Ethionamide-Induced Hypothyroidism in Children

8/9/2019 Ethionamide-Induced Hypothyroidism in Children

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161 2011;26(3)South Afr J Epidemiol Infect

Original Research:Ethionamide-induced hypothyroidism

Ethionamide is a second-line anti-tuberculosis drug used in the management of drug-resistant tuberculosis. Hypothyroidism is reported

to be a rare adverse effect. A retrospective descriptive study was done of all children started on treatment for multidrug-resistant

tuberculosis from 2006-2009, who received ethionamide as part of their drug regimen. Information collected included age, weight,

human immunodeficiency virus (HIV) status, ethionamide dose and thyroid function tests. Seven of 13 (54%) children developedhypothyroidism and received thyroxine for the duration of ethionamide treatment. Thyroid function returned to normal within two

months of completion of tuberculosis treatment in six of the seven children (one lost to follow-up). Ethionamide-induced hypothyroidism

is more common in this small number of patients than previously reported. The results warrant further studies to confirm these findings

and elucidate possible reasons.

Peer reviewed. (Submitted: 2010-07-29, Accepted: 2010-11-03). SAJEI South Afr J Epidemiol Infect 2011;26(3):161-163

Ethionamide-induced hypothyroidism in children

UM Hallbauer, HS Schaaf

Ute Hallbauer, Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Free State.

Simon Schaaf, Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University.

Correspondence to: Dr Ute Hallbauer, e-mail: [email protected]

Introduction

Ethionamide, a thioamide derived from isonicotinic acid, has

good clinical efficacy against Mycobacterium tuberculosis.1

Poor tolerability because of considerable gastrointestinaladverse effects, such as nausea, vomiting, anorexia, a metallic

taste and abdominal pain, prohibits this drug from being used

as a first-line therapy. It is, however, an important second-

line drug used in the treatment of drug-resistant tuberculosis.2

Other well-recognised adverse effects of ethionamide are

hepatotoxicity and nervous system effects similar to that of

isoniazid. Hypothyroidism, although a known adverse effect,

is described as rare.3

We report on the occurrence of hypothyroidism in a group of

children treated for multidrug-resistant tuberculosis (MDR-TB,

i.e. resistance to at least isoniazid and rifampicin).

Methods

This retrospective descriptive study of routine clinical data

includes 13 children (


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Results

Thirteen children were included in the study, with a mean

age of 7.3 years (range 212 years). These children were

diagnosed and treated for MDR-TB, and seven (54%)

of the participating children developed hypothyroidism.Demographic data, clinical features and thyroid function

data are summarised in Table I. Clinical examination did

not reveal a goitre in any of the children, nor any other

clinical features that could specifically be ascribed to

hypothyroidism.

The median time of onset of hypothyroidism was five months,

with a range of one to 11 months. Children who developed

hypothyroidism were somewhat younger (mean age 7.3

years) compared to those who did not develop hypothyroidism

(mean age 7.8 years), although this difference was not

significant (t-test, p=0.80). Underweight for age did not differ

significantly between the two groups. The mean ethionamidedosage (mg/kg body weight) was significantly higher in

children who developed hypothyroidism (20.9 mg/kg) versus

those who did not (16.8 mg/kg; t-test, p=0.03; 95% CI for

difference in mean dosage 0.4; 7.7 mg/kg). In six of the seven

hypothyroidism patients, TSH and fT4 returned to normal

within 12 months after stopping ethionamide treatment; one

was lost to follow-up.

At the time of writing, eight patients had completed their

treatment. They have been followed up for a year and have

not shown signs of TB recurrence. Five children are still on

treatment: four are responding well, and one child (case 11)

is not responding to treatment and is being evaluated for

extensive drug resistance.

Eleven (85%) of the 13 patients were HIV infected, with

patients number 3 and 9 (Table I) being HIV negative. All 11

HIV-infected patients accessed antiretroviral treatment: five

started antiretroviral treatment a median of 1.5 years (range

0.5 to 4 years) before the diagnosis of MDR-TB, four were

started within a month of being diagnosed with MDR-TB,one within three months, and one six months after MDR-TB

diagnosis.

