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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
Corresponding author:

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

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

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

Side Effects of Drugs Annual 455 2016 Elsevier B.V. All rights reserved.
ISSN: 0378-6080


relation between QOL and various parameters in hypo- Bone Loss

thyroid patients who were taking levothyroxine [3R]. Effects of levothyroxine (LT4) on bone and bone meta-
They evaluated the QOL in 90 patients (20 males and bolism are controversial [7C]. To address this author
70 females) who were treated for primary hypothyroid- examined mean bone losses in 93 patients with well-
ism using Short-Form 36, Hospital Anxiety and Depres- differentiated carcinoma over 12 months after initiating
sion Scale and MFI20. The Post hoc analysis was levothyroxine therapy. It was found that there was a mean
performed on the relation of QOL at baseline, BMI, thy- bone losses in the lumbar spine, femoral neck, and total
roid hormones, and other serum values. It was found that hip; however, the loss was more prominent in postmeno-
there exists an inverse relationship between QOL and pausal women. Authors also observed that the loss
BMI, and a decreased QOL was observed in hypothyroid was higher in postmenopausal women who received
patients on thyroxine treatment. This was mainly due to no supplementation of calcium/vitamin D. Hence, the
their higher body weight (BMI) and hence the authors authors concluded that TSH-suppressive levothyroxine
concluded that weight gain should be one of the focus therapy can accelerate bone loss predominantly in
while treating hypothyroid patients as it can decrease postmenopausal women and mainly during the early
their QOL. post-thyroidectomy period but the loss can be reduced
by adding calcium/vitamin D to the therapy.
Rheumatoid Arthritis (RA)
On the similar lines Nyandege and coworkers have
Levothyroxine has been shown to increase the risk of suggested that the concomitant use of bisphosphonates
developing rheumatoid arthritis for patients with auto- and other medications, which can stimulates bone metab-
immune disorders [4R]. In this study authors compared olism such as acid-suppressive therapy, levothyroxine,
1998 patients using levothyroxine along with 2252 con- thiazolidinediones (TZDs), and selective serotonin reup-
trols for incident RA cases. They found that patients on take inhibitors (SSRIs), can increase the risk of fracture
levothyroxine were at twofold risk for RA [4R]. [8R]. Authors found that the concomitant use of acid sup-
pressive agents with bisphosphonate can increase the risk
Vitamin D Deficiency
of fracture. However, they suggested that TZDs, SSRIs,
The use of levothyroxine has also been implicated and levothyroxine can have similar implications based
for vitamin D deficiency. Authors compared 25-hydroxy- on their pharmacological action. Hence, precaution
vitamin D and parathyroid hormone (PTH) levels should to be taken while using bisphosphonates along
between four groups of non-lactating women [5C]. Group with these other medications.
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 CARDIOVASCULAR DISORDERS
with non-autoimmune hypothyroidism, and group A prospective, controlled, single-blind study was
D was a control which included 15 healthy euthyroid conducted by Bakiner et al. to determine plasma Fetuin
females. The patients in both groups A and C were treated A levels in hypothyroid patients (n 39) before and
with L-thyroxine for 6 months. After 6 months, it was after levothyroxine treatment. Additionally, authors
found that the serum levels of 25-hydroxyvitamin wanted to figure out if there is any association
D were lowered in group A than in group B, as well as between Fetuin A levels and cardiovascular risk in
in group C in comparison with group D. Hence, the those patients [9C]. Authors found that there was no
authors concluded that there is an association of vitamin correlation between Fetuin A levels and cardiovascular
D status with post-partum thyroiditis and levothyroxine risk factors; however, the mean HDL cholesterol levels
treatment. decreased in those patients from 49.3 (2383.9) to
44 (28.369.0) [9C].
Multiple Subungual Pyogenic Granulomas
A 54-year-old woman who was taking levothyroxine
for hypothyroidism for 3 months presented with rapidly Drug Overdose
growing lesions in her nail beds [6R]. Examination The pharmacological effects of levothyroxine on car-
revealed red nodules that had invaded beneath the nail diac cells are well know where in high doses of levothyr-
plates. The patient also took venlafaxine 75 mg use once oxine can cause severe toxic effects in the patient [10A].
a day for depression for 10 years and intermittent ibupro- Stuijver et al. reported a case of 23-year-old woman who
fen use (which was stopped a year ago) for osteoarthritis. attempted suicide by ingesting 25 mg of levothyroxine
A wide excision was performed but the symptoms [10A]. The patient experienced hypercoagulation and
relapsed as noted during the 3-month follow-up period. a hypofibrinolytic effect, reflecting an increased risk of
Levothyroxine treatment was stopped and the symptoms venous thrombosis [10A]. Similarly, a 61-year-old
did not recur [6R]. patient who accidentally ingested 1000 times excess of

