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Case In Point: Hyperthyroidism: 5 Cases to Hone Your Diagnostic Skills

A 32-year-old woman presents with weight loss of 6.4 kg (14 lb) during the past 8 months and diarrhea of recentonset. Menstruation had ceased 10 weeks earlier. She appears anxious, with pressured speech. Physical examination detectsbaseline sinus tachycardia, sweaty palms, and a diffusely enlarged thyroid gland. Laboratory tests reveal a thyroid-stimulatinghormone (TSH) level of 0.00 µU/mL (normal, 0.45 to 4.5 µU/mL), a free thyroxine (FT4) level of 4.8 ng/dL (normal,0.61 to 1.76 ng/dL), and a positive thyroid-stimulating immunoglobulin (TSI) level with high titer.

Weight Loss and Anxiety in a Young Woman 1. A 32-year-old woman presents with weight loss of 6.4 kg (14 lb) during the past 8 months and diarrhea of recentonset. Menstruation had ceased 10 weeks earlier. She appears anxious, with pressured speech. Physical examination detectsbaseline sinus tachycardia, sweaty palms, and a diffusely enlarged thyroid gland. Laboratory tests reveal a thyroid-stimulatinghormone (TSH) level of 0.00 μU/mL (normal, 0.45 to 4.5 μU/mL), a free thyroxine (FT 4 ) level of 4.8 ng/dL (normal,0.61 to 1.76 ng/dL), and a positive thyroid-stimulating immunoglobulin (TSI) level with high titer.

This is a classic presentation of hyperthyroidism caused by Graves' disease. The diagnosis can be made basedon clinical presentation, physical examination, and selected laboratory tests. Further evaluation with a radioactive iodine(RAI) uptake and thyroid scan would reveal an enlarged gland with increased uptake and confirm the diagnosis.The tests would also yield necessary dosing information if the patient were to be treated with RAI ablation. Alternatively,she could be treated with antithyroid medications or surgery. Subsequent to surgery, thyroid hormone replacementtherapy with levothyroxine would be needed.If this patient were pregnant, treatment options would change. RAI ablation would now be contraindicated, andthe patient could be offered antithyroid treatment with propylthiouracil (PTU). Following pregnancy, RAI ablationwith subsequent thyroid replacement therapy would be recommended.

An Elderly Man With Recent Atrial Fibrillation 2. A 76-year-old man with known heart disease is admitted to the hospital because of new onset of shortness of breath,fatigue, and atrial fibrillation. He denies weight loss, nervousness, and insomnia. There is no evidence of an acute myocardialinfarction or pulmonary embolus. On physical examination, his heart rate is 136 beats per minute; beats are irregularlyirregular; and fine rales are heard at both lung bases. His blood pressure is 152/82 mm Hg, without orthostaticchanges. Results of laboratory tests indicate a hemoglobin level of 14.6 g/dL, a TSH level of 0.02 μU/mL (normal, 0.45to 4.5 μU/mL), and an FT 4 level of 3.3 ng/dL (normal, 0.61 to 1.76 ng/dL).

An elderly patient with hyperthyroidism secondary to Graves' disease, toxic multinodular goiter, or toxic adenomaoften presents without classic symptoms. A diagnosis of Graves' disease is confirmed by measurement of TSIand an RAI uptake and thyroid scan. Imminent treatment includes βblockers (and corticosteroids, if necessary) tocontrol the hyperthyroid state, which is now causing secondary atrial fibrillation and congestive heart failure.βBlockers will control the tachycardia and reduce the risk of heart failure; corticosteroids will block the peripheralconversion of T 4 to triiodothyronine (T 3 ). PTU might be useful for inhibiting intrathyroidal hormone production (oxidationand organification) and the peripheral conversion of T 4 to the metabolically active T 3 . Plans should be madefor RAI ablation, followed by thyroid hormone replacement therapy. In cases such as this, the atrial fibrillation isusually not converted to a normal sinus rhythm until the hyperthyroid state is successfully treated. Anticoagulationtherapy should be considered as well.

