Correspondence *Programma di Endocrinologia Molecolare Clinica, Padiglione H, 4 Piano, AOU Policlinico G Martino, 98125 Messina, Italy

Email s.benvenga@me.nettuno.it

The case

An 18-year-old, nonsmoking woman presented to her general practitioner with a 1-week history of weakness, fatigue, palpitations, nervousness, tremors, insomnia, heat intolerance, and enlargement of a euthyroid goiter that had been detected 2 years earlier. At the time when the goiter was detected, the patient's levels of free T₃, free T₄, TSH, and levels of serum autoantibodies against thyroglobulin (TgAb) and thyroperoxidase (TPOAb) had been normal. At presentation 2 years later, thyroid scintigraphy with ¹³¹I showed homogeneously distributed radioactivity throughout the thyroid gland. Radioactive iodine (¹³¹I) uptake values were high (79% at 6 h, normal range 15–30%; 62% at 24 h, normal range 30–50%). Thyroid ultrasonography showed a diffuse hypoechogenicity with rich vascularization at Color-Doppler imaging, two findings that had been absent when the goiter was first detected. Moreover, the volume of the goiter had significantly increased since it was first detected, from 41 ml to 50 ml. The patient and her parents attributed her symptoms to psychological stress (i.e. work problems that ended in job loss and subsequent relationship problems, and fear that the goiter enlargement could be due to thyroid cancer) that had started about 3 months before referral to the clinic (Figure 1).

Figure 1 Stressful life events (indicated by arrows), changes in serum free T₃ and free T₄ levels, thyroid autoantibodies (TgAb, TPOAb, TRAb) and pharmacological treatment in the patient described.

The grey areas indicate the reference values. Onset of hyperthyroidism (at month 3) and its two exacerbations (at month 21 and month 38) are indicated by the peaks of serum free T₃ and free T₄ levels. Abbreviations: TgAb, anti-thyroglobulin antibody; TPOAb, anti-thyroperoxidase antibody; TRAb, anti-TSH-receptor antibody.

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The patient was referred to the Endocrinology Clinic for further investigation. On physical examination, tachycardia (98 beats/min), tendon hyperreflexia, hand tremors, and warm and moist skin were observed. Serum assays for thyroid hormones revealed elevated serum levels of free T₃ (17.7 pmol/l; normal range 2.8–7.7 pmol/l) and free T₄ (49.3 pmol/l; normal range 11–24 pmol/l), and a low TSH level (<0.01 mIU/l; normal range 0.27–4.2 mIU/l). These findings confirmed the clinical diagnosis of hyperthyroidism. Immunoassays for serum autoantibodies were positive for autoantibodies against the TSH receptor (TRAb 9.3 IU/ml; normal range 0.0–1.0 IU/ml), TgAb (845 IU/ml; normal range 0–100 IU/ml) and TPOAb 968 IU/ml; normal range 0–10 IU/ml). This finding indicated the autoimmune nature of the hyperthyroidism; therefore, a diagnosis of Graves disease was made.

The patient was started on methimazole at a dose of 20 mg/day (gradually tapered during the following 2 years) and her thyroid hormone levels normalized shortly afterwards (free T₃ 4.9 pmol/l and free T₄ 21.6 pmol/l at 5 months' follow-up, Figure 1). Eight months after presentation, the patient reported negative life events (including personal and work-related problems, as well as exacerbation of chronic appendicitis, followed by influenza, tonsillitis and herpes labialis in succession). To help her cope with stress, the benzodiazepine bromazepam was added (at a dose of 3 mg/day, reduced to 1.5 mg/day 1 month later, and then withdrawn progressively). As a result of bromazepam treatment, the patient described herself as less anxious (which was confirmed by her family). At month 16, the patient became pregnant and stopped taking bromazepam. During pregnancy, the patient's methimazole dose was reduced to 10 mg/day and at the last trimester to 5 mg/day because of her concerns of the potential adverse effects of the drug on her unborn baby.