IODINE AND IODIDES [SED-15, 1896; SEDA-32, 764; SEDA-33, 883; SEDA-34, 680; SEDA-35, 752; SEDA-36; SEDA-37, 514] 457
levothyroxine rather than the actual dose of 50 mg preoperative octreotide are effective in suppressing
exhibited altered mental consciousness, acute respira- TSHoma and should be recommended to patients to
tory failure, and atrial fibrillation [11A]. avoid problems with hyperthyroidism.

DrugDrug Interaction
Levothyroxine can interact with various other drugs. IODINE AND IODIDES [SED-15, 1896;
In an observational study carried out by Irving and SEDA-32, 764; SEDA-33, 883; SEDA-34, 680;
coworkers, the authors wanted to evaluate the effect of SEDA-35, 752; SEDA-36; SEDA-37, 514]
drugs co-administered on thyroxine [12C]. This study
evaluated 10 999 patients (mean age 58 years, 82% female) Dietary Iodine
who were prescribed levothyroxine on at least three occa-
sions within a 6-month period, prior to the start of a Iodine is an essential component of thyroid hormones,
study. They found that both iron and calcium supple- and Iodine deficiency can have serious adverse effects on
ments, proton pump inhibitors, and oestrogen were ones growth and development. The deficiency of iodine
responsible for the increase in serum TSH concentration in pregnant women can result in spontaneous abortion,
(7.5%, 4.4%, 5.6% and 4.3%), respectively. However, there stillbirth, and cretinism. The World Health Organization
was a decrease in the TSH concentration (0.17 mU/L) for (WHO) recommends the use of iodinated salt to compen-
those patients on statins. Hence, the authors concluded sate for any iodine deficiency. Moreover, WHO also
that there is a significant interaction between levothyrox- reports the most common side effects reported for iodine
ine and iron, calcium, proton pump inhibitors, statins and deficiency [12C].
oestrogens. Co-administration of these drugs with Excessive iodine intake can severely effect TSH levels.
levothyroxine may reduce the effectiveness of levothyr- In one study, infants (aged 624 months), who were
oxine therapy, and hence the TSH concentrations in those exposed to excessive iodine, were found to have subclin-
patients should be carefully monitored. ical hypothyroidism [15C]. Water was assumed to be the
The amount of levothyroxine absorbed can also be source of excessive intake of iodine in lactating mother of
affected by the co-administration of other drugs such as cip- those infants [16C].
rofloxacin or rifampin [13A]. In a randomized, double- Higher dietary iodine in iodine-deficient areas can also
blind, placebo-controlled study on 8 healthy volunteers be correlated to thyroid cancer. In fact, it was observed that
who received either 1000 g of levothyroxine and placebo, patients who lived in iodine-deficient areas had a higher
or 1000 g of levothyroxine and 750 mg ciprofloxacin, risk of thyroid cancer if they had a diet high in iodine than
or 1000 g of levothyroxine and 600 mg rifampin authors those compared with the ones living in non deficient areas
found that the co-administration of ciprofloxacin signifi- [17M]. Similar correlation was found in cruciferous vege-
cantly decreased the area T4 levels by 39% (p 0.035), tables [17M]. Thus the authors implied that dietary roles
whereas, rifampin co-administration significantly increased play an important part in thyroid cancer [17M].
T4 by 25% (p 0.003). 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
Octreotide [18A]. His diet was restricted to cows milk protein, soya
(33.7 kUA/L), wheat and egg (>100 kUA/L), fish cod
The use of preoperative administration of octreotide in (65.2 kUA/L), shellfish and peanuts (>100 kUA/L) and
cohort of patients with TSH secreting pituitary adenomas tree nuts (1.46.8 kUA/L) (normal reference range
(TSHoma) was evaluated by Fukuhara et al. [14C]. <0.35 kUA/L). He was on Flixotide, salbutamol, cetiri-
Authors discovered that of 81 patients who underwent zine hydrochloride, and fluticasone propionate nasal
surgery for TSHoma at Toranomon Hospital between spray and steroid creams for his atopic disorders [18A].
January 2001 and May 2013, 44 received preoperative His TSH levels were slightly raised, whereas, his T4 levels
short-term octreotide. Further, among these 44 patients were low, suggesting secondary hypothyroidism. Later a
19 received octreotide as a subcutaneous injection, and soft and smooth goiter was found during following
24 patients received octreotide as a long-acting release assessments which was correlated to the severe defi-
(LAR) injection, and one of them was excluded due to ciency in dietary iodine [18A].
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
Iodine-125 Brachytherapy
effects such as mild diarrhea (5 patients), constipation
(1 patient), nausea and elevation of bilirubin (1 patient) Iodine-125 has a relatively long half-life (59.4 days)
were observed. Hence, the authors concluded that and emits low-energy photons (35 keV), making it a


