Pellagra associated with esophageal carcinoma and alcoholism1. Department of Dermatology and Venereology, Hospital S João, EPE, Porto, Portugal. firstname.lastname@example.org
Ana Nogueira MD1, Ana F Duarte MD1,2, Sofia Magina MD1,2, Filomena Azevedo MD1
Dermatology Online Journal 15 (5): 8
2. Faculty of Medicine, Oporto University
Pellagra is a nutritional disease caused by the deficiency of niacin. It presents with a photodistributed rash, gastrointestinal symptoms, and neuropsychiatric disturbances. In the Western world, this disease is mostly confined to alcoholics or the impoverished. However, this condition must be recognized in other clinical settings because it is easily treated and can be fatal if not identified. We describe a case of pellagra caused by esophageal carcinoma and alcoholism; we also review the literature.
Pellagra is a nutritional disease, caused by the deficiency of niacin, that has a characteristic presentation: a photodistributed rash, gastrointestinal symptoms, and neuropsychiatric disturbances . It was first described in 1762 by Gaspar Casal as "mal de la rosa," and was later renamed as pellagra in Italy, from "pelle agra," meaning rough skin [1, 2]. The etiology of pellagra was a matter of much debate, prejudice, and misconception until 1926, when the investigation of Goldberger ultimately clarified the central role of niacin in the prevention of this disease. This clinical findings were the basis for another designation for this vitamin cofactor - vitamin PP (from pellagra preventing factor) .
Pellagra is generally observed in eras of extreme poverty and is rather uncommon in the West today; most cases occur in chronic alcoholics. However, there seems to be a reemergence of pellagra that may be observed in patients with anorexia or HIV disease [4, 5]. Because this is an easily treatable condition that can be fatal if not recognized, it should be considered in patients who may have diseases associated with nutritional deficiency.
We report a patient with pellagra associated with esophageal carcinoma and alcoholism.
|Figure 1||Figure 2|
|Figure 1. Scaly butterfly rash on the face and Casal necklace
Figure 2. The gauntlet of pellagra
|Figure 3. Wet pellagra: erythema and bullae on the dorsum of the feet|
A 63-year-old man was sent for dermatological evaluation because of a three-month history of an evolving erythematous, scaly and bullous skin rash involving the face, neck, hands, and feet. Although he was a cooperative patient, he had periods of disorientation and emotional lability. Skin examination revealed a symmetric scaly erythematous eruption on the face and neck as well as the presence of cheilitis (Fig. 1). The dorsum of the hands exhibited bullae on an erythematous-brawny peeling base (Fig. 2). The dorsa of the feet were also erythematous and had large bullae (Fig. 3). In every affected location, a sharp demarcation between involved and healthy skin was evident. The patient lived alone and had scarce familial support. He admitted having a high alcohol intake, smoked 40 cigarettes a day, and wasn't aware of any major health problems except for two surgeries for "gastric ulcers" in the past. He wasn't taking any medication. When asked for associated symptoms, he reported repeated vomiting in the last three months, but denied diarrhea.
|Figure 4. Subepidermal bulla secondary to keratinocyte necrosis (H&E, x100)|
Laboratory studies revealed normocytic normochromic anemia with hemoglobin 10.8 g/dL (normal: 13-18), increased sedimentation rate (89 mm 1st hour, normal: <20) hypoalbuminemia (27.6 g/L, normal: 38 - 51), and normal hepatic and renal function. Immunologic study and HIV virus serology were negative. A cutaneous biopsy showed epidermal detachment with necrotic keratinocytes (Fig. 4).
He was admitted with the clinical diagnosis of pellagra and was started on multivitamin supplementation that included 200 mg of niacin daily. Meanwhile, his emesis was noticed to be immediately post-prandial. An endoscopic evaluation revealed a squamous cell carcinoma of the esophagus that was practically occluding the lumen. As the neoplasm was locally advanced and not amenable to surgery, a luminal prosthesis was placed for feeding; the skin lesions resolved within a few days.
Although the skin is inevitably the key to the diagnosis of pellagra, usually the first symptoms are gastrointestinal, with anorexia, abdominal pain, vomiting, and later watery diarrhea, accompanied by lassitude and irritability [6, 7]. The skin eruption is characteristically a photosensitive rash affecting the dorsal surfaces of the hands, face, neck, arms, and feet. In the acute phase it resembles sunburn with erythema and bullae (wet pellagra), but progresses to a chronic, symmetric, scaly rash that exacerbates following re-exposure to sunlight. The typical locations are neck (Casal necklace) and hands and forearms (pellagra gauntlet). As the disease advances, neuropsychiatric symptoms supervene and include photophobia, asthenia, depression, and memory loss that can evolve to frank psychosis and even death if the disease is not identified and treated .
