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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 10  |  Issue : 6  |  Page : 205-208

Predictors of relapse in graves' hyperthyroidism after treatment with antithyroid drugs


1 Department of Medicine, Benghazi Medical Center, Benghazi, Libya
2 Department of Medicine, Benghazi Medical Center; Department of Medicine, Faculty of Medicine, Benghazi University, Benghazi, Libya

Date of Web Publication10-Dec-2018

Correspondence Address:
Dr. Sami A Lawgaly
Department of Medicine, Benghazi Medical Center, Benghazi
Libya
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmbs.ijmbs_75_18

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  Abstract 


Background: Choice of the treatment for patients with Graves' hyperthyroidism depends on local preference, the higher recurrence risk, comorbidities, and the patient's preferences. About half of the patients relapse after a course of a standard antithyroid drug (ATD) therapy for Graves' disease. Objectives: The objective of this study was to determine the clinical and biochemical features of Graves' hyperthyroidism that can predict the relapse of the disease after a standard course of ATD therapy. Patients and Methods: We conducted a retrospective 6-month study of 79 patients with Graves' hyperthyroidism who were treated with ATD (carbimazole) therapy for 12–18 months and went into remission for at least 1 year after ATD withdrawal. Results: The relapse rate in Graves' hyperthyroidism after 1 year in remission was 40.5%; patients with younger age (<40 years) and with severe biochemical disease correlated significantly with relapse. Gender, presence of a palpable goiter, orbitopathy, and smoking habits were not significant predictors of relapse, perhaps because of the small sample size. Conclusions: Forty percent of Graves' hyperthyroidism relapsed after 1 year of remission. Younger age and severe biochemical disease at diagnosis predicted relapse.

Keywords: Antithyroid drugs, Graves' disease, hyperthyroidism, relapse, remission


How to cite this article:
Lawgaly SA, Kallousa HA, Gerryo S. Predictors of relapse in graves' hyperthyroidism after treatment with antithyroid drugs. Ibnosina J Med Biomed Sci 2018;10:205-8

How to cite this URL:
Lawgaly SA, Kallousa HA, Gerryo S. Predictors of relapse in graves' hyperthyroidism after treatment with antithyroid drugs. Ibnosina J Med Biomed Sci [serial online] 2018 [cited 2021 Dec 1];10:205-8. Available from: http://www.ijmbs.org/text.asp?2018/10/6/205/247168




  Introduction Top


Graves' hyperthyroidism is the most common cause of hyperthyroidism.[1] Treatment options include antithyroid drugs (ATDs), radioactive iodine, or surgical resection, although none of these options target the mechanism of the disease, and there is no single treatment that can target both hyperthyroidism and the main extrathyroidal manifestation (orbitopathy).[2]

ATDs act by inhibiting thyroid hormone synthesis, but they have some immunosuppressive action. In Europe and Japan, ATDs are still the first-line treatment,[1] but in North America, radioactive-iodine is much preferred.[3],[4] Endocrinologists in the Middle East and North Africa (MENA) seemed to practice in a hybrid fashion between these two groups depending on previous training and current affiliations.[5]

The major drawback of ATD is the high rate of relapse. Several studies have attempted to examine factors that can predict the relapse of the disease before the start of treatment which include some tests that are not routinely done in clinical practice; for example, human leukocyte antigen assessment, quantification of thyroid blood flow by Doppler sonography, thyrotropin-releasing hormone test, and thyroid-stimulating hormone (TSH) receptor antibody titer. However, other predictors had been studied frequently including age, gender, thyroid size, smoking, and the severity of the biochemical hyperthyroidism at the time of diagnosis, but none of these risk factors have sufficient sensitivity and specificity to predict recurrence. Patients with these factors at the time of diagnosis tend to relapse earlier after ATD withdrawal; therefore, a low dose of methimazole (or carbimazole) for a longer duration may be advisable in these groups of patients with a higher risk of relapse.[6]

