Pellagra and Alcoholism: A Biochemical Perspective

Alcohol and Alcoholism Vol. 49, No. 3, pp. 238–250, 2014 Advance Access Publication 13 March 2014 doi: 10.1093/alcalc/agu010 Pellagra and Alcoholism: A Biochemical Perspective Abdulla A.-B. Badawy* School of Health Sciences, Cardiff Metropolitan University, Western Avenue, Cardiff CF5 2YB, UK *Corresponding author: Tel.: +44-2920-416858; Fax: +44-2920-416982; E-mail: (Received 20 January 2014; first review notified 10 February 2014; in revised form 14 February 2014; accepted 17 February 2014) Abstract — Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid ! zinc deficiency ! decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5-ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5-ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra. INTRODUCTION This article was prompted by the review in this journal (López et al., 2013) of historical, clinical and psychopathological aspects of pellagra encephalopathy in the context of alcoholism. Pellagra presents with some of or all the 3 D’s: dermatitis, diarrhoea and dementia (or more appropriately delirium, see Oldham and Ivkovic, 2012) and excellent reviews have been published on historical and clinical aspects (e.g. Rajakumar, 2000; World Health Organisation, 2000; Wan et al., 2011). I should like to add here a biochemical perspective, with particular emphasis on metabolism of the essential amino acid tryptophan (Trp), as it is the precursor of the pellagrapreventing factor nicotinic acid (niacin: also known as vitamin B3). Known biochemical causes of pellagra and its symptoms are discussed and potential mechanisms are proposed. HISTORICAL PERSPECTIVE OF NUTRITIONAL CAUSES OF PELLAGRA Casal’s description of pellagra in 1735 was published in 1762. In 1771, Francesco Frapoli coined the name pellagra from the Italian pelle agra (i.e. sharp or rough skin). In 1926, Goldberg showed that pellagra is caused by deficiency of a nutritional substance, which was identified as niacin by Elvehjem in 1937. The link between niacin and Trp was finally established in 1945 by Krehl (for references, see Wan et al., 2011). As López et al. (2013) pointed out, introduction of maize from the Americas into Europe, wherein poverty and malnutrition were prevalent, was instrumental in the incidence of pellagra in Southern Europe during the 18th century. Arrival of pellagra in South Africa coincided with an outbreak of rinderpest in 1897 leading to the death of cattle, thus necessitating a change in the life style of the Bantu population from meat- to maize-eating, with little meat or milk intake (Bender, 1982). Pellagra in India has been associated with intake of maize and another staple, jowar (a variety of sorghum). In the Southern USA, pellagra became a serious medical problem following the American civil war, due to subsistence on a largely maizebased staple (Rajakumar, 2000). It was in the USA around the middle of the 20th century that most studies on the aetiology, prevention and cure of pellagra were undertaken. Pellagra is thus a disease of malnutrition involving deficiency not only of the ‘B vitamin’ niacin, but also its Trp precursor, and is compounded by deficiencies of other nutrients, notably other B vitamins and possibly also zinc. Thus, niacin deficiency alone would not induce pellagra if adequate amounts of Trp are consumed in meat, dairy products, eggs or certain plant sources, and if metabolism of Trp to niacin along the hepatic kynurenine pathway is not impaired. Thus, Trp metabolism along this pathway is the major determinant of pellagra. Synthesis of 1 mg of niacin requires 60 mg of dietary Trp (Horwitt et al., 1956). There are wide individual variations in this 1:60 ratio, with factors such as pregnancy, hormonal differences and levels of Trp ( protein) intake playing important roles (Bender, 1982). Daily niacin requirements of adults are ~15 mg. In the absence of niacin, a daily intake of ~1 g of Trp can meet these requirements. This necessitates intake of ~100 g of protein, as the Trp content of most proteins is ~1%, with some (richer) exceptions, notably milk, eggs, oats, sesame and sunflower seeds and soybeans. Truswell et al. (1968) reported average plasma Trp values in children with pellagra in South Africa of 12.7 μM (range: 4.9–23.5 μM), which rose upon recovery from protein calorie malnutrition to values of 19.6–36.2 μM. Adult controls exhibited values of 32–43 μM. Current adult normal plasma Trp values in the USA average 63 ± 20 μM (mean ± SD for n = 114) (Badawy et al., 2008). Maize is a poor source of Trp. Its Trp content (~40 mg/g nitrogen) is at most one half of that (80–100 mg/g nitrogen) of cereals, such as barley, oatmeal, rice, rye and wheat. The Trp content of sorghum could be as little as 6.7–11.3 mg/g nitrogen, depending on the protein content of samples (Ravindran © The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved Alcoholism, pellagra and tryptophan and Bryden, 1997), but higher values have also been reported (see below). Maize, however, contains significant amounts of niacin, but combined with polysaccharides in the form of niacytin, which cannot be hydrolysed by mammalian digestive enzymes (Bender, 1982). Most of the sorghum niacin (~90%) is also similarly bound. Although peasants in Mexico and Central America have for millennia used maize as the main staple, and suffered from protein malnutrition as much as people in Southern Europe during the 18th century, the former have been generally free from pellagra (Carpenter, 1983). This is (...truncated)