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Clinical Profile and Long-Term Remission in Patients with Graves’ Disease: The Tripoli Medical Centre Experience

Research Article | Open Access Volume 6 | Issue 1 |

  • 1. Department of Endocrine, Tripoli University for Medical Sciences, Libya
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Corresponding Authors
Hawa Juma El-Shareif, Endocrine Department, Tripoli Medical Center (Tripoli University for Medical Sciences, Faculty of Medicine),Tripoli, Libya, Tel: 0925431547.
Abstract

Background: Graves’ disease (GD) is an autoimmune disease characterized by goiter hyperthyroidism and ophthalmopathy. Treatment options include anti-thyroid drugs (ATD), radioactive iodine (RAI), and surgery.

Objective: To determine the clinical features at presentation, mode of treatment, and longterm outcome of GD in our region and to determine the whether the duration of ATD treatment, patient gender, and age at presentation can predict the long-term response rate.

Methods: Retrospective review of medical records of 145 consecutive Libyan patients with GD who were treated at the endocrine clinic of the Tripoli Medical Center (TMC) during the period between June 2005 and April 2007. Demographic data, presenting clinical features, and the results of thyroid function test at the time of the first presentation were obtained. Mode of treatment and the long-term outcome were recorded

Results: A total of 145 patients were reviewed, 71.7% were female and 28.3% were males. Mean age was 36.7±11.8 years (Range 16-70) and mean duration of follow up was 5.7±3.9 years (Range 1-12) years. Tremor (64.8%), weight loss (54.5%), and palpitation (53.1%) were the most common clinical manifestations. 76.6% were treated only with antithyroid drugs (ATD), 16.6% received radioactive iodine (RAI), and 6.9% underwent surgery. Long-term remission rates for ATD, surgery, and RAI were 59.1%, 88.9%, and 87% respectively.

Conclusion: Clinical manifestations of GD in our patients were comparable with those reported in the literature. There was an underuse of second-line treatment, namely surgery, and RAI therapy

Keywords

•    Graves disease
•    Hyperthyroidism
•    Anti-thyroid drugs
•    Radioactive iodine therapy
•    Tripoli medical center
•    Libya

Citation

El-Shareif HJ (2018) Clinical Profile and Long-Term Remission in Patients with Graves’ Disease: The Tripoli Medical Centre Experience. J Endocrinol Diabetes Obes 6(1): 1116.

INTRODUCTION

GD is the most common cause of hyperthyroidism, accounting for 50 to 80 percent of all cases [1,2]. GD affects about 0.5% of the population. The peak incidence is in the age group 40 to 60 years, but any age can be affected [1,2].

GD occurs with greater frequency in females, with a female to male ratio of 5:1 to 10:1, which may relate to the effects of estrogens on the immune system [3,4] .

Graves’ disease is an autoimmune disease caused by IgG antibodies, thyrotropin receptor antibodies (TRAb), which bind to and activate the TSH receptor, and causing thyroid enlargement (goiter), and increased thyroid hormone production (hyperthyroidism) [1].

Ophthalmopathy characterized by inflammation of periorbital and retro-orbital connective tissue, fat, and muscle are clinically evident in approximately one-third of patients [5]. Dermopathy and acropachy are rare extrathyroidal manifestations of GD. Several associated genetic loci have been identified, conferring susceptibility to GD [6]. In regions of iodine deficiency, iodine supplementation precipitates Graves’ hyperthyroidism and other types of hyperthyroidism, by means of the Jod–Basedow phenomenon.

The current management strategies for the treatment of patients with GD include ATD, thyroid ablation with radioiodine and surgery (near total or total thyroidectomy).

In our center, ATD is the first line therapy, while radioiodine and surgery are utilized as a second line therapy. The evidence suggests the optimal duration of anti-thyroid drug therapy for the titration regimen is 12–18 months. Long-term remission rate after the first episode of hyperthyroidism varies considerably between geographical areas [7-10].

The geographical differences in iodine intake account for some variations in remission rates. High iodine intake has been suggested to be associated with increased relapse rates in patients treated with ATD alone [11].