preferred isotope for radiation therapy (brachytherapy, In a nationwide multi-institutional study aimed at com-
BT) to treat prostate cancer and brain tumors. paring the use of I-125 brachytherapy for permanent seed
implant (PI) and combination therapy with PI and external
Ophthalmic Side Effect beam radiation therapy (EBRT), Ohashi and coworkers
Application of I-125 brachytherapy in the treatment of reported urinary and rectal toxicity profiles as the major
intraocular tumor has been associated with radiation- side effects [24R]. Grade 2+ acute urinary toxicities devel-
induced ophthalmic side effects. The radiation affects oped in 7.36% (172 of 2337) of patients and grade 2+ acute
the organs around the ocular cavity, eyelids, eyelashes, rectal toxicities developed in 1.03% (24 of 2336) of the
conjunctiva, tear production, corneal surface, sclera, patients. Grade 2+ late urinary and rectal toxicities devel-
and ocular muscles. Within the eye, radiation can cause oped in 5.75% (133 of 2312) and 1.86% (43 of 2312) of the
iritis, uveitis, synechiae, neovascular glaucoma, cataract, patients, respectively. A higher incidence of grade 2+ acute
posterior neovascularization, hemorrhage, retinal detach- urinary toxicity occurred in the PI group than in the EBRT
ment, retinopathy, and optic neuropathy [19S]. Radiation group (8.49% vs 3.66%; p < 0.01). Acute rectal toxicity out-
side effects from I-125 brachytherapy can result in loss comes were similar between the treatment groups.
of vision and quality of life. Keyes and coworkers evaluated the long-term effect of
Tsui and coworkers reported a decrease in visual acu- I-125 brachytherapy on erectile function (EF) of prostate
ity, contrast sensitivity, and color vision in patients with cancer patients [25R]. In this study (n 2929), EF was sig-
choroidal and ciliary body melanoma (CCM) [20C]. nificantly reduced 6 weeks after brachytherapy, with
Authors measured visual acuity, contrast sensitivity gradual decline thereafter. EF preservation at 5 years
and color vision in 37 patients, 1, 2, and 3 years after for age younger than 55, 5659, 6064, 6569, and 70 years
I-125 brachytherapy. These 37 patients were grouped into and older was 82%, 73%, 58%, 39%, and 23%, respec-
4 groups. Prior to (group 1), 1 year after (group 2), 2 years tively. Comparisons of the 5-year age-related and
after (group 3), and 3 years (group 4). It was found that treatment-related EF decline show that 50% of the long-
after brachytherapy, group 1, 2, 3, and 4 had mean best- term EF decline is related to aging.
corrected visual acuity of 77 letters (20/32), 65 letters Eriguchi and coworkers reported neoadjuvant andro-
(20/50), 56 letters (20/80) and 47 letters (20/125), respec- gen deprivation therapy (NADT) as a key factors associ-
tively, and a contrast sensitivity of 30, 26, 22 and 19 letters; ated with urinary toxicities in localizes prostate cancer
