Nicotinic Acid Deficiency

Article Author:
Tamara Mousa
Article Editor:
Omar Mousa
Updated:
8/10/2020 9:31:12 PM
PubMed Link:
Nicotinic Acid Deficiency

Introduction

Niacin (vitamin B), also known as nicotinamide or nicotinic acid, is an essential water-soluble vitamin. It is important for the metabolism of macronutrients (carbohydrate, protein, and fat) due to being part of the NAD (nicotinamide adenine dinucleotide) and NADP (nicotinamide adenine dinucleotide phosphate) coenzymes.[1][2] It is mainly found in protein-rich foods (e.g., cereals, legumes, meat, and milk) and yeast. The former food sources are high in tryptophan, which can be converted into niacin in the liver (60 mg tryptophan is needed to produce 1 mg niacin).[2][3] The recommended daily allowances for niacin is 2  to 4 mg for infants, 6 to 8 mg for children, 12 mg for teenagers, 16 mg for men, 14 mg for women, and 17 and 18 mg for lactating and pregnant women, respectively.[4]

Dietary deficiency of niacin results in pellagra. Pellagra was first described 250 years ago by the Spanish physician Don Gaspar Casal in 1763.[5] It is characterized by dermatitis, diarrhea, dementia, and eventually death if not treated by giving niacin. This is why it is called the 3 D syndrome, or 4 Ds disease.[6] However, diarrhea and dementia may not always be present. Recent studies also revealed that niacin deficiency might be associated with Alzheimer, Parkinson, Huntington diseases, cognitive impairment, or schizophrenia.[7][8] Early diagnosis and treatment are crucial.

Etiology

The main etiology of pellagra is consuming a diet deficient in niacin or eating uncooked grains.[9] The latter reason can be explained by the complex form of niacin (bound to polysaccharides and glycopeptides) in raw grains, which limits its bioavailability when ingested.[9][10] Yet, soaking and cooking the food releases niacin, making it available for absorption.[9] Additional reasons for low intakes of niacin is hunger, living in conflict zones such as in Africa, or having anorexia nervosa.[6][10]

Furthermore, pellagra could develop in the elderly population due to malabsorption.[1] Other important causes include long-term use of isoniazid (depletes tryptophan), carcinoid syndrome, Hartnup disease, or AIDS (acquired immune deficiency syndrome).[6][11] It is also reported that gluten-free foods may result in a low intake of niacin if these items are not fortified with it.[12] A recent case-study also showed that azathioprine immunosuppressant had induced pellagra in a 50-year old Chinese woman suffering from optic neuritis and transverse myelitis.[13] In another case-study, Das and colleagues stated that pellagra was seen in a 57-year old Nepali man who had pulmonary Koch disease, and a history of smoking and drinking.[14] Similarly, a 42-year old smoker and chronic drinker Malawian woman had pellagra.[5] In Nigeria, a 12-year old girl who worked as a cattle farmer developed pellagra, and her main meal was corn.[15]  A comparable case also was detected in a 13-year-old Sudanese teenage boy.[16] Thus, poor nutrition knowledge, unhealthy lifestyle behaviors, and limited availability or accessibility to food are believed to be the major contributors to insufficient consumption of niacin.

Epidemiology

Corn was the staple food in China, India, Africa, and Latin America, yet pellagra was common in African nations.[17] For instance, in 1990, pellagra was prevalent in 6.3% of Mozambican refugees in Malawi.[18] Over a 9-month period, 691 Malawians living in Kasese have developed pellagra, which primarily was due to eating a niacin-deficient diet.[19] In Angola, about one-third of 723 women and 6% of 690 infants and children (6 months to 5 years) had pellagra.[10] On the other hand, 0.7% of 142 Tanzanian patients (aged 55 to 99 years) with skin diseases were diagnosed with pellagra.[20] 

