Pellagra

Pellagra is a systemic disease caused by deficiency of niacin (vitamin B3) or its amino acid precursor tryptophan, classically presenting with the "4 Ds": dermatitis, diarrhea, dementia, and death if untreated. [1-2] It remains underdiagnosed, particularly in developed countries, where a high index of suspicion is critical — the full classic triad is present in only a minority of cases. [3-4]

The following figure demonstrates the characteristic photodistributed dermatitis and Casal's necklace seen in pellagra:

• Dietary intake: Ask about diet composition — maize/corn-based diets, food insecurity, restrictive diets, anorexia, failure to eat regularly [2][6]
• Alcohol use: Quantity, frequency, duration — chronic alcohol use is a major cause in developed countries (35% of reported cases in literature review) [7-8]
• Medication history: Isoniazid (leading drug cause, 14.3% of cases), pyrazinamide, ethionamide, 5-fluorouracil, 6-mercaptopurine, phenobarbital, phenytoin, chloramphenicol, carbidopa/benserazide [1][9-10]
• Symptom characterization: Onset and progression of skin changes (photosensitive distribution), GI symptoms (diarrhea, dysphagia, nausea), and neuropsychiatric symptoms (confusion, memory loss, depression, insomnia)
• Timing: Seasonal worsening in spring/summer with sun exposure; isoniazid-associated cases onset median 5–9 months after initiation [11]
• Associated symptoms: Fatigue, apathy, insomnia, weight loss, burning/pruritus of skin lesions [9][12]
• Important negatives: Not all components of the triad need be present — dermatitis alone (98.6%), GI symptoms (59.4%), or neurological signs (54.2%) may occur in isolation [1]

• Encephalopathy / delirium: Confusion, disorientation, hallucinations, stupor — indicates severe/advanced disease; fatal if untreated [12-13]
• Concurrent Wernicke's encephalopathy: Co-occurs in ~26% of alcoholic pellagra cases [3]
• Seizures: Reported in 16% of alcohol-dependent patients with pellagra [3]
• Cachexia / severe malnutrition: BMI <18.5 in 54% of alcoholic pellagra patients [3]
• Altered mental status not responding to thiamine: Should prompt consideration of pellagra, especially in alcoholic patients [13]
• Progressive worsening despite multivitamins that lack niacin: A key diagnostic clue [13]

Causative medications (interfere with tryptophan-to-niacin conversion or niacin metabolism):

• Isoniazid — most common drug cause (aOR 42.6 for pellagra risk); inhibits tryptophan-to-niacin conversion [11][14]
• Pyrazinamide, ethionamide (other anti-TB drugs)
• 5-Fluorouracil, 6-mercaptopurine (chemotherapy)
• Phenytoin, phenobarbital (anticonvulsants)
• Chloramphenicol
• Carbidopa/benserazide (Parkinson's drugs) — biochemical evidence of niacin depletion, though clinical pellagra is less common [10]

Treatment medications

• Nicotinamide (niacinamide): Preferred over nicotinic acid (avoids flushing); 300–1,000 mg/day PO for mild-moderate disease [9][15]
• Parenteral niacin: Mean dose ~1,500 mg/day for severe/alcoholic pellagra encephalopathy [3]
• Co-administer other B vitamins (thiamine, riboflavin, pyridoxine) — concurrent deficiencies are common and required for tryptophan-to-niacin conversion [8][12]

Caution: High-dose niacin carries risk of hepatotoxicity; blood levels are unreliable measures of deficiency [15]

• Maize/corn-dependent diets: Niacin in corn is bound (not bioavailable without nixtamalization); primary driver of pellagra globally (85% of cases) [1-2]
• Tryptophan-poor diets: Sorghum-based diets, severely restricted protein intake
• Excessive leucine intake: Inhibits tryptophan-to-niacin conversion [12]
• Niacin-rich foods for recovery/prevention: Eggs, peanuts, meat, poultry, fish, legumes, seeds, bran [9]
• Adequate protein nutrition is essential — tryptophan is the precursor to niacin [8]
• Hydration: Important given diarrhea-related losses

• Dermatologic: Photosensitive rash, burning, pruritus, hyperpigmentation, scaling, fissuring
• GI: Diarrhea (watery, occasionally bloody/mucoid), nausea, anorexia, dysphagia, glossitis, stomatitis, epigastric discomfort [9][16]
• Neuropsychiatric: Insomnia, fatigue, apathy → depression, anxiety, irritability → confusion, hallucinations, memory loss → psychosis, stupor, coma [9][12]
• Musculoskeletal: Weakness, tremors
• Neurologic: Peripheral neuropathy (32% in alcoholic pellagra), hyporeflexia [3][16]
• Genitourinary: Vaginitis (mucosal inflammation) [12]

