Azathioprine‐induced pellagra in a child with autoimmune hepatitis: A case report and literature review

Abstract Pellagra is a clinical syndrome resulting from niacin deficiency with variety of manifestations. Azathioprine is among drugs that can lead to such condition. Physicians should be aware as proper management can lead to full resolution.


| CASE PRESENTATION
Pellagra, a potentially fatal but easily treated disorder, is characterized by symmetrical photo-distributed skin lesions due to niacin deficiency. There are many known etiologies for pellagra including drug-induced cases. We, hereby, present a new case of azathioprine-induced pellagra and briefly review reported cases of azathioprineinduced pellagra in the literature. A 14-year-old girl was admitted with a 3-day history of abdominal pain and diarrhea. She had a recent diagnosis of autoimmune hepatitis 8 months ago and azathioprine (AZA) was initiated 4 weeks before. She was underweight (body mass index of 17.7 kg/m 2 ). Further history revealed poor nutritional intake due to decreased appetite, but she denied any specific dietary restrictions. The patient also complained of a 1-day history of new onset painful skin lesions. She had no personal or family history of skin diseases. Well-demarcated violaceous to brown skin lesions with scaly desquamation and hyperpigmentation were present on the neck, dorsum of the hands, and feet. The patient reported that the rash developed shortly after having sun exposure in the preceding days (Figures 1 and 2).
Based on the photo distribution of dermatitis and associated scaling and hyperpigmentation in the pattern of casal's necklace in association with the recent initiation of AZA, a clinical diagnosis of AZA-induced pellagra was made. Our patient's total Naranjo Scale score was 6 (possible adverse drug reaction).
Histopathological examination showed confluent parakeratosis, mild acanthosis, and regular elongation of rete ridges. There was focal subepidermal blistering with dermal capillary proliferation and a mild perivascular infiltrate ( Figure 3).
Discontinuation of azathioprine and administration of oral nicotinamide 50 mg twice daily resulted in significant improvement of the rash within 2 days. The dosage of nicotinamide was gradually increased over the following 4 weeks. After 2 months of treatment, only mild postinflammatory hyperpigmentation remained.

Azathioprine-induced pellagra in a child with autoimmune hepatitis: A case report and literature review 2 | DISCUSSION
Pellagra is a clinical syndrome resulting from niacin deficiency. It is an underdiagnosed but still existing disease. Pellagra is clinically characterized by the classic triad of 3 D's: (1) dermatitis (photo-distributed symmetrical skin lesions), (2) diarrhea, and (3) dementia (neurologic and psychotic disturbances) which can ultimately lead to death if left undiagnosed or untreated. 1 Histological features of pellagra are perivascular lymphocytic infiltrate in the upper dermis and edema in the papillary dermis which can be observed in the acute stages. Hyperkeratosis, parakeratosis, and epidermal atrophy are mostly seen in late stages. Although these features are unspecific, they can support the clinical diagnosis. 2 The main cause of pellagra is niacin or tryptophan (niacin precursor) deficiency. Pellagra has been reported to be associated with some medications including isoniazid, 6-mercaptopurine (6-MP), 5-fluorouracil, and also azathioprine (AZA). 1 AZA is metabolized to 6-MP. 6-MP decreases the synthesis of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, which are key coenzymes in niacin metabolism and other metabolic pathways. Consequently, lack of these coenzymes will result in major dysfunction in tissues with high energy demands such as brain, gut, and skin. [3][4][5] Thus, it is likely that AZA can lead to secondary niacin deficiency and development of pellagra.
In our patient, underlying poor nutrition as a result of her chronic disease may have caused a relative niacin deficiency that was exacerbated by addition of azathioprine, culminating in the clinical presentation.
To the best of our knowledge, there are only four cases of AZA-induced pellagra reported in the literature. All the reported cases were female patients, and only one case was in pediatrics. Duration of AZA use varied widely among patients from days to years. They all had the typical skin  manifestations of pellagra, some experienced diarrhea, and none had neurologic disturbance. AZA was discontinued in all the patients except one, and they were all initiated on nicotinamide with different dosages from 150 to 500 mg/day. Significant improvement in skin lesions was seen in all the cases. 2,3,5 Clinicians should consider AZA-induced pellagra in any patient who develops a photo-distributed dermatosis while undergoing treatment with AZA.