color vision of 26, 20, 17 and 14 test figures, respectively. treated with I-125 brachytherapy [26R]. In this study
Radiation-induced mid-choroid, macula melanoma, radi- authors evaluated 1313 patients, between 2003 and 2009
ation maculopathy and radiation optic neuropathy were to examine the role of base line international prostate
also reported for these patients [20C]. symptom score, biologically effective dose (BED), age,
In a study, comparing the transscleral resection with- and NADT. Urinary symptom flare and urinary Grade 2
out hypotensive anesthesia vs I-125 brachytherapy, for or higher (G2+) toxicity occurred in 51%, 58%, and 67%
the treatment of choroidal melanoma, radiation induce (p 0.025) and 16%, 22%, and 20% (p 0.497) of the
side effects were reported. The most common side effects <180, 180220, and >220 Gy BED groups, respectively.
for I-125 brachytherapy in 53 patients were radiation- When patients were divided into four groups according
induced retinopathy (45.3%), neovascular glaucoma to prostate volume (<30 or 30 cc) and NADT use, uri-
(28.3%), and macular oedema (24.5%) [21R]. nary G2+ toxicity was most commonly observed in those
A 69-year-old female who underwent I-125 brachy- patients with larger prostates who received NADT, and
therapy in scleral buckle was diagnosed with decreased least in the patients with smaller prostates and no NADT.
vision and occasional floaters in the left eye [22A]. Strom and coworkers reported a comparative study on
prostate cancer patients who were treated with either
Lower Abdominal Side Effects high-dose-rate (HDR) brachytherapy, low-dose-rate
Iodine-125 brachytherapy in the treatment of localized (LDR) brachytherapy, intensity-modulated radiation
prostate cancer is associated with radiation-induced bowl therapy (IMRT), and monotherapy to investigate the
symptoms, decrease erectile function, and lower urinary effect on their urinary, bowel, and sexual health-related
tract symptoms. Among these symptoms, lower urinary quality-of-life (HRQOL) [27R]. Study was conducted
tract symptoms are the most manifested. between years 2002 and 2013 with median follow-up of
In a single-center longitudinal study (19942007) con- 32 months. The authors observed that patients on both
ducted by Wilson and coworkers, 207 patients with HDR brachytherapy (n 85, 27002800 cGy in two frac-
localized prostate cancer were monitored for the bio- tion) and IMRT (n 79, monotherapy to 74008100 cGy
chemical disease-free survival and side effects of I-125 in 3745 fractions) had significantly less deterioration in
brachytherapy. The peak incidences of late grade 3 or their urinary incontinence and HRQOL than those on
higher urinary and rectal toxicities were 10.7% and LDR (n 249, monotherapy to 14 500 cGy in one fraction)
1.1%, respectively [23R]. brachytherapy patients as seen 1 and 3 months after

