Characterization, treatment preferences, and outcomes of 390 Egyptian Graves’ disease patients: a retrospective study

Graves’ disease is the most common cause of thyrotoxicosis worldwide. Patient characteristics may vary according to ethnicity, iodine status, and age. Studies on characterization of Graves’ disease in Egypt are lacking. The present study aims to report the patient characteristics, as well as treatment preferences and outcomes of Graves' disease patients from Alexandria, Egypt. A retrospective review of demographic, biochemical, serological, sonographic, and treatment data of Graves' disease patients attending endocrinology outpatient clinic, Alexandria faculty of medicine, Egypt. Three hundred ninety patients were included. Females were 75.9%, peak age was 21–40 years representing 53.1%, and family history of thyroid disease was positive in 60% of patients. Overt hyperthyroidism was present in 93.9%, TSH receptor antibodies were positive in 97.1%, and thyro-peroxidase antibodies in 74.8%. Goiter was present in 72.8%, nodularity in 18.4%, and thyroid eye disease in 17.7%. Medical treatment was used in 90% of patients, surgery in 5.4%, and radioiodine in 4.3%. For patients on medical treatment, 17.7% achieved remission, 29% relapsed, and 2.85% developed hypothyroidism. A typical Graves’ disease patient in Egypt is a middle-aged female with a positive family history of thyroid disease. Overt hyperthyroidism was the most common presentation and goiter was a common sign at presentation. The sensitivity of TRAb’s for diagnosing Graves’ disease was excellent (97.1%). ATD’s was the commonest treatment modality with a remission rate of 17.7% and a relapse rate of 29%.


Background
Graves' disease is the most common cause of thyrotoxicosis worldwide.It is an autoimmune disease where TSH receptor autoantibodies (TRAb's) -acting on thyrotropin (TSH) receptors -lead to a diffuse goiter and variable degrees of hyperthyroidism.It may be associated with extra-thyroidal manifestations like thyroid eye disease (TED), dermopathy, or acropachy.It is more common in females, middle age, and in iodine replete areas [1].
Lines of treatment include medical treatment with antithyroid drugs (ATD's), thyroidectomy, or radioiodine ablation.Treatment with antithyroid drugs (ATD's) may lead to remission of the disease, however, a patient may relapse even years after achieving remission.Ablative treatments whether surgery or radioiodine ablation, lead to hypothyroidism in almost all the patients.Hypothyroidism may occur after treatment with medical treatment in up to 20 percent of the patients [2,3].
Patient characteristics may vary according to ethnicity, iodine status, and age.Characterization of patients with Graves' disease has been previously reported from west Africa and Europe [4,5].Treatment preferences and outcomes were also reported from Europe and Asia [5,6].Studies on prevalence and characterization of Graves' disease in Egypt are lacking.
The present study aims to fill a part of the knowledge gap about Graves' disease in Egypt by reporting the demographic, biochemical, serological, sonographic data, treatment preferences and outcomes of 390 Graves' disease patients from Alexandria, Egypt.

