acta histochemica 113 (2011) 15

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acta histochemica
journal homepage: www.elsevier.de/acthis

Methimazole-induced hypothyroidism causes cellular damage in the spleen,

heart, liver, lung and kidney
Edgar Cano-Europa, Vanessa Blas-Valdivia, Margarita Franco-Colin,

Carlos Angel Gallardo-Casas, Rocio Ortiz-Butron
ogicas, I.P.N., Carpio y Plan de Ayala, Me xico, D.F., C.P. 11340, Mexico
Departamento de Fisiologa Mauricio Russek Berman, Escuela Nacional de Ciencias Biol

a r t i c l e in fo abstract

Article history: It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage
Received 1 April 2009 caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism
Received in revised form can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or
23 June 2009
hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-ve male
Accepted 6 July 2009
Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced
hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole
Keywords: (60 mg/kg) and a T4 injection (20 mg/kg/d sc). At the end of the treatments (4 weeks for the
Hypothyroidism pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with
Methimazole
sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart,
Thyroidectomy
liver, lung and kidney were removed and were processed for embedding in parafn wax. Coronal
Tissue damage
sections were stained with hematoxylineosin. At the end of treatment, animals with both the
methimazole- and thyroidectomy-induced hypothyroidism had a signicant reduction of serum
concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage
in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T4
showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal
cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by
T4 completely in the heart and partially in the kidney cortex. These results indicate that tissue damage
found in hypothyroidism is caused by methimazole.
& 2009 Elsevier GmbH. All rights reserved.

1. Introduction cellular protection because of its chemical structure (Tutuncu

The thyroid hormone 3,5,30 -triiodothyronine (T3) has a funda-
mental role in the development, differentiation and physiology of
all cells in an organism (Hulbert, 2000). One of the most studied
effects of T3 is the control of basal metabolic rate. The
hypermetabolic state caused by the hyperthyroidism-uncoupled-
respiratory mitochondrial chain generates free radicals causing
oxidative stress and cellular damage (Venditti and Di Meo, 2006).
However, the hypothyroidism-induced hypometabolic state pro-
tects against oxidative damage caused by toxins (Oren et al.,
1996). Some workers have demonstrated that antithyroid-induced
hypothyroidism can cause cellular damage (Bergman and Brittebo,
1999).
In order to study hypothyroidism, some investigators have
administrated antithyroid drugs, like methimazole, to develop a
hypothyroid model. Some results indicate that its use causes
et al., 2007; Bruck et al., 2007). Moreover, there is evidence of
extrathyroidal effects of antithyroid drugs, such as thionamides, in
humans and animals (Bandyopadhyay et al., 2002). One of the
effects of thionamides is a contribution to oxidative stress and
cellular damage. In general, cellular damage occurs when the
balance between oxidant and antioxidants is disturbed and the
antioxidant system does not neutralize the oxidants. An enhanced
oxidant system causes lipid peroxidation, an increase of reactive
oxygen species, and also nitration, carbonylation or glutathionyla-
tion of proteins and fragmentation of DNA (Halliwell and
Gutteridge, 2007; Valko et al., 2007). Our objective was to
determine if methimazole or hypothyroidism causes cellular
damage in the liver, kidney, lung, spleen and heart.
2. Material and methods

2.1. Animals and housing

 Corresponding author. Tel.: +52 5 729 6300/62381 and 52342;
fax: +52 5 729 62 06. Twenty-ve male Wistar rats from our animal care facilities

E-mail address: rocipn@yahoo.com.mx (R. Ortiz-Butron). were used. Animals were housed singly in 20 cm  30 cm  18 cm

0065-1281/$ - see front matter & 2009 Elsevier GmbH. All rights reserved.
doi:10.1016/j.acthis.2009.07.004
2 E. Cano-Europa et al. / acta histochemica 113 (2011) 15

metal cages with food and water ad libitum. The cages were
located together in racks (to maintain auditory and olfactory
contact) in a light (08.0020.00 lights on) and temperature
(2171 1C) controlled room. The rats were allowed to acclimatize
to the colony-room conditions for at least 1 week before starting
the experiments. All experimental procedures described were
approved by The Institutional Bioethics Committee in accordance
with the guidelines of the Laws and Codes of Mexico in The
Seventh Title of the Regulations of the General Law of Health
Regarding Health Research and Mexican Ofcial Standard NOM-
082-ZOO-1999 regarding technical specications for production,
care and use of laboratory animals. We used the minimum
number of animals required to attain the goals of this study.
2.2. Experimental design
read at 580 nm. Phosphorus was determined using the technique
described by Taussky and Shorr (1953).
2.4. Histological study
At the end of the treatment period, all animals were
anesthetized with sodium pentobarbital (Pisa-Mexico) (35 mg/kg
i.p.) and they were then transcardially perfused, rst with 0.9%
saline and then with 10% formaldehyde. The spleen, heart, liver,
lung and kidney were removed and they were processed by
routine protocol for embedding in parafn wax. Coronal sections
of 7 mm-thick were prepared. Each section was stained with
hematoxylineosin, according to standard protocols. The micro-
scopic description of each section was made by a person blinded
to the experimental design and at least 20 tissue sections for each
organ were assessed.