ANTITHYROID DRUGS [SEDA-32,765; SEDA-33, 884; SEDA-34, 681; SEDA-35, 754; SEDA-36, 638; SEDA-37, 518] 459
irradiation. Additionally, HDR brachytherapy patients ANTITHYROID DRUGS [SEDA-32,765;
had worse sexual HRQOL than both LDR brachytherapy SEDA-33, 884; SEDA-34, 681; SEDA-35, 754;
and IMRT patients after treatment. SEDA-36, 638; SEDA-37, 518]
Lower urinary tract symptoms and bowl symptoms
were also reported for the rectal cancer patients. In a study Thionamides, a class of antithyroid drugs (ATDs), are
of 17 rectal patients, I-125 brachytherapy was found as compounds that are known to inhibit thyroid hormone
independent risk factor for urinary dysfunction [28C]. synthesis. Iodine is incorporated into thyroglobulin for
Peters and coworkers reported the dose-dependent GI tox- the production of thyroid hormone, which is achieved
icity associated with I-125 brachytherapy in rectal cancer after the oxidation of iodide by peroxide. Thionamides
patients. Total salvage (TS) patients with severe GI toxicity inhibit organification of iodine to tyrosine residues in thy-
(41%, n 11) showed significantly higher rectal doses than roglobulin and the subsequent coupling of iodotyrosines
TS patients without GI toxicity (59%, n 16) [29C]. [35R]. The commonly available thionamides are pro-
pylthiouracil (PTU) and methimazole (MMI). MMI has
some intrinsic pharmacokinetic advantages over pro-
Iodine-131 pylthiouracil in terms of longer half-life, resulting in once
Iodine-131 (131I) is the most commonly used iodine daily dosing and higher patient compliance. MMI is also
radioisotope, and it decays mostly by beta-emission known to exhibit less hepatotoxicity compared to PTU.
(606 keV; 90%). It is notable for causing death in cells that Carbimazole (CBZ), which is a prodrug of methimazole,
it penetrates and other cells up to several millimeters is currently not available in the Unites States.
away. For this reason, 131I is used for the treatment of thy-
rotoxicosis (hyperthyroidism) and some types of thyroid COMMON SIDE EFFECTS
cancer that absorb iodine. The 131I isotope is also used as Some of the common side effects associated with PTU
a radioactive label for certain radiopharmaceutical thera- and MMI include pruritus, rash, urticaria, arthralgias,
pies, e.g. 131I-metaiodobenzylguanidine (131I-MIBG) for arthritis, fever, abnormal taste sensation, nausea, and
treating pheochromocytoma and neuroblastoma. Iodine- vomiting. These adverse effects were observed in 13%
131 also emits high-energy gamma radiation (364 keV, of patients (n 389) taking thionamide drugs in one
10%) that can be used for imaging [30C]. Adverse reactions study [36C].
with the use of 131I include myelotoxicity, swelling and
tenderness of salivary glands, nausea, vomiting, dry
mouth, and hypothyroidism [31C].
Agranulocytosis, although not common, is a serious
Hematological Toxicity complication of thionamide therapy. A prevalence of as
high as 0.5% has been observed within the first 2 months
Safety and efficacy of radio immunotherapy (RTI)
of treatment with thionamide drugs [37R,38R]. The risk of
using I-131 tositumomab in treatment of non-Hodgkins
agranulocytosis is higher for ATDs when compared to
lymphoma were reported by Hadid and coworkers [32C].
20 other classes of drugs associated with this rare complica-
This institutional study of 48 patients report manageable
tion [39R]. A 41-year-old woman receiving MMI for Graves
but predominantly hematological toxicity.
disease was reported to outpatient care with high fever,
lymphadenopathy and other symptoms. A diagnosis of
neutropenia was made and granulocyte colony-stimulat-
The incidence of hypothyroidism following the I-131 ing factor was administered leading to recovery [40A].
treatment in Graves disease was reported by Husseni A Chinese study reports a 51-year-old Chinese male diag-
[33C]. The retrospective analysis was performed on 272 nosed as hyperthyroidism. After 4 weeks treatment with
patients who were treated with low activity dose MMI 20 mg/day, the patient developed agranulocytosis
(370 MBq, 125 patients) vs those treated with high activ- and severe cholestatic hepatotoxicity. The patients symp-
ity dose (555 MBq, 147 patients). The incidence of hypo- toms and laboratory abnormalities disappeared after the
thyroidism following the first low activity was 24.8% withdrawal of MMI. The authors report this as one of the
with a high treatment failure rate of 58.4%, compared rare cases of synchronous ATD-induced agranulocytosis
with 48.3% and 32% following high activity. and severe hepatotoxicity in patients with hyperthyroidism
[41A]. In a unique case of a patient with agranulocytosis
Radio Necrosis that was caused by MMI and suffering from invasive pul-
Reulen and coworkers reported radio necrosis in six monary aspergillosis (IPA), the patient exhibited unusual
patients (n 55) who were treated with I-131 or Y-90 maxillofacial soft tissue swelling that required treatment
labeled anti-tenascin monoclonal antibody in WHO with voriconazole to normalize the tissue swelling
grade III and IV gliomas [34R]. and maxillofacial ulcer [42A]. For the first time, a Korean