Considerable variability in clinical practices is seen both between and within countries in the diagnosis and treatment of the disease.

The aim of this study is to determine the clinical features at presentation, mode of treatment, and long-term outcome of treatment of GD in our region and to determine whether the duration of treatment, patient gender, and age at presentation can predict the long-term response rate to treatment.

PATIENTS AND METHODS

This was a retrospective analysis of medical records of Libyan patients with Graves’ disease (GD) disease consecutively treated at the endocrine department of the Tripoli medical center during the period June 2005 through to April 2007.

Demographic data and clinical features at the time of presentation at our outpatient clinic were obtained. Results of thyroid function test, pulse and blood pressure at their initial presentation were also recorded.

Mode of therapy, antithyroid drugs, thyroidectomy, and/ or radioactive iodide was reported. Long-term outcome of treatment was recorded only for patients who had completed a follow-up duration of two years or more.

Patients who had a follow-up period less than 2 years after their diagnosis were excluded.

The outcome of treatment was defined as hyperthyroid (Toxic), if still on antithyroid medications, euthyroid, if on no medication or hypothyroid if on replacement therapy with L-thyroxine.

The patient was considered in remission, if maintained a euthyroid, or hypothyroid state requiring replacement therapy, for at least one year prior to the last follow up visit.

Statistical analysis

Data were analyzed using the Statistical Package for Social Science (SPSS Inc., IBM, US), 19th version. Continuous variables are expressed as mean ± standard deviation (SD) and range. Categorical data are expressed as numbers and percentages. Student’s t-test was used to compare continuous variables and qualitative variables were analyzed with the chi-square test.

This study was carried out in accordance with the principles of the Helsinki Declaration. A formal approval was obtained from institutional authorities.

RESULTS

Out of the 145 diagnosed cases of Grave’s disease, their mean age was 36.7±11.8 years (Range 16-70). 117 (80.7%) were below the age of 46 years 41 (28.3%) were males and 104 (71.7%) were female, the female to male ratio was 2.5:1.

The mean age for males was 37.6±12.1 years and for females 36.4±11.8 years. No significant difference in age at presentation between male and female gender (p-value =0.598). Table 1 Tremor 94 (64.8%), weight loss 79 (54.5%), palpitation 77 (53.1%), followed by increased sweating 53 (36.6%) were the most common clinical manifestations.

Other clinical features were heat intolerance 51 (35.2%), nervousness 31(21.4%), fatigability 27 (18.6%), increase appetite 16 (11.0%) and diarrhea 14(9.7%).

Cardiac clinical feature were present in 24 (16.4%) patients: 22 patients (15.2%) had dyspnea and 4 patients (2.8%) had atrial fibrillation (AF). Exophthalmos was present at diagnosis in 55 (37.9%) Table 2.

The frequency of exophthalmos among males was higher (43.90%) than in female patients (35.60%), but the difference was statistically insignificant, p-value=0.352.

Exophthalmos frequency was higher among those with duration of follow up less than five years (46.20%) than those with longer follow up (28.40%), p-value=0.028 and among those ≤ 25 years of age (56.50%) compared to older age groups, 35.6% of the age group (25-50) years and 25.0% of patients ≥ 50 years of age p-value=0.081.

The mean duration of follow up was 5.7±3.9 years (Range 1-12). 25 (17.2%) lost to follow-up in less than 2 years after diagnosis and 120 (82.8%) had continued their follow up for 2 years or more. All patients received ATD thionamides as a firstline therapy. Carbimazole was the treatment of all patients, except one pregnant patient treated with propylthiouracil. 111 patients (76.6%) received only medical treatment, 10 patients (6.9%) underwent surgery and 24 patients (16.6%) received RAI. For those who had continued the follow up for 2 years or more, 88 patients (73.3%) received only medical treatment, 9 patients (7.5%) underwent surgery and 23 patients (19.2%) received RAI. The final outcome of treatment was reviewed only in patients who completed duration of follow up for 2 years or more. The rate post-therapy hypothyroidism was higher in those treated with I131 (82.60%) or surgery (66.70%) comparing to those who had received only medical therapy (13.60%) (p-value=0.000). 45.50% of those who had received only medical therapy had achieved euthyroid state compared to those who had undergone surgery (22.20%) or received RAI therapy (4.30%) (p-value=0.000) Table 3. Males were more likely to undergo ablative therapy (36.4%) than female (20.6%), although the difference was not significant (p-value=0.171).