In the United States, pellagra is very rare due to the enrichment of processed flour with B vitamins. In the past, native people in North, Central, and South America consumed maize treated with lime or wood ashes, which increased the bioavailability of niacin in maize.[17] In India, niacin was deficient among 13% of 34 adolescent girls 10 to 13 years but not in boys.[21] In Thailand, the consumption of a traditional meal provides about 13% of the recommended intake of niacin. Traditional meals consisted of: canned fish and stir-fried roselle, or ivy gourd omelets and mung bean noodle soup; or canned fish curry with chili paste and pumpkin.[22] In Switzerland, compared with vegetarian (n = 53) and vegan (n = 53) adults, omnivores (n = 100) had the lows intake of niacin (P < 0.05). Yet plasma vitamin levels showed that vegetarians were the only deficient group (mu = 398 nmol/l).[23]

Pathophysiology

Niacin is important for the metabolism of macronutrients (carbohydrate, protein, and fat), due to being part of the NAD and NADP coenzymes.[1][24] Niacin deficiency results in decreased NAD and NADP coenzymes. This is seen in malnutrition or resource-limited countries. In addition, other mechanisms contribute to niacin deficiency. Altered metabolism of tryptophan is seen in carcinoid syndrome, impaired absorption of tryptophan is seen in the autosomal recessive condition Hartnup disease, and prolonged use of certain medications may decrease the production of tryptophan (isoniazid) or inhibit the conversion of tryptophan to niacin (azathioprine, 6-mercaptopurine, or 5-fluorouracil).[25][26][27]

Histopathology

Dermatitis in pellagra is characterized by erythematous bullous changes secondary to mild acute inflammation. This leads to degeneration of the stratum corneum, followed by increased cellularity and fibroblasts, capillary dilation, and increased proliferation and thickening of the epidermis. Inflammatory cells include lymphoid cells and few plasma cells. Hyperpigmentation also occurs.[28] In the gastrointestinal tract, inflammation can spread, causing chronic gastritis. Inflammation also leads to diarrhea. Neuronal chromatolysis was reported in motor neurons and edema in glial and ependymal cells.

History and Physical

The history should emphasize the presenting symptoms, which can include weight loss, anorexia, nausea, dyspepsia, abdominal pain, diarrhea, excessive salivation, skin rash, fatigue, headaches, dizziness, irritability, tremors, dementia, anxiety, and depression. Nutritional, past medical, family, social, and medication histories should be reviewed carefully.[29][2]

Physical examination should assess the general health and the mental status (progressive derangement with confusion, or tremors).[2] Head examination should include evaluation of the tongue, looking for a beefy red tongue, with swelling and tenderness.[6] Oral manifestations include gingivitis, stomatitis, and glossitis.[2][6] Assessment of skin rash which is usually symmetrical and bilateral (including sunburn-like rash, facial butterfly sign, Casal’s collar necklace like-rash in sun-exposed areas, hyperpigmentation, thick dry skin, and eruption with desquamation) and signs of malnutrition (example: weakness, weight loss, muscle wasting, dehydration or edema) are crucial.[15][5] Cardiac examination may reveal abnormal heart rate and blood pressure.[30][31] A pulmonary examination may show labored breathing due to weakness in respiratory muscles.[14] Abdominal examination may reveal a scaphoid abdomen and/or hepatosplenomegaly.[32] Further assessment may include the evaluation of wounds for poor healing.[32] Patients may also have lower extremity swelling.[20]

Evaluation

Overall, pellagra is a clinical diagnosis and biochemical testing is rarely used. If needed, niacin deficiency can be assessed by two methods:[3][6][31]

Biochemical Assessment

  • This approach is not widely used. Measurement of urinary N-methylnicotinamide or erythrocyte NAD: NADP (ratio) can be obtained to evaluate the metabolic rate of niacin in the body. Thus, high levels reflect adequate intakes of this vitamin.

Clinical Assessment

  • It is more widely used by assessing for diarrhea, glossitis, and dermatitis. The skin is assessed for hyperpigmentation, dryness and scaling, facial butterfly sign, and/or Casal’s collar (necklace) in sun-exposed areas. It is important to note that diarrhea and dementia may not always be present.

