COVID-19: Are We Facing Secondary Pellagra Which Cannot Simply Be Cured by Vitamin B3?

Immune response to SARS-CoV-2 and ensuing inflammation pose a huge challenge to the host's nicotinamide adenine dinucleotide (NAD+) metabolism. Humans depend on vitamin B3 for biosynthesis of NAD+, indispensable for many metabolic and NAD+-consuming signaling reactions. The balance between its utilization and resynthesis is vitally important. Many extra-pulmonary symptoms of COVID-19 strikingly resemble those of pellagra, vitamin B3 deficiency (e.g., diarrhoea, dermatitis, oral cavity and tongue manifestations, loss of smell and taste, mental confusion). In most developed countries, pellagra is successfully eradicated by vitamin B3 fortification programs. Thus, conceivably, it has not been suspected as a cause of COVID-19 symptoms. Here, the deregulation of the NAD+ metabolism in response to the SARS-CoV-2 infection is reviewed, with special emphasis on the differences in the NAD+ biosynthetic pathway's efficiency in conditions predisposing for the development of serious COVID-19. SARS-CoV-2 infection-induced NAD+ depletion and the elevated levels of its metabolites contribute to the development of a systemic disease. Acute liberation of nicotinamide (NAM) in antiviral NAD+-consuming reactions potentiates "NAM drain", cooperatively mediated by nicotinamide N-methyltransferase and aldehyde oxidase. "NAM drain" compromises the NAD+ salvage pathway's fail-safe function. The robustness of the host's NAD+ salvage pathway, prior to the SARS-CoV-2 infection, is an important determinant of COVID-19 severity and persistence of certain symptoms upon resolution of infection.

Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra.

Pellagra is a clinical syndrome caused by a deficiency of niacin (nicotinic acid) and/or its precursor tryptophan. The cardinal manifestations are 4 D's: dermatitis, diarrhoea, dementia and in worst case death. Increased use of isoniazid prophylaxis along with antiretroviral therapy in countries where latent tuberculosis is common has been associated with increased presentations with pellagra.

[Cutaneous manifestations of nutritional deficiencies]. / Manifestations cutanées de carences nutritionnelles, ou quand l'examen de la peau alimente le diagnostic.

In elderly or chronically ill patients, nutritional deficiencies are common and the presence of related skin lesions is not unusual. Recognition of such cutaneous involvement is important regarding the diagnosis essentially based on clinical elements. By using some clinical case reports, we will describe several pathologies related to nutritional deficiencies like scurvy, pellagra and acquired acrodermatitis enteropathica.

Dans nos populations de patients vieillissants ou atteints de maladies chroniques, les carences nutritionnelles sont fréquentes et la présence de manifestations dermatologiques associées n'est pas rare. La reconnaissance de telles atteintes cutanées est importante pour le diagnostic qui est essentiellement clinique. A l'aide de vignettes cliniques, nous allons discuter ici de pathologies carentielles comme le scorbut, la pellagre ainsi que l'acrodermatite entéropathique acquise.

Louis Sambon and the Clash of Pellagra Etiologies in Italy and the United States, 1905-14.

This article explores the extent to which the bacterial concept of disease acted as an obstacle to the understanding of deficiency diseases, by focusing on explorations into the cause of pellagra in the early twentieth century. In 1900, pellagra had been epidemic in Italy for 150 years and was soon to become so in the United States, yet the responses of medical investigators differed substantially. To account for these, the article reconstructs the sharply contrasting reactions to a provocative theory proposed by Louis Sambon. Applying a tropical diseases approach to pellagra, Sambon argued that pellagra had nothing at all to do with maize consumption, as the Italians had long thought, but was caused by the bite of a parasite-carrying insect. Italian pellagrologists, involved in a dogmatic quest for a toxin in maize, and with pellagra rates there on the decline, marginalized the Sambon hypothesis. By contrast, in the United States, with pellagra on the rise, the dominant infectious paradigm put Sambon center stage, his proposed etiology shaping the earliest American investigations. When the deficiency disease concept gained currency in 1913, the relatively closed world of Italian pellagrology was wrong-footed, while the more open-ended U.S. community was better able to follow up the new lead. The article discusses what these shifts and the resulting controversies reveal about the medical contexts. The actor-centered approach, with reaction to Sambon's intervention as a kind of test-case, is the key to understanding these controversies and why they mattered.

