Pellagra

Biochemistry & Pathophysiology

• NAD (nicotinamide adenine dinucleotide)
• NADP (nicotinamide adenine dinucleotide phosphate)

Harper's Illustrated Biochemistry, 32nd Ed.

Etiology & Risk Factors

Primary (Dietary)

• Diets predominantly based on corn (maize), millet, or sorghum — corn is low in both tryptophan and niacin, and much of its niacin is in bound form (niacytin), which is not bioavailable
• Pellagra can develop within 60 days of dietary niacin deficiency
• Historically endemic in the American South (early 1900s) and remains common in parts of Asia and Africa where corn is the dietary staple

Secondary (Disease/Malabsorption)

• Alcoholism — the most common cause in developed countries (impaired absorption and intake)
• Carcinoid tumors — divert tryptophan toward serotonin (5-HT) synthesis, accounting for up to 60% of tryptophan metabolism; depriving NAD synthesis
• Hartnup disease — autosomal recessive defect in the neutral amino acid transporter, causing intestinal malabsorption and renal wasting of tryptophan
• GI disorders: Crohn disease, celiac disease, gastroenterostomy, chronic colitis, jejunoileitis, prolonged diarrhea
• Prolonged IV nutritional support without adequate vitamins
• Anorexia nervosa and other restrictive eating disorders

Drug-Induced

Andrews' Diseases of the Skin; Bradley and Daroff's Neurology in Clinical Practice

Clinical Features

The "Three Ds"

1. Dermatitis

• Photosensitive eruption that worsens in spring/summer, distributed symmetrically on sun-exposed areas:
  • Face, neck ("Casal necklace" — a collar-like band across the lower neck and upper chest)
  • Dorsal hands and extensor forearms
  • Tops of feet
• Stages of skin change:
  1. Acute: Erythema, swelling, burning/itching after sun exposure — mimics sunburn but takes ~4× longer to recover
  2. Wet pellagra (severe): Vesicular or bullous eruption
  3. Chronic: Thickening, scaling, hyperpigmentation (copper/mahogany hue)
  4. Late: Dry, smooth, paper-thin, parchment-like skin; ultimately glassy in texture
• Nasal changes: Dull erythema of the bridge with fine yellow powdery scales ("sulfur flakes") over follicular orifices; dilated pores with inspissated sebum — resembles seborrheic dermatitis but by location

Pellagra showing Casal necklace and photodistributed scaly dermatitis (Andrews' Diseases of the Skin, courtesy Michelle Weir, MD)

2. Diarrhea (GI tract)

• Anorexia, abdominal pain, nausea
• Watery diarrhea — may be bloody
• Stomatitis, glossitis (bright red "beefy" tongue), cheilitis
• Fluid and electrolyte imbalance

3. Dementia / Neuropsychiatric

• Insomnia, fatigue, irritability, nervousness
• Mental dullness, apathy, mild memory impairment
• Depression — may resemble neurasthenia or a primary psychiatric disorder

• Acute confusional psychosis
• Hallucinations, delusions (including delusions of parasitosis)
• Paresthesias, muscle weakness, headaches, dizziness

• Spasticity, Babinski sign, gegenhalten (paratonia), startle myoclonus
• Seizures, stupor, coma
• Progressive dementia

Adams and Victor's Principles of Neurology; Bradley and Daroff's Neurology

Neuropathology

• Neuronal chromatolysis: Betz cells (large motor cortex neurons), basal ganglia cells, cranial motor nuclei, cerebellar dentate nuclei, and anterior horn cells become swollen and rounded with eccentric nuclei and loss of Nissl bodies — similar to a retrograde axonal injury pattern
• Spinal cord: Symmetrical degeneration of the dorsal columns (especially the columns of Goll/gracilis) and, to a lesser extent, the corticospinal tracts — closely resembles subacute combined degeneration (SCD) of vitamin B12 deficiency
• Peripheral nerves: Axonal degeneration resembling that of nutritional beriberi

Adams and Victor's Principles of Neurology; Bradley and Daroff's Neurology

Histopathology of Skin

• Pallor and vacuolar changes of keratinocytes in the upper stratum malpighii (just below the granular layer)
• Attenuation or loss of the granular layer
• In severe ("wet") pellagra: intraepidermal cleft formation (explaining vesiculation)
• Depletion of Langerhans cells in lesional skin — a distinctive and relatively specific finding

Andrews' Diseases of the Skin

Diagnosis

• Characteristic photodistributed dermatitis + GI + neuropsychiatric symptoms
• History of corn-based diet, alcoholism, relevant drugs, or malabsorptive disease
• Therapeutic response is diagnostic: skin lesions begin to resolve within 24 hours of niacin supplementation

• Measurement of urinary N-methylnicotinamide (a niacin metabolite) — reduced in deficiency, though not universally available
• Rule out other nutritional deficiencies (B12, thiamine) that may coexist

Treatment

• Skin response is often dramatic — improvement within 24 hours confirms the diagnosis
• Neurologic recovery may take longer and is not always complete in advanced cases
• Excess niacin (>500 mg/day of nicotinamide, or 1–6 g/day of nicotinic acid for hyperlipidemia) causes hepatotoxicity and flushing

Andrews' Diseases of the Skin; Bradley and Daroff's Neurology; Harrison's Principles of Internal Medicine 22E (2025)

Epidemiology

• Historical: Epidemic in the U.S. South in the early 20th century; largely eradicated after mandatory niacin enrichment of bread flour (~1940)
• Current burden: Remains a problem in sub-Saharan Africa, South Asia, and among displaced populations (refugees) on corn-dominant diets
• Sex: Twice as many women as men are affected in endemic areas — likely due to inhibition of tryptophan metabolism by estrogen metabolites
• Developed world: Confined almost entirely to alcoholics, institutionalized patients, and those on implicated drug regimens

Key Associations Summary