Choosing a treatment modality for a given patient with Graves' hyperthyroidism depends on multiple factors that include the local preference, a higher risk of relapse seen with ATD therapy, and a higher risk of hypothyroidism with radioactive-iodine and surgical resection; ATD therapy was the preferred treatment modality in the MENA region, although treatment plan can be shifted to a certain modality in the presence of Graves' orbitopathy (GO), large goiter, or pregnancy desire.[2],[5],[7],[8]

Relapse rate after a course of ATD (for 12–24 months) varies across several studies from 30% to 70% which are described as follows:[1],[2] Italy: 63.4%,[2],[6] the UK: 63.5%,[2],[7] Sweden: 43.5%,[2] and Japan: 34.2%.[8] Most of the relapses were in the 1st year after withdrawal of ATDs.[1],[2],[6],[8]


  Patients and Methods Top


We aimed to determine the clinical and biochemical features of Graves' hyperthyroidism that can predict the relapse of the disease after a standard course of ATD therapy in 79 Libyan patients with Graves' hyperthyroidism who were treated with ATD (carbimazole) therapy for 12–18 months and went into remission for at least 1 year after ATD withdrawal.

Patients diagnosed with Graves' hyperthyroidism between August 2010 and July 2012 were included. Diagnosis was based on clinical assessment, biochemical hyperthyroidism, and radiological examination (mainly ultrasound). Graves' hyperthyroidism was defined as the presence of biochemical hyperthyroidism (elevated T4 and undetectable TSH levels) with two of the following: diffuse goiter, significant peroxidase titer or thyroglobulin autoantibodies, and orbitopathy. Patients were recruited from six endocrine clinics in Benghazi Medical Center (a tertiary center) in Benghazi, Libya. Data were retrieved from medical charts. Inclusion criteria were adults (>18 years) diagnosed with Graves' hyperthyroidism who received ATD therapy for 12–18 months and went into remission for at least 1 year. Exclusion criteria were children and pregnant women. A total of 79 patients met these criteria. Baseline clinical parameters such as age, gender, goiter size (assessed clinically), smoking, and thyroid hormone status were recorded at the time of diagnosis. Goiter size and severity of orbitopathy could not be assessed accurately due to lack of documentation. However, the presence or absence of goiter and GO was based on the clinical assessment of the treating physician. Data were analyzed using the SPSS statistics version 18 (SPSS Inc., Chicago, IL, USA). The differences between the variables were explored using Chi-square test, and P < 0.05 was considered to be statistically significant.


  Results Top


A total of 79 patients diagnosed with Graves' hyperthyroidism between August 2010 and July 2012 were included in the study. Thirty-two patients (40.5%) had a recurrence of hyperthyroid state after remission for at least 1 year. The baseline factors are shown in [Table 1]. Younger patients had more relapse rate than the older age group (56.5% vs. 18.2%, respectively; P = 0.000) [Figure 1]. Furthermore, patients who had a recurrence of hyperthyroidism had a biochemically more severe hyperthyroidism as evident by the higher T4 levels (>2 normal), but no significant difference was found for gender, the presence of goiter, orbitopathy, or current smoking status at the time of diagnosis as predictors of recurrence.
Table 1: Characteristics of patients in the whole group: Those who remained in remission and those who relapsed

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Figure 1: The percentage of remission and relapse in patients older and younger than 40 years of age

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  Discussion Top


The outcome of therapy in Graves' disease varies between each patient, and choosing a treatment modality at the time of diagnosis has to be individualized, although identifying factors that could predict the relapse might be helpful.

Graves' hyperthyroidism is more common in adults, but it occurs in pediatrics. Winsa et al. found a higher relapse rate in younger age groups which occurred in 67% of patients aged <40 years and 52% of patients aged >40 years. Whereas, in other studies, results were similar with one exception when no significant correlation between age and relapse risk was detected.[10],[11] In our study, the relapse rate was greater among people younger than 40 years of age.