• Collateral: Assess housing status (homelessness is a major risk factor), access to meals/shelter-based food programs, social isolation, caregiver neglect [6]
• Alcohol use history from family/friends — patients may underreport
• Dietary habits: Who prepares meals, food access, food insecurity
• Family history: Hartnup disease (autosomal recessive disorder of tryptophan transport) — a rare hereditary cause of pellagra-like symptoms [17]
• Carcinoid syndrome: Family or personal history — diverts tryptophan to serotonin synthesis [17]

• Dietary deficiency / food insecurity — 85% of cases; 93% in humanitarian crisis settings [1]
• Chronic alcoholism — 9.6–35% of cases depending on the population studied [1][7]
• Isoniazid therapy — especially without pyridoxine supplementation [11][14]
• Poverty / low socioeconomic status — 64.5% from low-income groups [3]
• Homelessness [6]
• Malabsorption: Celiac disease, IBD, bariatric surgery, chronic GI disorders [7][18]
• HIV infection — independent risk factor, often co-occurs with isoniazid use [11]
• Lactation (in women) — increased niacin requirements [11]
• Anorexia nervosa / restrictive eating disorders
• Maize-dependent diets without nixtamalization [2]

• Photodermatitis / phototoxic drug reaction: Lacks GI and neuropsychiatric features; medication history key
• Systemic lupus erythematosus: Malar rash, but different distribution; check ANA
• Dermatomyositis: Heliotrope rash, Gottron's papules; proximal muscle weakness
• Porphyria cutanea tarda: Blistering on sun-exposed areas; check urine porphyrins
• Zinc deficiency (acrodermatitis enteropathica): Periorificial and acral distribution
• Hartnup disease: Pellagra-like rash with aminoaciduria — consider in children/young adults [17]
• Carcinoid syndrome: Flushing, diarrhea, wheezing — diverts tryptophan to serotonin [17]
• Wernicke's encephalopathy: Confusion, ataxia, ophthalmoplegia — frequently co-occurs with pellagra in alcoholics [3]
• Contact dermatitis / eczema: Distribution not photosensitive; no systemic features
• Kwashiorkor: Edema, skin changes, but different pattern

• Prior episodes of pellagra or nutritional deficiency
• Alcohol use disorder — most important in developed countries [7][13]
• Tuberculosis and anti-TB medication history [11][14]
• Bariatric surgery (Roux-en-Y, sleeve gastrectomy) [18]
• GI surgery or chronic GI disease causing malabsorption [1]
• HIV/AIDS [11]
• Cancer — chemotherapy with 5-FU or 6-MP [9]
• Eating disorders
• Chronic liver disease / cirrhosis [15]

Vital signs: Tachycardia (if dehydrated/malnourished), low BMI

Skin (most common finding, 98.6% of cases): [1]

• Casal's necklace: Broad band of hyperpigmented, scaling dermatitis around the neck — pathognomonic [19]
• "Gauntlet" distribution: Symmetric, well-demarcated erythema/hyperpigmentation on dorsal hands and forearms [19]
• Photosensitive distribution: face, neck, chest (V-sign), dorsal feet, extensor surfaces
• Acute: Erythema resembling sunburn, may have vesicles/bullae [9]
• Chronic: Hyperpigmentation, hyperkeratosis, thickened/leathery skin with sharp demarcation [16]

Oral: Glossitis (bright red, beefy tongue), stomatitis, angular cheilitis [9][12]

Neurologic: Altered mental status, confusion, tremors, hyporeflexia, peripheral neuropathy, ataxia [3][16]

General: Cachexia, muscle wasting, signs of other nutritional deficiencies

• Pellagra is primarily a clinical diagnosis — no definitive confirmatory lab test [20]
• Urinary N1-methylnicotinamide (1-MN) and 2-pyridone: Low levels support niacin deficiency, but not widely available [9][21]
• Serum niacin/NAD levels: Blood levels are unreliable measures of deficiency [15]
• CBC: Anemia (nutritional), macrocytosis if concurrent folate/B12 deficiency
• CMP: Electrolyte abnormalities from diarrhea/malnutrition, hepatic function
• Albumin/prealbumin: Assess nutritional status
• Thiamine level: Rule out concurrent Wernicke's (co-occurs in 26% of alcoholic cases) [3]
• B12, folate, zinc: Assess for concurrent deficiencies
• Serum tryptophan: May be low but not routinely measured
• Urine 5-HIAA: If carcinoid syndrome suspected as cause

