ARTICLE IN PRESS

Thyroid hormones, Iodine and Iodides,

and Antithyroid Drugs
Rahul Deshmukh*, Ajay N Singh, Mark Martinez{, Nidhi Gandhi{,
Karyn I. Cotta, Harish Parihar{, Vicky V. Mody,1
*Department of Pharmaceutical Sciences, College of Pharmacy, Rosalind Franklin University of Medicine and Science,
North Chicago, Il, USA

Department of Pharmaceutical Sciences, South University School of Pharmacy, Savannah, GA, USA
{
Department of Pharmacy Practice, PCOM School of Pharmacy, Suwanee, GA, USA

Department of Pharmaceutical Sciences, PCOM School of Pharmacy, Suwanee, GA, USA
1
Corresponding author: vickymo@pcom.edu

THYROID HORMONES [SED-15, 3409; Increase in Liver Enzymes

SEDA-31, 687; SEDA-32, 763; SEDA-33, 881;
SEDA-34, 679; SEDA-35, 747; SEDA-36, 635;
SEDA-37, 513]
Thyroid hormones mimicking agents such as eprotir-
ome, levothyroxine (T4), and triiodothyronine (liothyro-
nine, T3) are used in the treatment of both overt and
subclinical hypothyroidism. Both conditions are pre-
sented with elevated TSH levels; however, overt clinical
hypothyroidism is further defined by low levels of free
triiodothyronine (fT3) and free levothyroxine (fT4).
Patients presenting with overt or subclinical hypothy-
roidism are at increased risk of developing cardiovascu-
lar disease; hence, care has to be sought as soon as
discovered.
Angelin B and coworkers conducted a multicentre, ran-
domized, placebo-controlled, double-blind study to evalu-
ate the efficacy and safety of eprotirome, in 98 patients with
primary hypercholesterolaemia [2C]. These 98 patients
were divided into 3 subgroups of 20 patients in group 1,
38 patients in group 2, and 40 patients in group 3. The
patients in group 1 received a placebo, whereas, both
patients in group 2 and 3 received 100 and 200 g of epro-
tirome, respectively. While eprotirome was able to reduced
serum LDL cholesterol levels by 23
5% and 31
4%, in
group 2 and 3, respectively, as compared with 2
6% for
placebo (p < 0.0001), an increase in liver enzymes was
observed in all patients. In fact 7 patients withdrew from
the study as their serum ALT levels exceeded the prede-
fined limit [2C].

Eprotirome
Eprotirome, selectively acts on the hepatic receptor.
The use of eprotirome has been shown to lower serum
low-density lipoprotein (LDL) cholesterol concentra-
tions in patients with dyslipidemia. Abnormal lipid
levels put patients at risk for cardiovascular disease,
which sometimes becomes difficult to reverse with
stand-alone statin therapy [1R]. The use of thyroid hor-
mone mimetics in these patients can help lower levels of
LDL cholesterol.
Levothyroxine
Levothyroxine remains the mainstay of current treat-
ment for hypothyroidism, and the mean dosage pre-
scribed for levothyroxine therapy is 1.6 g/kg/day.
Intestinal absorption of levothyroxine varies from patient
to patient and is usually in the range of 6080% of the
dose administered.
Quality of Life
Primary hypothyroidism can affect the quality of life
(QOL). Kelderman-Bolk and coworkers studied the

Side Effects of Drugs Annual 455 2016 Elsevier B.V. All rights reserved.
ISSN: 0378-6080
http://dx.doi.org/10.1016/bs.seda.2016.08.026
 ARTICLE IN PRESS
456 THYROID HORMONES, IODINE AND IODIDES, ANTITHYROID DRUGS
relation between QOL and various parameters in hypo-
thyroid patients who were taking levothyroxine [3R].
They evaluated the QOL in 90 patients (20 males and
70 females) who were treated for primary hypothyroid-
ism using Short-Form 36, Hospital Anxiety and Depres-
sion Scale and MFI20. The Post hoc analysis was
performed on the relation of QOL at baseline, BMI, thy-
roid hormones, and other serum values. It was found that
there exists an inverse relationship between QOL and
BMI, and a decreased QOL was observed in hypothyroid
patients on thyroxine treatment. This was mainly due to
their higher body weight (BMI) and hence the authors
concluded that weight gain should be one of the focus
while treating hypothyroid patients as it can decrease
their QOL.
