Case report: Pellagra presentation with dermatitis and dysphagia.

Pellagra is a disorder caused by a deficiency of niacin or tryptophan, manifested by characteristic dermatitis on sun-exposed areas of the skin. Gastrointestinal involvement is common, and symptoms include glossitis, stomatitis, and diarrhea. Neurologic symptoms can occur in some patients, including dementia, anxiety, depression, tremors, hyporeflexia and, in severe cases, encephalopathy. We present the case of a woman with hyperpigmentation and hyperkeratosis on sun-exposed areas of the skin along with progressive dysphagia. Notably, she did not report diarrhea or any neurologic or psychiatric symptoms. Her symptoms were most consistent with pellagra, and niacin supplementation was initiated, leading to recovery. This case report highlights that dermatitis and dysphagia, the main gastrointestinal manifestations, can be the only symptoms in patients with pellagra, requiring a high index of suspicion in dermatologic settings to diagnose and treat this fatal condition early.

Atypical presentation of pellagra with black urine: A clinical conundrum.

Niacin (Vitamin B3) plays a crucial role as a vitamin in cellular energy production, metabolism, and DNA repair. A severe deficiency of this vitamin can lead to pellagra, which is characterized by dermatitis, dementia, diarrhoea and eventually death if untreated. A 68-year-old woman with a poor socioeconomic background presented with photosensitive dermatitis, fever, abdominal pain, and diarrhoea. Her urine changed to port wine colour following sun exposure. Porphyria cutanea tarda was excluded in the absence of demonstrable urine spectrophotometry. A diagnosis of pellagra was made, and timely management led to a complete cure. Proper diagnosis and effective treatment of pellagra are imperative as this condition can be life-threatening if left untreated.

Beyond the Bottle: Niacin Deficiency and Chronic Alcoholism.

Vitamin B3 is called niacin, an essential nutrient for the human body. In diet, it exists in three forms - niacin, nicotinamide, and nicotinamide riboside and can also be produced from an amino acid - tryptophan in the gut. During the digestive process, these dietary forms of vitamin B3 get converted into nicotinamide adenine dinucleotide (NAD), which behaves as a cofactor and substrate in critical cellular reactions and thus plays a pivotal role in energy metabolism. The deficiency of this particular vitamin in the body, which manifests in different ways, is called Pellagra. We discuss one such case of niacin deficiency presenting with multisystem involvement in a chronic alcoholic.

A Rare Case of Pellagra in a Chronic Alcoholic.

This case report documents a rare occurrence of pellagra in a chronic alcoholic individual, characterized by a pruritic rash and gastrointestinal symptoms. The patient, a Caucasian male in his 60s, with a history of alcohol use disorder, presented with worsening skin lesions and non-bloody diarrhea. Laboratory findings revealed significant deficiencies in niacin and related metabolites, confirming the diagnosis. Prompt initiation of niacin supplementation, dietary adjustments, and supportive care led to notable improvements. This case shows the critical importance of recognizing pellagra in chronic alcoholism, emphasizing the triad of symptoms - rash, diarrhea, and malnutrition - as key diagnostic markers. Early intervention holds the potential to significantly enhance the patient's well-being and prevent disease progression.

NAD+, Axonal Maintenance, and Neurological Disease.

Significance: The remarkable geometry of the axon exposes it to unique challenges for survival and maintenance. Axonal degeneration is a feature of peripheral neuropathies, glaucoma, and traumatic brain injury, and an early event in neurodegenerative diseases. Since the discovery of Wallerian degeneration (WD), a molecular program that hijacks nicotinamide adenine dinucleotide (NAD+) metabolism for axonal self-destruction, the complex roles of NAD+ in axonal viability and disease have become research priority. Recent Advances: The discoveries of the protective Wallerian degeneration slow (WldS) and of sterile alpha and TIR motif containing 1 (SARM1) activation as the main instructive signal for WD have shed new light on the regulatory role of NAD+ in axonal degeneration in a growing number of neurological diseases. SARM1 has been characterized as a NAD+ hydrolase and sensor of NAD+ metabolism. The discovery of regulators of nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) proteostasis in axons, the allosteric regulation of SARM1 by NAD+ and NMN, and the existence of clinically relevant windows of action of these signals has opened new opportunities for therapeutic interventions, including SARM1 inhibitors and modulators of NAD+ metabolism. Critical Issues: Events upstream and downstream of SARM1 remain unclear. Furthermore, manipulating NAD+ metabolism, an overdetermined process crucial in cell survival, for preventing the degeneration of the injured axon may be difficult and potentially toxic. Future Directions: There is a need for clarification of the distinct roles of NAD+ metabolism in axonal maintenance as contrasted to WD. There is also a need to better understand the role of NAD+ metabolism in axonal endangerment in neuropathies, diseases of the white matter, and the early stages of neurodegenerative diseases of the central nervous system. Antioxid. Redox Signal. 39, 1167-1184.

