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Journal of Tropical Pediatrics, 2015, 61, 301–303

doi: 10.1093/tropej/fmv021
Advance Access Publication Date: 30 March 2015
Case Report

CASE REPORT

Ethionamide-induced Pellagra

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by Yashashree Gupta1 and Ira Shah1,2
1
Pediatric TB Clinic, B J Wadia Hospital for Children, Mumbai 400012, India
2
Consultant in Pediatric Infectious Diseases and Pediatric Hepatology, Nanavati Hospital, Mumbai 400056, India
Correspondence: Ira Shah, 1/B Saguna, 271/B St Francis Road, Vile Parle (W), Mumbai 400056. E-mail <irashah@pediatriconcall.com>

ABSTRACT
Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death,
resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antitu-
berculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and
treatment with nicotinamide can prevent life-threatening complications. To date, only three cases
have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that
resolved after the administration of niacin.

K E Y W O R D S : Ethionamide, niacin, pellagra

INTRODUCTION consisting of isoniazid (5 mg/kg/day), rifampicin


Pellagra is a nutritional deficiency disorder caused by (10 mg/kg/day), pyrazinamide (30 mg/kg/day) and
niacin or tryptophan deficiency [1]. Drug-induced ethambutol (20 mg/kg/day) but had no response
pellagra is seen with the antituberculosis drug isonia- to treatment. On presentation, her weight was
zid [2]. Ethionamide, which is a second-line antitu- 32.6 kg (<3rd centile, z-score 0.76) and there was
berculosis drug, is rarely known to cause pellagra decreased air entry in the right side. Other systems
[2]. We present a child who had multidrug-resistant were normal. She was suspected to have drug-
tuberculosis (TB) and developed ethionamide- resistant (DR) TB, and sputum was sent for TB cul-
induced dermatitis that resolved with niacin therapy. ture. In August 2012, her TB culture grew
Mycobacterium tuberculosis that was resistant to HR,
and treatment was changed to amikacin, ofloxacin,
CASE PAS, cycloserine and ethionamide (15 mg/kg/day)
A 13-year-old girl was referred to us in July 2012 be- and pyrazinamide and ethambutol were continued
cause of nonresponse to antituberculosis therapy together with multivitamins. In October 2012, her
(ATT). In June 2012, she presented to her doctor thyroid-stimulating hormone level increased to
with cough and evening rise of temperature for a 6.34 mIU/ml but free T3 (2.31 pg/ml) and free T4
month. Her chest radiograph showed a right upper (0.976 ng/l) were normal. She was started on thyrox-
zone cavity, sputum was positive for acid fast bacilli ine (50 mg daily). In March 2013, multivitamins, ami-
3þ and Mantoux test was positive 14 mm. HIV Elisa kacin and ethambutol were omitted but pyridoxine
was nonreactive. She was put on four drugs (ATT) was continued. In October 2013 (after 14 months of

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V

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302  Ethionamide-induced Pellagra

medical report of pellagra is credited to Gaspar Casal


in Spain in 1735. He described an exposed-site
dermatitis on the dorsum of the hands and feet with
a collar-like rash on the upper part of the neck in
Asturian peasants [3]. Pellagra is a clinical syndrome
characterized by symmetric photosensitive skin erup-
tions, gastrointestinal manifestations and neurologic
and psychiatric disturbances. This well-known group

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of symptoms is traditionally remembered as pellagra’s
four D’s: dermatitis, diarrhea, dementia and when un-
treated, rarely, death. All manifestations of pellagra
may not be present and skin manifestations may vary
[4]. Pellagra is caused by deficiency of niacin or its
Fig. 1. Dermatitis of pellagra. precursor tryptophan. It is thought that the pathogen-
esis for ethionamide-induced pellagra is photosensi-
tivity. Photosensitivity is an adverse cutaneous
reaction that results when a chemical or drug is
applied topically or taken systemically when a person
is exposed to ultraviolet rays or visible light.
Photosensitivity reactions may be categorized as pho-
totoxic or photoallergic in nature. In a phototoxic re-
action, the photoactivated chemical causes direct
cellular damage, either by generation of a free radical
or through the generation of singlet oxygen, which in
turn results in the oxidation of biomolecules, damag-
ing critical cellular components and initiating the re-
lease of erythrogenic mediators. Photoallergic
reactions are immunologically mediated and deter-
Fig. 2. Resolution of rash after 15 days of nicotinamide. mined by delayed hypersensitivity responses or, more
rarely, by immediate hypersensitive reactions due to
treatment with ethionamide), she presented with IgE release in response to ultraviolet rays [5]. The
blackish discoloration and hardening of skin over skin pathogenic mechanism of photosensitivity in pellagra
creases of fingers and toes (Fig. 1) and perianal itch- remains unclear. Various other theories have been
ing. She had no other gastrointestinal or neurological proposed like cutaneous deficiency in urocanic acid
symptoms. She was suspected to have ethionamide- [4, 6], accumulation of kynurenic acid [4, 7], defi-
induced pellagra. As she had completed 14 months of ciency of Nicotinamide adenine dinucleotide
second-line antituberculosis agents and her chest (NAD)/Nicotinamide adenine dinucleotide phos-
radiograph showed resolution with healing of the cav- phate (NADP) [8] and altered porphyrin metabol-
ity, her ATT was stopped. She was started on nico- ism [9]. Pellagra is associated with several etiological
tinamide (100 mg) twice a day. Fifteen days later, all factors like diets high in maize, undernutrition, mal-
the skin lesions improved (Fig. 2). On last follow-up absorption, chronic alcoholism and biochemical
in November 2014, she continues to remain asymp- abnormalities of tryptophan metabolism, such as
tomatic and there is also no relapse of TB. carcinoid syndrome and Hartnup’s disease.
Chemotherapeutic agents such as 6-mercaptopurine,
DISCUSSION 5-fluorouracil, azathioprine are well-known causes of
The name pellagra is derived from the Italian word pellagra. Isoniazid, chloramphenicol, azathioprine,
‘pelle agra’, which means rough skin [1]. The first phenobarbital and ethionamide (rarely) are other
Ethionamide-induced Pellagra  303

drugs implicated to cause pellagra [2, 10]. treatment with ethionamide. This is important to re-
Ethionamide inhibits the conversion of tryptophan to port, as ethionamide is used more frequently in chil-
niacin. It competitively replaces NAD from the meta- dren and for a prolonged period in the treatment of
bolic pathways. Hence, tissues with high energy re- DR TB. Supplementation of niacin in patients who
quirements, like brain, skin and gut, which have a are on long-term ethionamide treatment should be
high turnover rate, are affected in pellagra [7]. considered.
Moreover, ethionamide is also hepatotoxic and this
further adds to the decreased utilization of absorbed REFERENCES

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