Pellagra

BackgroundAlcohol withdrawal delirium (AWD) is associated with significant morbidity and mortality. Pellagra (niacin deficiency) can be a cause of delirium during alcohol withdrawal that may often be overlooked.ObjectivesWe present a three-patient case series of pellagrous encephalopathy (delirium due to pellagra) presenting as AWD.MethodsWe provide a brief review of pellagra's history, data on pellagra's epidemiology, and discuss pellagra's various manifestations, particularly as related to alcohol withdrawal. We conclude by providing a review of existing guidelines on the management of alcohol withdrawal, highlighting that they do not include pellagrous encephalopathy in the differential diagnosis for AWD.ResultsThough pellagra has been historically described as the triad of dementia, dermatitis, and diarrhea, it seldom presents with all three findings. The neurocognitive disturbance associated with pellagra is better characterized by delirium rather than dementia, and pellagra may present as an isolated delirium without any other aspects of the triad.DiscussionAlthough endemic pellagra is virtually eradicated in Western countries, it continues to present as pellagrous encephalopathy in patients with risk factors for malnutrition such as chronic alcohol intake, homelessness, or AIDS. It may often be mistaken for AWD. Whenever pellagra is suspected, treatment with oral nicotinamide (100 mg three times daily for 3-4 weeks) prior to laboratory confirmation is recommended as an inexpensive, safe, and potentially life-saving intervention.

Research into the functions of nicotinamide adenine dinucleotide (NAD) has intensified in recent years due to the insight that abnormally low levels of NAD are involved in many human pathologies including metabolic disorders, neurodegeneration, reproductive dysfunction, cancer, and aging. Consequently, the development and validation of novel NAD-boosting strategies has been of central interest, along with the development of models that accurately represent the complexity of human NAD dynamics and deficiency levels. In this review, we discuss pioneering research and show how modern researchers have long since moved past believing that pellagra is the overt and most dramatic clinical presentation of NAD deficiency. The current research is centered on common human health conditions associated with moderate, but clinically relevant, NAD deficiency. In vitro and in vivo research models that have been developed specifically to study NAD deficiency are reviewed here, along with emerging strategies to increase the intracellular NAD concentrations.

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.

Neuronal central chromatolysis (CC) is the histopathological hallmark of pellagra encephalopathy, a neurological deficit resulting from vitamin deficiencies. Pellagrous CC neurons are morphologically similar to ballooned achromatic neurons in other conditions but the distinct pathomechanisms remain unclear. We performed a clinico-neuropathological analysis of 10 autopsy cases of pellagra encephalopathy. The pellagra encephalopathy cases were immunohistochemically compared with disease controls, including cases of axonal injury and neurodegenerative diseases. Electron microscopic evaluation and immunohistochemical examinations targeting mitochondrial fragmentation were performed for a representative case. Four of 10 pellagra encephalopathy patients exhibited prolonged impairment of consciousness distinguishable from alcohol withdrawal delirium. Pellagrous CC neurons were negative for cytoskeletal markers whereas ballooned achromatic neurons in the disease control cases were positive. Immunohistochemical analysis of mitochondrial markers revealed that CC neurons exhibited more intense immunoreactivity for COX-IV and mitochondrial fissure factor compared to the disease controls. Transmission electron microscopy of these CC neurons revealed a marked increase in the mitochondria with amorphous densities. These findings indicate that the pathomechanism of pellagrous CC is distinct from that of the ballooned achromatic neurons of other etiologies. Mitochondrial alterations in pellagrous CC neurons suggest that neuronal energy deficits resulting from nicotinamide adenine dinucleotide deficiency induce mitochondrial fragmentation.