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:
1. History
- 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]
2. Alarm Features
- 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]
3. Medications
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]
4. Diet
- 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
5. Review of Systems
- 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]
6. Collateral History and Family History
- 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]
7. Risk Factors
- 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]
8. Differential Diagnosis
- 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
9. Past Medical History
- 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]
10. Physical Exam
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
11. Lab Studies
- 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
12. Imaging
- 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
13. Special Tests
- 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
14. ECG
- 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
15. Assessment
- 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]
16. Treatment Plan
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]
17. Disposition
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
18. Follow Up / Return Precautions
- 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
References
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.