Treatment / Management

Pellagra can be reversed by giving niacin accompanied by a high energy diet that is rich in all other B-vitamins, zinc, and magnesium that are important for optimum metabolic reactions in the body.[3] Avoidance of sun exposure is helpful in the management of skin rash, and having a liquid diet temporarily is needed in the setting of difficulty swallowing related to glossitis. Nicotinamide 300 mg daily in divided doses is recommended for a total of 3 to 4 weeks. Nicotinamide is better tolerated than niacin (fewer side effects).[6][31] Referral to a nutritionist, psychiatrist, or neurologist may be needed.

To ensure sufficient intakes of niacin, several countries fortified some of the staple food items, such as wheat flour, milk, maize flour, cornmeal, and/or rice with niacin.[33] These nations include the United States, Latin American, Canada, Europe, Africa, Southeast Asian, and Middle Eastern countries, including Jordan.[33][34][35][36][37][38]

Differential Diagnosis

Some of the health conditions that can be mistaken for pellagra include deficiencies of vitamins B1, B2, and B12.[24] In addition, the differential diagnosis includes inflammatory bowel disease, cutaneous lupus erythematosus, drug-induced dermatitis, and porphyria cutanea tarda.

Prognosis

Diarrhea and glossitis usually improve in 2 to 3 days, while recovery from dementia and dermatitis is seen within 7 days of treatment.[5][39][31] However, a longer recovery may be seen in chronic cases.[19]

Complications

If pellagra is left untreated, it would result in patient death.[6]

Enhancing Healthcare Team Outcomes

Currently, niacin deficiency and pellagra are rare. However, it is important to educate the public about the importance of consuming a balanced diet that consists of all food groups that are adequate in all essential nutrients (macro- and micronutrients) for the achievement of optimal health. Health awareness campaigns, therefore, should be carried out to spread knowledge about the: foods that are rich in or fortified with niacin and tryptophan and health conditions and compounds (such as drugs) that adversely affect its bioavailability.



