Pellagra (niacin/vitamin B3 deficiency)

[1]

Meet the patient

A 52-year-old chronic alcoholic is brought to the ward confused, with a raw, weeping, sharply demarcated erythema across the backs of his hands, a band of dermatitis circling his neck at the collar line, and a scaly flush across his face. He has had profuse watery diarrhoea for a week and cannot remember the day. The registrar writes "sunburn and alcohol withdrawal" — and that single misattribution is the most dangerous sentence in the chart.[1]

Hold two questions and the diagnosis arrives. Is the rash photosensitive and clothing-line demarcated? and is there gut or brain involvement in an at-risk patient? Answer both "yes" and you reach for nicotinamide before you reach for the benzodiazepines. Everything below unpacks those two questions.[1]

The 4 Ds — one cluster, one clock, one biochemistry

Pellagra is the 4 Ds, and the fourth D is the one that kills you. The tetrad is not a coincidence of organs — it is a single biochemical failure (NAD depletion) read across the three tissues with the highest NAD turnover: sun-stressed epidermis, rapidly renewing gut mucosa, and the central nervous system. Hit one cofactor and three systems fall together.[1][4]

[1]

The cluster rule for the viva: a photosensitive rash alone is a dermatology problem; a photosensitive rash plus diarrhoea or cognitive change in an at-risk patient is pellagra until proven otherwise. The skin is the messenger, but the gut and the brain decide the prognosis.[3]

Primary versus secondary pellagra — two axes, one treatment

Sort every case by where the deficiency comes from, because that decides whether it recurs. Primary pellagra is a dietary disease of niacin and tryptophan scarcity — maize, sorghum, famine, anorexia. Secondary pellagra is a metabolic disease of normal intake sabotaged by malabsorption, diversion, or cofactor antagonism — and it is the form you will actually meet in a developed-country hospital.[2]

[2]

The one-line discriminator beneath the table: a normal dietary history does not exclude pellagra — it redirects you to alcohol, the gut, the drug chart, the carcinoid, and the gene.[1]

The tryptophan-to-niacin arc — one pathway, five ways to break it

Every cause of pellagra is a point on a single biochemical arc. Humans make NAD from two sources: preformed dietary niacin (meat, fish, poultry, peanuts, legumes, whole grains) and endogenous synthesis from tryptophan via the kynurenine pathway, at a ratio of roughly 60 mg of tryptophan to 1 mg of niacin (one niacin equivalent, NE). The daily need of about 14 to 16 mg NE is normally met by a mixture of both.[1]

[1]

The pathway is enzymatically greedy — it needs vitamin B6 (pyridoxal phosphate) for kynureninase, vitamin B2 (riboflavin) for kynurenine hydroxylase, and adequate vitamin B1. That is why B-complex deficiencies travel together, and why a single antagonism can topple the whole arc.[1]

This one arc explains every cause. Low intake (maize, alcohol, anorexia) depletes both substrate and vitamin. Maize binds its niacin as niacytin, biologically unavailable — which is why the Mesoamerican practice of soaking maize in alkaline lime water (nixtamalisation) liberated the vitamin and spared native American populations the epidemic that later ravaged European and American maize-eaters. Cofactor antagonism is the mechanism of isoniazid, which chelates pyridoxal phosphate and directly inhibits kynureninase. Transport failure is Hartnup disease. Diversion is carcinoid.[2]

Why does niacin deficiency cause a systemic disease and not just a skin disease?

NAD and NADP are among the most important coenzymes in human metabolism, participating in over 400 redox reactions across glycolysis, the TCA cycle, oxidative phosphorylation, fatty-acid oxidation, and steroidogenesis. Beyond redox chemistry, NAD is the obligate substrate for poly(ADP-ribose) polymerase (PARP) — the central enzyme of DNA repair — and for the sirtuins that govern chromatin, inflammation, and mitochondrial biogenesis. Deplete NAD and the cell loses both its energy handling and its DNA repair: gut mucosa stops renewing, neurons fail, and sun-exposed keratinocytes cannot repair UV damage.[1]

Why the rash is photosensitive — and why it stops at the clothing line

The rash is photosensitive because UV damage is an NAD emergency. Ultraviolet irradiation generates reactive oxygen species and DNA strand breaks in basal keratinocytes, demanding high NAD consumption by PARP for repair. NAD-depleted keratinocytes cannot sustain that repair load, so sun-exposed skin decompensates first — and the sharp cut-off at the collar, sleeve, and sock lines, with normal skin beneath clothing, is the pathognomonic pattern that follows.[3]