Evidence and conjecture about mechanisms of cutaneous disease in photodermatology.

Photosensitivity disorders are caused by a variety of mechanisms. Three common themes are as follows: excess chromophore allowing visible light energy to cause photodynamic damage, reduced DNA repair capacity to UV-induced DNA damage, and enhanced sensitivity to light-induced allergens mediated immunologically. Although the cause of each condition may be known, the precise pathogenesis underlying the photosensitivity has taken longer to understand. By focussing on three clinical disorders under each of these themes, we have explored the following: why erythropoietic protoporphyria differs so markedly from the other cutaneous porphyrias; how a DNA repair defect was eventually revealed to be the underlying cause of the vitamin B3 deficiency disorder of pellagra; an immunological explanation for the over reactivity to photoallergens in chronic actinic dermatitis.

Pellagra and alcoholism: a biochemical perspective.

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.

Niacin: vitamin and antidyslipidemic drug.

Niacin is defined collectively as nicotinamide and nicotinic acid, both of which fulfill the vitamin functions of niacin carried out by the bioactive forms NAD(P). In the last few decades numerous new enzymes that consume NAD(P) as substrates have been identified. The functions of these enzymes are emerging as exciting paradigm shifts, even though they are in early stages of discovery. The recent identification of the nicotinic acid receptor has allowed distinction of the drug-like roles of nicotinic acid from its vitamin functions, specifically in modulating blood lipid levels and undesirable side effects such as skin vasodilation and the more rare hepatic toxicities. This information has led to a new strategy for drug delivery for niacin, which, if successful, could have a major impact on human health through decreasing risk for cardiovascular disease. Understanding the many other effects of niacin has much broader potential for disease intervention and treatment in numerous diseases including cancer.

Letter: Pellagra as the initial presentation of Crohn disease.

Pellagra is a nutritional disease caused by the deficiency of niacin. We describe a case of pellagra as the initial presentation of Crohn disease, which has been rarely described in the literature.

Clinical analysis of alcoholic pellagra: A single-center retrospective study.

BACKGROUND: Pellagra caused by niacin deficiency in alcoholics can be easily misdiagnosed because of similar symptoms to other alcohol-related diseases and the lack of the classical triad of signs. AIM: This study aimed to define the clinical presentation of alcoholic pellagra for early diagnosis and timely treatment. METHODS: The clinical data of 16 alcohol-dependent patients who had pellagra and treated in our hospital from January 2002 to December 2019 were retrospectively analyzed. The local medical ethics committee approval (Medical Ethics Committee of Affiliated Hospital of XuZhou Medical University, XYFY2020-KL247-02) for this study has been obtained. RESULTS: The main complaints of the 16 patients were skin lesions (six cases), diarrhea (six cases), and mental disorders (four cases). Then, 13 cases had typical skin lesions, and 3 patients had a full spectrum of diarrhea, dementia, and dermatitis (3D). In terms of the main diagnosis, 2 patients had pellagra and Wernicke's encephalopathy, 3 patients had pellagra and alcohol-withdrawal syndrome, and the other patients had pellagra. After sufficient amounts of niacin and multivitamin B were given, clinical symptoms improved rapidly, and no sequelae were observed during follow-up. CONCLUSIONS: Pellagra is rarely manifested as a full 3D spectrum, with only one or two characteristics, which lack diagnostic specificity, especially in individuals with alcoholism. Physicians should maintain a high degree of suspicion of niacin deficiency in alcoholics. Alcohol-dependent patients with pellagra may be accompanied by complications of Wernicke's encephalopathy and alcohol-withdrawal syndrome. Prompt identification and timely treatment with a sufficient amount of niacin in combination with other vitamins and a certain amount of Zn can achieve a good prognosis of pellagra.

