Pellagra

 

Vitamin B3 and the skin

 

 

Introduction

 

Vitamin B3 (niacin) is a water‐soluble B‐complex vitamin and important component of two co‐enzymes, coenzyme I nicotinamide‐adenine dinucleotide (NAD) and coenzyme II NADP, which act as hydrogen donors and acceptors in numerous anabolic and catabolic reactions.

Half of the body's niacin is obtained from diet, while the other half is synthesized endogenously from the amino acid tryptophan. Dietary niacin exists primarily in the form of two coenzymes, coenzyme I [nicotinamide-adenine dinucleotide (NAD)] and coenzyme II [nicotinamide-adenine dinucleotide phosphate (NADP)] in meats, fish, nuts, eggs, dairy products, dried beans and fortified grains. NAD and NADP are hydrolyzed to nicotinamide in the intestinal lumen. Intestinal bacteria then convert nicotinamide into nicotinic acid. Both nicotinamide and nicotinic acid are absorbed and transported to the liver, kidneys and intestines, where they are converted back to NAD and NADP. These two agents act as hydrogen donors and acceptors in oxidation-reduction reactions involved in the synthesis and metabolism of carbohydrates, proteins and fatty acids.  Cellular deficiency of niacin results in pellagra, classically characterized by the four Ds: (1) dermatitis; (2) diarrhea; (3) dementia; and (4) death. Hartnup disease, a rare metabolic disorder, can be associated with niacin deficiency and a pellagra‐like presentation.

 

Epidemiology

 

Incidence and prevalence

 

Pellagra remains endemic in parts of the world, including South Africa, China, and India, where corn and maize continue to be a dietary mainstay. Corn and maize contain bound niacin, thus preventing intestinal absorption unless the niacin is released by alkaline hydrolysis (i.e. limewater washes). Jowar, a type of millet found in parts of India, contains adequate levels of niacin, but large quantities of leucine which inhibits conversion of tryptophan to niacin.

Age

 

Niacin deficiency can manifest at any age.

 

Predisposing factors

 

The symptom complex, which can develop under a diet low in niacin, is called pellagra (rough skin). Decreased dietary intake, defective absorption of niacin or tryptophan, and impaired conversion of tryptophan to niacin predispose individuals to the development of niacin deficiency.

Because niacin is absorbed from the gastrointestinal tract, gastrointestinal disorders can predispose to pellagra. Impaired absorption of tryptophan and niacin occurs in patients with jejunoileitis, gastroenterostomy, prolonged diarrhea, chronic colitis, ulcerative colitis, cirrhosis, Crohn disease, and subtotal gastrectomy.

Patients with Hartnup disease, a rare autosomal recessive disorder, develop pellagra-like symptoms in childhood. This is caused by a defect in the neutral brush border system, resulting in malabsorption of amino acids, including tryptophan.

Alcoholics develop pellagra from a combination of poor diet and malabsorption.

Patients with increased metabolic needs as seen in carcinoid syndrome can develop pellagra. Normally, about 1% of tryptophan is metabolized to serotonin, but in carcinoid syndrome, an excessive amount, about 60%, of tryptophan is converted to serotonin. Because of this diversion of tryptophan to serotonin production, less tryptophan is available to make niacin.

Medications can also induce pellagra symptoms. Isoniazid is a competitive inhibitor of NAD because of their similar structures, and also impairs pyridoxine functioning, which is essential for niacin synthesis from tryptophan. 5-fluorouracil inhibits conversion of tryptophan to niacin, and 6-mercaptopurine inhibits NAD phosphorylase, which inhibits NAD production. Other implicated medications include phenytoin, chloramphenicol, azathioprine, sulfonamides, and antidepressants.

Because of large tissue stores, symptoms develop after months of niacin or tryptophan deficiency.

In all these cases, there is usually an abortive pellagra, which is called a pellagroid and usually takes place without significant internal or neurological symptoms.

 

Clinical features

 

History

 

Dermatitis, diarrhea and dementia represent the classic manifestations of pellagra. Gastrointestinal symptoms may represent the earliest signs of pellagra and include diarrhea, nausea, vomiting, abdominal pain, and anorexia. Neurologic symptoms, such as insomnia, fatigue, nervousness, apathy, impaired memory, and depression, can progress to psychosis and dementia in later stages. Without treatment, pellagra leads to death.

 

Presentation

 

Pellagra is classically described with the four Ds of (1) dermatitis, (2) diarrhea, (3) dementia, and (4) death. Skin changes are determined by exposure to sunlight and pressure. The characteristic dermatitis begins as painful or pruritic erythematous patches in photo distributed areas after sun exposure.  The skin becomes progressively more edematous, and several days later may develop vesicles and bullae, which can rupture, leaving crusted erosions and lesions become scaly.  Over time, the skin thickens into sharply demarcated, hyperkeratotic, hyper pigmented plaques covered by dark scales and crusts; surface has shellac like appearance. Painful fissures can develop in the palms and soles, resembling goose skin. The dorsum of the hands is the most commonly affected sites, and when the rash extends proximally, more on the radial than ulnar side, it forms the “gauntlet” of pellagra. It also affects dorsa of feet up to malleoli with sparing of the heel. A symmetrical butterfly distribution may be apparent on the face when it extends from the nose to the cheeks, chins, and lips. When the dermatitis affects the upper central portion of the chest and neck, forming a well-demarcated band around the neck, it is referred to as “Casal's necklace”. It can sometimes extend down over the sternum to create a “cravat.” Mucous membrane involvement may manifest as cheilitis, angular stomatitis, glossitis (atrophic red tongue), and vaginitis with ulceration. Half and half nails may also be present.

 

 

Disease course and prognosis

 

Pellagra is progressive and can be fatal if not treated. Death can occur within 4–5 years from multiorgan failure.

 

Investigations

 

Diagnosis is primarily made on clinical grounds and through a rapid response to vitamin supplementation. Reduced niacin urinary metabolites, such as N‐methylnicotinamide (NMN) and 2‐pyridone, can be helpful in confirming diagnosis.

 

Treatment

 

Nicotinamide 300 mg/day in divided doses for 3-4 weeks is the treatment of choice. For gastrointestinal and neurological symptoms, additional treatment with other vitamins of the B complex and a protein-rich diet (about 100–150 g protein/day) should be taken.

Neuropsychiatric symptoms improve within the first 24–48 h of treatment, while skin lesions often take 3- 4 weeks to clear.