Table I: Demographic data, clinical features and thyroid function test (TFT) data of children with MDR-TB treated with ethionamide

Case number and

type of TB

Gender Age

(years)

Weight in kg

(z-score)

Ethionamide

daily dose

in mg

(mg/kg)

First TSH

level

(mIU/L)a

Highest

TSH level

(mIU/L)

Time on Rxb

at onset of

raised TSH

First fT4

level

(pmol/L)c

Lowest

fT4 level

(pmol/L)

Time on

thyroxine

to normal

TFTs

Time after

completion

of MDR-TB

Rx when

TFTs

normalised

1. Bilateral TB psoas

abscesses

M 9 25 (< -1) 375 (15.0) 6.09 11.28 10 mths 14.1 7.7 2 mths 2 mths

2. TB meningitis M 6 11 (< -3) 250 (22.7) 3.91 21.93 2 mths 11.1 7.6 1 mth 2 mths

3. TB abdomen and

adenitis

F 7 22 (< 0) 375 (17.0) 5.38 16.30 1 mth 14.7 8.1 1 mth 2 mths

4. Miliary TB F 5 14 (-2) 375 (26.8) 22.50 8 mths 8.5 1 mth 1 mth

5. Bilateral TB psoas

abscesses

M 8 22 (< -1) 500 (22.7) 2.50 50.90 2 mths 19.1 7.9 2 mths LTFd

6. Miliary TB M 5 17 (< -1) 375 (22.0) 3.30 10.27 5 mths 10.0 6.2 1 mth Still on Rx

7. Pulmonary TB M 11 25 (< -1) 500 (20.0) 4.70 14.45 11 mths 9.4 8.9 3 mths Still on Rx

8. Pulmonary TB F 8 15 (< -3) 250 (16.6) 1.97 8.25

(7 mths)

7 mths 12.4 7.5

(7 mths)

7 mths

spontaneous

recoverye

Still on Rx

(month 16)

9. Pulmonary TB M 12 31 (0) 500 (16.1) 1.59 3.70

(2 mths)

1 mth 6.3 6.2

(3 mths)

N/A Completed

Rx

10. Pulmonary TB F 12 32 (0) 500 (15.6) 1.90 3.05

(4 mths)

4 mths 14.3 7.7

(3 mths)

N/A Still on Rx

(month 12)

11. Pulmonary TB F 11 25 (< -1) 500 (18.7) 0.94 6.11

(9 mths)

9 mths 14.7 9.9

(5 mths)

N/A Stopped

ethionamide

Rxf

12. Abdominal and

pulmonary TB,

adenitis

F 2 7.0 (< -3) 125 (17.8) 1.05 7.67 6 mths 14.8 10.9

(3 mths)

N/A Still on Rx

(month 9)

13. Pulmonary TB F 2 7.7 (< -3) 125 (16.2) 2.13 5.82

(8 mths)

8 mths 9.5 9.5

(0 mths)

N/A Still on Rx

(month 9)

aTSH: thryroid stimulating hormone (normal range 0.44.2 mIU/L); bRx: treatment; cfT4: free thyroxine (normal range 10.335 pmol/L); dLTF: lost to follow-up; eSingle low TFT at 7 months with spontaneousrecovery; fEthionamide therapy terminated after 9 months due to resistance


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Discussion

Children generally tolerate second-line anti-tuberculosis

drugs, including ethionamide, better than adults.4

Gastrointestinal adverse effects usually improve in the first

week or two of treatment and can be overcome by splittingthe dose. A less-known and rarely reported adverse effect

of ethionamide is hypothyroidism.5The manufacturers of the

drug also regard it as a rare adverse effect. Therefore, the

finding of a 54% occurrence of hypothyroidism in this small

study, acknowledged as a limitation, was unexpectedly high.

Few studies report on hypothyroidism as an adverse effect

of MDR-TB therapy, but these do not distinguish between

hypothyroidism caused by ethionamide/prothionamide, PAS

or a combination of the two drugs. Hypothyroidism has been

reported in 61 (10%) of 608 adult MDR-TB cases and three

(8%) of 38 children treated for MDR-TB.6,7Keshavjee et al6

indicated that treatment change was necessary in eight of 61(13%) cases, but did not specify which drugs were changed.