Nodule in a Woman With Insomnia 3. A 29-year-old woman presents for her yearly pelvic examination and Pap smear. She complains of insomnia andnervousness. Physical examination reveals an enlargement of the left lobe of the thyroid gland, which suggests the presenceof a nodule. Laboratory test results reveal a TSH level of 0.02 μU/mL (normal, 0.45 to 4.5 μU/mL) and an FT 4 level of2.3 ng/dL (normal, 0.61 to 1.76 ng/dL).

To confirm a diagnosis of hyperthyroidism secondary to toxic adenoma . in a patient with abnormal levels of TSHand FT 4 , fine-needle aspiration and biopsy (FNAB) of the nodule are indicated. An RAI uptake and thyroid scan canbe used to investigate the possibility of "other" adenomas and to help determine the dosage of 131 I for subsequent radioiodinetherapy. Many physicians turn to ultrasonography, but the initial evaluation that consists of TSH and FT 4 measurement and FNAB is sufficient for diagnosis. Ultrasonography cannot distinguish benign from malignanttissue.

Treatment is either surgery (partial thyroidectomy) or RAI ablation. If the nodule persists following treatmentwith RAI ablation, a second tissue biopsy is indicated.

Woman With Tremors Following Weight Loss 4. A 28-year-old hospital nurse presents for evaluation of palpitations and tremors that occur with writing. She hasintentionally lost 10 kg (22 lb) during the past 4 months. She requests a sleeping pill and some lorazepam to relieveher "shakes." She is nervous and fidgets during the examination, and her reflexes demonstrate 2-beat clonus. Laboratorytests reveal a TSH level of 0.01 μU/mL (normal, 0.45 to 4.5 μU/mL)and an FT 4 level of 3.9 ng/dL (normal, 0.61 to1.76 ng/dL). You suspect hyperthyroidism and order an RAI uptake and thyroid scan. Surprisingly, results of the testsreveal "decreased uptake of 123 I and a normal-sized gland, with no hot or cold areas identified."

Factitious hyperthyroidism should be suspected--and confirmed with additional history taking. No doubt thiswoman has been taking exogenous thyroid hormone to facilitate weight loss. This syndrome is often found in hospitaland medical workers who are aware of this hormone's metabolic effect and have access to samples. Factitious hyperthyroidismis distinguished from iatrogenic hyperthyroidism by the fact that the latter occurs in patients for whommore than the recommended dose for the treatment of hypothyroidism is prescribed.Another cause of decreased RAI uptake is subacute thyroiditis. A suppressed serum thyroglobulin level is consistentwith factitious hyperthyroidism; this level is elevated in subacute thyroiditis.

Nervous New Mother 5. A 28-year-old woman presents with complaints of nervousness, trouble sleeping, and weight loss. She is 8 weekspostpartum and wants to return soon to her job as a coronary care unit nurse. Laboratory tests reveal a TSH level of0.03 μU/mL (normal, 0.45 to 4.5 μU/mL) and an FT 4 level of 3.4 ng/dL (normal, 0.61 to 1.76 ng/dL). Results of atest for TSI are negative.

Postpartum thyroiditis is a self-limited disease (lasting 6 to 9 months) that transiently evolves first through astate of hyperthyroidism, then hypothyroidism, before the patient returns to a euthyroid state. 1 Depending on thetime of testing and the clinical presentation, a presumptive diagnosis of hyperthyroidism or hypothyroidism may bemade. Thyroid 123 I uptake measurement is necessary to confirm the diagnosis. Because most patients return to aeuthyroid state, no specific treatment is recommended, although hypothyroidism may persist in 20% to 25% of patientsfor 4 years., 2,3 Serial TSH measurements, explanation of the problem to the patient, and reassurance are indicated. Thetransient symptoms of hyperthyroidism may be managed with β-blockers.

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• About the Case

31-year-old woman with nausea and increased thirst

• Medical history : Primary hyperthyroidism due to Graves disease treated with radioactive iodine 6 years prior with subsequent hypothyroidism; depression 5 years prior that resolved with medication and counseling; no other psychiatric disorder. No known diabetes, pulmonary, or renal disease.
• Surgical history : None
• Medications : Levothyroxine 125 mcg daily, vitamin D 800 U daily.
• Allergies : No known drug allergies.
• Family history : Mother has type 2 diabetes mellitus and primary hypothyroidism.
• Social history : Patient is married and has been a homemaker since the birth of her daughter 2 years ago. She used to work in an office. She is a nonsmoker, has no alcohol intake, and denies taking any recreational drugs. Her diet is healthy and balanced. She eats a moderate amount of dairy products, lean meat, fruit, and vegetables. She last traveled abroad 6 months ago to Portugal. She has not had any recent contact with anyone with febrile illness or GI symptoms.