The rats were randomly divided into ve groups: (1) the

2.5. Statistical analysis
euthyroid group (n 5), which received no drugs or treatment,
(2) false thyroidectomy (n 5), which received surgery
All results are presented as mean7SE. Serum concentrations
and postoperative treatment, (3) thyroidectomy-induced hypo-
of thyroid hormones (T3 and T4), body weights and rectal
thyroidism (n 5), which had the thyroid gland removed,
temperatures were analyzed using a one-way ANOVA and a
the parathyroid reimplanted, and postoperative treatment, (4)
post-hoc Dunnett test, using the euthyroid group as a control. The
methimazole-induced hypothyroidism (n 5), which received
serum concentrations of calcium and phosphorus were analyzed
60 mg/kg/d of the antithyroid drug methimazole (Sigma Chemical
using a Students t-test. Po0.05 was considered statistically
Co.) in drinking water daily during treatment. The dose was
signicant.
adjusted according to water intake and body weight every 3 d
throughout the experiment, as described by Ortiz-Butron et al.
(2003), and (5) methimazole (60 mg/kg/d) and T4 injection (Sigma 3. Results
Chemical Co., UK) (20 mg/kg/d sc) as previously reported (Cano-
Europa et al., 2008).
Table 1 shows the physical variables and chemical tests
Thyroidectomy was performed on rats anesthetized with
proving the hypothyroid state of the animal. At the end of
ketamine (Pisa-Mexico) (10 mg/kg, i.m.)-xylazine (Pisa-Mexico)
treatment, the methimazole- and thyroidectomy-induced
(5 mg/kg, i.m.). We used the method of Tenorio-Vela squez et al.
hypothyroidism reduced the rectal temperature (F4,20 10.01,
(2005). Briey, by using a stereomicroscope (Zeiss, Germany) for
Po0.001) and body weight (F4,20 16.97, Po0.001). The surgical
better observation, the stenothyroid muscle was cut and the
procedure and the group that received T4 had showed differences
trachea was exposed. The parathyroid gland was located,
in the rectal temperature and body weight compared to the
dissected from the thyroid gland, and reimplanted into the
euthyroid group. The hypothyroid groups showed the expected
surrounding neck muscle. The thyroid gland was carefully
changes according to their antithyroid treatment.
dissected out to avoid injury to the laryngeal nerve and
The hypothyroid state was corroborated by determination of
was completely excised. After surgery, ketorolac (Sintex-Mexico)
thyroid hormones. T3 and T4 concentration decreased in methi-
(50 mg/kg i.m.) and gentamicin (Shering Plough-Mexico)
mazole- and thyroidectomy-induced hypothyroidism compared
(10 mg/kg) were administered over 5 d to alleviate pain and
with the euthyroid group (for T3: F4,20 4.06, Po0.05; for T4:
prevent infection.
F4,20 50.22, Po0.001).
During treatment, the body weight and rectal temperature
The surgical groups did not differ in their calcium and
were evaluated to indirectly determine the thyroid state. At the
phosphorus serum concentrations from the control euthyroid
end of the treatment (4 weeks for pharmacological groups, 8
group (for Ca2+: t 1.01, P 0.34; for P5+: t 0.75, P 0.48).
weeks for surgical groups) we determined the serum concentra-
tion of the thyroid hormones (T3 and T4). In the surgical groups we
also measured the serum concentration of calcium and phos- 3.1. Histology
phorus.
Histology of tissues taken from animals of all groups is
illustrated in Figs. 1 and 2.
2.3. Chemical assays
3.2. Spleen
To observe the modications of serum thyroid-hormone
concentrations large enough to modify the rectal temperature of The normal spleen is formed by areas composed mostly of
the rats, blood samples from the rat-tail vein were taken at lymphocytes suspended on reticular bers named white pulp. The
the end of the treatment. Serum was separated and stored at 4 1C white pulp clusters form cuffs around the central arteries within
until the day of analysis. T3 and T4 concentrations were the organ and form what appears to be an island in a sea of red
determined by enzyme immunoassay (Immunometrics UK Ltd.) pulp. The red pulp is essentially all the remaining spleen tissue;
according to manufacturers instructions. The calcium serum the venous sinuses and the spleen cords formed by erythrocytes.
concentration was measured by using the Wiener Lab kit. Briey, In hematoxylin and eosin stained sections, the white pulp takes on
50 mL of serum was reacted with a mixture of 80 nmol a purplish hue and appears darker than the red pulp. The same
o-cresolphthalein complexone, 4 mmol 8-hydroxyquinoline, and morphology can be seen in the animals after thyroidectomy.
3.5 mmol AMP (Wiener Lab). The magenta complex formed was However, both groups, hypothyroid induced by methimazole and
 E. Cano-Europa et al. / acta histochemica 113 (2011) 15 3

Table 1
Effect of thyroidectomy- and methimazole-induced hypothyroidism on thyroid hormone (T3 and T4) concentration, rectal temperature, body weight and serum
concentration of calcium and phosphorus at the end of treatment.