• Imaging is generally not required for diagnosis of pellagra
• Brain MRI: Consider if encephalopathy is present — may show symmetric signal changes in the caudate nuclei (described in pellagra encephalopathy), but findings are nonspecific
• CT abdomen: Only if evaluating for malabsorption etiology or carcinoid tumor
• Chest imaging: If tuberculosis is suspected as the underlying context for isoniazid use

• Therapeutic trial of niacin: The most practical "test" — dramatic clinical improvement within days to weeks strongly supports the diagnosis [13][20]
• Skin biopsy: Nonspecific findings (hyperkeratosis, epidermal atrophy, perivascular inflammation); may help exclude other diagnoses [20]
• Urine amino acid analysis: If Hartnup disease is suspected (neutral aminoaciduria)
• 24-hour urine 5-HIAA: If carcinoid syndrome is in the differential

• Pellagra itself does not produce specific ECG findings
• ECG is indicated in malnourished/alcoholic patients to assess for:
  • Electrolyte-related changes (hypokalemia, hypomagnesemia from diarrhea)
  • QTc prolongation (nutritional deficiencies, electrolyte derangements)
  • Concurrent thiamine deficiency (wet beriberi — tachycardia, high-output failure) [22]
• Rule out other nutritional cardiomyopathies in severely malnourished patients

• Pellagra is a clinical diagnosis based on the combination of characteristic photosensitive dermatitis, GI symptoms, and/or neuropsychiatric findings in a patient with risk factors for niacin deficiency [9][20]
• The classic triad is present in a minority of cases — isolated dermatitis or partial presentations are far more common [1][3]
• Severity stratification:
  • Mild: Dermatitis only
  • Moderate: Dermatitis + GI symptoms (diarrhea, glossitis, dysphagia)
  • Severe: Neuropsychiatric involvement (encephalopathy, psychosis, delirium) — medical emergency
• Complications: Cachexia, secondary infections of skin lesions, aspiration (from dysphagia/encephalopathy), death if untreated [2]
• In alcoholic patients, always consider concurrent Wernicke's encephalopathy — altered mental status not improving with thiamine alone should prompt niacin supplementation [3][13]

Initial stabilization (severe/encephalopathic)

• Parenteral niacin (nicotinamide): 100–500 mg IV/IM three times daily (mean ~1,500 mg/day) for 7–10 days, then transition to oral [3]
• Concurrent thiamine 500 mg IV (if alcoholic — treat presumptive Wernicke's) [3]
• IV fluids and electrolyte repletion
• Nutritional support with adequate protein

Mild-moderate (outpatient)

• Nicotinamide 300–1,000 mg/day PO in divided doses [15][18]
• Alternatively, nicotinic acid 50–500 mg PO three times daily (causes flushing — nicotinamide preferred)
• Multi-B vitamin supplementation (riboflavin, thiamine, pyridoxine) — required cofactors for tryptophan-to-niacin conversion [8][12]
• Zinc and magnesium supplementation [9]
• High-calorie, protein-rich diet [9]

Skin care: Emollients, sun protection; topical corticosteroids with salicylic acid for symptomatic relief of dermatitis [18]

Address underlying cause: Discontinue offending medication (e.g., isoniazid — consider rifamycin-based alternative for TB prevention), treat alcohol use disorder, address food insecurity [11]

Expected response: Complete symptom resolution on average within 27 days of niacin supplementation; skin and GI symptoms improve within days, neuropsychiatric symptoms may take longer [1][13]

Admit if

• Encephalopathy, delirium, psychosis, or seizures [3][13]
• Severe dehydration from diarrhea
• Inability to tolerate oral intake
• Concurrent Wernicke's encephalopathy or complicated alcohol withdrawal [3]
• Severe malnutrition (BMI <18.5) with hemodynamic instability

Observation: Mild confusion with ability to take oral medications; monitor for clinical response to niacin

Discharge if

• Isolated dermatitis without neuropsychiatric or severe GI involvement
• Able to tolerate oral niacin and adequate diet
• Reliable follow-up and access to medications/nutrition

Consult

• Dermatology — if diagnosis uncertain or skin biopsy needed
• Psychiatry — if significant neuropsychiatric symptoms
• Nutrition/dietetics — for dietary counseling and meal planning
• Addiction medicine — if alcohol use disorder is the underlying cause

• Follow-up in 1–2 weeks to assess clinical response to niacin supplementation
• Dermatitis should begin improving within days; complete resolution expected within 3–4 weeks [1]
• GI symptoms typically resolve within 1–2 weeks
• Neuropsychiatric symptoms may take weeks to fully resolve; some cognitive deficits may persist if treatment was delayed