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• Review Article
• Published: 23 March 2018

Global epidemiology of hyperthyroidism and hypothyroidism

• Peter N. Taylor 1   na1 ,
• Diana Albrecht 2   na1 ,
• Anna Scholz 1   na1 ,
• Gala Gutierrez-Buey 3 ,
• John H. Lazarus 1 ,
• Colin M. Dayan 1 &
• Onyebuchi E. Okosieme 1  

Nature Reviews Endocrinology volume  14 ,  pages 301–316 ( 2018 ) Cite this article

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• Disease prevention
• Epidemiology
• Risk factors
• Thyroid diseases

Thyroid disease is a global health problem that can substantially impact well-being, particularly in pregnancy and childhood.

In advanced economies, the prevalence of undiagnosed thyroid disease is falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation.

Iodine nutrition remains a key determinant of thyroid function worldwide, and continued vigilance against the resurgence of iodine deficiency in previously sufficient regions remains essential.

More studies are needed in developing countries, especially within Africa, to understand the role of ethnicity and iodine nutrition fluxes in current disease trends.

Thyroid hormones are essential for growth, neuronal development, reproduction and regulation of energy metabolism. Hypothyroidism and hyperthyroidism are common conditions with potentially devastating health consequences that affect all populations worldwide. Iodine nutrition is a key determinant of thyroid disease risk; however, other factors, such as ageing, smoking status, genetic susceptibility, ethnicity, endocrine disruptors and the advent of novel therapeutics, including immune checkpoint inhibitors, also influence thyroid disease epidemiology. In the developed world, the prevalence of undiagnosed thyroid disease is likely falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation. However, continued vigilance against iodine deficiency remains essential in developed countries, particularly in Europe. In this report, we review the global incidence and prevalence of hyperthyroidism and hypothyroidism, highlighting geographical differences and the effect of environmental factors, such as iodine supplementation, on these data. We also highlight the pressing need for detailed epidemiological surveys of thyroid dysfunction and iodine status in developing countries.

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Peter N. Taylor, Diana Albrecht and Anna Scholz: These authors contributed equally: Peter N. Taylor, Diana Albrecht and Anna Scholz.

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Thyroid Research Group, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK

Peter N. Taylor, Anna Scholz, John H. Lazarus, Colin M. Dayan & Onyebuchi E. Okosieme

University Medicine Greifswald, Institute for Community Medicine, Greifswald, Germany

Diana Albrecht

Department of Endocrinology and Nutrition, Clinica Universidad de Navarra, Pamplona, Spain

Gala Gutierrez-Buey

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P.N.T., D.A., A.S., G.G. and O.E.O. researched data for the article, made substantial contributions to discussion of content, wrote the article and reviewed and/or edited the manuscript before submission. C.M.D. and J.H.L. made substantial contributions to discussion of content and reviewed and/or edited the manuscript before submission.

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The clinical state that results from too much thyroid hormone in the body. In the overwhelming majority of cases, this is due to excess production from the thyroid gland (hyperthyroidism).

A self-limiting subacute disorder that results in temporary hyperthyroidism, usually followed by a brief period of hypothyroidism and then recovery of normal thyroid function. It most commonly occurs in females in the post-partum period.

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Taylor, P., Albrecht, D., Scholz, A. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol 14 , 301–316 (2018). https://doi.org/10.1038/nrendo.2018.18

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Thymic hyperplasia is accurate to detect new-onset Graves’ hyperthyroidism and resolves after restoring euthyroidism

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Abnormal liver blood tests (ALBTs), neutropenia (NEU) and thymic hyperplasia (TH) are new features of Graves' disease (GD). Our objectives were: (a) to calculate the accuracy of TH in discriminating between Graves’ and non-Graves’ thyrotoxicosis, compared to ALBTs, NEU and Graves’ orbitopathy (GO); (b) to explore the outcome of GD-associated TH and non-GD-associated TH.