Variable Euthyroid False thyroidectomy Thyroidectomy-induced Methimazole-induced Methimazole+T4

(n 5) (n 5) hypothyroidism (n 5) hypothyroidism (n 5) administration (n 5)
Serum T3 (nmoles/l) 4.4070.68 5.7370.82 3.0870.32* 2.6970.54* 5.6670.80
Serum T4 (nmoles/l) 100.4710.4 101.2711.7 3.8873.25* 5.5672.19* 113.876.6
Rectal temperature (1C) 37.770.02 37.870.03 36.570.4* 37.170.02* 37.870.04
Body weight (g) 33476 352710 27775* 30578* 34177
Serum Ca2+ (mg/dl) N.E. 8.7670.62 7.8870.61 N.E. N.E.
Serum P5+ (mg/dl) N.E. 2.9170.33 3.2670.33 N.E. N.E.

Values are expressed as mean7SE. *Po0.05 vs. euthyroid group; NE not evaluated.

Euthyroid Thyroidectomy Methimazole Methimazole + T4

Spleen

50 m
m
50 50 m 50 m
Heart

50 m 50 m 50 m 50 m
Liver

50 m 50 m 50 m 50 m

50 m 50 m
50 m
Lung

50 m

Fig. 1. Representative images of spleen, heart, liver and lung tissues stained by hematoxylineosin. First row: normal spleen histology was not affected by thyroidectomy-
induced hypothyroidism; meanwhile methimazole-induced hypothyroidism caused cellular damage that was not prevented by T4 administration (arrows). Second row:
methimazole-induced damage to the heart (arrow) was prevented by T4 administration. Third row: methimazole-induced hypothyroidism caused liver damage (arrow) that
was partially prevented by T4 administration. Fourth row: methimazole- and thyroidectomy-induced hypothyroidism caused cellular damage (arrows) to lung.

