|MAIN SOURCES, CAUSES, AND SKIN FINDINGS OF PELLAGRA|
Pellagra is caused by inadequate dietary intake of niacin (nicotinic acid, vitamin B3) or its precursor amino acid, tryptophan. It has also been discovered to occur on occasion in patients with carcinoid syndrome. In this syndrome, tryptophan is used entirely to produce serotonin, and there is none left to produce niacin. Pellagra was first identified as a unique disease in the early 1700s by a Spanish physician, Gaspar Casal, who observed it in Spanish peasants who ate diets almost entirely made of corn and corn-based foodstuffs. He named the disease “Asturian leprosy” after the region of Spain he was studying. An Italian physician, Francesco Frapoli, who studied the disease in endemic regions of northern Italy, later named it pellagra.
Pellagra has been dominant in regions of the world that rely heavily on corn as the main dietary staple. In the early twentieth century, the southern United States was inundated with cases of pellagra. Joseph Gold-berger, a physician and epidemiologist studying the disease, discovered that pellagra was caused directly by a deficiency of vitamin B. He was unable at that time to isolate the specific B vitamin, but he has been given credit for discovering the cause of pellagra.
Clinical Findings: Pellagra can affect any individual regardless of race or gender. The incidence in the North America and Europe is low, and cases are mainly caused by abnormal diets and alcoholism. The disease can still be seen in endemic regions of the world where corn is the main food source. The clinical cutaneous hallmark of pellagra is a severe dermatitis. The dermatitis is photosensitive, and exposure to the sun often brings out the rash or exacerbates it. Patients often present initially after having spent many hours outdoors on an early spring day. The dermatitis is symmetric and is manifested by eczematous patches and thin plaques that tend to be tender to the touch. There is a fine line of demarcation between abnormal and normal skin. The head, neck, and arms are the most involved regions because of their higher level of sun exposure. The dermatitis along the anterior neck and upper thorax has been termed Casal necklace. This is represented by weeping pink and red patches and plaques in a distribution like that of a necklace touching the skin circumferentially around the neck. Because of its photosensitive nature, the dermatitis of pellagra often spares the skin directly behind the ears and beneath the chin. The nose, forehead, and cheeks are prime regions of involvement. Non–sun-exposed areas can also be involved, and the intertriginous regions are almost universally affected, including the perineum, axillae, and inframammary skin folds. The reason for the propensity to affect these non–sun-exposed regions is poorly understood but may be related to chronic friction that induces the dermatitis. In the areas of involvement, small vesiculations may occur because of separation of the epidermis from the dermis.
As time progresses, the dermatitis begins to desquamate. This process begins in the central portions of the dermatitis and spreads outward in a centrifugal manner. As the skin desquamates, it leaves behind red, eroded patches and plaques. Chronic involvement leaves permanent scarring and abnormal hyperpigmentation or hypopigmentation of the area. The epidermis over bony prominences (e.g., ulnar head) shows marked hyperkeratosis.
Mucous membrane involvement is common in all vitamin deficiency states, and pellagra is no exception. Angular cheilitis and a red, shiny, edematous tongue with atrophied papillae are seen routinely in patients with pellagra. The oral and gastrointestinal mucous membranes may be involved. Oral ulcerations are frequently seen. Patients routinely complain of a sore mouth and difficulty swallowing; these symptoms can lead to further lack of proper nutrition, exacerbating and compounding the disease.
Diarrhea is commonplace and is caused by the effect of niacin deficiency on the gastrointestinal tract. The diarrhea is watery and further complicates the patient’s nutritional status and electrolyte and fluid balances. Blood and purulence may be present in the watery diarrhea as a result of ulceration and abscess formation. Ulcerations can be seen throughout the gastrointestinal tract, as can cystic dilation of the mucous glands. The colon may show small submucosal abscesses.
Subtle neurological findings precede full-blown encephalopathy in pellagra. These clinical findings include poor concentration, headaches, and apathy. Dementia eventually sets in as the disease causes a diffuse encephalopathy. The encephalopathy may mimic psychiatric disease, especially depression with suicidal tendency. Other well-defined symptoms include confusion, hallucination, delirium, insomnia, tremor, seizures, and extrapyramidal rigidity. The entire central nervous system is involved in severe pellagra. Cortical nerve cells show degeneration. The Betz cells show chromatolytic changes with displacement of the nucleus toward the cell wall. There is an increased amount of adipose in the nerve cells as well as an increase in the lipofuscin pigment within the cytoplasm of these cortical cells. The posterior columns may undergo demyelination, leading to tremor, gait disturbance, and movement difficulties. Chromatolysis has been shown to occur in the pontine nuclei, spinal cord nuclei, and multiple cranial nerve nuclei. As the encephalopathy progresses, disorientation and delirium take over, and the patient eventually slips into a coma. Death may shortly ensue unless the disease is diagnosed and treated appropriately. These unique clinical findings seen in pellagra can be simplified in the oft-quoted mnemonic, “4 D’s”: dermatitis, diarrhea, dementia, and death.
The diagnosis is typically made on clinical grounds, and laboratory analysis is used for confirmation. One should always consider other vitamin deficiencies when evaluating a patient with pellagra. The 24-hour urine secretion of N-methyl nicotinamide is normally in the range of 5 to 15 mg/day; in patients with pellagra, it is less than 1.5 mg/day. Measurement of this metabolite serves as an easy, noninvasive test to confirm the deficiency of niacin. Serum niacin levels can be measured directly, although they are not as accurate as the urinary excretion levels.
Histology: The skin biopsy findings are nonspecific and show epidermal pallor with a mixed inflammatory infiltrate that is predominantly composed of lymphocytes in a perivascular location. Occasional areas of inflammatory vesiculation within the epidermis may be seen.
Pathogenesis: Niacin is an essential vitamin that is found in many food sources, including whole grain breads and meats. Patients whose diet is deficient in niacin are seen in regions of the world where corn is the main food source. Various levels of niacin deficiency occur. This disease can also be seen in alcoholics who do not maintain a balanced diet and receive almost all their caloric intake from alcoholic products. Patients who develop pellagra also have a diet deficient in tryptophan. Major sources of tryptophan include eggs and milk. Tryptophan is a precursor of niacin and can be converted to niacin. Niacin is required for the proper production of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), important coenzymes for many biochemical reactions. Both molecules are capable of acquiring two electrons and acting as reducing agents in various reduction-oxidation (redox) reactions. When a deficiency of niacin occurs, many biochemical reactions throughout the human body cannot be properly performed, and the clinical manifestations occur.
Carcinoid syndrome is a rare cause of pellagra. Carcinoid is a syndrome of excessive secretion of serotonin.
Tryptophan is the precursor for serotonin as well as niacin, and in this syndrome all tryptophan is shunted to make serotonin at the expense of tryptophan. This results in decreased production of niacin and, potentially, the clinical symptoms of pellagra.
|MUCOSAL AND CENTRAL NERVOUS SYSTEM MANIFESTATIONS OF PELLAGRA|
Treatment: Pellagra rapidly responds to supplementation with niacin. Niacin is given orally every 6 hours until the patient responds. If a patient does not respond, a coexisting vitamin deficiency should be sought. If possible, a nutritionist should be consulted to advise the patient on proper dietary intake. Alcoholics, who can be deficient in many B vitamins, are often treated with multiple B vitamins. Patients with carcinoid syndrome need to take supplemental niacin to avoid pellagra symptoms, but the goal of therapy is to treat the underlying tumor.