The patient experienced two exacerbations of hyperthyroidism during the 4 years after presentation when she was still taking methimazole; they occurred during her first pregnancy and 9 months after her first delivery (Figure 1). Exacerbations were associated with increased serum levels of TRAb and were preceded by stressful events. The patient was advised to start taking bromazepam when experiencing emotional stress in the future. In the following years the patient took a course of bromazepam twice, each time starting soon after she experienced emotional stress (the first time after having personal and work-related problems and the second time after delivery of her second child). During these years, no exacerbations of hyperthyroidism occurred. The patient's two babies, born by Cesarean section at weeks 41 and 39 of gestation, respectively, were healthy and tested negative for congenital hypothyroidism at newborn screening.

Discussion of diagnosis

The prevalence of thyrotoxicosis is 0.5–2.0% in women and about 10-fold rarer in men. Incidence of Graves disease in women approximates 1 case per 1,000 per year.¹ In iodine-deficient areas, Graves disease is rarer than toxic nodular goiter but Graves disease remains the most common cause of spontaneous hyperthyroidism in patients younger than 40 years.¹ Hyperthyroidism occurs in 0.1–0.4% of pregnancies, with 85% of cases due to Graves disease.^{2, 3} Prevalence of postpartum thyroid dysfunction is about 8% in the general population, and of these patients about 10% have Graves disease. After a course of antithyroid drugs (ATDs), recurrence of Graves disease is observed in approximately half of the patients, of whom about three-quarters experience recurrence within 6 months.^{1, 4}

Symptoms and signs of hyperthyroidism are nonspecific (Figure 2); nevertheless, their combination in a clinical syndrome is rather distinctive.⁵ Biochemical confirmation and differential diagnoses of hyperthyroidism (Box 1) are simple. The clinical suspicion of hyperthyroidism is promptly verified by detecting elevated concentrations of thyroid hormones with suppressed TSH level and, if the etiology is Graves disease, by the presence of TRAbs. Similarly to other autoimmune diseases, Graves disease is a remitting–relapsing disorder that is triggered by environmental factors in genetically predisposed individuals.¹ Human leukocyte antigen genes, which had been previously considered as the main hereditary factors contributing to Graves disease, are only partly responsible for the genetic susceptibility.¹ The relatively low concordance rate of Graves disease in monozygotic twins (35%)⁶ implies that nongenetic factors (Box 2) have an important role in the development of the disease.⁷

Figure 2 Most frequent symptoms and signs of hyperthyroidism.⁵

 

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Although there has been controversy about the role of emotional stress in triggering Graves disease, most papers have concluded in favor of its eliciting role.^{8, 9, 10, 11, 12} Previous studies have focused on the onset rather than on the exacerbations or relapses of Graves disease. Hypochondriasis, depression, paranoia and psychasthenia were the personality traits associated with the highest risk for relapse of Graves disease.¹¹ Stress might cause peculiar immunological perturbations in genetically predisposed individuals, with women having greater hypothalamic–pituitary–adrenal responsiveness to stress and greater autoantibody production than men.⁸ The stress-induced rise in levels of circulating glucocorticoids and catecholamines shifts the balance of intrathyroid type 1 and type 2 T-helper cells towards the type 2 T-helper cells.^{8, 9} Inflammatory cytokines secreted by the intrathyroid T-lymphocytes induce thyrocytes to aberrantly express human leukocyte antigen class II molecules. Consequently, thyrocytes can present autoantigens that trigger an autoimmune reaction against these cells. Similarly, other environmental factors, such as smoke, irradiations, drugs, endocrine disruptors (e.g. pesticides and plasticizers) and microbes induce Graves disease through secretion of cytokines and/or through direct thyrocyte lesion.^{1, 12} Further activation of resident thyroid-specific autoreactive T-cells leads to the development of Graves disease.¹ Hyperthyroidism amplifies the effects of glucocorticoids and catecholamines, and might increase T-cell and B-cell responses.⁸