We prospectively analyzed consecutive adult patients with newly diagnosed thyrotoxicosis from January 2018 to June 2023. TH was detected via neck ultrasound (nUS) then confirmed and followed by magnetic resonance imaging (MRI). For GD vs non-GD clinical sensitivity (SE) and specificity (SPEC), accuracy, positive predictive value (PPV) and negative predictive value (NPV) of GO, TH, ALBTs and NEU were calculated.

264 thyrotoxic patients were included. TH was found in 16.4% (20/122) of GD vs 1.4% (2/142) in non-GD ( p  < 0.001). SE, SPEC, accuracy, PPV and NPV of the four extrathyroidal manifestations of GD were as follows, respectively: GO 26%, 100%, 66%, 100%, 61%; ALBTs 41%, 89%, 69%, 76%, 66%; NEU 5%, 100%, 56%, 100%, 55%; TH 16%, 98%, 61%, 91%, 98%. In 18 of them, TH regressed within 12 months after achieving euthyroidism under anti-thyroid drug therapy, while in the remaining 2, TH regressed 6 months after thyroid surgery. In the two non-GD patients with TH, thymus disappeared along with euthyroidism.

Conclusions

TH in the hyperthyroidism scenario provides a high PPV for GD. A conservative approach for the diagnostic work‐up and initial management of thyrotoxicosis-associated TH should be adopted.

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Thymic hyperplasia in patients with Graves’ disease

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Introduction

Clinical phenotype is currently reported to be milder than in the past, with goiter, Graves’ orbitopathy (GO) and severe excess of thyroid hormones being less frequent to date [ 1 , 2 , 3 ]. Therefore, due to the absence of the pathognomonic features such as GO and thyroid function testing, it may become challenging to distinguish Graves’ hyperthyroidism from other forms of thyrotoxicosis [ 4 , 5 ]. For this reason, in hyperthyroidism scenario, other extrathyroidal manifestations of GD should be investigated in combination with reference laboratory [i.e., thyrotropin (TSH) receptor antibodies (TRAb)] and imaging tests (i.e., scintigraphy) to support the clinical diagnosis of GD [ 6 ]. Among the main emerging extrathyroidal manifestations of GD, we have abnormal liver blood tests (ALBTs) [ 7 ] and neutropenia (NEU) [ 8 ]. It has been proved that both ALBTs and neutropenia are quite common in untreated and new-onset GD patients, they do not usually represent a contraindication to anti-thyroid therapy (ATD) and they typically resolve while treating hyperthyroidism [ 7 , 8 ].

Thymus hyperplasia (TH) refers to gross, diffuse, and symmetric enlargement of the thymus [ 9 ]. The association between GD and TH is quite known to thyroidologists but it remains largely unrecognized in clinical practice of other physicians [ 9 ]. This is probably the consequence of limited thoracic radiological evaluations for most patients with hyperthyroidism as well as a lack of awareness of this association. The association between GD and TH was first described in 1912 [ 10 ] and has been reported numerous times thereafter mostly as case reports and case series [ 11 , 12 , 13 , 14 , 15 ]. Thymic hyperplasia in GD is commonly discovered incidentally by chest X‐ ray or computerized tomography (CT) for other reasons [ 11 ]. It is proposed to control hyperthyroidism to improve and lead to disappearance of TH [ 9 ]. Yet, biopsy and thymectomy are recommended to be deferred in the setting of thyrotoxicosis to avoid triggering a thyroid storm [ 16 ] and should be reconsidered if the thymus fails to regress with treatment to rule out malignancy [ 9 , 17 ].

Therefore, the knowledge of the relationship between these emerging extrathyroidal manifestations (i.e., ALBTs, neutropenia, TH) and hyperthyroidism is of paramount importance for proper diagnosis and therapeutic decision-making.

This study is designed to bring more light into the thyrotoxicosis-associated TH, and our specific objectives were (a) to calculate the prevalence of radiological TH in a cohort of unselected patients with thyrotoxicosis; (b) to calculate the accuracy of TH in discriminating between Graves’ and non-Graves’ thyrotoxicosis, compared to ALBTs, NEU and Graves’ orbitopathy (GO); (c) explore the outcome of GD and non-GD-associated TH.

