Original Research: Ethionamide-induced hypothyroidism

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: hallbute@ufs.ac.za

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 developed
hypothyroidism 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.
South Afr J Epidemiol Infect 2011;26(3):161-163

Peer reviewed. (Submitted: 2010-07-29, Accepted: 2010-11-03). SAJEI

Introduction

the recommended dosage of 1520 mg/kg body weight per

day.2 None of these children received para-aminosalicylic
acid (PAS), another second-line anti-tuberculosis drug that
could cause hypothyroidism.

Ethionamide, a thioamide derived from isonicotinic acid, has

good clinical efficacy against Mycobacterium tuberculosis.1
Poor tolerability because of considerable gastrointestinal
adverse 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 secondline 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

As these children were treated with many drugs,

investigations to detect possible drug adverse effects
were done monthly as cautious standard of care.3 In the
first few children, thyroid function tests were not done at
baseline, but delayed not longer than four months after
commencement of ethionamide treatment. All children
were screened for hypothyroidism by determining thyroidstimulating hormone (TSH) and free thyroxine (fT4) levels.
Measurements were done by an Advia Centaur analyser
(Siemens Medicare, USA) using immunoassay. The precision
for fT4 and TSH was CV% (coefficient variant) 45 and 56,
respectively, between batches. Blood samples taken from
patients were analysed as routine samples. Hypothyroidism
was defined as levels of fT4 <10 pmol/L in the presence
of a raised TSH >5 mIU/L on more than one occasion.
Children with hypothyroidism were treated with thyroxine
100 g/m2,which amounted to 0.050.1 mg per day.
Thyroxine supplementation was given until MDR-TB therapy
was completed. Ethionamide was never stopped as it was
an essential part of the treatment regimen.

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 (<13 years of age), who had been
diagnosed and treated for MDR-TB at Pelonomi Regional
Hospital in Bloemfontein, South Africa, from July 2006
through August 2009. In eight children the diagnosis of
MDR-TB was confirmed by culture and drug susceptibility
testing, while in five it was a clinical diagnosis because of
failure to respond to adherent first-line anti-tuberculosis
treatment. All children were treated for 1824 months
with ethionamide as part of their MDR-TB regimen.
Ethionamide (Ethatyl, Aventis, Midrand, South Africa) was
administered as half or full tablets (250 mg) to approximate

South Afr J Epidemiol Infect

Demographic and clinical data collected were age at

diagnosis, sex, weight, type of tuberculosis, human
immunodeficiency virus (HIV) status and treatment with
antiretroviral drugs. The study was approved by the
institutional Ethics Committee of the Faculty of Health
Sciences, University of the Free State.

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Original Research: Ethionamide-induced hypothyroidism

Results

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.

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.

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.

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 ethionamide
dosage (mg/kg body weight) was significantly higher in
children who developed hypothyroidism (20.9 mg/kg) versus

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 Ethionamide
(z-score)
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

25 (< -1)

375 (15.0)

6.09

11.28

10 mths

14.1

7.7

2 mths

2 mths

2. TB meningitis

11 (< -3)

250 (22.7)

3.91

21.93

2 mths

11.1

7.6

1 mth

2 mths

3. TB abdomen and
adenitis

22 (< 0)

375 (17.0)

5.38

16.30

1 mth

14.7

8.1

1 mth

2 mths

4. Miliary TB

14 (-2)

375 (26.8)

22.50

8 mths

8.5

1 mth

1 mth

5. Bilateral TB psoas
abscesses

22 (< -1)

500 (22.7)

2.50

50.90

2 mths

19.1

7.9

2 mths

LTFd

6. Miliary TB

17 (< -1)

375 (22.0)

3.30

10.27

5 mths

10.0

6.2

1 mth

Still on Rx

7. Pulmonary TB

11

25 (< -1)

500 (20.0)

4.70

14.45

11 mths

9.4

8.9

3 mths

Still on Rx

8. Pulmonary TB

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

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

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

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

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

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)

TSH: 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 spontaneous
recovery; fEthionamide therapy terminated after 9 months due to resistance

South Afr J Epidemiol Infect

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Original Research: Ethionamide-induced hypothyroidism

Discussion

children during periods of rapid physical growth and brain

development remain unknown.12

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 splitting
the dose. A less-known and rarely reported adverse effect
of ethionamide is hypothyroidism.5 The 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.

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 childfriendly 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.

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.6,7 Keshavjee 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

In conclusion, MDR-TB is an increasingly recognised problem

and more children are started on MDR-TB treatment.14
Hypothyroidism 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.

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 inhibited
by trapping the oxidised form of iodide.8 The 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.

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.

References

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more common in children treated with ethionamide than
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on longer courses of ethionamide, such as those on MDRTB treatment. Treatment with thyroxine may be warranted
even in children with asymptomatic hypothyroidism, as
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