That same mechanism explains the seasonal and occupational pattern: the eruption flares after a summer of outdoor work, on the dorsal hands of labourers, the face and V-neck of the hatless, and the dorsal feet of the open-shoed. The clothing draws the map of the disease.[3]

The dermatitis — Casal's necklace, the four stages, the morphology that wins marks

Casal's necklace is the single most examinable sign in pellagra. Named for the 18th-century Spanish physician Gaspar Casal, it is a band of dermatitis encircling the neck, demarcated anteriorly by the open shirt collar and posteriorly by the hairline — a perfect cast of the patient's sun-exposure geometry. Alongside it sit Casal's glove (dorsal hands), the butterfly facial distribution, the forearms, the dorsal feet, and the sternal shield.[3]

The eruption evolves in four stages, and the stage you meet tells you how long the deficiency has been running:[1]

[1]

The morphology is the discriminator. Pellagra gives you erythema with a sharp clothing-line cut-off that evolves to hyperpigmentation and fissuring — not the fragile bullae with milia and scarring of porphyria cutanea tarda, not the scaly annular plaques of lupus, and not the uniform exaggerated-sunburn of a drug phototoxic reaction. Add a beefy red, swollen, painful tongue with atrophic papillae and angular cheilitis, and the bedside picture is complete.[3]

Beyond the skin — the gut and the brain

The gut mirrors the skin, and the brain mirrors both. Profuse watery diarrhoea — often five to ten stools daily, occasionally bloody — reflects small-intestinal and colonic mucosal atrophy with failed epithelial renewal. Achlorhydria is common and compounds the malabsorption; abdominal pain, nausea, vomiting, and anorexia close the vicious cycle as glossitis makes eating painful.[1]

The neuropsychiatric spectrum is the most easily misattributed. Early disease produces irritability, headache, insomnia, anxiety, fatigue, and impaired concentration — dismissed as depression, anxiety, or "just the drink". As NAD depletion deepens, the picture evolves into apathy, confusion, disorientation, and frank psychosis with hallucinations, historically mistaken for schizophrenia or alcohol withdrawal. Severe untreated disease progresses to encephalopathy with myoclonus, grasping and sucking reflexes, stupor, coma, and death.[4]

Everyone forgets: pellagra is one of the few causes of acute psychosis that is completely reversible with a single vitamin. Empiric nicotinamide is increasingly recommended in any alcoholic or malnourished patient with unexplained encephalopathy — the cost of a therapeutic trial is trivial and the cost of missing it is irreversible brain injury.[4]

The photosensitive-rash differential — name the mimic, name the discriminator

A photosensitive rash is non-specific; a photosensitive rash plus gut or brain in an at-risk patient is pellagra. Isolated skin disease without GI or CNS features favours a primary photodermatosis. Use the morphology and the systemic context to split them.[3]

[3]

Three discriminating principles carry the viva. Look for the systemic tetrad — photosensitive rash plus diarrhoea or cognitive change in an at-risk patient points decisively to pellagra. Examine the morphology — clothing-line erythema evolving to hyperpigmentation and fissuring is pellagra; fragile bullae with milia is PCT; scaly annular plaques is lupus. Use the response — pellagra melts away with nicotinamide within days; the others do not.[1]

The three named traps — where pellagra hides

The classic trap — INH pellagra despite pyridoxine. Isoniazid causes pellagra by two mechanisms: it chelates pyridoxal phosphate (depleting the kynureninase cofactor) and it directly inhibits kynureninase. The syndrome is well described in patients on standard tuberculosis therapy, and it can occur despite routine B6 supplementation — so a patient on INH and pyridoxine who develops a photosensitive rash, diarrhoea, or confusion still has pellagra until proven otherwise. Do not let the B6 on the drug chart talk you out of the diagnosis.[6]

The classic trap — the alcoholic who is given glucose before thiamine. Alcoholic pellagra coexists with and is masked by Wernicke encephalopathy, Marchiafava-Bignami disease, and hepatic encephalopathy. Any alcoholic with confusion and a rash should receive both thiamine and nicotinamide empirically, and the thiamine must come before any glucose-containing fluid — glucose without thiamine precipitates Wernicke and is a recurrent, preventable disaster.[1]

The classic trap — 'it does not happen here'. In developed countries pellagra is sporadic and concentrated in chronic alcoholics, the socially isolated elderly, patients with eating disorders, post-bariatric patients, refugees, carcinoid patients, and those on unsupplemented restrictive diets. The diagnosis is missed not because it is rare but because it is 'not supposed to happen here' — and that assumption is the assumption that kills. Screen the marginalised, the malabsorbing, and the medicated.[5]