Table 4 summarizes the effect of patient’s gender, age, and duration of follow up with on the long-term outcome of treatment for hyperthyroidism in Libyan patients with Graves’ disease. The rate of hypothyroidism was higher in older age group (≥ 50 years), and the rate of achieving euthyroidism was higher in the ≤ 25 years age group, p-value =0.025.

The rate of hypothyroidism was more in those who had continued a follow up period of more than five years (41.8%) than those with lesser follow up periods (17.0%), p-value =0.001, and in male (48.5%) than female patients (24.1%), while the rate of achieving euthyroidism was more in female (43.7%) than male (15.2%), p-value =0.006.

DISCUSSION

Graves’ disease (GD) is an autoimmune disorder characterized by a variable combination of hyperthyroidism, ophthalmopathy, and dermopathy. Female sex is an important risk factor for GD in part as a result of the modulation of the autoimmune response by estrogen [1]. 71.7% of our GD patients were female, with a male to female ratio of 2.5:1. In studies from Saudi Arabia, the female to male ratio ranges from 1.4 to 3.8 [12].

Female predominance is typical of most thyroid diseases, including multinodular goiter and differentiated thyroid carcinoma [2]. One explanation is that the promoter for certain genes such as Class II HLA molecules may have estrogen receptor response elements and thus be activated more easily in women [4].

The mean age at onset in our study was 36.7 ±11.8 years and 64.8% of our patients were between 25-45 years, this is narrower than the age range reported in the literature [1,12].

The most common symptoms of GD are hand tremor, weight loss with a normal or increased appetite, palpitations, heat intolerance, and irritability.

Nordyke et al., reported that with increasing age, weight loss becomes more common, whereas heat intolerance is less common [13]. Compared to the present study where weight loss affected more than 50% of those younger than 55 and 28.6 % of those ≥ 55 years. In our study heat intolerance is less prevalent in those ≤25 years of age (13%) compared to older age groups. As reported elsewhere, cardiac symptoms are common at presentation in patients over 50 years of age [13,14]. In our patients, the mean heart rate was higher in the younger age group while the mean systolic blood pressure was higher in the older age group. Older patients are less likely to have tachycardia [14]. Graves’ ophthalmopathy (GO) is clinically evident in about 30 - 50% of patients with GD, and in more than 80% of patients who undergo orbital imaging [1,15].

GO has a bimodal peak in the fifth and seventh decades of life. It is more frequent in females but tends to be more severe in males [5,15]. 

Our study showed that 37.9% of Libyan patients with GD had GO, which seems to be more prevalent in males, and younger patients compared to females and those older than 55 years of age.

All patients received ATD as a first-line therapy. Carbimazole is the ATD used in Libya. Carbimazole is a pro-drug as after absorption it is converted to the active form, methimazole, so it has similar efficacy to methimazole [16].

Studies showed that methimazole had a better efficacy in restoring the euthyroid state much faster than propylthiouracil, although no difference between them in the recurrence rate after withdrawal of medication [17].

Serious hepatic side effects were linked to propylthiouracil, thus methimazole is the preferred drug for treatment of GD patients as recommended as by ATA guidelines [16]. The only indication for PTU is pregnant women during the first trimester [16,7].

ATDs are effective in restoring the euthyroid state, but the long-term remission rates are low, varying between 30–50% [8- 10,16].

The rest will need repeated courses of drug therapy to achieve remission or maintained on the drug for years or indefinitely or were given other treatment modalities [8,7,18].

The variation in remission rates with ATD between different studies may be related to geographical differences in iodine status, where increased iodine intake was associated with lesser response to medications. [11] Longer duration of treatment was found to be associated with increased response rate [19]. In the present study (27.9%) of patients who continue medical treatment for more than five years remained toxic compared to (53.3%) of those with lesser follow up duration (p-value=0.025). Those who failed to enter remission with antithyroid medication were well maintained the euthyroid status with small doses of thioamides. In a study with over 10 years of follow-up for 26 GD patients on low dose methimazole, no serious problems were reported, and the cost was approximated that of RAI therapy [20].

