Key-words:
Efficacy - Graves' disease - hyperthyroidism - primary hyperthyroidism - radioactive
iodine - toxic multinodular goiter - treatment
Introduction
Hyperthyroidism is frequently encountered in general clinical practice with an estimated
prevalence of 0.75%.[[1]] The most common causes of hyperthyroidism are Graves' disease (GD), toxic multinodular
goiter (TMNG), and toxic adenoma (TA). The management options include the use of antithyroid
drugs (ATDs), radioiodine (RI) ablation, or surgery. All of these modalities are effective
in controlling hyperthyroidism, and each has its pros and cons.
While ATDs are popular in Europe, RI therapy is the first choice in North America.[[2]],[[3]] In addition to patient preference, current guidelines favor RI for patients with
ATDs-related side effects or resistance, post thyroid surgery and as curative therapy
for GD, TA, or TMNG.[[4]] Except for small risk of worsening Graves orbitopathy (GO) in a subset of patients,
RI is generally safe and well tolerated.[[5]]
The efficacy of RI has been reported in several studies with a cure rate ranging between
50% and 90% after a single therapeutic dose.[[6]],[[7]],[[8]],[[9]],[[10]] In addition to other established factors, a recent report from New Zealand suggested
that ethnicity may influence RI therapy outcomes.[[11]] To the best of our knowledge, to date, no studies have evaluated the use and efficacy
of this modality of treatment in the UAE. Such information is valuable when counseling
our patients and will help the informed decision process.
This study aims to assess the clinical characteristics and treatment outcomes of patients
with hyperthyroidism treated with RI therapy.
Patients and Methods
Setting
The nuclear medicine electronic database at Tawam hospital, the largest tertiary care
center in the city of Al Ain, UAE, was used. All patients treated with RI for hyperthyroidism
between January 2009 and March 2017 were included in the study.
Patients' demographics, diagnosis, duration of disease, time to RI therapy, the dose
of RI, treatment efficacy, and adverse effects were collected from the medical records.
The diagnosis was verified using clinical, laboratory thyroid function tests, thyroid
antibodies including thyroid receptor antibodies, and/or imaging (scintigraphy or
ultrasound) data as per established guidelines.[[4]] As per the hospital protocol, following RI therapy, patients were followed 4–6
weeks initially and then every 2–3 months at the discretion of the treating physician
to assess response to treatment. Treatment is considered efficacious if cure, defined
as development of hypothyroidism (high thyroid-stimulating hormone [TSH] or low-free
thyroxine [FT4]) or euthyroidism (normal FT4, normal TSH) off ATDs, is achieved within
6 months of therapy. The study was approved by Al Ain Medical District Ethical Committee
(AAMDEC) (CRD 506/17).
Radioiodine dose
The dose of RI was decided by the treating nuclear medicine physician, and it was
estimated according to goiter size, diagnosis, and percentage of RI uptake on the
diagnostic thyroid scan.
Statistical analysis
Continuous data are presented as means and standard deviations (SDs) or median and
range according to the studied variable. Categorical comparisons were performed with
the Chi-Square test. Simple binary logistic regression was used to find the degree
of association with independent and dependent variables. Statistical significance
was considered if P < 0.05.
Results
Demographic and clinical characteristics
A total of 125 patients (68.8% women) were included in the study [[Table 1]]. The mean age at RI therapy was 40 years ± 15.1 (range: 10–71). The UAE nationals
were 50.4% (n = 63) of the studied patients. About 32.8% of patients (n = 41) were
referred from outside our center.
Table 1: Patientsʼ demographic characteristics and indications for use of radioiodine therapy
The etiology of hyperthyroidism was available for 121 patients; GD (n = 83, 68.6%),
TMNG (n = 31, 25.6%), and TA (n = 7, 5.8%). Only 9.8% of patients with GD patients
had abnormal eyes' findings of GO. The three most common reasons for selecting RI
therapy were patient/physician preference (71.6%), relapse of hyperthyroidism off
ATDs (15.5%), and neutropenia (6%). The complete data on the status of ATDs pre-RI
therapy were available in 114 out of 125 patients. Most patients (n = 109, 87.2%)
were pretreated with ATDs, and 70.3% of these were treated for more than 18 months.
