Normalization of thyroid function tests among thyrotoxicosis patients attending a University Hospital in North-West Ethiopia

Thyrotoxicosis is a clinical state that results from inappropriately high thyroid hormone action in tissues [1]. It affects 1–3% of the general population and is 10 times more common in women than in men [2]. In the United States, the prevalence of thyrotoxicosis is approximately 1.2% [1]. The extent of thyroid disorders in Africa remains unknown because of under-diagnosis and underreporting but the few available studies note prevalence rate of 1.2 to 9.9% [3]. In Ethiopia, the prevalence of thyroid disease is reported to be 1.2% [3].

Graves’ disease (GD) is the most common cause of thyrotoxicosis. It accounts for 70–80% of cases in iodine-sufficient population and approximately 50% of cases in iodine-deficient areas [4]. Other etiologies include thyroiditis, toxic nodular goiter, toxic multinodular goiter (TMNG), toxic adenoma, and exogenous thyrotoxicosis (iatrogenic, factitious, iodine induced) [5].

Untreated thyrotoxicosis can lead to serious complications such as thyroid storm, arrhythmia, hypertension, cardiac dilation, congestive heart failure (CHF), and sudden cardiac arrest [6, 7]. The three principal treatment options for the management of thyrotoxicosis include thionamides or anti-thyroid drugs (ATDs), radioactive iodine, and surgery [1].

Ethiopia is among iodine-deficient countries in the globe. Even though, the mandatory salt iodization that was implemented in 2011 has led to significant improvements, the country has a long way to go to eradicate iodine deficiency disorders [8]. Despite the availability of studies on pharmacologic treatment outcomes among patients with thyrotoxicosis, most of the previous studies were conducted in other countries and there is scarcity of data in Ethiopia context. To the best of the authors’ knowledge, this is the first study to evaluate pharmacologic treatment outcomes among hyperthyroid patients from Ethiopia. The aim of this study was to investigate rates and determinants of normalization of thyroid function tests (TFTs) among hyperthyroid patients on ATDs attending University of Gondar Comprehensive Specialized Hospital (UoGCSH).

Evaluation of management of thyrotoxicosis requires the periodic determination of the serum level of thyroid hormones. Despite the efforts made to measure these hormones in routine clinical practice, little is known about outcome of thyrotoxicosis management in Ethiopia. The primary outcomes of this research were to determine normalization of TFTs and time needed for normalization of these tests after initiation of ATDs. TSH measurement is very important for the determination of treatment outcome in hyperthyroidism because it is more specific and sensitive indicator than other TFT values [9]. Compared to all three TFTs most patients had normalization of TSH. But TSH normalization took longer period of time as compared to T3 and FT4. This is contrary to what other studies report. Previous studies revealed that thyroid hormone levels begin to drop in 2 to 3 weeks of starting ATDs. After 6 weeks of starting ATDs, 90% of patients with GD will be euthyroid but more than 24 months ATD treatment is usually necessary to normalize TFTs in patients with TMNG [10]. The high proportion of patients with TMNG in the present study may be the main reason for low TSH normalization rates. A prospective study reported the cumulative recovery rates of serum TSH among GD patients to be: 36.7% (33/90) at 3 months, 72.2% (65/90) at 6 months, 86.7% (78/90) at 9 months, 95.6% (86/90) at 12 months [11].

In the present study, age slightly increased rate of TSH normalization. Mohlin et al. found that age and gender had no significant relation for prognosis of the disease [12]. Martin et al. study also reported that GD patients, family and personal history of thyroid and autoimmune disorders, age at diagnosis, gender, goiter size, and ophthalmopathy presence did not influence the time to TSH recovery [11]. On the other hand higher baseline FT4 levels were shown to reduce rate of TSH normalization by 0.8%. Other than these two, none of the other factors showed a statistically significant effect on the TSH values. Upon univariate analysis older age (CHR = 0.983, p = 0.009) and duration of symptoms before seeking treatment (CHR = 0.998, p = 0.047) showed a statistically significant but modest effect on FT4 normalization. The mean duration of symptoms before seeking treatment was 88 months which is a very long time. It may indicate the knowledge and attitude of the society towards hyperthyroidism and may require awareness creation with regard to early medical seeking behavior. It showed that as patients’ age gets older, the rate of FT4 normalization decreased by 1.7%. Likewise, as duration of symptom before seeking treatment increased the rate of FT4 normalization was decreased by 0.2%. But, they failed to maintain this effect up on multivariate analysis. Mohlin et al. reported that palpable goiter, or according to WHO goiter size classification stage II goiter size, was associated with worse prognosis compared with no goiter (51.2 vs. 68.9% in remission after 5 years; P = 0.014 [12]. However, the present study did not identify WHO goiter size as independent predicator of FT4 normalization. Mohlin et al. study also found that previous smokers had a higher remission rate than either current smokers or non-smokers (85.7 vs. 55.8 vs. 50.5%) respectively, in remission after 5 years; P = 0.003) but there was no difference in prognosis between smokers and non-smokers [12]. On the other hand, the present study was not able to made relation with smokers and nonsmokers.

Though most patient had symptom resolution, it took longer time than what was reported by other studies. A retrospective multicenter study by Tagami et al. reported that the signs and symptoms of patients with hyperthyroidism showed a significant improvement after just 4 weeks of taking beta-adrenergic blocking agents [13].

Because of less frequency of administration and lower risk of adverse effects, MMI is recommended as preferred ATD over PTU and should be used among all patients except during the first trimester of pregnancy, in the treatment of thyroid storm or in patients with minor adverse reactions to MMI [1, 14‐16]. However, all of the patients in the present study used only PTU. MMI is yet to be included in the national medicines formulary [17] and standard treatment guideline [18] of Ethiopia. As a result, availability of MMI remains a challenge rendering clinicians to rely mainly on the routinely available PTU.

If hyperthyroidism is left untreated, it can lead to cardiovascular complications. According to our study 11 (5.245%), 2 (0.96%) and 16 (7.62%) patients developed CHF, AF and CHF + AF, respectively. Another 3 (1.43%) patients also developed thyroid storm. A recent review article stated that the prevalence of AF among hyperthyroidism was 16–60% [19], which is more than what was found in the present study. On the other hand, Akamizu et al. found that the incidence of thyroid storm in Japan was estimated to be 0.20 persons per 100,000 population per year, accounting for 0.22% of all thyrotoxic patients and 5.4% of hospitalized thyrotoxic patients [20].

There are several adverse effects that may occur during ATD treatment. One meta-analysis found that minor complications such as a rash, gastric intolerance and arthralgia were observed in up to 19% of patients taking ATDs, while major complications occur rarely [21]. Minor allergic side effects, such as a limited, minor rash, may occur in up to 5% of patients taking either MMI or PTU [9]. In the present study, only one patient experienced arthralgia side effect (0.47%). However, as this was a retrospective study, it was difficult to objectively assess adverse effects.

Despite international guidelines’ recommendation of MMI, PTU was the only agent used for the management of hyperthyroidism. TSH and all TFT were normalized in only less than one-third of the participants. Though most patients achieved resolution of symptoms, it took longer period of time than the expected. The study showed that most of the patients were not able to achieve the state of euthyroidism within the recommended period of time. In order to identify the reasons for poor treatment outcomes, a large-scale, multicenter prospective study needs to be conducted giving emphasis mainly on medication adherence and adverse effects.