Some patients opt for long-term ATD therapy for years or even decades, and there is no theoretical reason why not to continue antithyroid drug therapy indefinitely if the euthyroid state is maintained with small doses of antithyroid drugs [9,16]. Graves’ disease as other autoimmune diseases, may fluctuate in its activity, and patients may occasionally enter remission without any specific therapy being given [21]. Although such spontaneous remission may be the reason that a fraction of patients treated with ATD remains euthyroid after the stop of medication, evidence accumulated that treatment with antithyroid drugs was accompanied by remission of GD beyond the natural history of the autoimmune aberration [22].

Most patients who become euthyroid with drug therapy will eventually develop spontaneous hypothyroidism [23,24]. The annual incidence of subclinical hypothyroidism is 2.5%, and of overt hypothyroidism 0.6% [24].

Many retrospective studies showed that younger age (<40 years), smoking, male gender, thyroid gland size, the presence of ophthalmopathy and high titers of TRAb at the beginning and at the end of therapy are associated with a relatively poor response to ATD and higher recurrence risk [25-27].

The prevalence of cigarette smokers was low in our study, therefore, future large cohort studies with more smokers are required in order to investigate the association between GD and smoking among Libyan patients.

Age less than twenty-five years (53.8%) and female gender (52.9%) were more likely to be associated with the euthyroid state with medical treatment compared to older age groups (10.0%) and male gender (20.0%) (p<0.05).

The rate of hypothyroidism in response to medical treatment was higher in those ≥ 50 years of age (20.0%) and with a male gender (30.0%) compared to those younger than 25 years (0%) and female gender (8.8%) (p<0.05).

In a retrospective study of long-term prognosis after the medical treatment of GD in northern Swedish patients with a median follow-up of 2.8 years and maximal follow-up of 10 years, the long-term remission rate during 10 years was 56.5% and age, gender, current smoking, and ophthalmopathy did not predict relapse. [10] Another prospective study included 306 Chinese patients with GD treated with ATD demonstrated that gender, family history of thyroid diseases and smoking, did not significantly affect disease relapse rates [27].

Medical treatment with ATD requires adherence to the prescribed medications and follow up schedules for many months or years, more frequent visits to the doctor, monitoring for the occasional side effects, and it has a lower permanent remission rate compared to other treatment modalities.

In Europe, most physicians prefer to treat Graves’ disease initially with antithyroid drugs, and secondarily with 131-I or less frequently surgery [28].

In the United States, RAI has been the therapy most preferred by physicians, but a trend has been present in recent years to increase use of ATDs and reduce the use of RAI [7].

Less than 10% of our patients underwent surgery as a second line treatment for Graves’ disease. Surgery is seldom recommended for the treatment of hyperthyroid Graves’ disease, it may be appropriate when other modalities are contraindicated, or when a thyroid nodule thought to be malignant also requires surgical intervention.

The disadvantages of surgery include the expense, the risks of surgery itself, and the risks of damage to recurrent laryngeal nerve, hypoparathyroidism, hypothyroidism, and recurrence.

None of them developed complications, the remission rate was better than RAI, and more patients achieved euthyroid state than those in the RAI group.

In presence of experienced surgeons, thyroidectomy is a safe and effective treatment for GD. Furthermore, surgical treatment gives the fastest results with lower recurrence rates than RAI or ATD [29]. Only 19.2% of GD patient in our study were treated with RAI as a second line after medical treatment failure. Although radioiodine is a more effective means of curing hyperthyroidism and is used as both first-line treatment and in those who relapsed disease after medical therapy, the risk of permanent hypothyroidism is high and it is difficult to titrate doses for individual patients accurately in order to guarantee a euthyroid state [30].

Nevertheless, RAI treatment early in the course of GD management will allow the patient to achieve a stable thyroid status earlier in the course of therapy and save several years of regular outpatient clinic visits and possible upsets caused by the frequent relapses of the hyperthyroid state. Thus, RAI treatment should be discussed at an early stage with patients.