The mean dose ± SD of RI for the whole cohort was 14.56 ± mCi (range: 8–25). The mean
doses were 14.7 ± 3.7, 13.7 ± 3.5, and 16.7 ± 3.9 mCi for GD, TMNG, and TA, respectively.
The median time from diagnosis to RI treatment was 30.6 months (range: 0.25–168) and
63% of the patients received RI after 18 months of the diagnosis.
Radioiodine response and treatment outcomes
Proper follow-up after RI therapy was available for 97 patients. Of those, 89 (91.8%)
patients achieved cure [[Table 2]]. Patients with GD developed hypothyroidism more frequently than TMNG or TA (80.6%
vs. 65.2% vs. 33.3%, respectively). In contrast, patients with TA were more likely
to develop euthyroid status and be free off thyroxine replacement [33.3%; [[Figure 1]]. Data on time to achieve cure were available in 76 patients. Of those, 16 (21%)
patients were cured within 3 months and 60 (79%) patients between 3 and 6 months.
There were eight patients out of 97 (8.3%) who remained thyrotoxic 6 months post-RI
therapy. Of those, five patients needed a 2nd dose of RI, and all were rendered hypothyroid,
two patients continued on ATDs, and one patient developed hypothyroidism 7 months
post-RI therapy.
Table 2: Doses and response to radioiodine therapy
Figure 1: Response rates to radioiodine therapy by etiology. X-axis shows the rates and type
of response as percentages and Y-axis indicates the etiology of hyperthyroidism. TA:
Toxic adenoma, GD: Gravesʼ disease, TMNG: Toxic multinodular goiter
Predictive factors of treatment response
Predictors of cure in response to RI treatment were analyzed using a logistic regression
model. The variables included age, gender, nationality, diagnosis, time to RI Therapy,
RI dose, pretherapy ATDs' use, presence of GO, percentage of RI uptake on diagnostic
scan, and thyroid hormone levels. Out of these parameters, only RI dose was higher
in the cured group (14.7 ± 3.7 SD vs. 11.9 ± 3.2 SD; P < 0.05) with an odds ratio
of 1.26 (confidence interval: 1.01–1.62); each 1 mCi increase of RI dose (above 8
mCi) will increase the chance of cure by 26%. Age did not show any statistically significant
association with cure rate, and data on other variables were not enough to perform
further analysis.
Radioiodine adverse events
Three patients presented shortly after RI therapy with worsening symptoms of hyperthyroidism
and biochemical evidence of further elevation thyroid hormones. Of those, one was
treated with ATD, prednisone was added in another, and one required short hospital
admission and was treated with steroids and had an uncomplicated course. One patient
developed new orbitopathy and needed intravenous steroids followed by surgical intervention.
Two patients with mild orbitopathy were treated with prednisone before RI treatment,
and none of those has any worsening of the preexisting condition.
Discussion
RI is an important modality for the treatment of hyperthyroidism and has been in clinical
use for about 80 years.[[10]] It is the first-line therapy for hyperthyroidism in North America in contrast to
Europe and Asia where ATDs are popular. In our study, the time from diagnosis of hyperthyroidism
to receiving RI therapy was more than 18 months in the majority of patients. This
may suggest that RI is not the preferred treatment modality in our patients or by
our physicians. This finding is in keeping with a recent survey of physicians treating
GD in the Middle East and North Africa region, 40% of participants from UAE, showing
that 60% would use ATDs as their first-line therapy.[[12]] Since there is a delay in resorting to RI treatment, future studies are needed
to explore the patient–physician barriers to utilizing RI as a mode of treatment.
