For many years, chiefly in regions where maize is the staple diet, a condition has been known which was characterized by cutaneous, mucosal and neurological abnormalities. This condition is known as pellagra. The disease derives its name from an old Italian description. It had been established that prisoners on a prolonged diet consisting solely of maize developed a skin problem. Pelle agra ("pelle", "skin"; "agra", rough). In the 18^th century the inexpensive polenta, based on maize meal, was a staple of many rural regions of Italy. It was initially thought that the disease was caused by a fungal toxin in the food. In 1796, Dr Casper Casal, of Oviedo (Spain), described the disease mal de la rosa. The illustration in his work shows manifest skin lesions of the neck. Since that time, this symptom has been known as Casal’s necklace. In the early 20^th century, pellagra was a major problem among the poor Southerners of the USA. The work of the American scientist Joseph Goldberger represented a milestone in the history of epidemiology when he discovered that orphans whose diet consisted mainly of maize with molasses developed pellagra and that others (who had a more varied diet) were not affected by the disease. None of the staff ever contracted the disease (they had the first choice of the food). He injected himself and several volunteers with blood from pellagra patients. Not one of them developed the disease. Even eating faecal matter of the patients (!) was likewise unable to induce the disease in these intrepid volunteers, which was a strong argument against an infectious origin. After milk, eggs and meat were put on the menu of the orphanages, pellagra disappeared. A controlled experiment at a State Prison Farm in Mississippi manifestly demonstrated that pellagra only develops after living on an unbalanced diet. An animal model was developed using dogs that were fed on maize and subsequently developed so-called ‘black-tongue’. In 1937, Conrad A. Elvehjem, an agricultural chemist at the University of Wisconsin, discovered that nicotinic acid cures black tongue. It was discovered that the disease has its origins in a deficiency of a compound present in small quantities in food. The compound was designated as vitamin PP (pellagra preventing factor). Sometimes the term vitamin B3 is used. The identification of pellagra as a deficiency disease was not evident. There were sometimes apparently contradictory data. Early in the 20^th century, for instance, pellagra was rife in the maize-eating population of Romania. Paradoxically, however, their maize contained more niacin than the food of the indigent population of India, where pellagra did not occur. The explanation was only discovered later when it became clear that maize contained very little tryptophan and that much of the niacin in maize is present as a bound form called niacytin (which is not absorbed in the intestine). The reason why pellagra did not occur in the indigenous maize-eating population of Central America was found to be based on the fact that they used alkali in the preparation of their maize meal, which released niacin from niacytin. They also had a more varied diet, which included a lot of beans (i.e. another food that contains niacin).

Niacin is also known as nicotinic acid, although the latter term is avoided in order not to evoke an association with tobacco and thus make people suspicious. The amide is likewise active (nicotinamide). Niacin is absorbed from food in the stomach and small intestine. A small quantitiy of niacin is produced endogenously from tryptophan, an essential amino acid. Food that is rich in tryptophan and deficient in niacin will not give rise to clinically manifest deficiency. Alcoholics and people with hyperthyroidism are at higher risk of contracting pellagra. The conversion from tryptophan to niacin is more difficult in people with vitamin B2 (riboflavin) and B6 (pyridoxine) deficiency.

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Niacin is required for adequate cellular function and metabolism as an essential component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These compounds are important coenzymes for glycolysis, protein and amino acid metabolism, pyruvate metabolism, pentose biosynthesis, generation of high-energy phosphate bonds, glycerol metabolism, and fatty acid metabolism. In case of deficiency, all sorts of cell functions become deranged.

On average, a person needs approximately 15 mg niacin on a daily basis. Pellagra may be caused by niacin and/or tryptophan deficiency in the diet. A generally poor balance of amino acids in the diet could also give rise to pellagra. For instance, pellagra frequently affects people who eat sorghum (millet) as a staple food. This grain crop contains high concentrations of leucine. Although this grain contains adequate tryptophan, excessive concentrations of leucine interfere with tryptophan metabolism and subsequent niacin synthesis. Maize (=corn), which is the staple food in many parts of the world, contains very small amounts of tryptophan. Niacin in maize is chemically bound and is not absorbed in the intestine unless the food is treated with alkali. An example of the latter is the tortilla. Food products that contain large quantities of niacin are liver, kidney and yeast and, to a lesser extent, wheat and green vegetables. The bioavailability of niacin from meat, milk, beans and eggs is excellent.