One randomized, controlled trial compared the effects of the three modalities of therapy of Graves’ hyperthyroidism. After 18 months of treatment with methimazole, 16% had adverse reactions, 6% had an inadequate response to therapy, and 37% had a relapse. Of patients who underwent surgery, 6% had a relapse and none had complications. And hypothyroidism developed in all patients treated with radioiodine [31].

Our study has highlighted the current practice in the treatment of Grave’s thyrotoxicosis in our center. Considerable variability in clinical practices is seen both between and within countries in the diagnosis and treatment of the disease.

The initial management of GD among American thyroidologists is to prescribe radioiodine therapy at an early stage of management, although a trend has been present in recent years to increase the use of ATDs and reduce the use of RAI. A 2011 survey of clinical endocrinologists showed that 59.7% of respondents from the United States selected RAI as primary therapy for an uncomplicated case of GD, compared with 69% in a similar survey performed 20 years earlier [7].

While in Europe and Asia GD was treated initially with antithyroid drugs, and secondarily with 131-I or less frequently surgery [7,8].

Our study has a number of limitations, including its retrospective nature, a small sample size, and the fact that it was conducted at a single endocrine center.

Further large-scale prospective studies are needed to assess the protocols adopted by Libyan endocrinologists for the management of GD patients in real practices.

Table 1: Baseline characteristics of patients.

                             Variable Patients n (%)
                      Total no. of patients 145 (100%)
                            Age (Years) * 36.7±11.8(16-70)
Gender Female 104 (71.7%)
  Male 41(28.3%)
Age group ≤25 23(16.0%)
  25-50 101(70.1%)
  ≥50 20(13.9%)
                           TSH (μIU/ml) *† 0.01±0.02(0.00-0.07)
                      Total T4 ((nmol/l) *‡ 254.4±58.9(83.0-320.0)
                Follow up duration (Years) * 5.7±3.9(1-12)
Duration of follow up ≤ 5 years 78(53.8%)
> 5 years 67(46.2%)
Treatment modality medical 111(76.6%)
surgery 10 (6.9%)
RAI 24(16.6%)
*Mean±SD (Range), †Normal range of total T4 in adults is 64 to 154 nmol/L.
‡Normal range of TSH is 0.1-5 μIU/ml.

Table 2: Frequency of thyrotoxic symptoms in decreasing frequency.

Hand Tremor 94 (64.8%) Headache 5 (3.4%)
Weight loss 79 (54.5%) Atrial fibrillation (AF) 4 (2.8%)
Palpitation 77 (53.1%) Hyperpigmentation 3 (2.1%)
Exophthalmos 55 (37.9%) Weight gain 3 (2.1%)
Increased sweating 53 (36.6%) Hair loss 2 (1.4%)
Heat intolerance 51 (35.2%) Decreased appetite 2 (1.4%)
Nervousness 31 (21.4%) Hyperemesis gravidarum 1 (0.7%)
Fatigability 27 (18.6%) Hyperactivity 1 (0.7%)
Breathlessness 22 (15.2%) lymphadenopathy (LAP) 1 (0.7%)
Increased appetite 16 (11.0%) Related to menstrual cycle * 8 (7.7%)
Diarrhea 14 (9.7%) Incidental diagnosis 2 (1.4%)
* Oligomenorrhea, Amenorrhea or Menorrhagia (For female patients)

Table 3: Long term outcome according to the modes of therapy.

Mode of therapy Euthyroid Toxic Hypothyroid P value
ATD (88) 40 (45.50%) 36 (40.90%) 12 (13.60%)  0.000
Surgery (9) 2 (22.20%) 1 (11.10%) 6 (66.70%)
RAI(23) 1 (4.30%) 3 (13.00%) 19 (82.60%)
Total(120) 43 (35.80%) 40 (33.30%) 37 (30.80%)
Abbreviations: ATD: Anti-thyroid drugs, RAI: Radioactive iodine.
p < 0.05 considered significant.