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References

[1] Williams AC,Hill LJ,Ramsden DB, Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra. Current gerontology and geriatrics research. 2012;     [PubMed PMID: 22536229]
[2] Hill LJ,Williams AC, Meat Intake and the Dose of Vitamin B{sub}3{/sub} - Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures? International journal of tryptophan research : IJTR. 2017;     [PubMed PMID: 28579801]
[3] Pitche PT, [Pellagra]. Sante (Montrouge, France). 2005 Jul-Sep;     [PubMed PMID: 16207585]
[4] Eldridge AL, Comparison of 1989 RDAs and DRIs for Water-Soluble Vitamins. Nutrition today. 2004 Mar;     [PubMed PMID: 15100498]
[5] Segula D,Banda P,Mulambia C,Kumwenda JJ, Case report--A forgotten dermatological disease. Malawi medical journal : the journal of Medical Association of Malawi. 2012 Mar;     [PubMed PMID: 23638264]
[6] Savvidou S, Pellagra: a non-eradicated old disease. Clinics and practice. 2014 Mar 27;     [PubMed PMID: 24847436]
[7] Gasperi V,Sibilano M,Savini I,Catani MV, Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications. International journal of molecular sciences. 2019 Feb 23;     [PubMed PMID: 30813414]
[8] Periyasamy S,John S,Padmavati R,Rajendren P,Thirunavukkarasu P,Gratten J,Vinkhuyzen A,McRae A,Holliday EG,Nyholt DR,Nancarrow D,Bakshi A,Hemani G,Nertney D,Smith H,Filippich C,Patel K,Fowdar J,McLean D,Tirupati S,Nagasundaram A,Gundugurti PR,Selvaraj K,Jegadeesan J,Jorde LB,Wray NR,Brown MA,Suetani R,Giacomotto J,Thara R,Mowry BJ, Association of Schizophrenia Risk With Disordered Niacin Metabolism in an Indian Genome-wide Association Study. JAMA psychiatry. 2019 Jul 3;     [PubMed PMID: 31268507]
[9] Carpenter KJ, The relationship of pellagra to corn and the low availability of niacin in cereals. Experientia. Supplementum. 1983;     [PubMed PMID: 6357846]
[10] Seal AJ,Creeke PI,Dibari F,Cheung E,Kyroussis E,Semedo P,van den Briel T, Low and deficient niacin status and pellagra are endemic in postwar Angola. The American journal of clinical nutrition. 2007 Jan;     [PubMed PMID: 17209199]
[11] Monteiro JP,da Cunha DF,Filho DC,Silva-Vergara ML,dos Santos VM,da Costa JC Jr,Etchebehere RM,Gonçalves J,de Carvalho da Cunha SF,Jordão AA,Chiarello PG,Vannucchi H, Niacin metabolite excretion in alcoholic pellagra and AIDS patients with and without diarrhea. Nutrition (Burbank, Los Angeles County, Calif.). 2004 Sep;     [PubMed PMID: 15325687]
[12] Allen B,Orfila C, The Availability and Nutritional Adequacy of Gluten-Free Bread and Pasta. Nutrients. 2018 Sep 25;     [PubMed PMID: 30257431]
[13] Zhao C,Liu T,Ma C,Li H,Li Z,Guo J, Azathioprine-induced pellagra in neuromyelitis optica: A case report and review of literature. Multiple sclerosis and related disorders. 2018 Oct;     [PubMed PMID: 30059893]
[14] Das R,Parajuli S,Gupta S, A rash imposition from a lifestyle omission: a case report of pellagra. The Ulster medical journal. 2006 Jan;     [PubMed PMID: 16457414]
[15] Usman AB,Emmanuel P,Manchan DB,Chinyere A,Onimisi OE,Yakubu M,Hirayama K, Pellagra, a re-emerging disease: a case report of a girl from a community ravaged by insurgency. The Pan African medical journal. 2019;     [PubMed PMID: 31692657]
[16] Spector JM,     [PubMed PMID: 16040872]
[17] Ramirez-Cabral NYZ,Kumar L,Shabani F, Global alterations in areas of suitability for maize production from climate change and using a mechanistic species distribution model (CLIMEX). Scientific reports. 2017 Jul 19;     [PubMed PMID: 28724952]
[18] Malfait P,Moren A,Dillon JC,Brodel A,Begkoyian G,Etchegorry MG,Malenga G,Hakewill P, An outbreak of pellagra related to changes in dietary niacin among Mozambican refugees in Malawi. International journal of epidemiology. 1993 Jun;     [PubMed PMID: 8359968]
[19] Matapandeu G,Dunn SH,Pagels P, An Outbreak of Pellagra in the Kasese Catchment Area, Dowa, Malawi. The American journal of tropical medicine and hygiene. 2017 May;     [PubMed PMID: 28219990]