Rheumatoid Arthritis (RA)
Levothyroxine has been shown to increase the risk of
developing rheumatoid arthritis for patients with auto-
immune disorders [4R]. In this study authors compared
1998 patients using levothyroxine along with 2252 con-
trols for incident RA cases. They found that patients on
levothyroxine were at twofold risk for RA [4R].
Vitamin D Deficiency
The use of levothyroxine has also been implicated
for vitamin D deficiency. Authors compared 25-hydroxy-
vitamin D and parathyroid hormone (PTH) levels
between four groups of non-lactating women [5C]. Group
A consisted of 14 hypothyroid women with post-partum
thyroiditis, Group B included 14 euthyroid females
with post-partum thyroiditis, Group C included 16 female
with non-autoimmune hypothyroidism, and group
D was a control which included 15 healthy euthyroid
females. The patients in both groups A and C were treated
with L-thyroxine for 6 months. After 6 months, it was
found that the serum levels of 25-hydroxyvitamin
D were lowered in group A than in group B, as well as
in group C in comparison with group D. Hence, the
authors concluded that there is an association of vitamin
D status with post-partum thyroiditis and levothyroxine
treatment.
Multiple Subungual Pyogenic Granulomas
A 54-year-old woman who was taking levothyroxine
for hypothyroidism for 3 months presented with rapidly
growing lesions in her nail beds [6R]. Examination
revealed red nodules that had invaded beneath the nail
plates. The patient also took venlafaxine 75 mg use once
a day for depression for 10 years and intermittent ibupro-
fen use (which was stopped a year ago) for osteoarthritis.
A wide excision was performed but the symptoms
relapsed as noted during the 3-month follow-up period.
Levothyroxine treatment was stopped and the symptoms
did not recur [6R].
Bone Loss
Effects of levothyroxine (LT4) on bone and bone meta-
bolism are controversial [7C]. To address this author
examined mean bone losses in 93 patients with well-
differentiated carcinoma over 12 months after initiating
levothyroxine therapy. It was found that there was a mean
bone losses in the lumbar spine, femoral neck, and total
hip; however, the loss was more prominent in postmeno-
pausal women. Authors also observed that the loss
was higher in postmenopausal women who received
no supplementation of calcium/vitamin D. Hence, the
authors concluded that TSH-suppressive levothyroxine
therapy can accelerate bone loss predominantly in
postmenopausal women and mainly during the early
post-thyroidectomy period but the loss can be reduced
by adding calcium/vitamin D to the therapy.
On the similar lines Nyandege and coworkers have
suggested that the concomitant use of bisphosphonates
and other medications, which can stimulates bone metab-
olism such as acid-suppressive therapy, levothyroxine,
thiazolidinediones (TZDs), and selective serotonin reup-
take inhibitors (SSRIs), can increase the risk of fracture
[8R]. Authors found that the concomitant use of acid sup-
pressive agents with bisphosphonate can increase the risk
of fracture. However, they suggested that TZDs, SSRIs,
and levothyroxine can have similar implications based
on their pharmacological action. Hence, precaution
should to be taken while using bisphosphonates along
with these other medications.
CARDIOVASCULAR DISORDERS
A prospective, controlled, single-blind study was
conducted by Bakiner et al. to determine plasma Fetuin
A levels in hypothyroid patients (n 39) before and
after levothyroxine treatment. Additionally, authors
wanted to figure out if there is any association
between Fetuin A levels and cardiovascular risk in
those patients [9C]. Authors found that there was no
correlation between Fetuin A levels and cardiovascular
risk factors; however, the mean HDL cholesterol levels
decreased in those patients from 49.3 (2383.9) to
44 (28.369.0) [9C].
Drug Overdose
The pharmacological effects of levothyroxine on car-
diac cells are well know where in high doses of levothyr-
oxine can cause severe toxic effects in the patient [10A].
