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.

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.

Pellagra secondary to selective eating in a child with autism.

Once a significant cause of morbidity and mortality, health care providers rarely see primary pellagra in developed countries where fortification of foods with niacin is commonplace and niacin-rich foods are generally widely available. We report a ten-year-old boy with autism spectrum disorder who presented with photosensitive dermatitis which resolved after vitamin supplementation and dietary changes. In this child, the pellagra developed as the result of a long-term pattern of selective eating. Restricted diets, even to the point of nutrient deficiencies, are well-documented among children with autism spectrum disorders (ASD).

Pellagra and Alcohol Dependence Syndrome: Findings From a Tertiary Care Addiction Treatment Centre in India.

AIM: To define the prevalence and clinical presentation of pellagra, a multi-systemic disease caused by the deficiency of niacin, in patients admitted to a tertiary addiction treatment centre in southern India, with alcohol dependence syndrome (ADS)-(ICD10). METHODS: Review of the health records of 2947 patients who received inpatient care for ADS between 2015 and 2017. RESULTS: Out of 2947, 31 (1%) were diagnosed with pellagra. Nearly two-thirds (64.5%) of those with pellagra were from a low-income group. Of the clinical-triad of pellagra, all patients had dermatitis, more than half (58%) had delirium, a minority (19%) had diarrhoea. Nearly two-thirds (61%) had presented in a complicated-withdrawal state. Associated conditions included peripheral neuropathy (32%); Wernicke's encephalopathy (26%); seizures (16%).Seventeen (54%) had BMI <18.5 kg/m2. Treatment was a high dose of parenteral vitamins including niacin (mean dose: 1500 mg/day) for an average of 7.5 days followed by oral multivitamin supplements. All had complete resolution of pellagrous symptoms by the end of the three weeks of inpatient care. CONCLUSIONS: Pellagra is an acute medical condition, frequently encountered in the context of alcohol dependence and poverty. It often presents with other disabling and life-threatening comorbidities like delirium tremens and Wernicke's encephalopathy. The classical triad of pellagra is only seen in a minority of cases. Thus a high index of suspicion is required lest pellagra may remain undiagnosed. Prompt identification and treatment with a high dose of niacin in combination with other vitamins result in complete recovery.

Severe pellagra masked by concurrent plaque psoriasis: a case report of a hidden diagnosis.

Despite characteristic features, psoriasis can mimic other dermatologic conditions, such as seborrheic dermatitis, lichen simplex chronicus, and certain nutritional deficiencies such as pellagra. We present a patient with a longstanding history of severe plaque psoriasis who presented with disfiguring scaly plaques involving greater than 80% body surface area. The patient's disease was minimally responsive to multiple therapies. Repeat punch biopsies demonstrated parakeratosis, psoriasiform hyperplasia, and dilated blood vessels consistent with psoriasis. Given atypical clinical features and overall poor treatment response additional work up was obtained. A serum nutritional panel was consistent with niacin deficiency and the patient later revealed extensive alcohol intake. A diagnosis of concurrent pellagra was made and the patient was started on niacin supplementation and instructed to reduce alcohol intake, while continuing adalimumab and high potency topical steroids. Within two weeks, his disease had markedly improved. Pellagra presents characteristically with a photosensitivity dermatitis that may appear clinically and histologically similar to psoriasis. It is important to maintain an index of suspicion for a secondary pathology in treatment-resistant psoriasis.

Ethionamide-induced Pellagra.

Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin.

Phenobarbital-induced pellagra resulted in death.

Pellagra is caused by deficiency of niacin or its precursor tryptophan. While cutaneous lesions are the most prominent feature of the disease, gastrointestinal, neurological and psychiatric signs and symptoms are the other characteristics of the disease. In this case report, we present a 29-year-old female patient with discoloration of hands and feet diagnosed with 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.

Pellagra in Zanzibar: a rare diagnosis.

BACKGROUND: Pellagra is a nutritional disease resulting from a deficiency of vitamin B3 (niacin) primarily due to corn consumption, especially in developing countries, but in developed countries, it can occur secondarily as a consequence of chronic alcoholism, malabsorption, certain drugs, and bariatric surgery. RESULTS: We present a case of a 32-year-old woman from a rural area in Zanzibar who was a heavy alcohol consumer and came in with features suggestive of pellagra. CONCLUSION: Our therapeutic approach consisted of niacin 500 mg once daily and betamethasone + salicylic acid ointment twice a day until lesions resolved and showed noticeable improvement.

The discovery of niacin, biotin, and pantothenic acid.

The aim was to describe the discovery of niacin, biotin, and pantothenic acid. By the 1920s, it became apparent that 'water-soluble B' (vitamin B) is not a single substance. In particular, fresh yeast could prevent both beriberi and pellagra, but the 'antipolyneuritis factor' in yeast is thermolabile, while the antipellagra factor is heat stable, suggesting that there are at least two water-soluble vitamins. Various terms were proposed for these water-soluble factors, but vitamins B(1) and B(2) were most widely used to refer to the thermolabile and heat-stable factors, respectively. Although vitamin B(1) proved to be a single chemical substance (thiamin), vitamin B(2) was ultimately found to be a complex of several chemically unrelated heat-stable factors, including niacin, biotin, and pantothenic acid. Recognition that niacin is a vitamin in the early 20th century resulted from efforts to understand and treat a widespread human disease - pellagra. American epidemiologist and US Public Health Service officer Joseph Goldberger (1874-1929) had been instrumental to elucidating the nutritional basis for pellagra. Goldberger conducted a classic series of observational and experimental studies in humans, combined with an extensive series of experiments with an animal model of the condition (black tongue in dogs). In contrast, recognition that biotin and pantothenic acid are vitamins occurred somewhat later as a result of efforts to understand microbial growth factors. The metabolic roles in humans of these latter substances were ultimately elucidated by human experiments using particular toxins and by studies of rare inborn errors of metabolism. Symptomatic nutritional deficiencies of biotin and pantothenic acid were, and continue to be, rare.

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.

Pellagra as a differential diagnosis in the confused patient on the acute medical unit.

A man in his 80s was admitted via the acute medical take after presenting with increased confusion and features of alcohol withdrawal. He had a several-month history of a worsening pruritic rash surrounding his neck, arms and legs in addition to new, profuse diarrhoea. In view of the background of known chronic alcoholism and the coexisting symptoms of rash, confusion and diarrhoea, pellagra was diagnosed via a multidisciplinary approach. Oral nicotinamide supplementation was commenced and his symptoms responded rapidly. The bias and challenge of reaching a unified diagnosis in the context of a multisystem condition are exemplified in this case report.

Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study.

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.