Pellagra Patients Research Articles

Pathophysiology and clinical management of pellagra - a review.

Pellagra is a rare disease caused by niacin deficiency or a disruption of its metabolism. Its manifestations are dermatitis with pronounced photosensitivity, gastrointestinal symptoms, and neuropsychiatric ailments. Currently pellagra is developed in people who chronically abuse alcohol or are treated with medications from specific pharmacological groups (immunosuppressive and anti-tuberculosis drugs). Although the root cause of the disease was established in the mid-twentieth century, a detailed explanation of the processes leading to the development of symptoms has not yet been proposed. They include complex abnormalities at the molecular, metabolic, and immunological levels. Diagnostics is based primarily on the clinical presentation of the disease, while auxiliary tests play secondary role. The low prevalence of the disease, meaning that physicians are unfamiliar with its recognition, often leads to delays in diagnosis and appropriate treatment. The therapy is causal and based on administering niacinamide. Failure to implement treatment in the early stages of the disease leads to the patient's death. The aim of this literature review is to summarize the current state of knowledge on the pathomechanisms of pellagra, highlighting the clinical implications, and key elements of diagnostic and therapeutic management that are important in the treatment of pellagra patients.

ペラグラ患者のナイアシン栄養状態 : 尿中のナイアシン異化代謝産物量は低下するが,血液中のNAD含量は低下しない

ペラグラ患者のナイアシン栄養状態 : 尿中のナイアシン異化代謝産物量は低下するが,血液中のNAD含量は低下しない

Depletion of Epidermal Langerhans Cells in the Skin Lesions of Pellagra Patients.

Pellagra is a nutrient deficiency disease caused by insufficient niacin levels. Recent studies have shown that numbers of epidermal Langerhans cells decreased in other diseases caused by nutritional deficiencies, including necrolytic migratory erythema and acrodermatitis enteropathica. Epidermal Langerhans cells are capable of modulating or even halting the inflammatory reaction. The aim of this study was to examine changes in the number of Langerhans cells and other dendritic cells, and maturation of epidermal Langerhans cells in the lesional and adjacent non-lesional skin in pellagra patients. Seven pellagra patients and 10 healthy individuals who served as controls were included. The number and distribution of dendritic cells and other cutaneous cells were examined by immunohistochemistry. Epidermal Langerhans cells decreased considerably in the skin lesions of pellagra patients, whereas other dendritic cells did not change. The decrease in the number of Langerhans cells was positively correlated with the histological severity of skin lesions. As the number of Langerhans cells was not reduced in the undisturbed neighboring skin, the depletion of epidermal Langerhans cells did not precede skin damage but was a cause of prolonged severe inflammation.

Role of inflammation in pellagra: an observational study

Background and objectives: Recent studies in medical science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. Earlier studies documented the role of inflammation in pathophysiology of many diseases. But the information regarding the role of inflammation in pellagra is less. Therefore we hypothesized that, high levels of inflammatory markers like C Reactive Proteins (CRP), Tumor Necrosis Factor alpha (TNF alpha) and Interleukin 6 (IL6) will be present in pellagra patients. Materials and methods: Clinically diagnosed pellagra patients aged between 18 to 40 years were recruited (n=63) from department of dermatology. Age and gender matched controls were recruited among staff and residents. Inflammation was assessed by using markers like C Reactive Proteins (CRP), Tumor Necrosis Factor alpha (TNF alpha) and Interleukin 6 (IL6) Results: There was no significant difference in anthropometric parameters. But, inflammatory markers hs CRP, TNF alpha and IL6 were significantly high in patients suffering from pellagra, when compared to age and gender matched controls (p<0.001) Conclusion: From this study, we can conclude that, the estimation of levels of inflammatory markers in pellagra patients at early stage will help to take measures to prevent the progression of disease.