Stuijver et al. reported a case of 23-year-old woman who
attempted suicide by ingesting 25 mg of levothyroxine
[10A]. The patient experienced hypercoagulation and
a hypofibrinolytic effect, reflecting an increased risk of
venous thrombosis [10A]. Similarly, a 61-year-old
patient who accidentally ingested 1000 times excess of
 ARTICLE IN PRESS
IODINE AND IODIDES [SED-15, 1896; SEDA-32, 764; SEDA-33, 883; SEDA-34, 680; SEDA-35, 752; SEDA-36; SEDA-37, 514]
levothyroxine rather than the actual dose of 50 mg
exhibited altered mental consciousness, acute respira-
tory failure, and atrial fibrillation [11A].
DrugDrug Interaction
Levothyroxine can interact with various other drugs.
In an observational study carried out by Irving and
coworkers, the authors wanted to evaluate the effect of
drugs co-administered on thyroxine [12C]. This study
evaluated 10 999 patients (mean age 58 years, 82% female)
who were prescribed levothyroxine on at least three occa-
sions within a 6-month period, prior to the start of a
study. They found that both iron and calcium supple-
ments, proton pump inhibitors, and oestrogen were
responsible for the increase in serum TSH concentration
(7.5%, 4.4%, 5.6% and 4.3%), respectively. However, there
was a decrease in the TSH concentration (0.17 mU/L) for
those patients on statins. Hence, the authors concluded
that there is a significant interaction between levothyrox-
ine and iron, calcium, proton pump inhibitors, statins and
oestrogens. Co-administration of these drugs with
levothyroxine may reduce the effectiveness of levothyr-
oxine therapy, and hence the TSH concentrations in those
patients should be carefully monitored.
The amount of levothyroxine absorbed can also be
affected by the co-administration of other drugs such as cip-
rofloxacin or rifampin [13A]. In a randomized, double-
blind, placebo-controlled study on 8 healthy volunteers
who received either 1000 g of levothyroxine and placebo,
or 1000 g of levothyroxine and 750 mg ciprofloxacin,
or 1000 g of levothyroxine and 600 mg rifampin authors
found that the co-administration of ciprofloxacin signifi-
cantly decreased the area T4 levels by 39% (p 0.035),
whereas, rifampin co-administration significantly increased
T4 by 25% (p 0.003).
Octreotide
The use of preoperative administration of octreotide in
cohort of patients with TSH secreting pituitary adenomas
(TSHoma) was evaluated by Fukuhara et al. [14C].
Authors discovered that of 81 patients who underwent
surgery for TSHoma at Toranomon Hospital between
January 2001 and May 2013, 44 received preoperative
short-term octreotide. Further, among these 44 patients
19 received octreotide as a subcutaneous injection, and
24 patients received octreotide as a long-acting release
(LAR) injection, and one of them was excluded due to
side effects. It was found that the use of short-term preop-
erative octreotide administration was highly effective in
suppressing TSHoma shrinkage. Some common side
effects such as mild diarrhea (5 patients), constipation
(1 patient), nausea and elevation of bilirubin (1 patient)
were observed. Hence, the authors concluded that
457
preoperative octreotide are effective in suppressing
TSHoma and should be recommended to patients to
avoid problems with hyperthyroidism.
IODINE AND IODIDES [SED-15, 1896;
SEDA-32, 764; SEDA-33, 883; SEDA-34, 680;
SEDA-35, 752; SEDA-36; SEDA-37, 514]
Dietary Iodine
Iodine is an essential component of thyroid hormones,
and Iodine deficiency can have serious adverse effects on
ones growth and development. The deficiency of iodine
in pregnant women can result in spontaneous abortion,
stillbirth, and cretinism. The World Health Organization
(WHO) recommends the use of iodinated salt to compen-
sate for any iodine deficiency. Moreover, WHO also
reports the most common side effects reported for iodine
deficiency [12C].
Excessive iodine intake can severely effect TSH levels.
In one study, infants (aged 624 months), who were
exposed to excessive iodine, were found to have subclin-
ical hypothyroidism [15C]. Water was assumed to be the
source of excessive intake of iodine in lactating mother of
those infants [16C].
