INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Pellagra is a systemic disease of niacin deficiency. Don Gasper Casal, a Spanish court physician, first described pellagra among the poor peasants of the Asturias province of Spain in 1735. In Italian vernacular, pellagra means "rough skin" and refers to the thickened skin noted in patients with pellagra. Pellagra remained endemic among the maize-eating poor peasants of southern Europe for nearly 2 centuries before being recognized in the United States.

Pellagra was reported first in the United States in 1902. Soon, pellagra began to occur in epidemic proportions in the American South. Poverty and dietary consumption of corn were the most frequently observed risk factors. The exact cause of pellagra was not known. Dr. Joseph Goldberger of the US Public Health Service hypothesized that the clinical syndrome was the consequence of an inadequate diet and demonstrated that pellagra could be induced and prevented by dietary modification.

In 1937, Conrad A. Elvehjem, an agricultural chemist at the University of Wisconsin, discovered that nicotinic acid cured black tongue (a condition analogous to pellagra) in dogs. Human clinical trials soon followed and confirmed that nicotinic acid (niacin) represented the key preventive factor to pellagra. Diets based on unfortified maize (corn) are pellagragenic for 2 reasons: (1) These diets are low in tryptophan, the amino acid precursor of niacin and (2) Any endogenous niacin in them is bound and nonbioavailable. Following the discovery of niacin, food fortification with niacin became feasible. Improved socioeconomic conditions, change in dietary practices, and food fortification with niacin were all responsible for the eradication of pellagra from the post–World War II United States.

Despite subsisting on a staple diet of corn, populations of Mexico and Central America have remained essentially pellagra-free. Among these people, the tradition of presoaking maize in alkaline lime prior to cooking liberates bound niacin, enhancing the dietary content of niacin and ensuring protection against pellagra. In contrast, endemic pellagra has been noted among poor peasants of the Deccan Plateau of India who subsist on a staple diet of sorghum (millet). Although this grain contains adequate tryptophan (a precursor of niacin), excessive concentrations of leucine interfere with tryptophan metabolism and subsequent niacin synthesis.

Pathophysiology: Niacin is required for adequate cellular function and metabolism as an essential component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). These compounds are important coenzymes for glycolysis, protein and amino acid metabolism, pyruvate metabolism, pentose biosynthesis, generation of high-energy phosphate bonds, glycerol metabolism, and fatty acid metabolism.

Because cellular functions in multiple organs and tissues are impacted by niacin deficiency, the clinical expression of pellagra is diverse. Pathological changes in the skin include vascular dilatation, proliferation of endothelial lining, perivascular lymphocytic infiltration, and hyperkeratinization and subsequent atrophy of the epidermis. Mucosal inflammation and atrophy involves most of the GI tract. Evidence of glossitis and atrophy of the papillae of the tongue are characteristic findings, along with gastritis and subsequent gastric mucosal atrophy. Acute inflammation of the small intestine and colon also are commonly noted. Pathological changes in the nervous system can be found in the brain, spinal cord, and peripheral nerves. Findings include patchy demyelinization and degeneration of the various affected parts of the nervous system.

Frequency:

• In the US: Current incidence of pellagra in the United States is unknown. Epidemics of pellagra no longer occur. Sporadic cases of pellagra could occur among chronic alcoholics, food faddists, and patients with malabsorption states.

• Internationally: Although the exact incidence of pellagra in other countries is not known, chronic seasonal endemic cases of pellagra are observed among the sorghum-eating population of the Deccan Plateau in India.

Mortality/Morbidity: Untreated pellagra results in death from multiorgan failure. Morbidity of pellagra is related to its effects on the various organ systems involved.

• Dermatitis tends to be painful during the acute phase and eventually becomes disfiguring.

• Systemic effects of the disease include malaise, apathy, weakness, and lassitude.

• GI involvement leads to a malabsorptive state and subsequent failure to thrive.

• Neurological manifestations include anxiety, depression, delusions, hallucinations, and stupor.

Race: No racial predilection for the development of pellagra exists, other than its rate of occurrence in ethnic populations with diets deficient in niacin/tryptophan.