Niacin deficiency and cutaneous immunity

Niacin, also known as vitamin B3, is required for the synthesis of coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin binds with G protein-coupled receptor (GPR) 109A on cutaneous Langerhans cells and causes vasodilation with flushing in head and neck area. Niacin deficiency due to excessive alcohol consumption, certain drugs or inadequate uptake in diet causes pellagra, a photosensitivity dermatitis. Recently several studies have revealed the mechanism of photosensitivity in niacin deficiency, which may pave a way for new therapeutic approaches. The expression level of prostaglandin E synthase (PTGES) is up-regulated in the skin of both pellagra patients and niacin deficient pellagra mouse models. In addition, pellagra is mediated through prostaglandin E₂-EP4 (PGE₂-EP4) signaling via reactive oxygen species (ROS) production in keratinocytes. In this article, we have reviewed the role of niacin in immunity and the mechanism of niacin deficiency-induced photosensitivity.

Oxidative stress and anti oxidants status in pellagra

Background and objectives: Pellagra was vanished from most parts of the world where it was formerly present due to its dietary modification. However, it is still encountered among the jowar eating populations of India. The information about the role of oxidative stress in pellagra was not established. Therefore, in this study we assessed the oxidative stress status by using malondialdehyde (MDA), total anti oxidant status (TAOS) and redox ratio (RER) in clinically diagnosed pellagra patients. Materials and methods: Clinically diagnosed pellagra patients aged between 18 to 40 years, both male and females were recruited (n=78) from department of Dermatology. Age and gender matched controls (n=78) were recruited from the student and residents of the hospital. Malondialdehyde (MDA) is a marker of lipid peroxidation, Total Anti Oxidant Status (TAOS) and Redox Ratio (RER) markers were assessed by using commercially available kits. Results: There were no significant differences in the anthropometric parameters. However, the oxidative stress markers MDA (p<0.05), RER (p<0.001) were significantly high and TAOS was low (P<0.001) in pellagra patients in comparison with age and gender matched controls. Conclusion: The results of this study showed the increased MDA, RER levels and decreased TAOS levels. Estimation of these markers at early stage will help to take measures to prevent the progression of disease and develop antioxidant strategies.

Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

Pellagra is a photosensitivity syndrome characterized by three “D's”: diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

Novel nucleoside reverse transcriptase inhibitor (4’-Ethynyl-2-Fluoro-2’-Deoxyadenosine) completely blocks HIV Infection of Langerhans Cells

Pellagra is caused by niacin deficiency and characterized by hotosensitive dermatitis, diarrhea, dementia, however, the exact athomechanism of these symptoms is not yet known. Since the athological and clinical anomalies of pellagre aremostly common o those of zinc defiency,we suspected the alteration of Langerhans ells might be the clue of pellagra lesion, whose disappearance is lso noted in acrodermatitis enteropathica recently. We analysed he presence of various cells in pellagra patients, and confirmed he selective disappearance of dendritic cells componens assumed y the immunohistochemical staining for langerin, HLA-DR, CD1a nd S100 at lesiona skin. Mast cells, merkel cells and melanocytes id not largely change their numbers compared with normal skin. e relvealed that the degeneration of kerationcytes in the upper pinous layer is not by the pure apoptotic pathway represenred y the expresion of cleaved caspase 3 and TUNEL method. We furher analyzed the temporal change of the dendritic cells at skin and ntestines using the pellagra model treated with niacin antagonist, AN, or the niacin defient diet. From the observations,we supposed hat losses of the cutaneous dendritic cells are the commonandpriary pathophysiological mechanism of the trophic skin diseased ncluding pellagra and acrodermatitis enteropathica.

Langerhans cells are selectively depleted in pellagra skin: the niacin deficiency as immuno-pathogenesis of one more trophic skin disorders