Protective effect of Bifidobacterium longum BB536 against nausea caused by pirfenidone in a mouse model of pellagra.

Pellagra is caused by abnormal intake and/or use of nicotinic acid and is known in part to be induced by the use of medications such as isoniazid or pirfenidone. We previously investigated atypical phenotypes of pellagra, such as nausea, using a mouse model of pellagra and found that gut microbiota play an important role in the development of these phenotypes. Here, we investigated the effect of Bifidobacterium longum BB536 on pellagra-related nausea caused by pirfenidone in our mouse model. Our pharmacological data indicated that pirfenidone (PFD) causes modulation of the gut microbiota profile, which appeared to play an important role in the development of pellagra-related nausea. A gut microbiota-mediated protective effect of B. longum BB536 against nausea caused by PFD was also identified. Finally, the urinary ratio of nicotinamide/N-methylnicotinamide was shown to be a biomarker of pellagra-like adverse effects induced by PFD, and it may contribute to the prevention of these effects in patients with idiopathic pulmonary fibrosis.

NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota.

The oxidized form of nicotinamide adenine dinucleotide (NAD+) is a critical metabolite for living cells. NAD+ may act either as a cofactor for many cellular reactions as well as a coenzyme for different NAD+-consuming enzymes involved in the physiological homeostasis of different organs and systems. In mammals, NAD+ is synthesized from either tryptophan or other vitamin B3 intermediates that act as NAD+ precursors. Recent research suggests that NAD+ precursors play a crucial role in maintaining the integrity of the gut barrier. Indeed, its deficiency has been associated with enhanced gut inflammation and leakage, and dysbiosis. Conversely, NAD+-increasing therapies may confer protection against intestinal inflammation in experimental conditions and human patients, with accumulating evidence indicating that such favorable effects could be, at least in part, mediated by concomitant changes in the composition of intestinal microbiota. However, the mechanisms by which NAD+-based treatments affect the microbiota are still poorly understood. In this context, we have focused specifically on the impact of NAD+ deficiency on intestinal inflammation and dysbiosis in animal and human models. We have further explored the relationship between NAD+ and improved host intestinal metabolism and immunity and the composition of microbiota in vivo. Overall, this comprehensive review aims to provide a new perspective on the effect of NAD+-increasing strategies on host intestinal physiology.

Variable Presentations of Photodermatoses - A Case Series.

Photodermatoses represent a broad spectrum of skin diseases caused because of exposure to ultraviolet radiation. It is categorized mainly as idiopathic photosensitive disorders, drug or chemical induced photosensitivity reactions, DNA repair-deficiency photodermatoses and photoaggravated dermatoses. Despite being under the photodermatoses umbrella, the pathophysiology of each type of photodermatoses varies. We reported 4 cases of photodermatoses including azathioprine induced pellagra, adult onset actinic prurigo, and photoallergic contact dermatitis due to NSAIDs and cutting fluids. Photoprotection with the usage of photoprotective clothing, broad-spectrum sunscreen application and avoidance of photosensitizing drugs and chemicals are crucial.

Prevention and Control Strategies for Non-Communicable Disease: Goldberger, Pellagra and Rose Revisited.

This paper argues that the public health conceptual framework of epidemiologist Geoffrey Rose, first published as "Sick Individuals and Sick Populations" in 1985, provides a useful way to critically analyze prevention and control options for modern non-communicable diseases (NCD) and their forerunner, obesity, a pandemic now engulfing Lower-and-Middle-Income-Countries. That framework is based on the notions of primordial, primary, secondary and tertiary prevention-the full spectrum of "more upstream and more downstream" approaches, each with its pros and cons. These are illustrated using the pellagra epidemic in the southeastern USA from 1900 to the 1940s, which still has much to teach us about these same basic policy options for controlling the modern NCD pandemic. In particular, Rose's dictum, "Seek the causes of (population) incidence, not of (individual) cases", points up the compelling advantages of upstream prevention for controlling both epidemics.

Systemic tryptophan homeostasis.

Tryptophan is an essential amino acid, which is not only a building block for protein synthesis, but also a precursor for the biosynthesis of co-enzymes and neuromodulators, such as NAD/NADP(H), kynurenic acid, melatonin and serotonin. It also plays a role in immune homeostasis, as local tryptophan catabolism impairs T-lymphocyte mediated immunity. Therefore, tryptophan plasmatic concentration needs to be stable, in spite of large variations in dietary supply. Here, we review the main checkpoints accounting for tryptophan homeostasis, including absorption, transport, metabolism and elimination, and we discuss the physiopathology of disorders associated with their dysfunction. Tryptophan is catabolized along the kynurenine pathway through the action of two enzymes that mediate the first and rate-limiting step of the pathway: indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO). While IDO1 expression is restricted to peripheral sites of immune modulation, TDO is massively expressed in the liver and accounts for 90% of tryptophan catabolism. Recent data indicated that the stability of the TDO protein is regulated by tryptophan and that this regulation allows a tight control of tryptophanemia. TDO is stabilized when tryptophan is abundant in the plasma, resulting in rapid degradation of dietary tryptophan. In contrast, when tryptophan is scarce, TDO is degraded by the proteasome to avoid excessive tryptophan catabolism. This is triggered by the unmasking of a degron in a non-catalytic tryptophan-binding site, resulting in TDO ubiquitination by E3 ligase SKP1-CUL1-F-box. Deficiency in TDO or in the hepatic aromatic transporter SLC16A10 leads to severe hypertryptophanemia, which can disturb immune and neurological homeostasis.