The prevalence of Graves' hyperthyroidism is more in females than males (four to five times more common in females) as suggested by several studies, and the outcome after ATD therapy is less favorable in men. A higher relapse rate was demonstrated in males than females (80% vs. 60%) in a large prospective study.[7] However, no difference in relapse rate was noted between males and females in our patient groups, perhaps due to the smaller sample size in comparison with the study of Allahabadia et al. from the UK.[7] Two studies from Lithuania and China found no relation between the gender and the risk of relapse.[8],[12],[13]

The presence of a large goiter at the time of diagnosis was observed as a risk of relapse since the early 1950s;[14] since then, studies have shown an association between thyroid volume and relapse rate. Higher relapse rates were found with larger goiters;[15] while in our study, the exact size of goiter could not be retrieved because of lack of documentation, but the presence or absence of a palpable goiter does not affect the outcome.

About 20%–30% of patients with Graves' hyperthyroidism have associated orbitopathy. Our data showed that 24.1% of the patients had GO at the time of diagnosis, but this was not significantly associated with the risk of relapse (P = 0.078). Previous studies regarding the relation between the relapse rate and the presence of GO were conflicting, but some studies have found a positive relation between GO and relapse rate.[16],[17]

In the present study, severe biochemical hyperthyroidism was associated with a higher relapse rate (P = 0.001). This is in agreement with previously reported concordant results demonstrating that severe biochemical disease at the time of diagnosis predicts increased risk of relapse.[7],[9],[10]

The risk of relapse in Graves' hyperthyroidism increases with smoking, and smoker's risk disappears few years after abstaining smoking.[16],[17] The response to the medical therapy is less in smokers as the serum thyrotropin receptor antibody concentration decreases to a much slower rate in smokers than nonsmokers.[18] Glinoer et al. reported that relapse rate was 57% in smokers and 18% in nonsmokers with a significant risk for relapse;[19] while in this study, relapse rate in current male smokers was 60% compared with 28.6% in nonsmoker males (P = 0.320).


  Conclusions Top


In the present study, relapse rate in Graves' hyperthyroidism after 1 year in remission was 40.5% in the younger age group and in those with severe biochemical disease at diagnosis. No significant association was detected with gender, the presence of goiter, orbitopathy, or smoking status, perhaps due to the smaller sample size or duration of the study. Further studies are needed with larger sample size.

Acknowledgments

The authors are grateful to Dr. Salem Eltabal, Dr. Wafa Berhula, Dr. Rafik Elmehdwi, Dr. Abdulwahab Elbarsha, Dr. Naema Elwhaishi, Dr. Amina Bengasher, Dr. Maison Elhemri, and Dr. Amal Fadllalah for allowing us to report on some of their patients. In addition, we would like to thank Miss. Azza Alkeza and Miss. Salma Alzeletany for their help in data collection and analysis.

Authors' contribution

SAL: study design, literature search, data acquisition, data analysis, statistical analysis, and manuscript preparation. HK: Study design, literature search, data acquisition, manuscript editing, and review. SEG: Study design, manuscript editing, and review. The final manuscript was reviewed and approved by all the authors prior to submission.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Compliance with ethical principles

This study was approved by the Research Ethical Committee at Benghazi Medical Center, Benghazi, Libya.



 
  References Top

1.
Bartalena L. Diagnosis and management of Graves' disease: A global overview. Nat Rev Endocrinol 2013;9:724-34.  Back to cited text no. 1
    
2.
Piantanida E, Lai A, Sassi L, Gallo D, Spreafico E, Tanda ML, et al. Outcome prediction of treatment of graves' hyperthyroidism with antithyroid drugs. Horm Metab Res 2015;47:767-72.  Back to cited text no. 2
    
3.
Bartalena L, Burch HB, Burman KD, Kahaly GJ. A 2013 European survey of clinical practice patterns in the management of Graves' disease. Clin Endocrinol (Oxf) 2016;84:115-20.  Back to cited text no. 3
    