Materials and methods

Study design and patients.

In the current study, the Standards for Reporting Diagnostic Accuracy (STARD) statement was followed [ 18 ]. We prospectively examined consecutive adult patients with newly diagnosed and untreated thyrotoxicosis at our academic center from January 2018 to July 2023. Patients were being referred to our multidisciplinary team as they developed clinical manifestations of thyrotoxicosis (mainly cardiovascular and neurological symptoms) or, more rarely, to investigate incidental subnormal TSH. It needs to be specified that in our center patients with thyrotoxicosis routinely underwent baseline liver blood tests (LBTs) [i.e., alanine transaminase (ALT), Ɣ-glutamyl transferase (GGT), total bilirubin (BIL)], absolute neutrophil count (ANC), thyrotropin receptor antibodies (TRAb) measurement, neck ultrasonography (nUS), and thyroid scintigraphy in the same day or within few days (few weeks at the most) from the first examination.

Biochemical diagnosis of thyrotoxicosis/hyperthyroidism was based on TSH < 0.1 mIU/L with normal (subclinical) or elevated thyroid free thyroxine (fT4) and/or free triiodothyronine (fT3) alone (overt). Diagnosis of GD was confirmed by thyroid scintigraphy based on diffuse and homogeneous thyroid overactivity and reduced uptake in major salivary glands. In our center, visits were planned every 3–6 months, and clinical examination was also oriented to find extrathyroidal manifestations [i.e., GO, Graves’ dermopathy (GDerm), ALBTs, NEU and TH]. Activity and severity of GO were assessed according to the evidence-based recommendations of current guidelines [ 19 ]. Initial and ongoing therapies followed the current guidelines and recommendations [ 4 ] and patient preferences. In all patients with GD, medical therapy represented the first-line treatment for at least 18 months, and the starting dose of anti-thyroid drug (ATD) therapy (i.e., namely methimazole which was the preferred initial therapy) was established according to fT4 levels to promptly reach and stably maintain euthyroidism. Dose adjustment of ATD was pursued at every outpatient visit and controlled hyperthyroidism was defined by both fT4 and fT3 in normal ranges [ 4 ]. After 18 months of ATD therapy, medical therapy was continued for other 12–24 months or a definitive therapy (i.e., radioiodine or surgery) was adopted [ 4 ]. The Human Research Ethics Committee at the AOU University of Campania "Luigi Vanvitelli" (Naples, Italy) approved the study, and written informed consent was obtained from each study participant (Campania 2, 0003042/i).

The inclusion criteria were (a) follow-up of at least 18 months; (b) detection of TH via nUS then confirmed and followed every 6 months also by magnetic resonance imaging (MRI) until disappearance. The exclusion criteria were (a) concomitant liver disease/dysfunction; (b) preexisting diseases/drugs influencing the ANC; (c) incomplete diagnostic and follow-up test results; (d) previous history of thyroid disease or use of levothyroxine; (e) pregnancy; (f) uncontrolled hyperthyroidism at the 6-month follow-up under ATD therapy.

Laboratory tests

Thyroid function (i.e., TSH, fT3, fT4, fT3/ fT4 ratio) and antibodies [i.e., TRAb, anti-thyroglobulin (TgAb), anti-thyroid peroxidase (TPOAb)] was assessed with immunoassay method in automated platform (Elecsys ® e801 Roche Diagnostics). TSH assay had analytical sensitivity of 0.001 mIU/L, and reference range was between 0.27 and 4.2 mIU/L. Normal reference ranges for fT3 and fT4 were 3.1–6.8 pmol/L and 12–22 pmol/L, respectively. The lower cut-off of TRAb for a positive sample was > 1.7 IU/L. TRAb values exceeding 40 IU/L were reported by the laboratory as > 40 IU/L. In GD patients TRAb measurement was performed after 12 months of ATD therapy and in GD patients with TH every 6 months thereafter. TgAb and TPOAb were only assessed at baseline. The lower cut-off of TgAb and TPOAb for a positive sample was > 115 IU/mL and > 35 IU/mL, respectively.