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.

NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction.

The NAD(P)HX repair system is a metabolite damage repair mechanism responsible for restoration of NADH and NADPH after their inactivation by hydration. Deficiency in either of its two enzymes, NAD(P)HX dehydratase (NAXD) or NAD(P)HX epimerase (NAXE), causes a fatal neurometabolic disorder characterized by decompensations precipitated by inflammatory stress. Clinical findings include rapidly progressive muscle weakness, ataxia, ophthalmoplegia, and motor and cognitive regression, while neuroimaging abnormalities are subtle or nonspecific, making a clinical diagnosis challenging. During stress, nonenzymatic conversion of NAD(P)H to NAD(P)HX increases, and in the absence of repair, NAD(P)H is depleted, and NAD(P)HX accumulates, leading to decompensation; however, the contribution of each to the metabolic derangement is not established. Herein, we summarize the clinical knowledge of NAXE deficiency from 30 cases and lessons learned about disease pathogenesis from cell cultures and model organisms and describe a metabolomics signature obtained by untargeted metabolomics analysis in one case at the time of crisis and after initiation of treatment. Overall, biochemical findings support a model of acute depletion of NAD+, signs of mitochondrial dysfunction, and altered lipidomics. These findings are further substantiated by untargeted metabolomics six months post-crisis showing that niacin supplementation reverses primary metabolomic abnormalities concurrent with improved clinical status.

Analysis of the gut microbiome to validate a mouse model of pellagra.

Pellagra is caused by an abnormal intake and/or use of niacin, but its phenotypes are diverse. The phenotypes of pellagra can also be atypical, such as nausea. We previously reported a mouse model of pellagra-related nausea. However, the mechanism of this model is unclear. In this study, we found that the gut microbiota, which is thought to be a source of niacin, played an important role in the development of pellagra-related nausea in germ-free mice. We also investigated the gut microbiome. We compared urinary niacin metabolite levels and the dermal response between mice fed a normal diet and those fed a low-niacin diet to investigate the putative trigger of pellagra. Epoxyeicosatrienoic and hydroxyeicosatetraenoic acid levels were higher in mice fed a low-niacin diet compared with those fed a normal diet. Furthermore, histological studies indicated a dermatological response to the low-niacin diet. Interestingly, higher levels of oxidised fatty acids in response to the germ-free state were also observed. These findings indicate successful establishment of our newly established mouse model of pellagra via the gut microbiota. We believe that this model could enable the discovery of the putative cause of pellagra and phenotypes of pellagra that have not been recognised yet.

Effect of niacin supplementation on nausea-like behaviour in an isoniazid-induced mouse model of pellagra.

Niacin deficiency causes pellagra, the symptoms of which include dermatitis, diarrhoea and dementia. Investigating the mechanism underlying these phenotypes has been challenging due to the lack of an appropriate animal model. Here, we report a mouse model of pellagra-related nausea induced by feeding mice a low-niacin diet and administering isoniazid (INH), which is thought to induce pellagra. Mice fed a normal or low-niacin diet received INH (0·3 or 1·0 mg/mg per animal, twice daily, 5 d), and nausea was evaluated based on pica behaviour, which considered the rodent equivalent of the emetic reflex. Furthermore, the effect of therapeutic niacin administration on nausea was evaluated in this model. Urinary and hepatic metabolite levels were analysed by LC coupled with MS. INH-induced pica was observed in mice fed a low-niacin diet but not in those fed a normal diet. Levels of urinary metabolites, such as 1-methyl-2-pyridone-5-carboxamide, kynurenic acid and xanthurenic acid, were significantly reduced in the mice treated with INH compared with those that did not receive INH. Furthermore, niacin supplementation prevented pica and restored the levels of some metabolites in this mouse model. Our findings suggest that INH-related nausea is pellagra-like. We also believe that our newly established method for quantifying pica is a useful tool for investigating the mechanisms of pellagra-related nausea.

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.

Azathioprine-induced pellagra in a child with autoimmune hepatitis: A case report and literature review.

Pellagra is a clinical syndrome resulting from niacin deficiency with variety of manifestations. Azathioprine is among drugs that can lead to such condition. Physicians should be aware as proper management can lead to full resolution.