Pellagra is caused by niacin deficiency and characterized by photosensitive dermatitis, diarrhea, dementia, however, the exact pathomechanism of these symptoms is not yet known. Since the pathological and clinical anomalies of pellagre are mostly common to those of zinc defiency, we suspected the alteration of Langerhans cells might be the clue of pellagra lesion, whose disappearance is also noted in acrodermatitis enteropathica recently. We analysed the presence of various cells in pellagra patients, and confirmed the selective disappearance of dendritic cells componens assumed by the immunohistochemical staining for langerin, HLA-DR, CD1a and S100 at lesiona skin. Mast cells, merkel cells and melanocytes did not largely change their numbers compared with normal skin. We relvealed that the degeneration of kerationcytes in the upper spinous layer is not by the pure apoptotic pathway represenred by the expresion of cleaved caspase 3 and TUNEL method. We further analyzed the temporal change of the dendritic cells at skin and intestines using the pellagra model treated with niacin antagonist, 6AN, or the niacin defient diet. From the observations, we supposed that losses of the cutaneous dendritic cells are the common and primary pathophysiological mechanism of the trophic skin diseased including pellagra and acrodermatitis enteropathica. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF

Whole Blood NAD and NADP Concentrations Are Not Depressed in Subjects with Clinical Pellagra ,

Population surveys for niacin deficiency are normally based on clinical signs or on biochemical measurements of urinary niacin metabolites. Status may also be determined by measurement of whole blood NAD and NADP concentrations. To compare these methods, whole blood samples and spot urine samples were collected from healthy subjects (n = 2) consuming a western diet, from patients (n = 34) diagnosed with pellagra and attending a pellagra clinic in Kuito (central Angola, where niacin deficiency is endemic), and from female community control subjects (n = 107) who had no clinical signs of pellagra. Whole blood NAD and NADP concentrations were measured by microtiter plate-based enzymatic assays and the niacin urinary metabolites 1-methyl-2-pyridone-5-carboxamide (2-PYR) and 1-methylnicotinamide (1-MN) by HPLC. In healthy volunteers, inter- and intra-day variations for NAD and NADP concentrations were much lower than for the urinary metabolites, suggesting a more stable measure of status. However, whole blood concentrations of NAD and NADP or the NAD:NADP ratio were not significantly depressed in clinical pellagra. In contrast, the concentrations of 2-PYR and 1-MN, expressed relative to either creatinine or osmolality, were lower in pellagra patients and markedly higher following treatment. The use of the combined cut-offs (2-PYR <3.0 μmol/mmol creatinine and 1-MN <1.3 μmol/mmol creatinine) gave a sensitivity of 91% and specificity of 72%. In conclusion, whole blood NAD and NADP concentrations gave an erroneously low estimate of niacin deficiency. In contrast, spot urine sample 2-PYR and 1-MN concentrations, relative to creatinine, were a sensitive and specific measure of deficiency.

Serum electrolytes in hospitalized pellagra alcoholics.

Owing to high diarrhoea and protein malnutrition frequencies in pellagra, we hypothesised that pellagra patients would have higher electrolyte disturbances than non-pellagra alcoholics. To compare serum electrolytes of hospitalised alcoholics with or without pellagra. Retrospective and descriptive case-control study. Internal Medicine wards at a University Hospital, Medical School of Uberaba, Brazil. Medical records were reviewed to obtain relevant clinical details, main diagnosis and laboratory data, including serum electrolytes on hospital admission of pellagra patients (n=33) and a randomly chosen control group of alcoholics (n=37), matched in age, gender and socio-economic status. Anaemia was ascertained by haemoglobin <12.5 g/dl (men) and 1.5 g/dl (women), and hypoalbuminemia by serum albumin <3.3 g/dl. Pellagra and controls showed similar age (39.4+/-13.1 vs 45.0+/-11.4 years) and a male predominance of gender (69.7 vs 78.4%), and similar associated diagnoses, including high blood pressure (21.2 vs 16.2%), peripheral neuropathy (12.1 vs 13. 5%), and pneumonia (9.1 vs 13.5%). Despite displaying similar serum sodium (136.6+/-6.1 vs 137.8+/-5.7 mEq/I), magnesium (1.72+/-0.74 vs 1.62+/-0.34 mg/dl), phosphorus (3.79+/-0.87 vs 3.87+/-0.78 mEq/1) than controls,in addition to higher hypoalbuminemia (76.2 vs 33%) and anaemia (60.6 vs 35.1%) frequencies. Higher anaemia and hypoalbuminemia frequencies associated with lower serum potassium levels suggest increased protein malnutrition prevalence among pellagrins.