Methods
The medical records of all patients who received a diagnosis of graves' disease, attending endocrinology outpatient clinic, Alexandria faculty of medicine were retrospectively reviewed.This clinic is a tertiary referral center serving patients from 3 Egyptian governorates; Alexandria, Beheira, and Mersa Matruh.All Graves' disease patients attending the clinic in the period from October 2020 to September 2022 were included in the review.When available, a diagnosis of Graves' disease was made based on a positive TSH receptor autoantibodies (TRAb's) (Roche Diagnostics, Mannheim, Germany on Cobas E 8000 platform, [Normal < 1.75 IU/L]).When TRAb's were not available, a diagnosis of Graves' disease was made based on the presence of persistent thyrotoxicosis showing a good response to antithyroid drugs plus a single or a combination of other parameters: an increased radioactive iodine uptake, the presence of thyroid eye disease, high thyro-peroxidase (TPO) autoantibodies, or a sonographic pattern consistent with autoimmune thyroid disease.
Demographic data included sex of the patient and age at the time of presentation.Clinical data included the presence of a goiter, the presence of thyroid eye disease, family history of thyroid disease, and comorbidity history.Biochemical data of thyroid function tests at the time of presentation were reviewed.Patients were classified into 3 categories: T3-toxicosis, subclinical, and overt hyperthyroidism [2].T3-toxicosis was diagnosed when the patient presents with suppressed TSH, a normal free T4, and a high free T3.Subclinical hyperthyroidism was diagnosed when TSH is suppressed and both Free T3 and Free T4 are normal.Overt hyperthyroidism (OH) was diagnosed when TSH was suppressed and Free T4 was high.Overt hyperthyroidism was further subdivided according to degree of elevation of Free T4 into mild hyperthyroidism when free T4 was 1.7 to 3.9 ng/dl, moderate when free T4 was 3.9 to 7.7 ng/dl, and severe when free T4 was > 7.8 ng/dl [7] (Roche Diagnostics, Mannheim, Germany on Cobas E 411 analyzer [Normal 0.93-1.7 ng/dL]).
Treatment modality whether medical treatment, surgery, or radioiodine ablation were reviewed.Antithyroid drugs (ATD's) dose and duration of treatment were reviewed.Remission was defined as maintenance of euthyroidism for six months after discontinuation ATD's [9].The numbers of patients who achieved remission and time to remission were reviewed.Numbers of patients who relapsed and time to relapse were also reviewed.Lastly, time to ablation and doses of radioiodine were reviewed.
The protocol of the study was approved by the ethical committee of Alexandria faculty of medicine [IRB number 12098].

Results
A total of 390 graves' disease patients were included in this retrospective review.Main findings of the review are summarized in Table 1.

Demographic data
Most of the patients were females 296/390 (75.9%), males were only 94/390 (24.1%), with a female to male ratio of 3.1:1.The age of patients at the time of presentation ranged from 7 to 78 years.The median age was 33 years, the mean ± standard deviation (SD) was 35.3 ± 13.6 years.Peak age was from 21 to 40 years of age representing 53.1% of all patients (Fig. 1).

Family and comorbidity history
Family history of thyroid disease was positive in 234/390 (60%) of patients, with the number of affected relatives ranging from 1 to 10 relatives and a mean and a median of 2 relatives.The history of comorbidity was significant for metabolic syndrome components; hypertension in 62, dyslipidemia in 28, prediabetes in 12, type 2 diabetes in 26, and polycystic ovary syndrome in 2 patients.Autoimmune endocrinopathies; type 1 diabetes in 5, and primary ovarian insufficiency in one patient.Non-endocrine autoimmune diseases; vitiligo in 3, systemic lupus in 2, rheumatoid arthritis in 5, Crohn's disease in 1, ulcerative colitis in 1, celiac disease in 1, and myasthenia gravis in 1 patient.Cancer breast in 5 patients.Cardiovascular disease; heart failure in 3, atrial fibrillation in 7, coronary heart disease in 3, wolf Parkinson white syndrome in 1, and peripheral arterial disease in 1 patient.Allergic disorders; bronchial asthma in 14, and allergic rhinitis in 8 patients.Gastrointestinal disorders; irritable bowel syndrome in 15, peptic ulcer disease in 8, and gastro-esophageal reflux in 3 patients (Table 2).

Serological data
TRAb's were available for 340 patients (87.2%) at the time of initial presentation.330 patients were positive and only 10 patients were negative yielding a sensitivity of the used assay of 97.1% for the diagnosis of Graves' disease.The 10 patients who were negative for TRAb's and the remaining 50 patients received a diagnosis of Graves' disease based on the presence of a single or a combination of other parameters.An increased RAIU in 3 patients, high TPO antibodies in 20 patients, a sonographic pattern consistent with AITD in 45 patients, or the presence of TED in 18 patients.Thyroperoxidase antibodies were available for 226 patients.TPO antibodies were positive in 169/226 (74.8%).Thyroglobulin antibodies were available for 119 patients.Tg antibodies were positive in 65/119 (54.6%) (Table 1).

Thyroid eye disease
Thyroid eye disease was present in 69 patients at the time of presentation representing 17.7% of the whole cohort.