4.
Burch HB, Burman KD, Cooper DS. A 2011 survey of clinical practice patterns in the management of Graves' disease. J Clin Endocrinol Metab 2012;97:4549-58.  Back to cited text no. 4
    
5.
Beshyah SA, Khalil AB, Sherif IH, Benbarka MM, Raza SA, Hussein W, et al. Asurvey of clinical practice patterns in management of Graves' disease in the Middle East and North Africa. Endocr Pract 2017;23:299-308.  Back to cited text no. 5
    
6.
Vitti P, Rago T, Chiovato L, Pallini S, Santini F, Fiore E, et al. Clinical features of patients with graves' disease undergoing remission after antithyroid drug treatment. Thyroid 1997;7:369-75.  Back to cited text no. 6
    
7.
Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SC, Franklyn JA. Age and gender predict the outcome of treatment for Graves' hyperthyroidism. J Clin Endocrinol Metab 2000;85:1038-42.  Back to cited text no. 7
    
8.
Ohye H, Minagawa A, Noh JY, Mukasa K, Kunii Y, Watanabe N, et al. Antithyroid drug treatment for Graves' disease in children: A long-term retrospective study at a single institution. Thyroid 2014;24:200-7.  Back to cited text no. 8
    
9.
Allahabadia A, Daykin J, Sheppard MC, Gough SC, Franklyn JA. Radioiodine treatment of hyperthyroidism-prognostic factors for outcome. J Clin Endocrinol Metab 2001;86:3611-7.  Back to cited text no. 9
    
10.
Winsa B, Dahlberg A, Jansson R, Agren H, Karlsson FA. Factors influencing the outcome of thyrostatic drug therapy in Graves' disease. Acta Endocrinol (Copenh) 1990;122:722-8.  Back to cited text no. 10
    
11.
Anagnostis P, Adamidou F, Polyzos SA, Katergari S, Karathanasi E, Zouli C, et al. Predictors of long-term remission in patients with Graves' disease: A single center experience. Endocrine 2013;44:448-53.  Back to cited text no. 11
    
12.
Wang PW, Chen IY, Juo SH, Hsi E, Liu RT, Hsieh CJ, et al. Genotype and phenotype predictors of relapse of Graves' disease after antithyroid drug withdrawal. Eur Thyroid J 2013;1:251-8.  Back to cited text no. 12
    
13.
Dauksenie D, Dauksa A, Mickuviene N. Independent pretreatment predictors of Graves' disease outcome. Medicina (Kaunas) 2013;164:801-9.  Back to cited text no. 13
    
14.
Laurberg P, Buchholtz Hansen PE, Iversen E, Eskjaer Jensen S, Weeke J. Goitre size and outcome of medical treatment of Graves' disease. Acta Endocrinol (Copenh) 1986;111:39-43.  Back to cited text no. 14
    
15.
Nedrebo BG, Holm PI, Uhlving S, Sorheim JI, Skeie S, Eide GE, et al. Predictors of outcome and comparison of different drug regimens for the prevention of relapse in patients with Graves' disease. Eur J Endocrinol 2002;147:583-9.  Back to cited text no. 15
    
16.
Vestergaard P. Smoking and thyroid disorders – A meta-analysis. Eur J Endocrinol 2002;146:153-61.  Back to cited text no. 16
    
17.
Wiersinga WM. Smoking and thyroid. Clin Endocrinol (Oxf) 2013;79:145-51.  Back to cited text no. 17
    
18.
Nyirenda MJ, Taylor PN, Stoddart M, Beckett GJ, Toft AD. Thyroid-stimulating hormone-receptor antibody and thyroid hormone concentrations in smokers vs. nonsmokers with Graves' disease treated with carbimazole. JAMA 2009;301:162-4.  Back to cited text no. 18
    
19.
Glinoer D, de Nayer P, Bex M; Belgian Collaborative Study Group on Graves' Disease. Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: A double-blind prospective randomized study. Eur J Endocrinol 2001;144:475-83.  Back to cited text no. 19
    


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