Emotional stress might affect thyroid function also via neural pathways. The thyroid gland, as well as other endocrine glands harboring chronic lymphocyte infiltrates, is surrounded by a rich innervation.^{13, 14} The nerve terminals reaching the thyroid gland include adrenergic and cholinergic terminals as well as peptidergic terminals containing vasoactive intestinal peptide and substance P. Of these neurotrasmitters, norepinephrine and vasoactive intestinal peptide can release thyroid hormones in the absence of TSH.¹⁴ Lymphocytes have been demonstrated to express receptors for neurotransmitters and hormones, such as norepinephrine, vasoactive intestinal peptide, substance P, adrenocorticotropic hormone and glucocorticoids.¹⁵ Thus, stress-elicited release of these molecules can lead to lymphocyte activation.

Pregnancy and delivery are typical hyperthyroidism-precipitating events in patients with Graves disease.^{1, 2, 3} In women, Graves disease has a peak incidence in the child-bearing third to fourth decades. During pregnancy, patients' levels of serum thyroid antibodies generally fluctuate, reflecting the clinical course of the disease. TRAbs can be detected in the first trimester, but their levels often decrease in the second and third trimesters and might become undetectable before increasing again postpartum. Patients can experience relapse or exacerbation of clinical symptoms by 10–15 weeks of gestation. Graves disease, however, can remit later in the second and third trimester. In rare cases, 'thyroid storm' can occur during pregnancy. This very severe, life-threatening form of Graves disease-related hyperthyroidism can be triggered by pre-eclampsia, placenta previa, labor, Cesarean section or infection.^{1, 2, 3} Women who are TRAb-positive early in pregnancy, as the patient described, are at a high risk of developing Graves disease after delivery.⁸ Possible explanations include enhanced immune activation after delivery upon release from gestational immune suppression, and persistence of fetal cells within the maternal circulation (fetal microchimerism).

At presentation, the patient described had new-onset Graves disease which she attributed to stressful events. During the 11-year follow-up, she had two exacerbations of hyperthyroidism, both preceded by environmental triggers. The patient reported four potential environmental triggers (stressful emotions, exacerbation of chronic appendicitis, infections and pregnancy) during the 5 months preceding the first exacerbation, and three potential triggers (parturition, Cesarean section, and stressful emotions) during the year preceding the second exacerbation (Figure 1). A major stressful emotion reported by the patient was concern about a potential relapse of her hyperthyroidism. Furthermore, she was worried about the possibility of her baby having neonatal thyrotoxicosis, which did not occur. Neonatal thyrotoxicosis was unlikely in this case, as it occurs in only 1% of infants of women with thyrotoxic Graves disease. Furthermore, in most cases, the mother has severe hyperthyroidism with significant orbitopathy or infiltrative dermopathy during pregnancy, elevated levels of TRAb during the third trimester and delivery, has had a baby with neonatal thyrotoxicosis, or has undergone ¹³¹I ablative treatment.^{1, 2}

Treatment and management

Treatment modalities for Graves disease include medical, radioisotopical and surgical treatment options.¹ The most widely used ATDs are propylthiouracyl and methimazole; these drugs inhibit thyroid hormone synthesis and thyroid autoimmunity.¹ At initiation of treatment with ATDs or ¹³¹I, -blockers are used as adjuncts to control for catecholamine-related symptoms, such as palpitations, tremulousness, excessive sweating and eyelid retraction.¹ The main adverse effects of ATDs are agranulocytosis, liver damage, skin rashes, arthralgias and vasculitis. As ATDs can have serious adverse effects on the fetus, including thyroid abnormalities (goiter, hypothyroidism) and teratogenicity (choanal or esophageal atresia, aplasia cutis, or more rarely a severe embryopathy), they should only be used at low doses in pregnant women, as in the patient described.³