Treatment preferences
Most of the patients were treated medically using antithyroid drugs 351/390 (90%).Both carbimazole and propylthiouracil (PTU) are available in Egypt, so basically patients were treated with carbimazole except during the first 16 weeks of pregnancy when they are switched to PTU.One patient was diagnosed early in pregnancy with subclinical hyperthyroidism and was observed throughout pregnancy without treatment.Thirty-eight patients (9.7%) received definitive treatment in the form of surgery in 21 patients (5.4%) and radioiodine ablation in the remaining 17 patients (4.3%).

Medical treatment outcomes
A record of carbimazole doses and duration of treatment were available for 350 patients.Maximum carbimazole dose prescribed for patients during their treatment ranged from 5 mg/day to 100 mg/day.The median dose was 30 mg/day, the mean ± SD was 27 ± 14 mg/day.Among patients who did not achieve remission nor opted for a definitive treatment, the duration of treatment ranged from 1 to 240 months.The median duration of treatment was 16 months, while the mean was 34 ± 44 months.Four patients developed agranulocytosis.Two opted for surgery, one opted for RAI ablation, and one achieved remission.Sixty-two patients achieved remission in the reviewed cohort representing 15.9% of the total cohort, 17.7% after excluding those who opted for ablative therapies.Time to remission ranged from 4 to 180 months, with a median of 23.5 months and a mean ± SD of 34 ± 30.2 months.TRAb's were available for 44 patients at the time of ATD's discontinuation.They ranged from 0.1 to 40, they were positive in 13/44 patients (29.5%), with a median of 0.97 and a mean ± SD of 2.62 ± 6.2.18 patients relapsed after achieving remission (29%).Time to relapse ranged from 6 to 180 months, with a median of 21 months and a mean ± SD of 29.44 ± 39.7 months.TRAb's were available for 11 patients at the time of relapse.They ranged from 1.13 to 34.4, they

Ablative treatments
Time to surgery ranged from 3-180 months.The median time was 17 months, the mean ± SD was 17 ± 36.9 months.Two patients who opted for surgery were found to have papillary thyroid carcinoma.Time to radioiodine ranged from 1-240 months.The median time was 24 months, the mean ± SD was 49.4 ± 63.4 months.5 patients required 2 doses of radioiodine to achieve hypothyroidism.One patient required 3 doses of radioiodine to achieve hypothyroidism.A single dose of radioiodine ranged from 6 to 25 millicurie (mCi).Cumulative doses of radioiodine ranged from 6 to 45 mCi.