Interaction of niacin and zinc metabolism in patients with alcoholic pellagra

The effect of zinc supplementation on the metabolism of tryptophan conversion to niacin was studied in 14 alcoholic patients with pellagra and in 7 male control subjects aged 21-45 y. The pellagrins received chemically defined diets based on crystalline amino acids through an enteral tube for 7 d. Patients were divided into two groups (A and B), both receiving a diet from which tryptophan, Zn, and niacin were excluded. Patients in group B, however, received 220 mg Zn sulfate orally. Upon admission the pellagra patients had low plasma Zn levels and low urinary excretion values of N'methylnicotinamide (N'MN) and N'methyl-2-pyridone-5-carboxamide (2-PYR) in relation to the control subjects (p less than 0.01). During the experimental period there was an increase in plasma Zn levels (p less than 0.005) and in urinary N'MN (p less than 0.05) and 2-PYR (p less than 0.05) excretion in the patients receiving Zn supplementation (group B). These results suggest that Zn interacts with niacin metabolism in alcoholic patients with pellagra through a probable mediation by vitamin B-6.

Tryptophan metabolism in alcoholic pellagra patients: measurements of urinary metabolites and histochemical studies of related muscle enzymes

Biochemical and enzymatic aspects of tryptophan-niacin metabolism were studied in 15 adult alcoholic pellagra patients and in 14 controls. In addition to the clinical signs of niacin deficiency, most of the pellagra patients had other signs of malnutrition. Plasma tryptophan in pellagra patients was 2.07 +/- 1.27 mumol/dl, and in the controls 4.84 +/- 2.21 mumol/dl (p less than 0.001). The erythrocyte glutamic oxaloacetic transaminase index was 1.94 +/- 0.77 in the pellagra patients and 1.58 +/- 0.73 in the controls. The urinary levels of 3-hydroxyanthranilic acid were 34.49 +/- 21.47 mumol/g of creatinine in the pellagra patients and 14.51 +/- 8.02 mumol/g creatinine in the controls (p less than 0.02). The urinary levels of N'methylinicotinamide were 2.13 +/- 1.18 mg/g creatinine in the pellagra patients and 4.76 +/- 1.94 mg/g creatinine in the controls (p less than 0.01). The excretion of N'-methyl-2-pyridone-5-carboxamide (2-pyridone) was 2.94 +/- 2.37 mg/g creatinine in the pellagra patients and 10.19 +/- 7.49 mg/g creatinine in the controls (p less than 0.01). The histoenzymological activity of 3-hydroxyanthranilate oxidase in the deltoid muscle was higher in the pellagra patients than in the controls, whereas alpha-glycerophosphate dehydrogenase activity was higher in the controls. These results suggest that for alcoholic pellagra patients the tryptophan-niacin pathway is inhibited after the 3-hydroxyanthranilate oxidase step.

Comparison of intravenous glucose tolerance tests and serum insulin levels in kwashiorkor and pellagra.

Intravenous glucose tolerance tests and serum insulin responses were estimated on admission to hospital as well as after recovery in 16 kwashiorkor and 15 pellagra children. Only the kwashiorkor group showed impairment of glucose utilization on admission, and the glucose disappearance rate of the two groups differed significantly. After clinical recovery the glucose utilization of the kwashiorkor patients was much improved, and similar to that of the pellagra patients. These findings are different from those of others who reported persistent glucose intolerance after kwashiorkor. The glucose tolerance tests were normal in the pellagra group, both on admission and after recovery. The kwashiorkor group9s insulin response was less than that of the pellagra group on admission, and the values of the two groups differed significantly at 5, 15, and 30 minutes after glucose administration. After recovery, the insulin levels of the two groups were similar. The improvement in glucose utilization which took place on recovery of the kwashiorkor patients, as well as the low incidence of diabetes mellitus in the Bantu, cast doubt on the concept of permanent impairment of pancreatic endocrine function as a result of protein-calorie-malnutrition. It is speculated that glucose intolerance may be related to body potassium deficiency.