Secondary deficiency may develop in persistent chronic diarrhoea with malabsorption, liver cirrhosis and alcoholism and in the event of prolonged parenteral nutrition being given without vitamin supplements. During treatment with isoniazid (INH) the drug is substituted for nicotinamide in the synthesis of NAD. The resulting molecule is inactive. In prolonged treatment with INH (tuberculosis) it is possible for iatrogenic induced pellagra to be provoked. There are also several situations where tryptophan metabolism is disrupted. For instance, pellagra may develop in carcinoid syndrome, due to the conversion of tryptophan into serotonin (5-hydroxytryptamine). Pellagra also occurs in Hartnup’s disease, an autosomal recessive metabolic disorder associated with defective renal tubular resorption of neutral amino acids. Furthermore there is a disturbed intestinal absorption that leads to degradation of tryptophan in the intestine. The clinical picture is characterized by a pellagra-like skin rash and cerebellar ataxia. In AIDS-patients, tryptophan metabolism is disturbed (low levels of tryptophan in plasma), but this does not lead to pellagra.

Clinically, the disease is identified by the so-called classical three Ds: dermatitis, diarrhoea and dementia. Mucositis should also be added to these characteristic symptoms. The symptoms may develop alone or in combination. Several types of skin lesions are recognized. Patients initially present with erythematous skin lesions followed by vesicles, bullae, crusting and desquamation. Secondary infection may develop, including wound myiasis. These fairly rapid developing symptoms are located on parts of the body that are usually exposed to the sun and on trauma sites. The most conspicuous is a sharply defined symmetrical, desquamating rash in the neck area (Casal’s necklace) and on the forearms. A butterfly-shaped rash may appear on the face, which must be distinguished from skin abnormalities in SLE patients. These skin lesions may be associated with acute intertrigo with erythema, maceration and abrasion; surinfection may develop in the predilection areas (folds of the groin, genitals). In persistent lesions the skin may become thick and rough. Deep cracks or fissures and hyperpigmentation may develop. The lesions resemble those of cutaneous porphyria. Lastly, the lesions may become atrophic, with a dry, scaly and inelastic skin. Pellagra sometimes occurs without skin lesions (pellagra sine pellagra).

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Mucositis develops in the mouth, vagina and urethra. A red tongue and stomatitis are characteristic of acute deficiency. The tip and edges of the tongue are the first to be affected. This is followed by a generalized painful, burning glossitis, with swelling of the tongue and hypersalivation. Lip and tongue ulcers may develop. The area around the parotid duct orifice may become necrotic (the area opposite the molar teeth). Deeper mucosae may be affected, with sore throat, oesophageal damage with dysphagia, and abdominal pain. Some patients report loose stools but these complaints are not usually predominant. Caution: chronic malabsorption in itself may induce niacin deficiency. Gastrointestinal hyperaemia, ulceration and proctitis may lead to bloody diarrhoea. When angular stomatitis is present, this usually indicates an associated riboflavin deficiency (vitamin B2).

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Neurological symptoms are due to an organic encephalopathy. Psychosis may occur with sleep and memory disorders, anxiety, agitation, rapid irritability, disorientation, confusion and confabulation (compare this with Wernicke-Korsakoff’s syndrome in thiamine deficiency). Mania, delirium, paranoia and depression occur in later stages of the disease. At one time, many pellagra patients were incarcerated in mental institutions. Muscular rigidity may develop together with a cogwheel phenomenon, hyperreflexia and a positive Babinski’s sign. In the motor cortex, lysis of Betz’s cells and, to a lesser extent, lysis of Purkinje’s cells are found. In the spinal cord, the posterior columns are chiefly affected (proprioception tracts; cfr vitamin B12 deficiency). In peripheral nerves there is myelin degeneration, but to what extent this overlaps with the findings in beriberi is unclear (nutritional deficiencies are often mixed). Post-mortem examination may reveal cardiac, adrenal gland, liver and spleen atrophy.

When all symptoms and signs are present, the clinical diagnosis is simple. In most cases, however, there are only a few symptoms present. The diagnosis is confirmed by measuring the urinary excretion of N´-methylnicotinamide (NMN). NMN excretion of <0.8 mg/day suggests niacin deficiency. Patients with pellagra also have increased urinary excretion of coproporphyrins. In clinical practice, a successful test-therapy will confirm the original diagnosis. Diagnosis of Hartnup’s disease is confirmed by the specific pattern of aminoaciduria in these children.

As there is seldom a deficiency of only one vitamin, treatment should obviously include a polyvitamin preparation in addition to a balanced diet. Specifically for pellagra, nicotinamide (precursor of niacin) is given as a supplement in a dose ranging from 300 to 1000 mg daily using divided doses. If niacin itself were to be administered, the patient would complain of flushing, paraesthesia and a burning sensation. If no oral supplement can be given (severe stomatitis, severe diarrhoea, uncooperative patient), 100 to 250 mg can be injected SC twice daily. A rapid improvement of the skin lesions and the general condition is usually seen. Neurological improvement is rather slow. A balanced diet is essential for prophylaxis. In some countries flour is systematically enriched with extra niacin.

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