Higher dietary iodine in iodine-deficient areas can also
be correlated to thyroid cancer. In fact, it was observed that
patients who lived in iodine-deficient areas had a higher
risk of thyroid cancer if they had a diet high in iodine than
those compared with the ones living in non deficient areas
[17M]. Similar correlation was found in cruciferous vege-
tables [17M]. Thus the authors implied that dietary roles
play an important part in thyroid cancer [17M].
In another case a 4-year-old boy who had severe
allergy and was on highly restrictive iodine-deficient diet
developed goitre and significant thyroid dysfunction
[18A]. His diet was restricted to cows milk protein, soya
(33.7 kUA/L), wheat and egg (>100 kUA/L), fish cod
(65.2 kUA/L), shellfish and peanuts (>100 kUA/L) and
tree nuts (1.46.8 kUA/L) (normal reference range
<0.35 kUA/L). He was on Flixotide, salbutamol, cetiri-
zine hydrochloride, and fluticasone propionate nasal
spray and steroid creams for his atopic disorders [18A].
His TSH levels were slightly raised, whereas, his T4 levels
were low, suggesting secondary hypothyroidism. Later a
soft and smooth goiter was found during following
assessments which was correlated to the severe defi-
ciency in dietary iodine [18A].
Iodine-125 Brachytherapy
Iodine-125 has a relatively long half-life (59.4 days)
and emits low-energy photons (35 keV), making it a
 ARTICLE IN PRESS
458 THYROID HORMONES, IODINE AND IODIDES, ANTITHYROID DRUGS
preferred isotope for radiation therapy (brachytherapy,
BT) to treat prostate cancer and brain tumors.
Ophthalmic Side Effect
Application of I-125 brachytherapy in the treatment of
intraocular tumor has been associated with radiation-
induced ophthalmic side effects. The radiation affects
the organs around the ocular cavity, eyelids, eyelashes,
conjunctiva, tear production, corneal surface, sclera,
and ocular muscles. Within the eye, radiation can cause
iritis, uveitis, synechiae, neovascular glaucoma, cataract,
posterior neovascularization, hemorrhage, retinal detach-
ment, retinopathy, and optic neuropathy [19S]. Radiation
side effects from I-125 brachytherapy can result in loss
of vision and quality of life.
Tsui and coworkers reported a decrease in visual acu-
ity, contrast sensitivity, and color vision in patients with
choroidal and ciliary body melanoma (CCM) [20C].
Authors measured visual acuity, contrast sensitivity
and color vision in 37 patients, 1, 2, and 3 years after
I-125 brachytherapy. These 37 patients were grouped into
4 groups. Prior to (group 1), 1 year after (group 2), 2 years
after (group 3), and 3 years (group 4). It was found that
after brachytherapy, group 1, 2, 3, and 4 had mean best-
corrected visual acuity of 77 letters (20/32), 65 letters
(20/50), 56 letters (20/80) and 47 letters (20/125), respec-
tively, and a contrast sensitivity of 30, 26, 22 and 19 letters;
color vision of 26, 20, 17 and 14 test figures, respectively.
Radiation-induced mid-choroid, macula melanoma, radi-
ation maculopathy and radiation optic neuropathy were
also reported for these patients [20C].
In a study, comparing the transscleral resection with-
out hypotensive anesthesia vs I-125 brachytherapy, for
the treatment of choroidal melanoma, radiation induce
side effects were reported. The most common side effects
for I-125 brachytherapy in 53 patients were radiation-
induced retinopathy (45.3%), neovascular glaucoma
(28.3%), and macular oedema (24.5%) [21R].
A 69-year-old female who underwent I-125 brachy-
therapy in scleral buckle was diagnosed with decreased
vision and occasional floaters in the left eye [22A].
Lower Abdominal Side Effects
Iodine-125 brachytherapy in the treatment of localized
prostate cancer is associated with radiation-induced bowl
symptoms, decrease erectile function, and lower urinary
tract symptoms. Among these symptoms, lower urinary
tract symptoms are the most manifested.
In a single-center longitudinal study (19942007) con-
ducted by Wilson and coworkers, 207 patients with
localized prostate cancer were monitored for the bio-
chemical disease-free survival and side effects of I-125
brachytherapy. The peak incidences of late grade 3 or
higher urinary and rectal toxicities were 10.7% and
1.1%, respectively [23R].