In the past, management strategies for Graves disease considered the avoidance of stressful events. Larsen,¹⁶ for instance, suggested bed rest, and the extrication of the patient from the usual occupational or domestic pressures. Baschieri and colleagues¹⁷ recommended the use of tranquillizers (with a preference for benzodiazepines) in the initial weeks of medical treatment to alleviate the neuropsychological disturbance. Coping strategies for unavoidable stressful events have also been suggested to improve the prognosis of Graves disease.¹¹ Indeed, in a study including 44 patients with Graves disease who were followed up for an average of 62 months, remission correlated significantly with the duration of combined treatment with methimazole (20–30 mg/day, gradually reduced to 5 mg/day) and bromazepam (3.0–1.5 mg/day). Combined treatment with methimazole and bromazepam for 2 months lead to the remission of Graves disease in 20% (6/23) of patients, whereas treatment for at least 7 months lead to remission in 75% (15/21) of patients.¹⁸ Previous studies have suggested that benzodiazepines, further to facilitating transmission of the inhibitory neurotransmitter gamma-aminobutyric acid, interfere with thyroid hormone signaling by decreasing the nuclear T₃ maximal binding intensity in the brain¹⁹ and the uptake of T₃ by both neurons and non-neural cells.²⁰

In the patient described, TRAb levels increased and thyroid hormones were near the upper limit of the normal range between 8 and 14 months of follow-up (after she had experienced stressful events), but these changes did not coincide with the addition of bromazepam. After her first delivery (29 months after presentation), when her TRAb levels were still high, she decided to postpone the initiation of bromazepam therapy until month 36, because she was concerned that it would affect her ability to take care of the baby. The commencement of bromazepam therapy was associated with a mild elevation of thyroid hormone levels at month 38. By contrast, no relapse occurred 3 years later when the patient was taking bromazepam in the 18 months preceding the second pregnancy (between month 74 and month 90), in spite of exposure to stressful events. The patient also remained euthyroid during the 2 years when she was taking bromazepam alone (between month 100 and month 124, starting soon after delivery of her second baby).

Overall, treatment with bromazepam had a favorable effect on the clinical course of Graves disease in the patient described. This beneficial effect might be partly because peripheral benzodiazepine receptors are widely expressed throughout the human body (including the thyroid gland, adrenal glands²¹ and lymphocytic infiltrates²²) and ligands for these receptors have been shown to have beneficial therapeutic effects on autoimmune diseases, such as rheumatoid arthritis, in tested animal models.²²

Despite the widespread use of benzodiazepines during pregnancy and lactation, little information is available about their effect on the developing fetus and on nursing infants.²³ Although there is insufficient evidence that benzodiazepines are human teratogens,²⁴ pregnant women should only receive benzodiazepines that have a long record of safety, and should take the benzodiazepine as a monotherapy at the lowest effective dosage for the shortest possible duration to avoid the potential risk of congenital defects (the patient described was not taking benzodiazepines during her pregnancies). Furthermore, as benzodiazepines can be addictive when used chronically, caution should be exerted when prescribing these drugs for patients with a current or past history of drug and/or alcohol abuse.²⁵ For the same reason, benzodiazepines should be withdrawn progressively, as in the patient described.

Conclusions

This Case Study highlights the importance of environmental factors, particularly psychological stress, in triggering the clinical syndrome associated with Graves disease. In cases in which the onset of Graves disease is related to stress, exacerbations of hyperthyroidism are also likely to be triggered by stressful events. Exacerbations and relapses are milder or absent if environmental factors, such as negative life events, are avoided when possible or if anxyolitics (benzodiazepines) are given to help the patient cope with stress.

Acknowledgments

Written consent for publication was obtained from the patient. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Subject areas under which this article appears: Thyroid gland | Autoimmunity (including infection)