Tryptophan: Abnormal metabolism in pellagra patients

South African Bantu subjects with pellagra excreted abnormally elevated levels of kynurenine, acetylkynurenine, 3-hydroxykynurenine and several other metabolites of the kynurenine-niacin pathway after an oral load of 2 Gm. of L-tryptophan. The data suggest that tryptophan pyrrolase activity may be elevated in these subjects either as the result of a stress-mediated induction or as the result of lack of negative feedback by tissue pyridine nucleotides.

Serum globulin polymorphism in pellagra.

IN recent work on the serum iron and total iron-binding capacity of groups of healthy and diseased Africans, we found the total iron-binding capacity of pellagra patients to be approximately 60 per cent of healthy controls1. Zone electrophoresis on filter paper in an earlier work2 did not show that the concentration of the β-globulins in pellagra was any lower than healthy controls and this suggested that there may be a relationship between transferrin polymorphism and incidence of this disease, in view of the findings of Gibbett et al.3 that the faster-migrating transferrins take up more iron.

Serum iron and iron binding capacity of the African in Southern Rhodesia

1. 1) Serum iron and total iron binding capacity are reported for a number of different groups of Africans in Southern Rhodesia. 2. 2) Healthy African groups were as follows: Labourers, hospital orderlies, baTonga tribesmen and an old-age group. Africans suffering from pellagra, cirrhosis of the liver, anaemia, diabetes and porphyria were also tested and a further group of sick Africans with “black face” were included. 3. 3) The results for healthy Africans were above the normal ranges reported elsewhere, with a further slight increase in serum iron in the case of hospital orderlies and baTonga tribesman. 4. 4) Patients suffering from porphyria and “black face” both showed elevated serum irons, and in anaemia subjects it was reduced. Total iron binding capacity was reduced in porphyrics and cirrhotics, and drastically reduced in the case of pellagra patients, otherwise the figures were in normal ranges. 5. 5) The results are discussed in relation to siderosis and to work done elsewhere in Africa.

Gastroscopic Findings in Pellagra

Pellagra in Egypt is nearly always second­ ary to parasitic infestation of the intestines and undernutrition. It is therefore often accompanied by other diseases such as avitaminosis and hepatic schistosomiasis. Autopsies of patients dying of pellagra re­ vealed atrophy and thinning of the mucosa of the gastrointestinal tract, including the stomach.1 Gastric analysis frequently shows achlorhydria or marked hypochlorhydria which may return to normal under treat­ ment, but Castle's intrinsic factor is present in the gastric juice. 2 Reviewing the English literature in the English language covering the past 20 years,3. 4 I did not come across any record of gastroscopic examination in pellagra patients; this encouraged me to perform the present study.

Further Observations on the Red Pigments of Pellagra Urines

Conclusions1. The color noted in positive Beckh-Ellinger-Spies tests is not due to porphyrin. While a marked increase in urinary porphyrin, such as occurs in porphyria, would be productive of color, the color reaction as observed in pellagra and other diseases, is due to urorosein, first described by Nencki and Sieber. There is no evidence that the color reaction is due to any bile pigment derivative. 2. The urines of pellagra patients may contain either the chromogen of urorosein, or a red pigment extracted by the toluene preservative. It appears highly probable that this pigment is indirubin, although exact identification has not yet been made. 3. Both of the red substances may be noted in the urines of patients not having clinical pellagra. Further investigation is necessary to decide whether their appearance is related to deficiency of nicotinic acid or other essential substances.

The demonstration of the haemopoietic principle in chronic pellagric achylia

1. 1. Hyperchromic megalocytic anaemia was not found in 118 chronic pellagra patients. 2. 2. The achylic gastric juice from five chronic pellagra cases was shown by Singer's method to contain the haemopoietic principle. 3. 3. The gastric secretion of two ankylostome anaemia patients was shown to contain the haemopoietic principle by the same method. 4. 4. It is thus concluded that the extrinsic haemopoietic principle is different from the pellagra-preventing factor.