Table 4: The relationship of gender, age and duration of follow up with the long term outcome of treatment for hyperthyroidism in Libyan patients with Graves’ disease.

Long term Response in all treatment modalities
Total number =120
No (%) Euthyroid 43 (35.8%) Toxic 40 (33.3%) Hypothyroid 37 (30.8%) P value
Age group ≤ 25 18 (15.0%) 9 (50.0%) 7 (38.9%) 2 (11.1%) 0.025
  26-49 85 (70.8%) 33 (38.8%) 26 (30.6%) 26 (30.6%)  
  ≥ 50 17 (14.2%) 1 (5.9%) 7 (41.2%) 9 (52.9%)  
Duration of follow up ≤5 53 (44.2%) 18 (34.0%) 26 (49.1%) 9 (17.0%) 0.001
  >5 years 67 (55.8%) 25 (37.3%) 14 (20.9%) 28 (41.8%)  
Sex Male 33 (27.5%) 5 (15.2%) 12 (36.4%) 16 (48.5%)  
  Female 87 (72.5%) 38 (43.7%) 28 (32.2%) 21 (24.1%) 0.006
Long term Response to drug treatment Total number =88 No (%) Euthyroid 40 (45.5%) Toxic 36 (40.9%) Hypothyroid 12 (13.6%) P value
Age group ≤25 13 (14.8%) 7 (53.8%) 6 (46.2%) 0 (0%) 0.091
  26-49 65 (73.9%) 32 (49.2%) 23 (35.4%) 10 (15.4%) (0.043)*
  ≥ 50 10 (11.4%) 1 (10.0%) 7 (70.0%) 2 (20.0%)  
Duration of follow up ≤ 5 45 (51.1%) 18 (40.0%) 24 (53.3%) 3 (6.7%) 0.025
  >5 years 43 (48.9%) 22 (51.2%) 12 (27.9%) 9 (20.9%)  
Sex Male 20 (22.7%) 4 (20.0%) 10 (50.0%) 6 (30.0%)  
  Female 68 (77.3%) 36 (52.9%) 26 (38.2%) 6 (8.8%) 0.01
*Difference in response between age group ≤25 & ≥50, p < 0.05 considered significant.
Abbreviations: ATD: Anti-Thyroid Drugs, RAI: Radioactive Iodine

 

CONCLUSIONS

Clinical manifestations of GD in our patients were comparable with those reported in the literature. There was an underuse of second-line treatment, namely surgery, and RAI therapy. Longer duration of ATD treatment seems to increase the remission rate in our GD patients.

REFERENCES

1. Weetman AP. Graves’ disease. N Engl J Med. 2000; 343: 1236-1248.

2. Vanderpump MPJ, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. Incidence of thyroid disorders in the community based on a twenty-year follow-up of the Whickham survey population. Clin Endocrinol (Oxf). 1995; 1: 55-68.

3. Da Silva JAP. Sex Hormones, glucocorticoids, and autoimmunity: facts and hypotheses. Ann Rheum Dis. 1995; 1: 6-16.

4. Kisiel B, Bednarczuk T, Kostrzewa G, Kosi?ska J, Mi?kiewicz P, P?azi?ska MT, et al. Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease. Clin Endocrinol (Oxf). 2008; 68: 429-434.

5. Bartley GB. The epidemiological characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am Ophthalmol Soc. 1994; 92: 477-588.

6. Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity. Thyroid. 2007; 17: 949-961.

7. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016; 26: 1343-1421.

8. Shizume K, Irie M, Nagataki S, Matsuzaki F, Shishiba Y, Suematsu H, et al. Long-term result of antithyroid drug therapy for Graves’ disease: Follow-up after more than 5 years. Endocrinol Jpn. 1970; 17: 327-332.

9. Slingerland DW, Burrows BA. Long-term antithyroid treatment in hyperthyroidism. JAMA. 1979; 242: 2408-2410.

10. Mohlin E, Nystrom HF, Eliasson M. Long-term prognosis after medical treatment of Graves’ disease in a northern Swedish population 2000- 2010. Eur J Endocrinol. 2014; 170: 419-427.