[20] Mponda K,Masenga J, Skin diseases among elderly patients attending skin clinic at the Regional Dermatology Training Centre, Northern Tanzania: a cross-sectional study. BMC research notes. 2016 Feb 22;     [PubMed PMID: 26905256]
[21] Schmid MA,Salomeyesudas B,Satheesh P,Hanley J,Kuhnlein HV, Intervention with traditional food as a major source of energy, protein, iron, vitamin C and vitamin A for rural Dalit mothers and young children in Andhra Pradesh, South India. Asia Pacific journal of clinical nutrition. 2007;     [PubMed PMID: 17215184]
[22] Banjong O,Menefee A,Sranacharoenpong K,Chittchang U,Eg-kantrong P,Boonpraderm A,Tamachotipong S, Dietary assessment of refugees living in camps: a case study of Mae La Camp, Thailand. Food and nutrition bulletin. 2003 Dec;     [PubMed PMID: 14870623]
[23] Schüpbach R,Wegmüller R,Berguerand C,Bui M,Herter-Aeberli I, Micronutrient status and intake in omnivores, vegetarians and vegans in Switzerland. European journal of nutrition. 2017 Feb;     [PubMed PMID: 26502280]
[24] Darnton-Hill I, Public Health Aspects in the Prevention and Control of Vitamin Deficiencies. Current developments in nutrition. 2019 Sep;     [PubMed PMID: 31598578]
[25] Kvols LK,Reubi JC, Metastatic carcinoid tumors and the malignant carcinoid syndrome. Acta oncologica (Stockholm, Sweden). 1993;     [PubMed PMID: 8323761]
[26] Seow HF,Bröer S,Bröer A,Bailey CG,Potter SJ,Cavanaugh JA,Rasko JE, Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nature genetics. 2004 Sep;     [PubMed PMID: 15286788]
[27] Wan P,Moat S,Anstey A, Pellagra: a review with emphasis on photosensitivity. The British journal of dermatology. 2011 Jun;     [PubMed PMID: 21128910]
[28] Gurd FB, A HISTOLOGICAL STUDY OF THE SKIN LESIONS OF PELLAGRA. The Journal of experimental medicine. 1911 Jan 5;     [PubMed PMID: 19867399]
[29] Cao S,Wang X,Cestodio K, Pellagra, an Almost-Forgotten Differential Diagnosis of Chronic Diarrhea: More Prevalent Than We Think. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2019 Oct 9;     [PubMed PMID: 31599018]
[30] ABDALLA A,GAD-EL-MAWLA N, Electro-cardiographic changes in pellagra. The Journal of the Egyptian Medical Association. 1962;     [PubMed PMID: 14010565]
[31] Terada N,Kinoshita K,Taguchi S,Tokuda Y, Wernicke encephalopathy and pellagra in an alcoholic and malnourished patient. BMJ case reports. 2015 Oct 21;     [PubMed PMID: 26490997]
[32] Ho EY,Mathy C, Functional abdominal pain causing Scurvy, Pellagra, and Hypovitaminosis A. F1000Research. 2014;     [PubMed PMID: 24715978]
[33] Park YK,Sempos CT,Barton CN,Vanderveen JE,Yetley EA, Effectiveness of food fortification in the United States: the case of pellagra. American journal of public health. 2000 May;     [PubMed PMID: 10800421]
[34] Dwyer JT,Wiemer KL,Dary O,Keen CL,King JC,Miller KB,Philbert MA,Tarasuk V,Taylor CL,Gaine PC,Jarvis AB,Bailey RL, Fortification and health: challenges and opportunities. Advances in nutrition (Bethesda, Md.). 2015 Jan;     [PubMed PMID: 25593151]
[35] Flynn A,Hirvonen T,Mensink GB,Ocké MC,Serra-Majem L,Stos K,Szponar L,Tetens I,Turrini A,Fletcher R,Wildemann T, Intake of selected nutrients from foods, from fortification and from supplements in various European countries. Food     [PubMed PMID: 20011225]
[36] Steyn NP,Wolmarans P,Nel JH,Bourne LT, National fortification of staple foods can make a significant contribution to micronutrient intake of South African adults. Public health nutrition. 2008 Mar;     [PubMed PMID: 17610752]
[37] Gayer J,Smith G, Micronutrient fortification of food in Southeast Asia: recommendations from an expert workshop. Nutrients. 2015 Jan 19;     [PubMed PMID: 25608937]
[38] Serdula MK,Nichols EK,Aburto NJ,Masa'd H,Obaid B,Wirth J,Tarawneh M,Barham R,Hijawi B,Sullivan KM, Micronutrient status in Jordan: 2002 and 2010. European journal of clinical nutrition. 2014 Oct;     [PubMed PMID: 24986824]
[39] Prousky JE, Pellagra may be a rare secondary complication of anorexia nervosa: a systematic review of the literature. Alternative medicine review : a journal of clinical therapeutic. 2003 May;     [PubMed PMID: 12777163]