Discussion
This is the first study to characterize a large cohort of Graves' disease patients from the north African country, Egypt.A retrospective review of the medical records of 390 graves' disease patients attending endocrinology outpatient clinics, Alexandria faculty of medicine in the period from October 2020 to September 2022 was reported.
Graves' disease is the most common cause of hyperthyroidism in iodine sufficient areas accounting for about 80% of the cases, especially in adults below 50 years of age [1,10].84.7% of the patients reviewed in the present study were 50 years of age or younger.Egyptian national universal salt iodization has started in 1996.The latest Egyptian national health survey has demonstrated that 91% of household used iodized salt.A large subnational survey showed that only 10% of school children were iodine deficient defined as urinary iodine excretion of less than 100 µg/L [11,12].Salt iodization initially increases incidence of hyperthyroidism, mainly due to thyroid autonomy, however it does not affect the incidence of Graves' disease [10].
In the present study, the mean age was 35.3 years compared to 39.9 in a west African cohort of 182 patients, 36.3 in an Asian cohort of 2736 patients, and 43.3 in a French cohort of 802 patients [4][5][6].
TSH receptor auto-antibodies (TRAb's) has been recommended by the European thyroid association (ETA) to be the test of choice to confirm the diagnosis of Graves' disease.Compared to radioactive iodine uptake, TRAb's saves time to diagnosis and costs by almost 50% [2].TRAb's were ordered for 87% of our patients, whereas only 3 patients were diagnosed using radioactive iodine uptake studies (less than 1%).Reported sensitivities of second and third generation TRAb's assays were 97.1%, and 97.4% respectively, which is the same sensitivity found in our patients, 97.1% [13].In the west African cohort, the test was performed in 67% and it was positive in 99%, while in the French cohort, the test was performed in 60.6% and it was positive in 95.8% [4,5].The test was least used in the Asian cohort where only 3.7% had the test at initial presentation [6].
Ultrasound thyroid is currently recommended to support the diagnosis of Graves' disease after serology [2].Sonographic signs of autoimmune thyroid disease include hypo-echogenicity, heterogenicity, pseudo-nodules, micro-nodulation, fibrous septae and pseudo-lobulation.The infiltration by immune cells and decreased colloid leads to a decreased colloid cell interface resulting in the hypo-echogenicity characteristic of Graves' disease [8,14].Heterogenicity, septae with pseudolobulation, and hypo-echogenicity were the most common sonographic signs in our patients.
Currently, medical treatment using antithyroid drugs is the recommended first line treatment for Graves' disease.In the latest ETA guidelines, lifelong medical treatment has been suggested for patients who did not achieve remission after 30 months of treatment or those who relapsed who prefer this line of treatment.It was also considered a satisfactory treatment for older individuals with mild disease [2].In a recent systematic review, long term antithyroid drugs of more than 18 months was considered safe, in low doses and in adults, with only 0.8% incidence of major complications [15].Ninety percent of our patients were treated with antithyroid drugs for a mean duration of 34 ± 44 months.Some of the patients received medical treatment for durations up to 20 years.4/351 patients (1.1%) developed agranulocytosis, 3 patients required definitive treatment, while one patient achieved remission.
In the French cohort, treatment preferences were 91%, 6.1%, and 2.9% for medical treatment, surgery, and radioiodine, respectively [5].For the Asian cohort, treatment preferences were 72.6%, 0.9%, and 26.5% for medical treatment, surgery, and radioiodine, respectively [6].The combination of ATD's and levothyroxine or the blockreplace regimen was never used in the present cohort.In the French cohort, it was used in 41.2%, while in the Asian cohort, it was used in only 1.9% [5,6].
Among patients who opted for medical treatment, 17.7% achieved remission, and later 29% of whom relapsed.In the Asian cohort, 30.7% achieved remission, and 56.3% relapsed, while in the west African cohort, remission rate was 54.9% [4,6].The low rates of remission in the present study may be related to racial or environmental factors.A prospective trial with focus on known predictors of remission is needed to confirm this rate and provide predictive factors in Egyptians.
Spontaneous persistent hypothyroidism occurs as a sequel of Graves' disease patients treated with antithyroid drugs in 5-20% of the cases.The mechanisms involved were either blocking TSH receptor antibodies or destructive thyroiditis [16].In the present study, 10 patients (2.85%) developed hypothyroidism following treatment with ATD's.time to hypothyroidism ranged from 2 months and up to 5 years after stopping ATD's.A similar incidence was reported from the Asian cohort of 2.3% [6].
The present study has the strength of being the first and only to characterise graves' disease patients in Egypt with a relatively large number of patients compared to similar studies conducted in Africa [17].
The present study has few limitations.The data about initial clinical presentation were lacking in most of the reviewed records, such data would have been useful in reporting the pattern of clinical presentation of Egyptian patients with Graves' disease.Variable length of follow up data for the reviewed patientsfrom 3 months and up to 20 years -may have affected the reported rates of remission and adverse events of ATD's.The record of 20 pregnancies were found in the patients' files, pregnancy may have affected treatment preferences and outcomes.

Conclusions
In conclusion, a typical Graves' disease patient in Egypt is a middle-aged female with a positive family history of thyroid disease, overt hyperthyroidism was the most common presentation and goiter was a common sign at presentation, the sensitivity of TRAb's for diagnosing Graves' disease was excellent (97.1%), thyroid eye disease was present in 17.7%, and ATD's was the commonest treatment modality with a remission rate of 17.7% and a relapse rate of 29%.

Fig. 1
Fig. 1 Distribution of age at the time of presentation

Table 1
Demographic, biochemical, serological characteristics, treatment preferences and outcomes of 390 graves' disease patients

Table 2
History of comorbidity in graves' disease patients