hypothyroid that received T4 showed distortion of the normal 3.4. Liver

architecture, so the structure of pulp nodules was altered, being
smaller in size and containing macrophages with fuchsinic
pigments.
3.3. Heart
Normal heart tissue is formed by striated branched muscle
bers. All the bers have a central nucleus. This architecture was
present in the hypothyroid groups, with thyroidectomy and
hypothyroid induced by methimazole with T4. Only in the
methimazole-induced hypothyroid heart was loss of striation
and nuclei observed.
The liver parenchyma in control and thyroidectomy groups had
a similar appearance with hepatocytes in a radial distribution. The
hypothyroid groups (induced by methimazole and methimazole
with T4 treatment) showed cellular discontinuity, loss of hepato-
cytes in a radial distribution, altered nucleuscytoplasm ratio,
picnotic nuclei and hyperchromatic cells.
3.5. Lung
Analyses of the lung architecture of control animals showed
the normal appearance of the alveoli and epithelial lining of the
4 E. Cano-Europa et al. / acta histochemica 113 (2011) 15
Euthyroid Thyroidectomy
Renal cortex
50 m
Renal medulla
50 m 50 m
Fig. 2. Representative images of kidney stained by hematoxylineosin. First row: renal cortex. Second row: renal medulla. Thyroidectomy-induced hypothyroidism has no
effect on kidney histology. Methimazole-induced hypothyroidism caused cellular damage that was not prevented by T4 administration (arrows).
bronchioles. None of the other groups (thyroidectomy, hypothyr-
oid, or hypothyroid plus T4 groups) had normal lung architecture.
The alveoli and epithelial lining of the bronchioles had altered
cytoarchitecture, cellular discontinuity, loss of cilia and cellular
atrophy.
3.6. Kidney
A normal appearance of cortex with normal glomeruli and
proximal and distal tubule histology was found in the thyroidec-
tomized animals (Fig. 2). The methimazole-treated animals had
glomerulosclerosis, edema and cellular atrophy of the distal and
proximal tubules, distortion of cellular continuity and nucleus
loss. These alterations were less pronounced in hypothyroid rats
that received T4.
The medulla of the kidney from normal and thyroidectomized
animals had collector ducts accompanied with smaller tubular
structures, the loops of Henle. Methimazole caused cellular
atrophy in the loops of Henle and cellular discontinuity. These
alterations were not prevented when animals received methima-
zole plus T4.
4. Discussion
It has been proposed that the basal metabolic rate reduced by
hypothyroidism has two effects on the intracellular redox
environment and cellular damage. One effect is a protective
mechanism against toxin-caused oxidative stress (Elfarra et al.,
1994; Oren et al., 1996) and the other is the mechanism
of hypothyroidism-induced oxidative stress and cellular damage
(Liu and Ng, 1991; Bergman and Brittebo, 1999). The majority of
research has been done in pharmacological models of hypothyr-
oidism induced by using thionamides. However, there are reports
noting that the extrathyroidal action of the antithyroid drugs,
especially the thionamide group, causes undesirable effects
(Bandyopadhyay et al., 2002). To remove the possibility that the
drug contributes to cellular damage in the hypothyroid state, it is
important when studying this variable in a hypothyroidism model
not to modify other physiological variables such as thyroidectomy
with a parathyroid reimplant.
In our work, we investigated if thyroidectomy- or methima-
zole-induced hypothyroidism causes cellular damage in different
organs. Histologically, we demonstrated that only methimazole-
induced hypothyroidism causes cellular damage in the kidney,
Methimazole Methimazole + T4
50 m 50 m 50 m
50 m 50 m
lung, liver, heart and spleen. Animals treated with methimazole
and with a T4 supplement showed cellular damage in the lung,
spleen and renal medulla with lesser damage in the liver, renal
cortex and heart. Hypothyroidism did not produce cellular
damage in any organ except the lung: the thyroidectomy group
showed no other tissue alterations.
These results are in accordance with others observed in
humans and animals. Five percent of patients with hyperthyroid-
ism treated with antithyroid drugs are reported to have damage
to the liver (Casallo Blanco et al., 2007; Woeber, 2002), lung
(Tsai et al., 2001) and kidney (Calan as-Continente et al.,
2005). Also, methimazole-induced hypothyroidism in animals
has tumorigenic effects (Jemec, 1977) and modies pulmonary
function (Liu and Ng, 1991). No tissue damage was seen in a model
of hypothyroidism caused by a thyroidectomy with parathyroid
reimplant (Tenorio-Vela squez et al., 2005).
Methimazole can participate in cellular damage by different
mechanisms because of its chemical structure or the interaction of
this chemical structure and the physiological changes caused by
the hypothyroid state. This drug irreversibly inactivates different
peroxidases with a heme group at the active center (Bandyopad-
hyay et al., 1995, 2002). It is possible that methimazole causes an
inactivation of the heme group of peroxidases involved in
scavenging H2O2, as catalase (EC 1.11.1.6). The reduction in the
antioxidant system could cause an increase in an oxidation
reaction and cellular damage because H2O2 participates in the
HaberWeiss and Fenton reactions in the cells that generate it,
and in neighboring cells because H2O2 diffuses through mem-
branes (Halliwell and Gutteridge, 2007).
Hypothyroidism per se can modify the acyl composition in
plasma membranes by increasing the synthesis of polyunsatu-
rated fatty acids, such as the 18:2, 18:3, and 20:3 (Hoch, 1988).
This lipid change enhances the sensitivity to lipid peroxidation in
membranes of methimazole-induced hypothyroid rats. The re-
duction of the antioxidant system observed in methimazole-
induced hypothyroidism could contribute to the oxidant reaction
that causes oxidative stress and cellular damage (Das and Chainy,
2001, 2004; Sarandol et al., 2005; Hulbert, 2000).
Pulmonary damage was observed in thyroidectomy-induced
hypothyroid animals. We suggest that decrease of the thyroid
hormones reduced the activity of Na+K+-ATPase (EC 3.6.3.9),
modied the apical Na+ conductance and accumulated extra-
cellular uid that caused alveolar damage (Lei et al., 2007).
There is a partial protection in some organs of rats treated with
methimazole and supplemented with T4. This effect is attributed
 E. Cano-Europa et al. / acta histochemica 113 (2011) 15
to the action of the thyroid hormones on the regulation of the cell
cycle (Puzianowska et al., 2006).
This is the rst report that demonstrates that methimazole
causes cellular damage in the liver, kidney, spleen and heart and
these effects are not caused by hypothyroidism itself. Hypothyr-
oidism also causes pulmonary damage.
Acknowledgment
This study was partially supported by CONACyT grants 53227
and SIP-IPN 2008038 and 20090485. R.O.-B. is fellow of EDI and
DEDICT-COFFA-I.P.N., E.C.-E. is fellow of CONACyT, V.B.-V. is fellow
of PIFI-COFFA-I.P.N. and CONACyT. C.A.G.-C. is fellow of PIFI-
COFFA-I.P.N, M. F.-C. is fellow of SNI. Thanks to Dr. Ellis Glazier for
editing this English-language text.
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