Diagnosis is clinical — the response is the test

Pellagra is a bedside diagnosis, and the therapeutic response to niacin is itself the confirmation. No single investigation should delay the initiation of nicotinamide in a convincing case — the dramatic improvement in dermatitis, diarrhoea, and mental state within 24 to 72 hours is more compelling than any laboratory value.[1]

The laboratory exists to support the diagnosis in uncertain cases, to exclude mimics, and to identify the underlying cause. Urinary N1-methylnicotinamide (N-MN) is the most useful functional marker — a low N-MN to 2-pyridone ratio supports deficiency — but the assay is not available in most hospitals and should never delay treatment. A skin biopsy is non-specific (epidermal atrophy with parakeratosis, basal layer vacuolar change) and its value is exclusion of lupus (negative direct immunofluorescence), porphyria, and drug eruption.[1][3]

The cluster of bedside clues that should trigger empiric niacin: a photosensitive, well-demarcated eruption on the dorsal hands and neck plus diarrhoea or cognitive change, in a chronic alcoholic, refugee, fad-dieter, carcinoid patient, or patient on isoniazid. Start oral nicotinamide immediately. In any alcoholic with confusion, give thiamine before glucose.[1]

Treatment — nicotinamide, the dose that is both therapy and diagnosis

The agent of choice is nicotinamide, not nicotinic acid — and the doses are the numbers that win the stem. Nicotinamide repletes NAD without the prostaglandin-mediated flushing, pruritus, headache, and dyslipidaemia of nicotinic acid, and is equally effective. Nicotinic acid (the lipid-lowering form) activates GPR109A on Langerhans cells, keratinocytes, and mast cells, releasing prostaglandin D2 and producing the distressing niacin flush that drives non-adherence — nicotinamide bypasses that receptor entirely.[1]

[1]

The standard regimen is oral nicotinamide 100 mg QID for 3 to 4 weeks, then 50 mg TDS as maintenance until the cause is corrected and the diet is adequate. For severe disease with vomiting, coma, or intractable diarrhoea, give parenteral nicotinamide 25 to 100 mg IV or IM two to three times daily until oral therapy is tolerated. Children receive 10 to 50 mg TDS. The cutaneous eruption, glossitis, and diarrhoea typically begin to improve within 24 to 72 hours; cognition recovers over 1 to 2 weeks, though full cognitive recovery may lag for months in chronic depletion.[1]

Specific replacement is necessary but never sufficient — the cause must be addressed or the disease recurs. In alcoholic pellagra, treat the alcohol use disorder and correct coexisting thiamine, folate, and B12. In isoniazid pellagra, add pyridoxine 25 to 50 mg daily and review the regimen with the TB team — pellagra can persist despite B6, so niacin replacement is mandatory. In carcinoid syndrome, optimise somatostatin analogue therapy and pursue tumour control. In Hartnup disease, lifelong nicotinamide prevents relapse.[2]

[1]

Resuscitation is reserved for fulminant disease — severe encephalopathy, coma, intractable vomiting, or overwhelming diarrhoea with dehydration — but must not be delayed once the diagnosis is entertained. Give parenteral nicotinamide, fluid and electrolyte resuscitation with potassium and magnesium, thiamine 100 mg IV before any glucose in the alcoholic, empirical antibiotics only if sepsis is present, and strict photoprotection.[1]

The subtypes that bite — Hartnup, carcinoid, isoniazid, the alcoholic

Hartnup disease is an autosomal-recessive defect of neutral amino-acid transport from mutations in SLC6A19, expressed in the intestinal and renal proximal tubule. The defect wastes tryptophan in the gut and the urine, depleting the substrate for niacin synthesis and producing a pellagra-like phenotype — photosensitive rash, cerebellar ataxia, episodic psychiatric disturbance — that presents in childhood. The diagnostic test is urinary amino acid chromatography showing neutral aminoaciduria, and the treatment is the same as endemic pellagra: lifelong nicotinamide.[1]

Carcinoid syndrome pellagra is one of the most frequently missed causes in developed countries. A neuroendocrine tumour can divert up to 60 per cent of dietary tryptophan toward serotonin, depleting the niacin substrate pool. The carcinoid is the focus of attention and the rash is attributed to flushing, photodamage, or drug reaction. The presentation may include the usual tetrad, sometimes with vulvovaginal or perianal involvement and an overlap with lichen sclerosus. Management combines nicotinamide with somatostatin analogue therapy and definitive tumour control.[7]