Pellagra: a review with emphasis on photosensitivity.

Niacin has recently been demonstrated to lower blood pressure in hypertensive patients and to reduce cardiovascular events when combined with a statin. As a consequence, niacin has been elevated from being of historical interest as the treatment for pellagra, to being a compound with possible relevance to contemporary therapeutics. In spite of this, niacin deficiency leading to pellagra continues to be a health problem in some countries. Characterized by an exposed-site hyperpigmented dermatitis, pellagra is generally accepted to have been the first photosensitivity syndrome described. At its worst, pellagra manifests as one of the most striking examples of systemic photosensitivity. This is the only photosensitivity syndrome where death is included as a cardinal clinical feature (the often quoted four 'Ds': dermatitis, diarrhoea, dementia and death). However, the pathogenetic mechanism for the photosensitivity caused by niacin deficiency has yet to be determined. This review seeks to update the classification and phenotypic characterization of the various forms of niacin-deficient photosensitivity. Previous speculation about possible mechanisms for the pathogenesis of photosensitivity due to niacin deficiency is reviewed in the context of advances in the understanding of the photochemical basis of photosensitivity reactions. The review concludes by highlighting research required to advance the understanding of this photosensitivity syndrome.

[Pellagra: an ancient disease in a modern world]. / Pelagra: una enfermedad antigua en un mundo moderno.

INTRODUCTION: Introduction: pellagra is a systemic disease due to deficiency of vitamin B3 or tryptophan, its precursor. Vitamin B3 is needed for several metabolic processes, cell signaling, and DNA repair. It is characterized by a classic tetrad of dermatitis, diarrhea, dementia, and death. Pellagra is considered rare nowadays; however, due to the popularity of restrictive diets without necessary supplementation such us veganism, there has been an increase in cases in recent years. Clinical case: we report the case of a young strict vegan female patient in which a pellagra diagnosis was made, and early treatment was administered with an excellent outcome. Discussion: the interest of this case lies in the importance of clinical suspicion and directed history taking focused on social and nutritional factors, as adapted for the current times, in order to make the diagnosis of a rare, subdiagnosed disease that is life-threatening if treatment is delayed.

INTRODUCCIÓN: Introducción: la pelagra es una enfermedad sistémica secundaria a la deficiencia de vitamina B3 o de su precursor, el triptófano. La vitamina B3 es necesaria para varios procesos metabólicos, de señalización celular y reparación del ADN. Se caracteriza por la tétrada clásica de dermatitis, diarrea, demencia y muerte. La misma es considerada una enfermedad rara hoy en día; sin embargo, con el auge de las dietas restrictivas sin la adecuada suplementación, como es el caso del veganismo, se ha visto un aumento de los casos en los últimos años. Caso clínico: exponemos el caso de una paciente adulta joven, vegana estricta, a la cual se le realizó el diagnóstico de pelagra y se le instauró un tratamiento de forma precoz, con una excelente evolución. Discusión: el interés del caso radica en la importancia de la sospecha clínica y la anamnesis dirigida a factores sociales y nutricionales, adaptados a la época actual, para poder hacer el diagnóstico de una enfermedad rara e infradiagnosticada que es potencialmente mortal de retrasarse el inicio del tratamiento.

Cyclone Idai as a Trigger for Pellagra Outbreak in Nhamatanda, Mozambique: A Case-Control Study.

