with this disease in an attempt to demonstrate a pyridoxine deficiency by determining xanthurenic acid after loading wiA L-tryptophan (100 mg/kg). The results obtained (C13) show that an abnormal excretion of xanthurenic acid occurred in 5 of 12 patients. Furthermore, the clinical picture of the disease does not differ in patients with normal or abnormal xanthurenic acid output. These data provide no definite information in regard to this disease, in which more than one metabolite would have to be measured. 

Pellagra-like symptoms can occur in Hartnup s disease and carcinoid syndrome. Hartnup s disease is an inherited disorder of amino acid transport (Chapter 17) in which niacin deficiency presumably develops because niacin intake is inadequate to supply metabolic needs when combined with the decreased absorption of dietary tryptophan. In carcinoid syndrome, up to 60% of available dietary tryptophan is diverted to formation of 5-hydroxytryptamine (serotonin) by what is normally a minor pathway. 

The literature contains many studies relating to tryptophan depletion and various psychiatric diseases. Before beginning a discussion of human conditions in which decreased availability of L-tryptophan may play a role in the symptomatology of the disorder, one must mention pellagra, which is caused by a deficiency of niacin. Pellagra was described as being associated with poverty and diets that relied heavily on corn, which is low in both niacin and its precursor, tryptophan.29,30 Nonetheless, since it is not due per se to tryptophan deficiency itself, this condition is not included in the diseases reviewed in this chapter. 

However, some patients with the Hartnup biochemical phenotype eventually develop pellagra-like manifestations, which usually include a photosensitivity rash, ataxia, and neuropsychiatric symptoms. Pellagra results from a dietary deficiency of the vitamin niacin or the essential amino acid tryptophan, which are both precursors for the nicotinamide moiety of NAD and NADP. In asymptomatic patients, the transport abnormality may be incomplete and so subtle as to allow no phenotypic expression of Hartnup disease. These patients also may be capable of absorbing some small peptides that contain the neuttal amino acids. 

Niacin is not strictly a vitamin, as it can be synthesized in the body from the essential amino acid tryptophan. Indeed, it is only when tryptophan metabolism is deranged that dietary preformed niacin becomes important. Nevertheless, niacin was discovered as a nutrient during studies of the deficiency disease pellagra, which was a major public health problem in the southern USA throughout the first half of the twentieth century, and continued to be a problem in parts of India and sub-Saharan Africa until the 1990s. 

Deficiency in animals affects the skin and digestive tract. Ruminants on green fodder usually do not require extra niacin, but niacin supplements improve milk yield in cows. Pellagra is a disease resulting from a combined deficiency of niacin and tryptophan. The symptoms of pellagra include dermatosis, dementia, diarrhoea and nervous disorders. Pellagra is rarely seen in industrialized countries and is associated with alcohol abuse. In other parts of the world where maize is the major staple diet, pellagra persists. 

A number of drugs that react with carbonyl compounds are capable of causing vitamin Bg deficiency on prolonged use. These include the antituberculosis drug isoniazid (iso-nicotinic acid hydrazide), penicillamine, and the anti-Parkinsonian drugs, benser-azide and carbidopa. In general, the main effect is impairment of tryptophan metabolism by inhibition of kynureninase, and hence the development of the niacin-deficiency disease, pellagra. The condition therefore responds to the administration of either vitamin Bg or niacin. 

A deficiency of niacin in the diet results in the disease known as pellagra, characterized by the four D s diarrhea, dermatitis, dementia, and death. In the early years of the twentieth century in the United States, pellagra was common among poor tenant farmers and mill workers in the rural South. The diet there at that time was rich in com that contained little niacin and little available tryptophan from which to synthesize it. 

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