Aetiology

Vitamin B3, also known as niacin, is an essential water-soluble vitamin obtained only from the diet or supplements.[3]​ Niacin in cereals is largely bound and unavailable for absorption unless treated with alkaline hydrolysis.[1]​ An example of this is soaking corn in lime before cooking. In meats, it is found in the form of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADPH) and is thus more available.[1][2][3][4]​​​​​ The US Department of Health and Human Services’s National Institutes of Health have published a fact sheet for healthcare professionals on niacin, including a section on niacin deficiency. NIH: Niacin - fact sheet for health professionals Opens in new window

In developed countries, vitamin B3 deficiency rarely occurs alone as good sources of niacin and tryptophan are also sources of other B vitamins, such as B2 and B6, and are relatively widely distributed in animal products, legumes, and fortified cereals. Good sources of niacin include lean meats, liver, poultry, fish, beans, peanuts, and yeast. Milk and green leafy vegetables provide smaller amounts. Milk, meat, and eggs are good sources of tryptophan, the precursor of niacin. In the US and other developed countries, many cereals are fortified with niacin.

Primary vitamin B3 deficiency results from a diet deficient in niacin and/or tryptophan and is therefore frequently associated with poverty and malnutrition (usually undernutrition from a diet poor in nutrient quantity and quality). Studies have shown that vulnerable populations who have limited access to meat products and thus consume diets that are low in meat and meat products are more likely to have vitamin B3 deficiency.​​[21]

Consumption of a corn-based, low-protein diet, or of a vegan diet (no animal products) with few niacin sources predisposes to the development of vitamin B3 deficiency.[1][3]​​[8]

Secondary vitamin B3 deficiency may result from a number of underlying conditions.

  • Pellagra may be a secondary outcome of eating disorders, such as anorexia nervosa and bulimia nervosa,[22][23][24][25][17] and has been found in a number of cases of Crohn's disease secondary to the malabsorption of nicotinic acid.[26][27][28][29]

  • Chronic alcohol use disorder can lead to pellagrous encephalopathy.[30][31][32][7][33][34] Although the exact mechanism is not clear, it has been proposed that intestinal permeability due to gastrointestinal (GI) changes or the action of oxygen-free radicals during ethanol metabolism may be contributory mechanisms.[30]

  • Hartnup's disease is an autosomal recessive disease characterised by the impaired transport (GI absorption and renal reabsorption) of neutral amino acids, including tryptophan. It has been associated with vitamin B3 deficiency, and symptoms of the disease usually resolve with niacin therapy.

  • There is an increased requirement for niacin during pregnancy and lactation. Pregnant women and those taking exogenous oestrogens (e.g., oral contraceptives) have been found to excrete elevated levels of xanthurenic acid.[35][36] Pyridoxine (coenzyme for kynureninase, an enzyme involved in the conversion of tryptophan to niacin) therapy normalises xanthurenic acid excretion, suggesting that the conversion of tryptophan to niacin is adversely affected.

  • In carcinoid syndrome, circulating neuroendocrine mediators are produced by carcinoid tumours, particularly those of the midgut. Pellagra results from the depletion of tryptophan, which is used by carcinoid tumours for serotonin synthesis.[37][38]

  • Some studies have reported that infection with HIV-1 in vitro leads to a significant decrease in the intracellular concentration of NAD.[39][40][41] Nicotinamide has been found to inhibit HIV infection in a dose-dependent manner in cell culture.

  • Diarrhoea episodes in patients with Ehlers-Danlos interfere with niacin absorption and may result in pellagra.[42]

A number of factors are known to antagonise the niacin pathway.[3]​​[43]

  • The conversion of tryptophan to niacin is inhibited by deficiencies in vitamins B2 and B6. Riboflavin (vitamin B2) and pyridoxine (vitamin B6) are the coenzymes for kynurenine hydroxylase and kynureninase, respectively, enzymes involved in the conversion of tryptophan to niacin.[3]​​[8][44] Their deficiency can therefore lead to impairment in the biosynthesis of niacin from tryptophan and may result in pellagra despite an adequate intake of niacin.[45]

  • Copper deficiency can also inhibit the conversion of tryptophan to niacin.[46]​​

  • Antituberculosis and antiretroviral drugs are strongly associated with the development of pellagra. Isoniazid has a similar structure to niacin and therefore interferes with the conversion of tryptophan to niacin by inducing a deficiency of the coenzyme pyridoxine.[47][48][49][50][51][52][53] Isoniazid-induced pellagra has been reported despite pyridoxine supplementation.[54] Rifampicin inhibits the absorption of niacin.

  • Other drugs associated with the development of pellagra are pyrazinamide, ethionamide, fluorouracil, mercaptopurine, hydantoins, phenobarbital, chloramphenicol, and penicillamine.[43][48] The latter chelates copper, leading to copper deficiency and subsequent inhibition of the conversion of tryptophan to niacin.

Pathophysiology

Tryptophan, an essential amino acid, is converted to niacin in the body and adds considerably to the amount of niacin available. The conversion factor (by weight) is 60 mg of tryptophan to 1 mg of niacin (i.e., 1 niacin equivalent). Niacin is essential for growth and is involved in the synthesis of hormones. It is also found in the form of the pyridine nucleotide coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADPH).​​​​[1]​[2]​[3]​[4]​ De novo synthesis of NAD and NADP occurs from quinolinic acid, a metabolite of the essential amino acid tryptophan. These are essential in all cells for energy production, metabolism, and DNA repair.

After digestion, NAD and NADP are converted to nicotinamide (Nam) and nicotinic acid (NA), which are absorbed from the stomach and small intestine.​​​​​​​​[1]​[2]​[3]​[4]​ Many plants and grains contain niacin in covalently bound complexes (niacytin) with carbohydrates and peptides that are not released during digestion. However, the niacytin can become available with alkaline hydrolysis. At low concentrations, NA and Nam enter the intestine via sodium-dependent facilitated diffusion, while at higher concentrations, passive diffusion predominates.​​​​[1]​[2]​[3]​[4]​ ​​​​Nam is the major form in the bloodstream and arises from enzymatic digestion of NAD in the intestinal mucosa and liver. It is taken up by tissues and can again be converted to NAD as required.

Excess niacin is methylated in the liver to form N-methylnicotinamide (NMN).​​​​​​​​[1]​[2]​[3]​[4]​ This is excreted in the urine with the products of NMN, namely the 2- and 4-pyridones. Niacin oxide and hydroxyl forms are also excreted to a lesser degree. The amount and type of metabolites excreted depend on the form of niacin ingested, as well as on the niacin status of the individual.

Classification

Marginal deficiency

Dietary history is indicative of a diet marginally and chronically deficient in niacin, without the development of signs and symptoms.

Primary (endemic) pellagra

Severe niacin deficiency resulting in dermatitis, dementia, and diarrhoea as a result of a diet deficient in niacin and/or tryptophan.

Secondary pellagra

Deficiency associated with an underlying condition, such as chronic alcohol use disorder, anorexia nervosa, cancer/carcinoid syndrome, vitamin B2 and B6 deficiencies, and medications (e.g., isoniazid).

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