A thorough review of niacin metabolism is necessary to understand the pathophysiology of pellagra. Niacin can be obtained directly from the food or synthesized from tryptophan; this synthesis requires vitamins B2 and B6 as cofactors. Dietary niacin is mainly in the form of nicotinamide adenine nucleotide (NAD) and NADPH. These molecules undergo hydrolysis in the intestinal lumen to form nicotinamide, which can be converted to nicotinic acid by intestinal bacteria or absorbed directly into the bloodstream. Nicotinamide and nicotinic acid are then reincorporated as a component of coenzymes NAD and NADP, which in turn intervene in essential oxidation-reduction reactions. The ubiquitous presence of these coenzymes explains the multiorgan afflictions associated with pellagra. Tissues with high energy requirements such as the brain or high turnover rates such as gut or skin are primarily affected [1, 8]. The exquisite photosensivity seen in pellagra may result from a deficiency of urocainic acid and/or cutaneous accumulation of kynirenic acid that may induce a phototoxic reaction [1, 6]. High niacin contents are found in meat, poultry, fish, dry beans, mushrooms, nuts, dairy products, and eggs . The recommended daily allowance is 5-20 mg a day, depending upon age and sex. However, in wealthy countries such as the United Kingdom, the average daily intake is ~45 mg [6, 8]. There is some debate whether this excess could contribute to Parkinson disease, diabetes, or cancer .
Pellagra is caused not only by a poor diet but also can also be secondary to conditions that interfere with niacin intake, absorption, or processing, such as Crohn disease, severe ulcerative colitis, prolonged diarrhea, gastrectomy, hepatic cirrhosis, chronic alcoholism, or anorexia nervosa. Metabolic derangements, such as Hartnup disease or carcinoid syndrome may also lead to pellagra. Pellagra has been increasingly reported in HIV patients [1, 5, 6, 7, 9]. Drugs that interfere with niacin or tryptophan metabolism, such as isoniazid, pyrazinamide, 6-mercaptopurine, 5-flurouracil, phenytoin, azathioprine, chloramphenicol, and ethionamide can also cause pellagra-like symptoms [6, 10, 11]. Lastly, a diet rich in leucine can also lead to pellagra because this aminoacid interferes with the enzymatic conversion of tryptophan to niacin .
The diagnosis of pellagra is based on the characteristic clinical presentation and rapid response to oral niacin supplementation. Biopsy findings can support the diagnosis but are not specific. Histologically, the acute stage may show a variety of changes including infiltration of the epidermis with neutrophils, intracellular edema, and intra- or subepidermal vesicle formation secondary to spongiosis or vacuolar degeneration of the basal layer. Older lesions may present with hyperkeratosis, parakeratosis, and variable acantosis, with increased basal layer melanin [1, 6, 10]. Low serum niacin, tryptophan, and nicotinamide adenine dinucleotide levels, or a reduced urinary excretion of their metabolites, N-methylnicotinamide and pyridone, also assist in the diagnosis, although they may not correlate directly with body stores [1, 6, 8, 10]. Niacin level testing is not readily available.
The differential diagnosis includes phototoxic and photoallergic skin reactions, porphyrias and pseudoporphyria, lupus erythematosus, and polymorphous light eruption. Also, primary pellagra should be differentiated from secondary pellagra [1, 6, 10].
This patient had a classic cutaneous presentation of pellagra with the Casal necklace and gauntlet distribution of exudative lesions and bullae on the hands and feet. He had significant risk factors for this disease because he was an alcoholic and presumably had a deficient diet. The challenging issue here is that the emesis could have been considered merely a pellagra symptom and not a cause of the disease. Once the patient was evaluated in the inpatient setting, the presence of emesis was observed to occur immediately after eating, suggesting esophageal obstruction. Curiously, alcoholism is also a risk factor for esophageal squamous cell carcinoma and may have been a factor .
The treatment of pellagra is with oral nicotinamide supplementation, 100-300 mg/daily in 3 to 4 separate doses, until resolution of the major acute symptoms. The dosage can then be reduced to 50 mg every 8-12 hours until the skin lesions heal. Severe cases or those patients with poor absorption may require 100 mg of parenteral niacin administered 3 to 4 times a day. It is also recommended to include other B vitamins, zinc, and magnesium as well as a diet rich in calories and protein to address malnutrition. Usually neuropsychiatric symptoms subside first, after a few days. Resolution of dermatitis occurs in 3 to 4 weeks [1, 6]. In our case, the esophageal prosthesis was essential for successful oral vitamin supplementation and the resolution of pellagra.
This case calls attention to pellagra when considering the differential diagnosis of photodermatoses. We also emphasize the acute bullous presentation (wet pellagra) on the hands and feet; chronic scaly eruptions are most often reported.
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