Sex: Logically, no sexual predilection for the development of pellagra exists. The only risk factor for development of pellagra should be dietary deprivation of niacin. Epidemiological data collected during the pellagra epidemic in the United States reflect that women, children, and elderly persons of both sexes were the most common individuals affected with pellagra; while infants, adolescents, and working young males were affected least frequently. Such disparity in prevalence resulted from an unbalanced distribution of food within households.

Age: Pellagra typically is an adult disease. Adolescents and young children could develop pellagra if exposed to a pellagragenic diet. Pellagra rarely occurs during infancy. Historically, the dermatitis of Kwashiorkor has been mistaken as infantile pellagra.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: Typically, classic pellagra is defined by the 3 Ds: dermatitis, diarrhea, and dementia. Pellagra can be induced experimentally in 6-8 weeks with exposure to a pellagragenic diet. In endemic cases, pellagra tends to be seasonal and occurs during spring and early summer. Early symptoms are nonspecific. Patients express weakness, lassitude, and anorexia. Soon, classic symptoms of dermatitis, mental state disturbances, and GI involvement follow.

• Skin

• Affected skin lesions initially are erythematous and are associated with itching and a burning sensation. The distribution of the cutaneous eruption is typically symmetrical and bilateral on areas prone to sunlight exposure.

• Blistering and vesiculation of affected skin may follow.

• As the dermatitis progresses, the affected skin becomes hyperpigmented and thickened.

• GI

• Patients with pellagra tend to suffer from poor appetite, nausea, epigastric discomfort, abdominal pain, and increased salivation.

• Glossitis typically causes soreness of the mouth and dysphagia.

• Diarrhea is the manifestation of GI inflammation. Diarrhea typically is watery but occasionally can be bloody and mucoid.

• Neuropsychiatric

• Early neuropsychiatric symptoms of pellagra include depression, anxiety, irritability, and poor concentration.

• As the disease advances, patients become disoriented, confused, and delirious. Eventually, the patient becomes stuporous and comatose, and then the patient dies.

Physical:

• Skin

• Typically, the skin lesions of pellagra are represented by a photosensitive dermatitis noted over parts of the body that have been exposed to the sun. They tend to be bilateral and symmetrical in distribution.

• Skin lesions initially resemble a typical sunburn and tend to be symmetrical. Lesions may blister, vesiculate, and denude.

• Eventually, the affected skin thickens and becomes hyperpigmented.

• Parts of the body usually involved include the dorsum of the hands, feet, forearms, and legs; the face presents with a butterfly distribution over the cheeks, forehead, tip of the nose, and front V of the neck. The neck lesion is referred to as the Casal necklace, named after Don Gasper Casal who first described pellagra. Facial seborrheic dermatitis also is observed in some patients. The scrotum, perineum, and pressure points also may be involved.

• GI tract

• Anorexia and malabsorptive diarrhea lead to a state of malnutrition.

• Often, the glossitis is severe and is associated with swelling and tenderness of the tongue. The tongue becomes beefy red and has a raw appearance secondary to atrophy of the papillae.

• Neurologic

• Muscle weakness leads to gait problems.

• Paraesthesia and a burning sensation are noted in some patients.

Causes:

• Dietary deficiency of niacin or its amino acid precursor tryptophan results in pellagra.

• Dietary amino acid imbalances also are associated with the development of pellagra. Excessive leucine noted in diets in which sorghum is a staple causes an amino acid imbalance, which interferes with tryptophan metabolism resulting in the development of pellagra.

• Risk factors for pellagra genesis include the following:

• Poverty

• Poor nutrition

• Chronic alcoholism

• Food faddism

• Malabsorptive states

• Isoniazid therapy: Pyridoxine deficiency secondary to isoniazid treatment could cause pellagra, because pyridoxine is required for the conversion of tryptophan to niacin.

• Other medications: 5-flurouracil, pyrazinamide, 6-mercaptopurine, hydantoins, ethionamide, phenobarbital, azathioprine, and cholramphenicol

• Hartnup disease: This is an inborn error of tryptophan metabolism and a cause of infantile pellagra.

• Cirrhosis of the liver

• Diabetes mellitus

• Prolonged febrile illness

• Prolonged diarrhea

• Anorexia nervosa

• Neglect and abuse, resulting in malnutrition

• Famine

• Human immunodeficiency virus (HIV) disease