Among LBTs, ALT was determined through kinetic ultraviolet methodology and values over 31U/L were considered high; GGT was measured through kinetic colorimetric methodology and values over 38U/L were considered abnormal; BIL was determined through a colorimetric method and values over 1.2 mg/dL were considered high. ALBTs condition was defined by the presence of at least one abnormal LBT among ALT, GGT and BIL. LBTs were assessed at each visit under ATD therapy [ 4 ].

Measurement of ANC was determined through colorimetric test (Siemens Advia 2120) and neutropenia was defined as an ANC ≤ 1.8 × 10 9 /L. Baseline diagnostic and follow-up laboratory results were extracted for the present study. ANC was assessed at each visit under ATD therapy [ 4 ].

Neck ultrasonography

nUS was performed by an experienced thyroidologist (LS) through an ultrasound device (MyLab™Six, Esaote) with a 7–14 MHz wide band linear transducer. The color gain was adjusted, so that artefacts were prevented. nUS was performed at each visit. Specifically, the ultrasound examination of thyroid vascularity (qualitative assessment) and volume, along with nodules and cervical lymph nodes detection and characterization, were systematically conducted.

In our study, nUS aimed to explore the presence of TH (i.e., cervical portion) and served to request MRI examination. On nUS TH appeared as a cervical mass located next clavicular fossa with partial immersion in superior mediastinum. TH typically had trapezoidal shape, overall decreased echogenicity (compared to thyroid), heterogeneous “marbled” echo pattern and reduced/nearly absent vascularity (see Fig.  2 below).

Magnetic resonance imaging

All MRI examinations were performed on 1.5 Tesla MRI scanner (GE Signa Voyager HD, GE Healthcare, Milwaukee, WI, USA) by using a phased-array body coil centered on the mediastinum before and after the intravenous injection of paramagnetic contrast medium (Gadobutrol, 0.1 mL/kg, Gadovist ® , Schering AG, Berlin, Germany). The imaging protocol was chosen following the most recent recommendations in thoracic MRI imaging reports [ 20 , 21 ]. Our imaging protocol included: (1) axial thin Sect. (3 mm) T2-weighted single shot fast spin-echo sequence, (2) axial thin Sect. (3 mm) T2-weighted with fat-suppression (STIR), (3) axial thin Sect. (3 mm) T1-weighted dual-echo in- and opposed-phase; (4) axial diffusion-weighted (b-values 0, 100, 800 s/mm 2 ) and relative apparent diffusion coefficient (ADC) maps; (5) precontrast axial T1-weighted fast gradient-echo; (6) post-contrast axial T1-weighted fast gradient-echo (acquisition at 20–30 s, 60–70 s, 3-min and 5-min delays); (7) sagittal and coronal T1-weighted fast gradient-echo acquisitions between 3 and 5 min. Thoracic MRI examinations were performed to confirm and further assess TH initially detected on nUS. MRI aimed to calculate volume values of TH and the interval time of TH disappearance. In thyrotoxic patients with TH, MRI was performed at diagnosis (when TH was first detected on nUS) and every 6 months to follow gradual remission of TH under euthyroidism. When disappearance of TH was recorded, MRI was not repeated. If volume of TH did not reduce at the 6-month follow-up under euthyroidism, other causes of TH would be investigated (i.e., neurological, rheumatological, dermatological and hematological diseases) and proper algorithms for other conditions would be followed through consultations. All MRI examinations were evaluated by two radiologists [5- (A.C.) and 15- (A.R.) years experienced]. TH was assessed when a lobulated soft tissue mass with homogeneous appearance throughout the various MRI sequences and relatively uniform loss of signal intensity on in- and opposed-phase images was found in the mediastinal prevascular space (see Fig.  3 below).

Thyroid scintigraphy

Fifteen minutes after intravenous administration of 185 MBq (5 mCi) of Technetium-99m (99mTc) pertechnetate, anterior images of the neck were acquired using a gamma-camera equipped with high-resolution parallel-hole collimator (Symbia ® , Siemens) with an acquisition time of 10 min, using a 20% window centred around the 140 keV peak of 99mTc and a 128 × 128 computer matrix. Baseline scintigraphy patterns 0–2 [0, normal gland uptake; 1, decreased uptake; 2, unifocal or multifocal overactive areas with reduced or suppressed uptake in the remaining thyroid tissue, consistent with autonomously functioning thyroid nodule( s ) (AFTN)] corresponded to non-Graves’ hyperthyroidism cases, as previously described [ 6 ].