study reported that a patient with Graves disease devel- and necrotic bullous lesions of lower extremities. The vas-
oped post-infectious GuillainBarre syndrome (GBS) dur- culitis resolved after termination of MMI therapy. The case
ing a course of MMI-induced agranulocytosis [43A]. highlights the importance of monitoring for variable man-
MMI-induced neutropenia and ecthyma was also ifestations of vasculitis in patients treated with MMI [48A].
reported in a pregnant patient with hyperthyroidism. The A case of a young girl with Graves disease with symptoms
patient subsequently had to undergo a thyroidectomy of fatigue, fever, episcleritis, and arthritis was investigated.
[44A]. A 37-year-old female who was started on MMI for A multidisciplinary diagnostic work-up was used to diag-
hyperthyroidism was presented to medical facility for eval- nose a case of PTU-induced ANCA-positive vasculitis.
uation of suspected thyroid storm. The patient was diag- PTU-withdrawal, along with high-dose corticosteroids
nosed with sepsis mimicking thyroid storm as a result of treatment resulted in a favorable clinical outcome [49A].
MMI-induced agranulocytosis [45A]. In a Korean study, A 42-year-old woman, on PTU for management of Graves
researchers identified a susceptibility locus of antithyroid disease, was being evaluated for acute renal and hepatic
drug (ATD)-induced agranulocytosis. A single-nucleotide failure. Renal and hepatic failures were attributed to
polymorphism (SNP), rs185386680, showed the strongest PTU-induced c-ANCA production. Despite multiple clin-
association with ATD-induced agranulocytosis. HLA- ical interventions, the patients condition deteriorated and
B*38:02:01 was associated with carbimazole (CMZ)/ eventually leads to a fatal outcome after 20 days of inter-
methimazole (MMI)-induced agranulocytosis. The authors vention. The medical team report that PTU can cause
concluded that screening for the risk allele may help ANCA-associated vasculitis resulting in multi-organ fail-
prevent agranulocytosis in populations in which the ure [50R]. In another case study, a 27-year-old woman pre-
frequency of the risk allele is high [46C]. senting with refractory hypoxaemic respiratory failure,
The EIDOS and DoTS descriptions of thionamide- haemoptysis, and thyrotoxicosis was attributed by the
induced agranulocytosis are shown in Figure 1. authors as a rare manifestation of propylthiouracil therapy
resulting from the development of c-ANCA [51A].
ANCA-POSITIVE VASCULITIS A 34-year-old female was being treated for autoimmune
Propylthiouracil (PTU)-associated vasculitis is nor- hyperthyroidism, 6 weeks later she exhibited purpuric pla-
mally associated with tetrad of fever, sore throat, arthral- ques with central necrosis on the gluteal areas [52A]. Lab-
gia, and skin lesions but may also involve multiple oratory results showed the presence of cryoglobulin,
systems. Recently a perinuclear antineutrophil cytoplas- cryofibrinogen, and c-ANCA. PTU is considered to be
mic antibody-associated vasculitis developed during treat- the most common inducer of ANCA-associated micro-
ment with PTU for Graves disease was reported [47R]. scopic polyangiitis [53R]. When PTU was stopped and
A case of a 55-year-old man with toxic multinodular goiter replacing it with MMI, the skin lesions improved within
on MMI treatment for 6 months developed ANCA- a week, but the cryoglobulins, cryofibrinogens, c-ANCA
positive leukocytoclastic vasculitis with hemorrhagic and anti-SSA remained positive even after 5 months.