Return precautions — seek immediate care for

• Worsening confusion, hallucinations, or inability to care for self
• Inability to eat or drink
• Bloody diarrhea or severe dehydration
• New seizures

Patient counseling

• Importance of dietary diversification — include niacin-rich foods (meat, fish, poultry, eggs, peanuts, legumes) [9]
• Alcohol cessation
• If on isoniazid: discuss with prescribing provider about niacin co-supplementation or alternative regimens [11]
• Continue niacin supplementation as directed; do not stop prematurely

1. Pellagra in Contemporary Clinical Practice (2000-2023): A Systematic Review. — Litaiem N, Sboui K, Zeglaoui F. International Journal of Dermatology. 2026.

2. An Outbreak of Pellagra in the Kasese Catchment Area, Dowa, Malawi. — Matapandeu G, Dunn SH, Pagels P. The American Journal of Tropical Medicine and Hygiene. 2017.

3. Pellagra and Alcohol Dependence Syndrome: Findings From a Tertiary Care Addiction Treatment Centre in India. — Narasimha VL, Ganesh S, Reddy S, et al. Alcohol and Alcoholism. 2019.

4. Pellagra, an Almost-Forgotten Differential Diagnosis of Chronic Diarrhea: More Prevalent Than We Think. — Cao S, Wang X, Cestodio K. Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition. 2020.

5. Pellagra a review exploring causes and mechanisms, including isoniazid‐induced pellagra. — Prabhu D, Dawe RS, Mponda K. Photodermatology, Photoimmunology & Photomedicine. 2021.

6. Pellagra in 2 Homeless Men. — Kertesz SG. Mayo Clinic Proceedings. 2001.

7. Pellagra Secondary to Medication and Alcoholism: A Case Report and Review of the Literature. — Li R, Yu K, Wang Q, et al. Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition. 2016.

8. Pellagra and Alcoholism: A Biochemical Perspective. — Badawy AA. Alcohol and Alcoholism. 2014.

9. Pellagra. — Pitche PT. Sante. 2005.

10. Inhibition in Vitro of the Enzymes of the Oxidative Pathway of Tryptophan Metabolism and of Nicotinamide Nucleotide Synthesis by Benserazide, Carbidopa and Isoniazid. — Bender DA. Biochemical Pharmacology. 1980.

11. Isoniazid-Associated Pellagra During Mass Scale-Up of Tuberculosis Preventive Therapy: A Case-Control Study. — Nabity SA, Mponda K, Gutreuter S, et al. The Lancet. Global Health. 2022.

12. A.S.P.E.N. Position Paper: Recommendations for Changes in Commercially Available Parenteral Multivitamin and Multi-Trace Element Products. — Vanek VW, Borum P, Buchman A, et al. Nutrition in Clinical Practice : Official Publication of the American Society for Parenteral and Enteral Nutrition. 2012.

13. Alcoholic Pellagra as a Cause of Altered Mental Status in the Emergency Department. — Luthe SK, Sato R. The Journal of Emergency Medicine. 2017.

14. Pellagra Encephalopathy Among Tuberculous Patients: Its Relation to Isoniazid Therapy. — Ishii N, Nishihara Y. Journal of Neurology, Neurosurgery, and Psychiatry. 1985.

15. Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. — Lai JC, Tandon P, Bernal W, et al. Hepatology. 2021.

16. Case Report: Pellagra Presentation With Dermatitis and Dysphagia. — Mengistu SB, Ali I, Alemu H, Melese EB. Frontiers in Medicine. 2024.

17. Pellagra. — DesGroseilliers JP, Shiffman NJ. Canadian Medical Association Journal. 1976.

18. Pellagra in Zanzibar: A Rare Diagnosis. — Hassan HS, Pandu SM, Said SS. International Journal of Dermatology. 2023.

19. The "Gauntlet" of Pellagra. — Isaac S. International Journal of Dermatology. 1998.

20. Pathophysiology and Clinical Management of Pellagra - A Review. — Hołubiec P, Leończyk M, Staszewski F, et al. Folia Medica Cracoviensia. 2021.

21. Protocol for a Case-Control Study to Investigate the Association of Pellagra With Isoniazid Exposure During Tuberculosis Preventive Treatment Scale-Up in Malawi. — Nabity SA, Mponda K, Gutreuter S, et al. Frontiers in Public Health. 2020.

22. Nutritional Heart Disease And Cardiomyopathies: JACC Focus Seminar 4/­4. — Sliwa K, Viljoen CA, Hasan B, Ntusi NAB. Journal of the American College of Cardiology. 2022.