In a nationwide multi-institutional study aimed at com-
paring the use of I-125 brachytherapy for permanent seed
implant (PI) and combination therapy with PI and external
beam radiation therapy (EBRT), Ohashi and coworkers
reported urinary and rectal toxicity profiles as the major
side effects [24R]. Grade 2+ acute urinary toxicities devel-
oped in 7.36% (172 of 2337) of patients and grade 2+ acute
rectal toxicities developed in 1.03% (24 of 2336) of the
patients. Grade 2+ late urinary and rectal toxicities devel-
oped in 5.75% (133 of 2312) and 1.86% (43 of 2312) of the
patients, respectively. A higher incidence of grade 2+ acute
urinary toxicity occurred in the PI group than in the EBRT
group (8.49% vs 3.66%; p < 0.01). Acute rectal toxicity out-
comes were similar between the treatment groups.
Keyes and coworkers evaluated the long-term effect of
I-125 brachytherapy on erectile function (EF) of prostate
cancer patients [25R]. In this study (n 2929), EF was sig-
nificantly reduced 6 weeks after brachytherapy, with
gradual decline thereafter. EF preservation at 5 years
for age younger than 55, 5659, 6064, 6569, and 70 years
and older was 82%, 73%, 58%, 39%, and 23%, respec-
tively. Comparisons of the 5-year age-related and
treatment-related EF decline show that 50% of the long-
term EF decline is related to aging.
Eriguchi and coworkers reported neoadjuvant andro-
gen deprivation therapy (NADT) as a key factors associ-
ated with urinary toxicities in localizes prostate cancer
treated with I-125 brachytherapy [26R]. In this study
authors evaluated 1313 patients, between 2003 and 2009
to examine the role of base line international prostate
symptom score, biologically effective dose (BED), age,
and NADT. Urinary symptom flare and urinary Grade 2
or higher (G2+) toxicity occurred in 51%, 58%, and 67%
(p 0.025) and 16%, 22%, and 20% (p 0.497) of the
<180, 180220, and >220 Gy BED groups, respectively.
When patients were divided into four groups according
to prostate volume (<30 or 30 cc) and NADT use, uri-
nary G2+ toxicity was most commonly observed in those
patients with larger prostates who received NADT, and
least in the patients with smaller prostates and no NADT.
Strom and coworkers reported a comparative study on
prostate cancer patients who were treated with either
high-dose-rate (HDR) brachytherapy, low-dose-rate
(LDR) brachytherapy, intensity-modulated radiation
therapy (IMRT), and monotherapy to investigate the
effect on their urinary, bowel, and sexual health-related
quality-of-life (HRQOL) [27R]. Study was conducted
between years 2002 and 2013 with median follow-up of
32 months. The authors observed that patients on both
HDR brachytherapy (n 85, 27002800 cGy in two frac-
tion) and IMRT (n 79, monotherapy to 74008100 cGy
in 3745 fractions) had significantly less deterioration in
their urinary incontinence and HRQOL than those on
LDR (n 249, monotherapy to 14 500 cGy in one fraction)
brachytherapy patients as seen 1 and 3 months after
 ARTICLE IN PRESS
ANTITHYROID DRUGS [SEDA-32,765; SEDA-33, 884; SEDA-34, 681; SEDA-35, 754; SEDA-36, 638; SEDA-37, 518]
irradiation. Additionally, HDR brachytherapy patients
had worse sexual HRQOL than both LDR brachytherapy
and IMRT patients after treatment.
Lower urinary tract symptoms and bowl symptoms
were also reported for the rectal cancer patients. In a study
of 17 rectal patients, I-125 brachytherapy was found as
independent risk factor for urinary dysfunction [28C].
Peters and coworkers reported the dose-dependent GI tox-
icity associated with I-125 brachytherapy in rectal cancer
patients. Total salvage (TS) patients with severe GI toxicity
(41%, n 11) showed significantly higher rectal doses than
TS patients without GI toxicity (59%, n 16) [29C].