FIG. 1 EIDOS and DoTS description of thionamide-induce agranulocytosis.


HEPATOTOXICITY fistulas, also called MMI embryopathy, have also been
Hepatotoxicity is a rare complication of drug-induced associated with MMI use. A recent review article ana-
liver injury (DILI). DILI is a major problem for pharma- lyzed 92 papers discussing use of MMI and birth defects.
ceutical industry and drug development. Although The review concludes that MMI use in early pregnancy
MMI has been associated with liver disease, it is typically may lead to birth defects in 23% of the exposed children
due to cholestatic dysfunction, not hepatocellular inflam- and that the defects are often severe. Proposals are given
mation [54R]. Due to the idiosyncratic nature of the on how to minimize the risk of birth defects in fertile
injury, the understanding of the mechanism of these women treated for hyperthyroidism with ATDs [62R].
toxicities is limited. It appears that reactive metabolite In a recent study, authors conducted a review to identify
formation and immune-mediated toxicity may play a role reports associated with aplasia cutis congenital (ACC)
in antithyroids liver toxicity, especially those caused by under MTZ/CMZ reported in the literature. In most
MMI, though other mechanism including reactive metab- instances, exposure occurred in the first weeks of gestation.
olites formation, oxidative stress induction, intracellular Six familial cases involving siblings were identified. The
targets dysfunction may be possible [55H]. In a retrospec- authors recommend that practitioners should be aware of
tively study analyzing 77 patients presenting with newly ACC following MTZ/CMZ exposure in utero [63R].
diagnosed overt hyperthyroidism, the authors evaluated Another study explored the association of genetics with
the liver function tests (LTF). The researchers found that MMI/CBZ therapy. The case reports 2 siblings with phys-
MMI treatment can induce insignificant LFT elevation. ical features consistent with carbimazole/MMI embryopa-
They concluded that MMI can be safely administered thy. Also reported is a previously unreported minor dental
in hyperthyroid patients with abnormal LFT [56R]. In anomaly in this sibling pair with antenatal exposure of CBZ
another retrospective study, authors examined the [64A]. A Danish study looked at the use of MMI/CMZ and
prevalence of thyrotoxicosis and gestational ATD use in PTU in early pregnancy, and its association with an
women who delivered from 1996 to 2010. The authors increased prevalence of birth defects. The prevalence of
report that gestational ATD exposure occurred in 1.29 birth defects was higher in children exposed to ATDs
per 1000 motherinfant pairs but a much larger maternal in early pregnancy (PTU, 8.0%; MMI/CMZ, 9.1%; MMI/
population had thyrotoxicosis but no drug exposure. CMZ and PTU, 10.1%; no ATD, 5.4%; nonexposed, 5.7%;
Infants of mothers with gestational ATD use or diag- p < 0.001). Both maternal use of MMI/CMZ (adjusted
nosed thyrotoxicosis were more likely to be preterm OR 1.66 [95% CI 1.352.04]) and PTU (1.41 [1.031.92])
and admitted to the neonatal intensive care unit. Further- and maternal shift between MMI/CMZ and PTU in early
more, rates of congenital malformation in babies had not pregnancy (1.82 [1.083.07]) were associated with an
association with drug exposure [57R]. increased odds ratio (OR) of birth defects. MMI/CMZ
and PTU toxicities were also associated with the urinary
PANCREATITIS system. Choanal atresia, esophageal atresia, omphalocele,
omphalomesenteric duct anomalies, and aplasia cutis were
Pancreatitis has very rarely been reported in associa- common in MMI/CMZ-exposed children (combined,
tion with MMI treatment [58A]. A population-based adjusted OR 21.8 [13.435.4]) [37R].
casecontrol study analyzing the database of the Taiwan
National Health Insurance Program involving 5764 indi-
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