Cases of ethionamide-induced goitre and hypothyroidism

have also been reported in adults.8-10

Ethionamide has a thioamide side chain and is related to

mercaptomethylimidazole, also known as methimazole, a

drug used to treat hyperthyroidism. Prothionamide, the propyl

analog of ethionamide, is used as an alternative to ethionamide

and also induces hypothyroidism. Propylthiouracil, related

to prothionamide, is a thioamide also used in the treatment

of hyperthyroidism. Thioamides inhibit thyroid hormone

formation. Thyroid peroxidase-catalysed iodination is inhibitedby trapping the oxidised form of iodide.8The reaction may be

reversible or irreversible, depending on the drug to iodide

ratio. When the ratio is high, the reaction may be irreversible.11

In our study, six of seven cases in whom ethionamide and

thyroxine had been stopped at the end of MDR-TB treatment,

had normal thyroid function tests within two months; one case

was lost to follow-up.

Ethionamide is used infrequently in childhood tuberculosis. It

is used as an alternative to streptomycin in short-course (six to

nine months) treatment regimens for tuberculous meningitis

and miliary tuberculosis, and is also an important drug inMDR-TB treatment regimens (duration 1824 months).2,3

The recommended dosage for both these regimens is

1520 mg/kg daily.3This study found hypothyroidism to be

more common in children treated with ethionamide than

previously reported. Hypothyroidism was documented from

as early as one month of ethionamide treatment, but the

median time was at five months of treatment. Children were

not clinically symptomatic, therefore thyroid function tests

are probably not indicated in shorter courses (six months)

of ethionamide, but screening for hypothyroidism should

be done at least at three-monthly intervals in all children

on longer courses of ethionamide, such as those on MDR-

TB treatment. Treatment with thyroxine may be warrantedeven in children with asymptomatic hypothyroidism, as

the prolonged effects of subclinical hypothyroidism in

children during periods of rapid physical growth and brain

development remain unknown.12

The high rate of hypothyroidism in this study could partially

be attributed to high doses of ethionamide in some cases.

This highlights the problem of non-availability of child-

friendly formulations of anti-tuberculosis drugs. However,

even some children receiving the recommended dosage

did develop hypothyroidism. Other drugs, such as PAS,

although not given to any of the children included in this

study, and possibly HIV infection itself, may be additional

factors causing hypothyroidism.13 We also considered sick

euthyroid syndrome as possible cause, but because all

children initially had normal TSH and fT4 levels and only

later developed hypothyroidism, we thought this diagnosis

less likely in these children.

In conclusion, MDR-TB is an increasingly recognised problem

and more children are started on MDR-TB treatment.14Hypothyroidism as an adverse effect of prolonged ethionamide

administration is probably more common than previously

recognised. Regular screening of thyroid functions should be

done in any child on prolonged treatment with ethionamide.

Thyroid functions returned to normal within two months of

starting thyroxine replacement therapy, and also returned to

normal within two months of stopping thyroxine replacement

on the completion of MDR-TB treatment. Further larger

studies are necessary to confirm the rate of hypothyroidism

and identify additional factors which influence this adverse

effect.

Acknowledgements

We thank Gina Joubert, Department of Biostatistics, Faculty

of Health Sciences, University of the Free State, for statistical

analysis of data, and Daleen Struwig, medical writer, for

technical and editorial preparation of the manuscript for

publication.

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update 2008. WHO, Geneva, Switzerland, 2008. WHO/HTM/TB/2008.402

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11. Bandyopadhyay U, Biswas K, Banerjee RK. Extrathyroidal actions of antithyroid thionamides. Toxicology Letters 2002;

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12. OGrady MJ, Cody D. Subclinical hypothyroidism in childhood. Arch Dis Child 2010. doi:10.1136/adc.2009.18180013. Afhami S, Haghpanah V, Heshmat M, et al. Assessment of the factors involved in the development of hypothyroidism

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Ethionamide-Induced Hypothyroidism in Children

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