Iodine-131
Iodine-131 (131I) is the most commonly used iodine
radioisotope, and it decays mostly by beta-emission
(606 keV; 90%). It is notable for causing death in cells that
it penetrates and other cells up to several millimeters
away. For this reason, 131I is used for the treatment of thy-
rotoxicosis (hyperthyroidism) and some types of thyroid
cancer that absorb iodine. The 131I isotope is also used as
a radioactive label for certain radiopharmaceutical thera-
pies, e.g. 131I-metaiodobenzylguanidine (131I-MIBG) for
treating pheochromocytoma and neuroblastoma. Iodine-
131 also emits high-energy gamma radiation (364 keV,
10%) that can be used for imaging [30C]. Adverse reactions
with the use of 131I include myelotoxicity, swelling and
tenderness of salivary glands, nausea, vomiting, dry
mouth, and hypothyroidism [31C].
Hematological Toxicity
Safety and efficacy of radio immunotherapy (RTI)
using I-131 tositumomab in treatment of non-Hodgkins
lymphoma were reported by Hadid and coworkers [32C].
This institutional study of 48 patients report manageable
but predominantly hematological toxicity.
Hypothyroidism
The incidence of hypothyroidism following the I-131
treatment in Graves disease was reported by Husseni
[33C]. The retrospective analysis was performed on 272
patients who were treated with low activity dose
(370 MBq, 125 patients) vs those treated with high activ-
ity dose (555 MBq, 147 patients). The incidence of hypo-
thyroidism following the first low activity was 24.8%
with a high treatment failure rate of 58.4%, compared
with 48.3% and 32% following high activity.
Radio Necrosis
Reulen and coworkers reported radio necrosis in six
patients (n 55) who were treated with I-131 or Y-90
labeled anti-tenascin monoclonal antibody in WHO
grade III and IV gliomas [34R].
459
ANTITHYROID DRUGS [SEDA-32,765;
SEDA-33, 884; SEDA-34, 681; SEDA-35, 754;
SEDA-36, 638; SEDA-37, 518]
Thionamides, a class of antithyroid drugs (ATDs), are
compounds that are known to inhibit thyroid hormone
synthesis. Iodine is incorporated into thyroglobulin for
the production of thyroid hormone, which is achieved
after the oxidation of iodide by peroxide. Thionamides
inhibit organification of iodine to tyrosine residues in thy-
roglobulin and the subsequent coupling of iodotyrosines
[35R]. The commonly available thionamides are pro-
pylthiouracil (PTU) and methimazole (MMI). MMI has
some intrinsic pharmacokinetic advantages over pro-
pylthiouracil in terms of longer half-life, resulting in once
daily dosing and higher patient compliance. MMI is also
known to exhibit less hepatotoxicity compared to PTU.
Carbimazole (CBZ), which is a prodrug of methimazole,
is currently not available in the Unites States.
COMMON SIDE EFFECTS
Some of the common side effects associated with PTU
and MMI include pruritus, rash, urticaria, arthralgias,
arthritis, fever, abnormal taste sensation, nausea, and
vomiting. These adverse effects were observed in 13%
of patients (n 389) taking thionamide drugs in one
study [36C].
AGRANULOCYTOSIS
Agranulocytosis, although not common, is a serious
complication of thionamide therapy. A prevalence of as
high as 0.5% has been observed within the first 2 months
of treatment with thionamide drugs [37R,38R]. The risk of
agranulocytosis is higher for ATDs when compared to
20 other classes of drugs associated with this rare complica-
tion [39R]. A 41-year-old woman receiving MMI for Graves
disease was reported to outpatient care with high fever,
lymphadenopathy and other symptoms. A diagnosis of
neutropenia was made and granulocyte colony-stimulat-
ing factor was administered leading to recovery [40A].
A Chinese study reports a 51-year-old Chinese male diag-
nosed as hyperthyroidism. After 4 weeks treatment with
MMI 20 mg/day, the patient developed agranulocytosis
and severe cholestatic hepatotoxicity. The patients symp-
toms and laboratory abnormalities disappeared after the
withdrawal of MMI. The authors report this as one of the
rare cases of synchronous ATD-induced agranulocytosis
and severe hepatotoxicity in patients with hyperthyroidism
[41A]. In a unique case of a patient with agranulocytosis
that was caused by MMI and suffering from invasive pul-
monary aspergillosis (IPA), the patient exhibited unusual
maxillofacial soft tissue swelling that required treatment
with voriconazole to normalize the tissue swelling
and maxillofacial ulcer [42A]. For the first time, a Korean
 ARTICLE IN PRESS
460 THYROID HORMONES, IODINE AND IODIDES, ANTITHYROID DRUGS
study reported that a patient with Graves disease devel-
oped post-infectious GuillainBarre syndrome (GBS) dur-
ing a course of MMI-induced agranulocytosis [43A].