Isoniazid-induced pellagra is the iatrogenic form every TB programme generates. INH chelates pyridoxal phosphate and directly inhibits kynureninase, and — critically — the syndrome occurs despite routine pyridoxine supplementation. A photosensitive rash, diarrhoea, or confusion in a patient on INH is pellagra until proven otherwise. Management is nicotinamide plus pyridoxine 25 to 50 mg daily, with a review of the INH regimen.[6]

Alcoholic pellagra is the commonest form in developed countries, from the triad of poor intake, ethanol-induced malabsorption, and impaired hepatic tryptophan conversion. It coexists with and is masked by Wernicke encephalopathy and hepatic encephalopathy, so any alcoholic with confusion and a rash receives both thiamine and nicotinamide empirically while the work-up proceeds.[1]

Endemic and refugee pellagra persists where untreated maize or sorghum is the staple and erupts in epidemics during drought, economic collapse, or displacement — documented in southern Africa in 2001 to 2002 and continuously in parts of India and sub-Saharan Africa. The public-health interventions are dietary diversification, fortification of maize and wheat flour, and nixtamalisation. Refugee feeding must ensure adequate niacin and protein, not just calories.[5]

How pellagra patients come to harm — the preventable list

• Death from untreated pellagra misdiagnosed as alcohol withdrawal or primary psychosis — the preventable death of a fully reversible disease.[1]
• An alcoholic given glucose before thiamine, precipitating Wernicke alongside the missed pellagra.[1]
• A patient on INH whose rash is attributed to drug reaction while the niacin deficiency runs on — because B6 was 'already covered'.[6]
• A carcinoid patient whose pellagra is mistaken for tumour flushing, delaying the one treatment that relieves the rash.[7]
• Using nicotinic acid instead of nicotinamide — flushing, distress, non-adherence, and a patient labelled 'allergic'.[1]
• Waiting for the N1-methylnicotinamide level before treating — the dramatic response to a therapeutic trial is the diagnostic confirmation.[1]
• Treating niacin without correcting the cause — guaranteed relapse in ongoing alcoholism, INH, carcinoid, or Hartnup.[1]

Etymology and the names that earn viva gold

Etymology for viva gold: pellagra is Italian pelle (skin) plus agra (sour or rough) — 'rough skin', coined in 18th-century Mediterranean Europe when the disease ravaged peasant populations on untreated maize imported from the Americas. Casal's necklace honours Gaspar Casal, the Spanish physician who first described the disease in 1735 as mal de la rosa. Joseph Goldberger (1914 to 1929) proved the nutritional rather than infectious origin through dietary experiments — feeding trials, orphanage studies, and even self-injection of pellagrous blood — paving the way for Elvehjem's 1937 identification of niacin as the curative factor. Two and a half centuries of one disease, and the treatment is still a single vitamin.[5]

The mantra, and the mnemonic

[1]

The mantra: photosensitive rash plus gut or brain in an at-risk patient — give niacin now, ask questions later.[1]

Why does isoniazid cause pellagra even when pyridoxine is supplemented?

INH both chelates pyridoxal phosphate (depleting the B6 cofactor for kynureninase) and directly inhibits kynureninase, blocking the tryptophan-to-niacin pathway. Routine B6 prophylaxis does not fully prevent the syndrome — persistent symptoms demand nicotinamide replacement, not more pyridoxine.[6]

Why is the pellagra rash photosensitive?

Ultraviolet irradiation generates reactive oxygen species and DNA strand breaks in basal keratinocytes, which require high NAD consumption by poly(ADP-ribose) polymerase (PARP) for repair. NAD-depleted keratinocytes cannot sustain that repair load, so sun-exposed skin fails first — producing the sharp demarcation between exposed and covered sites that is the hallmark of the disease.[3]

Prognosis, disposition, and the recovery that gratifies

The prognosis of treated pellagra is excellent, and the recovery is among the most satisfying in medicine. The cutaneous eruption and glossitis begin to settle within 24 to 72 hours; the diarrhoea resolves within days to a week; cognition recovers over 1 to 2 weeks, though full cognitive recovery may lag for months in chronic depletion. Most patients are managed as outpatients; fulminant encephalopathy, coma, or intractable diarrhoea need admission and parenteral niacin.[4]

[1]

