The Core Deficiency: A Lack of Niacin and Tryptophan
At its most fundamental level, what causes pellagra is a shortage of niacin, also known as vitamin B3, and the amino acid tryptophan, which the body can convert into niacin. Niacin is a water-soluble vitamin essential for converting food into energy, supporting the central nervous system, and maintaining healthy skin and a properly functioning digestive system. When the body's supply of niacin and tryptophan becomes critically low, it cannot produce enough of the vital coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). This shortfall affects tissues with high energy turnover rates—such as the skin, gastrointestinal tract lining, and brain—triggering the classic symptoms of the disease.
Primary Pellagra: The Nutritional Causes
Primary pellagra is the result of insufficient dietary intake of niacin and tryptophan. This is historically and currently a major problem in parts of the world where specific food choices dominate the diet, often due to poverty or limited access to food.
- Reliance on Untreated Corn: Maize (corn) is a poor source of bioavailable niacin, meaning the niacin it contains is in a 'bound' form that is not easily absorbed by the body. Historically, populations in Central and South America avoided pellagra by practicing 'nixtamalization,' soaking corn in an alkaline solution (limewater) to release the niacin. This process was not adopted everywhere, leading to pellagra outbreaks in other areas, such as the American South in the early 20th century.
- Tryptophan Deficiency: Corn protein is also deficient in tryptophan, further reducing the body's ability to produce its own niacin. Tryptophan-rich foods like meat, milk, and eggs can compensate for low dietary niacin, but these are often scarce in the diets of impoverished populations.
- Amino Acid Imbalances: In some cases, like among those who eat a diet high in sorghum, excessive levels of other amino acids like leucine can interfere with the conversion of tryptophan to niacin, contributing to the deficiency.
Secondary Pellagra: The Malabsorption Causes
Even with an adequate diet, some individuals can develop pellagra due to secondary causes that interfere with niacin absorption or metabolism. This is the most common cause in developed countries.
- Chronic Alcoholism: Heavy alcohol use is a significant cause of secondary pellagra. It can lead to general malnutrition and malabsorption issues, inhibiting the body's ability to process and utilize nutrients, including niacin and tryptophan.
- Gastrointestinal Diseases: Conditions that cause malabsorption, such as inflammatory bowel disease (Crohn's disease) or cirrhosis of the liver, can prevent the body from absorbing niacin from food.
- Genetic Disorders: Rare genetic conditions like Hartnup disease impair the body's absorption of amino acids, including tryptophan, leading to niacin deficiency.
- Carcinoid Syndrome: This rare disorder is caused by neuroendocrine tumors that divert tryptophan from niacin synthesis to produce excess serotonin. This metabolic steal depletes the body's tryptophan reserves, causing pellagra-like symptoms.
- Certain Medications: Some drugs can interfere with niacin metabolism. The anti-tuberculosis medication isoniazid is a notable example, as it reduces available vitamin B6, a necessary cofactor for tryptophan conversion. Certain chemotherapy drugs have also been linked to niacin deficiency.
- Bariatric Surgery: Gastric bypass surgery can alter the digestive tract and its ability to absorb essential nutrients, including niacin.
The Pathophysiology: What Happens Inside the Body
Niacin is a precursor for NAD and NADP, which are critical coenzymes involved in over 400 enzymatic reactions in the body. These coenzymes are integral to cellular respiration, helping convert food into usable energy (ATP). When niacin levels are low, tissues with high cellular turnover, like the skin, gut, and brain, are the first to be affected, leading to the hallmark signs of the disease. The distinctive skin rash, for instance, results from a depletion of energy resources in skin cells, making them more sensitive to sunlight (photosensitive). The inflammation of the gastrointestinal tract and the neurological symptoms of dementia stem from similar cellular energy deficiencies.
Distinguishing Between Primary and Secondary Pellagra
| Feature | Primary Pellagra | Secondary Pellagra |
|---|---|---|
| Underlying Cause | Inadequate dietary intake of niacin and tryptophan | Impaired absorption or metabolism of niacin and tryptophan |
| Root of Deficiency | Lack of niacin-rich food or a diet high in untreated corn | Pre-existing medical conditions, drugs, or chronic alcoholism |
| Prevalence | More common in impoverished or food-limited regions where nutrition is unbalanced | More common in developed countries where underlying health issues are the primary trigger |
| Treatment Focus | Niacin supplementation and dietary changes to increase intake | Niacin supplementation combined with treating the underlying medical condition |
| Prevention | Food fortification programs and nutritional education | Management of chronic illnesses and lifestyle factors like alcohol use |
Conclusion: Diagnosis, Treatment, and Prevention
Understanding what causes pellagra is the first step toward effective treatment and prevention. Whether the result of a restricted diet (primary) or an underlying medical condition (secondary), the root problem is a severe deficiency of niacin. Diagnosis is typically based on the characteristic symptoms—the 'four Ds' of dermatitis, diarrhea, dementia, and eventually, death—combined with a thorough dietary and medical history. The treatment involves aggressive niacin supplementation, often with nicotinamide, which typically leads to rapid improvement. For secondary pellagra, treating the underlying medical cause is essential for a full recovery. Prevention focuses on ensuring adequate niacin intake through a balanced diet, food fortification programs in at-risk areas, and managing any health issues that affect nutrient absorption.
For more information on the pathophysiology of pellagra and related dermatological manifestations, see the detailed review on the subject on the Wiley Online Library.