MMI-induced neutropenia and ecthyma was also
reported in a pregnant patient with hyperthyroidism. The
patient subsequently had to undergo a thyroidectomy
[44A]. A 37-year-old female who was started on MMI for
hyperthyroidism was presented to medical facility for eval-
uation of suspected thyroid storm. The patient was diag-
nosed with sepsis mimicking thyroid storm as a result of
MMI-induced agranulocytosis [45A]. In a Korean study,
researchers identified a susceptibility locus of antithyroid
drug (ATD)-induced agranulocytosis. A single-nucleotide
polymorphism (SNP), rs185386680, showed the strongest
association with ATD-induced agranulocytosis. HLA-
B*38:02:01 was associated with carbimazole (CMZ)/
methimazole (MMI)-induced agranulocytosis. The authors
concluded that screening for the risk allele may help
prevent agranulocytosis in populations in which the
frequency of the risk allele is high [46C].
The EIDOS and DoTS descriptions of thionamide-
induced agranulocytosis are shown in Figure 1.
ANCA-POSITIVE VASCULITIS
Propylthiouracil (PTU)-associated vasculitis is nor-
mally associated with tetrad of fever, sore throat, arthral-
gia, and skin lesions but may also involve multiple
systems. Recently a perinuclear antineutrophil cytoplas-
mic antibody-associated vasculitis developed during treat-
ment with PTU for Graves disease was reported [47R].
A case of a 55-year-old man with toxic multinodular goiter
on MMI treatment for 6 months developed ANCA-
positive leukocytoclastic vasculitis with hemorrhagic
FIG. 1 EIDOS and DoTS description of thionamide-induce agranulocytosis.
and necrotic bullous lesions of lower extremities. The vas-
culitis resolved after termination of MMI therapy. The case
highlights the importance of monitoring for variable man-
ifestations of vasculitis in patients treated with MMI [48A].
A case of a young girl with Graves disease with symptoms
of fatigue, fever, episcleritis, and arthritis was investigated.
A multidisciplinary diagnostic work-up was used to diag-
nose a case of PTU-induced ANCA-positive vasculitis.
PTU-withdrawal, along with high-dose corticosteroids
treatment resulted in a favorable clinical outcome [49A].
A 42-year-old woman, on PTU for management of Graves
disease, was being evaluated for acute renal and hepatic
failure. Renal and hepatic failures were attributed to
PTU-induced c-ANCA production. Despite multiple clin-
ical interventions, the patients condition deteriorated and
eventually leads to a fatal outcome after 20 days of inter-
vention. The medical team report that PTU can cause
ANCA-associated vasculitis resulting in multi-organ fail-
ure [50R]. In another case study, a 27-year-old woman pre-
senting with refractory hypoxaemic respiratory failure,
haemoptysis, and thyrotoxicosis was attributed by the
authors as a rare manifestation of propylthiouracil therapy
resulting from the development of c-ANCA [51A].
A 34-year-old female was being treated for autoimmune
hyperthyroidism, 6 weeks later she exhibited purpuric pla-
ques with central necrosis on the gluteal areas [52A]. Lab-
oratory results showed the presence of cryoglobulin,
cryofibrinogen, and c-ANCA. PTU is considered to be
the most common inducer of ANCA-associated micro-
scopic polyangiitis [53R]. When PTU was stopped and
replacing it with MMI, the skin lesions improved within
a week, but the cryoglobulins, cryofibrinogens, c-ANCA
and anti-SSA remained positive even after 5 months.