In mid-June 2019, 3 months after cyclone Idai landfall in Mozambique, health authorities of Nhamatanda district reported an outbreak of Pellagra. Applying a mixed-method protocol, we carried out an investigation to characterize cases of pellagra, identify the associated factors for the outbreak using a case-control study, and explore the perceived impact on food security (availability, access, and usage) before and after Idai. We collected data from 121 cases and 121 controls and conducted in-depth interviews with 69 heads of households. The cases were more likely to be female (P < 0.01) and less educated (P < 0.01) than controls. Insufficient consumption of chicken and peanut before cyclone Idai arrival were statistically associated with pellagra (P < 0.05). From interviewed households' heads, 51% were experiencing food shortages even before the cyclone hit. Cyclone Idai served as a trigger to reduce niacin consumption below the threshold that protected Nhamatanda population from pellagra and caused a ≈2,300 case (707.9/100,000 inhabitants) outbreak.

Pellagra: an old enemy of timeless importance.

BACKGROUND: In the United States, pellagra is infrequently reported. Yet this disorder does occur among malnourished persons. OBJECTIVE: The author seeks to clarify diagnosis and treatment. METHOD: The author describes various presentations and effects of this disorder. RESULTS: Knowledge of classic and atypical presentations can assist in making the diagnosis. The author presents two cases of pellagra that exemplify the classic and atypical presentations. CONCLUSION: The typically robust response of the disorder to physiologic doses of niacin can assist in confirming the diagnosis.

Pellagra associated with esophageal carcinoma and alcoholism.

Pellagra is a nutritional disease caused by the deficiency of niacin. It presents with a photodistributed rash, gastrointestinal symptoms, and neuropsychiatric disturbances. In the Western world, this disease is mostly confined to alcoholics or the impoverished. However, this condition must be recognized in other clinical settings because it is easily treated and can be fatal if not identified. We describe a case of pellagra caused by esophageal carcinoma and alcoholism; we also review the literature.

Pellagra: rekindling of an old flame.

Pellagra is a disease largely associated with alcohol abuse, poverty, and malnutrition and is very common in developing countries. However, in the wake of "slimmer is better" fads and the ever-growing population of patients infected with human immunodeficiency virus, it may be on the surge in the United States. This vitamin deficiency disorder, though easy to diagnose and treat, can be easily missed and requires a high index of suspicion. We describe a case involving a patient who presented with the classic triad of "diarrhea, dermatitis, and dementia" and was promptly diagnosed and appropriately treated.

The diagnostic importance of photosensitivity dermatoses in chronic alcoholism: report of two cases.

Many of the vitamin deficiency diseases have been almost completely eliminated in developed countries. Niacin deficiency is considered one of them. However, cases of pellagra are recently reported in West Europe, USA, Australia, and Japan in connection with chronic alcoholism, gastrointestinal malabsorption, and some medications. We report two cases of pellagra, manifesting as photosensitivity dermatoses with mental deterioration in chronic alcoholic abusers in the Mediterranean basin, the island of Crete in Greece. The report highlights the fact that all physicians should be alerted to photosensitivity dermatoses in alcoholics; early treatment with multiple vitamin therapy, including nicotinic acid should be initiated in these patients.

[Case of non-alcoholic pellagra following gastrectomy].

A 67-year-old man was admitted to our hospital in May 2006 because of gait disturbance, delirium and myoclonus along with dermatitis and diarrhea. Those symptoms became worse in 3 months. He had undergone a gastrectomy, including a fundectomy and jejunal pouch interposition, for early gastric cancer at the age of 65 years. He had no habit of drinking alcohol or unbalanced diet. The triad of typical dermatitis, delirium, and diarrhea led to a diagnosis of pellagra, and all the symptoms disappeared after intravenous administration of nicotinate and vitamins. With a gastrectomy, fundectomy performed with jejunal pouch interposition has been regarded as a superior method for postoperative nutrition, but may cause vitamin deficiency. Thus, vitamin deficiency must be considered as a potential cause in neurologic patients who underwent surgical treatment for disorders of digestive tract, regardless of the procedure utilized.