11. Wartofsky L. Low remission rates after therapy for Graves’ disease: possible relation of dietary iodine with antithyroid therapy results. JAMA. 1973; 226: 1083-1088.

12. Akaber D, Mushtag M, AL-Sheikh A. Etiology and outcome of thyrotoxicosis at a university hospital. Saudi Med J. 2000; 21: 352-354.

13. Nordyke RA, Gilbert FI Jr, Harada ASM. Graves’ disease: influence of age on clinical findings. Arch Intern Med. 1988; 148: 626-631.

14. Toft AD, Boon NA. Thyroid disease, and the heart. Heart 2000; 84: 455-460.

15. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010; 362: 726-738.

16. Cooper DS. Antithyroid drugs. N Engl J Med. 2005; 352: 905-917.

17. Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N. Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves’ disease. J Clin Endocrinol Metab. 2007; 92: 2157-2162.

18. Shizume K. Long-term antithyroid drug therapy for intractable cases of Graves’ disease. Endocrinol Jpn. 1978; 25: 377-379.

19. Allannic H, Fauchet R, Orgiazzi J, Madec AM, Genetet B, Lorcy Y, et al. Antithyroid drugs and Graves’ disease: A prospective randomized evaluation of the efficacy of treatment duration. J Clin Endocrinol Metab.1990; 70: 675-679.

20. Azizi F, Ataie L, Hedayati M, Mehrabi Y, Sheikholeslami F. Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine. Eur J Endocrinol. 2005; 152: 695-701.

21. Codaccioni JL, Orgiazzi J, Blanc P, Pugeat M, Roulier R, Carayon P. Lasting remissions in patients treated for Graves’ hyperthyroidism with propranolol alone: a pattern of spontaneous evolution of the disease. J Clin Endocrinol Metab. 1988; 67: 656-662.

22. McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR, Hall R. Carbimazole and the autoimmune response in Graves’ disease. N Engl J Med. 1980; 303: 302-307.

23. Wood LC, Ingbar SH. Hypothyroidism as a late sequela in patients with Graves’ disease treated with antithyroid drugs. J Clin Invest. 1979; 64: 1429-1436.

24. Lamberg BA, Salmi J, Wagar G, Makinen T. Spontaneous hypothyroidism after antithyroid treatment of hyperthyroid Graves’ disease. J Endocrinol Invest. 1981; 4: 399-402.

25. Vos XG, Endert E, Zwinderman AH, Tijssen JG, Wiersinga WM. Predicting the risk of recurrence before the start of antithyroid drug therapy in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab. 2016; 101: 1381-1389.

26. Allahabadia A, Daykin J, Holder RL, Sheppard MC, Gough SCL, Franklyn JA. Age and gender predict the outcome of treatment for Graves’ hyperthyroidism. J Clin Endocrinol Metab. 2000; 85: 1038-1042.

27. L. Liu L, Lu H, Liu Y, Liu C, Xun C. Predicting relapse of Graves’ disease following treatment with antithyroid drugs. Exp Ther Med. 2016; 11: 1443-1458.

28. Glinoer D, Hesch D, Lagasse R, Laurberg P. The management of hyperthyroidism due to Graves’ disease in Europe in 1986. Results of an international survey. Acta Endocrinologica. 1987; 115: 3-23.

29. Grodski S, Stalberg P, Robinson BG, Delbridge LW. Surgery versus radioiodine therapy as definitive management for Graves’ disease: the role of patient preference. Thyroid. 2007; 17: 157-160.

30. Franklyn JA. The management of hyperthyroidism. N Engl J Med. 1994; 330: 1731-1738.

31. Törring O, Tallstedt L, Wallin G, Lundell G, Ljunggren JG, Taube A, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine — a prospective, randomized study. J Clin Endocrinol Metab. 1996; 81: 2986-2993.

El-Shareif HJ (2018) Clinical Profile and Long-Term Remission in Patients with Graves’ Disease: The Tripoli Medical Centre Experience. J Endocrinol Diabetes Obes 6(1): 1116.

Received : 20 Nov 2018
Accepted : 20 Mar 2018
Published : 22 Mar 2018
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ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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