 ARTICLE IN PRESS
REFERENCES
HEPATOTOXICITY
Hepatotoxicity is a rare complication of drug-induced
liver injury (DILI). DILI is a major problem for pharma-
ceutical industry and drug development. Although
MMI has been associated with liver disease, it is typically
due to cholestatic dysfunction, not hepatocellular inflam-
mation [54R]. Due to the idiosyncratic nature of the
injury, the understanding of the mechanism of these
toxicities is limited. It appears that reactive metabolite
formation and immune-mediated toxicity may play a role
in antithyroids liver toxicity, especially those caused by
MMI, though other mechanism including reactive metab-
olites formation, oxidative stress induction, intracellular
targets dysfunction may be possible [55H]. In a retrospec-
tively study analyzing 77 patients presenting with newly
diagnosed overt hyperthyroidism, the authors evaluated
the liver function tests (LTF). The researchers found that
MMI treatment can induce insignificant LFT elevation.
They concluded that MMI can be safely administered
in hyperthyroid patients with abnormal LFT [56R]. In
another retrospective study, authors examined the
prevalence of thyrotoxicosis and gestational ATD use in
women who delivered from 1996 to 2010. The authors
report that gestational ATD exposure occurred in 1.29
per 1000 motherinfant pairs but a much larger maternal
population had thyrotoxicosis but no drug exposure.
Infants of mothers with gestational ATD use or diag-
nosed thyrotoxicosis were more likely to be preterm
and admitted to the neonatal intensive care unit. Further-
more, rates of congenital malformation in babies had not
association with drug exposure [57R].
PANCREATITIS
Pancreatitis has very rarely been reported in associa-
tion with MMI treatment [58A]. A population-based
casecontrol study analyzing the database of the Taiwan
National Health Insurance Program involving 5764 indi-
viduals aged 2084 years with a first attack of acute pan-
creatitis from 1998 to 2011 was evaluated to estimate the
relative risk of acute pancreatitis associated with the use
of MMI. The study did not detect a substantial association
between the use of MMI and risk of acute pancreatitis
[59C]. Recently, a sixth case of MMI-induced pancreatitis
(according to the authors), in a patient with toxic multi-
nodular goiter was reported. The authors suggest to
explore the possibility of pancreatitis in subjects treated
with MMI in the presence of suggestive symptoms. Dis-
continuation of the drug is recommended if the diagnosis
is confirmed by elevated pancreatic enzymes [60A].
TERATOGENICITY AND BIRTH DEFECTS
MMI has been associated with a rare fetal scalp defect,
an aplasia cutis [61R]. More serious congenital malforma-
tions such as choanal atresia and tracheoesophageal
461
fistulas, also called MMI embryopathy, have also been
associated with MMI use. A recent review article ana-
lyzed 92 papers discussing use of MMI and birth defects.
The review concludes that MMI use in early pregnancy
may lead to birth defects in 23% of the exposed children
and that the defects are often severe. Proposals are given
on how to minimize the risk of birth defects in fertile
women treated for hyperthyroidism with ATDs [62R].
In a recent study, authors conducted a review to identify
reports associated with aplasia cutis congenital (ACC)
under MTZ/CMZ reported in the literature. In most
instances, exposure occurred in the first weeks of gestation.
Six familial cases involving siblings were identified. The
authors recommend that practitioners should be aware of
ACC following MTZ/CMZ exposure in utero [63R].
Another study explored the association of genetics with
MMI/CBZ therapy. The case reports 2 siblings with phys-
ical features consistent with carbimazole/MMI embryopa-
thy. Also reported is a previously unreported minor dental
anomaly in this sibling pair with antenatal exposure of CBZ
[64A]. A Danish study looked at the use of MMI/CMZ and
PTU in early pregnancy, and its association with an
increased prevalence of birth defects. The prevalence of
birth defects was higher in children exposed to ATDs
in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/
CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%;
p < 0.001). Both maternal use of MMI/CMZ (adjusted
OR 1.66 [95% CI 1.352.04]) and PTU (1.41 [1.031.92])
and maternal shift between MMI/CMZ and PTU in early
pregnancy (1.82 [1.083.07]) were associated with an
increased odds ratio (OR) of birth defects. MMI/CMZ
and PTU toxicities were also associated with the urinary
system. Choanal atresia, esophageal atresia, omphalocele,
omphalomesenteric duct anomalies, and aplasia cutis were
common in MMI/CMZ-exposed children (combined,
adjusted OR 21.8 [13.435.4]) [37R].
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