In addition to patients' preference, RI therapy is used for patients developing agranulocytosis
or derangement of liver enzymes on ATDs.[[4]] In this study, about a quarter of the patients were referred to RI due to other
compelling medical reasons including ATDs intolerance, neutropenia, and hepatotoxicity.
The cure rate after a single dose of RI treatment in our cohort was slightly higher
(91.8%) than in many other studies.[[6]],[[7]],[[8]],[[9]],[[10]] This difference could be attributed to other factors such as patients' characteristics,
the definition of cure, RI dose, or its method of calculation. In general, there are
two ways of selecting the treatment of RI; fixed or calculated dose. There is no definitive
evidence that one is superior to the other.[[4]] In our center, using semicalculated method by a single treating nuclear medicine
physician, almost for the entire study period, may have resulted in such a higher
cure rate.
The majority of our patients achieved cure 3–6 months after RI therapy while some
made it earlier. Furthermore, all the five patients treated with the 2nd dose of RI
were cured. Our findings are in agreement with the current guidelines that recommend
monitoring thyroid functions test 4–6 weeks after RI therapy and advice repeating
RI therapy at 6 months mark for those with persistent hyperthyroidism.[[4]] In our study, hypothyroidism developed more commonly in GD patients following RI
while euthyroid status was seen more frequently in patients with TA and TMNG. This
differential response to RI therapy has been reported in other studies and is attributed
to the sparing effect of RI therapy on the suppressed nontoxic normal thyroid tissue
in TA and TMNG.[[5]],[[13]]
In our study, only the higher RI dose predicted a favorable response to RI therapy.
Similarly, other studies showed that higher RI dose was not only associated with higher
cure rate but also reduced time to achieve cure.[[14]] Data on other known predictors of successful RI such as goiter size and levels
of thyroid receptors antibodies were not available in our study. Identification of
those patients is essential so that a proper RI dose can be selected, and careful
follow-up posttherapy is considered primarily for elderly patients or those with cardiovascular
disease. It is critical to develop structured clinical practice guidelines in following
up patients post-RI treatment for short- and long-term adverse effects.
De novo or worsening GO is one of the main limiting factors when considering RI therapy.
It has been reported to occur in 7.5%–15% of patients with GD following RI.[[15]] In our study, only one patient developed severe GO requiring surgery and radiation
therapy. This low risk could be due to preselection of patients with no or mild GO
to undergo RI therapy. In a landmark study, Bartalena L et al. demonstrated in a prospective
randomized controlled trial that steroid coverage mitigates the adverse effects of
RI on GO.[[5]] Two of our patients with established GO were pretreated with steroids before RI
and none developed worsening of GO.
The limitations of our study include its retrospective nature with inadequate documentation
of variables predictive of treatment response such as goiter size and thyroid receptor
antibodies for many of the patients. Besides, response to RI treatment lacked in a
proportion of the referred cases due to loss of structured follow-up.
Conclusions
The present study showed that a single dose of RI is highly effective in controlling
hyperthyroidism in our cohort. The prolonged duration of hyperthyroidism from the
diagnosis to RI therapy suggests that ATDs remain as the primary modality of choice
for the majority of our patients. Hence, further studies are needed to explore the
patient–physician barriers in the delay of utilizing RI as the mode of treatment in
hyperthyroidism in the appropriately selected patients.
Author's contributions
KA: Study design, ethical approval, data collection, data entry, data analysis, and
drafting the manuscript; BA: Study design, data verification, data analysis, and revising
the manuscript; MA: Data collection and data cleansing; JS: Statistical analysis;
and KA, BA, SY, JA reviewed and edited the manuscript.
Compliance with ethical principles
The study was approved by AAMDEC (CRD 506/17). Patients in our hospital provide a
general consent allowing the anonymized use of their data for education, quality assurance,
and research without the need for specific consent.
Reviewers:
Kamal Abouglila (Durham, UK)
Aly B Khalil (Abu Dhabi, UAE)
Editors:
Salem A Beshyah (Abu Dhabi, UAE)
Elmahdi A Elkhammas (Columbus, OH, USA)