Untreated pellagra is fatal within 4 to 5 years, and fulminant cases kill within weeks from cachexia, intercurrent TB or pneumonia, or neurological decline. The lesson is unambiguous: treat on suspicion, treat early, and treat the cause.[1]

Special populations — where the thresholds move

[1]

Evidence, guidelines, and regional differences

The evidence base for pellagra is observational and physiological rather than randomised — no placebo-controlled trial of niacin for pellagra exists, and none is ethical given the dramatic, well-established response. The landmark history is itself the evidence: Casal's 1735 description, Goldberger's dietary experiments proving a nutritional origin, and Elvehjem's 1937 identification of niacin as the curative factor in canine black-tongue. The WHO and FAO set the adult RDA at about 14 to 16 mg NE per day (roughly 6.6 mg NE per 1000 kcal), and fortification of maize and wheat flour remains the population-level intervention.[5]

[1]

[1]

Exam pearls

[1] [1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the alcoholic with the rash and the confusion (answer)

A 52-year-old chronic alcoholic is confused, with a sharply demarcated erythematous rash on his dorsal hands and neck, and profuse diarrhoea. What is the diagnosis, and what do you do in the next hour? Model: This is pellagra — the 4 Ds (dermatitis, diarrhoea, dementia) in a chronic alcoholic, the classic developed-country presentation. Give oral nicotinamide 100 mg QID immediately — do not wait for biochemistry — and give thiamine 100 mg IV before any glucose-containing fluid, because Wernicke encephalopathy coexists and is precipitated by glucose without thiamine. The rash, gut, and cognition will begin to improve within 24 to 72 hours, and that response is itself the confirmation. Then address the alcohol use disorder and the coexisting folate and B12 deficiency.[1]

Stem 2 — the TB patient on INH and pyridoxine (answer)

A 38-year-old on isoniazid for pulmonary tuberculosis, already receiving routine pyridoxine supplementation, develops a photosensitive rash on the dorsal hands and neck with mild diarrhoea and irritability. The registrar says 'it cannot be pellagra, the B6 is covered'. What is the right call? Model: This is pellagra, and the B6 does not exclude it. INH causes pellagra by two mechanisms — chelating pyridoxal phosphate and directly inhibiting kynureninase — and the syndrome is well described despite routine pyridoxine supplementation. Start oral nicotinamide 100 mg QID, continue pyridoxine 25 to 50 mg daily, and review the regimen with the TB team. The 'INH covers it' assumption is the classic trap.[6]

Stem 3 — the photosensitive rash that is not pellagra (answer)

A 45-year-old presents with fragile bullae, milia, hypertrichosis, and sclerodermoid change on the dorsal hands, with no diarrhoea or cognitive change. What is the most likely diagnosis, and how do you distinguish it from pellagra at the bedside? Model: This is porphyria cutanea tarda (PCT), not pellagra. The discriminator is morphology and systemics: PCT gives fragile bullae with milia and scarring on the dorsal hands, plus hypertrichosis and sclerodermoid change, without the GI or CNS tetrad — whereas pellagra gives clothing-line erythema evolving to hyperpigmentation and fissuring, with Casal's necklace and a beefy glossitis. Confirm PCT with urine and faeces porphyrins. Pellagra responds to niacin; PCT responds to phlebotomy or hydroxychloroquine.[3]

References

1. [1]Hołubiec P, Leończyk M, Staszewski F, et al. Pathophysiology and clinical management of pellagra - a review Folia Med Cracov, 2021.PMID 34882669
2. [2]Prabhu D, Dawe RS, Mponda K Pellagra a review exploring causes and mechanisms, including isoniazid-induced pellagra Photodermatol Photoimmunol Photomed, 2021.PMID 33471377
3. [3]Wan P, Moat S, Anstey A. Pellagra: a review with emphasis on photosensitivity Br J Dermatol, 2011.PMID 21128910
4. [4]Wuerch E, Urgoiti GR, Yong VW The Promise of Niacin in Neurology Neurotherapeutics, 2023.PMID 37084148
5. [5]Viljoen M, Bipath P, Tosh C Pellagra in South Africa from 1897 to 2019: a scoping review Public Health Nutr, 2021.PMID 33769244
6. [6]Darvay A, Basarab T, McGregor H, Russell-Jones R. Isoniazid induced pellagra despite pyridoxine supplementation Clin Exp Dermatol, 1999.PMID 10354170
7. [7]Reichman O, Sobel JD Vulvovaginal pellagra and lichen sclerosus complicating carcinoid syndrome Obstet Gynecol, 2009.PMID 19155950