Statistical analysis

The quantitative variables were described as median and interquartile range and analyzed by the Mann–Whitney test, as they were not normally distributed. The dichotomous qualitative variables, on the other hand, were presented in the form of “YES”, “NO”, “Male” and “Female”, and compared with each other through the Chi-Square test. Based on the tests applied, statistical significance is obtained for p -values as close to 0. In our case, statistical significance is obtained for p -values < 0.05.

For GD vs non-GD clinical sensitivity (SE) and specificity (SPEC), accuracy, positive predictive value (PPV) and negative predictive value (NPV) of GO, TH, ALBTs and NEU were calculated based on the reference cut-off and expressed as a percentage. The graph shown (see Fig.  4 below) relates the variables "TH Volume" and "TRAb" belonging to the subgroup “GD with TH” (GD patients with TH), respectively, for the time “0”, “6”, “12”, “18”, “24” months, and it was created with the “GraphPad Prism” software, version 9.5.1 (528). All analyses were performed using the "SigmaStat" Software, version 3.5, Build 3.5.0.54, 2006.

GD vs non-GD group

After applying our selection criteria, we eventually included 264 untreated thyrotoxic patients (GD, n  = 122 vs non-GD, n  = 142) (Fig.  1 ). Non-GD patients included the following etiologies: 66 AFTNs, 24 toxic multinodular goiters, 22 subacute thyroiditis, 17 silent thyroiditis, 8 amiodarone-induced thyrotoxicosis, 4 Iodine-Induced hyperthyroidisms, 1 iatrogenic thyrotoxicosis secondary to thyroxine (T4) + triiodothyronine (T3) combination therapy. Several baseline characteristics (i.e., demographic, laboratory, and imaging characteristics) significantly differed between the two groups (GD vs non-GD), among which are the following: age was higher in non-GD group [57 (50–71) years vs 45 (31–53) years in GD group, p  < 0.001]; prevalence of preexisting autoimmune diseases was higher in GD group (15% vs 1.4%, p 0.001); higher ALT serum levels, higher number of patients with abnormal ALT and higher ALT levels when over the cut-off in GD group [22 (15–43) U/L vs 16 (14–20) U/L in non-GD group, p  < 0.001; 34.4% vs 8.4% in non-GD group, p  < 0.001; 58 (43–72) U/L vs 39.5 (33–41) U/L in non-GD group, p 0.004]; higher GGT serum levels and higher number of patients with abnormal GGT in GD group [20 (16–34) U/L vs 16 (13–19) U/L in non-GD group, p  < 0.001; 23% vs 1.4% in non-GD group, p  < 0.001]; lower ANC and higher number of patients with neutropenia in GD group [3 (2.5–3.6) × 10 9 /L vs 3.7 (3.4–3.9) 10 9 /L in non-GD group, p  < 0.001; 4.9% vs 0% in non-GD group, p  < 0.001]; GO and GDerm were present only in GD group (26.2% and 1.6%, respectively); higher prevalence of TH in GD group (16.4% vs 1.4% in non-GD group, p  < 0.001). Table 1 summarizes and compares the main characteristics of the two groups (GD vs non-GD).

Flowchart of patients’ selection

Accuracy diagnostic tests of GO, ALBTs, NEU and TH

To calculate ALBTs accuracy tests, we considered that ALT and/or GGT were high overall in 57.4% (70/122) of GD vs 9.8% (14/142) in non-GD ( p -value < 0.001). SE, SPEC, accuracy, PPV and NPV of the four extrathyroidal manifestations of GD (i.e., GO, ALBTs, NEU and TH) were as follows, respectively: GO 26%, 100%, 66%, 100%, 61%; ALBTs 41%, 89%, 69%, 76%, 66%; NEU 5%, 100%, 56%, 100%, 55%; TH 16%, 98%, 61%, 91%, 98%. Table 2 summarizes the accuracy diagnostic tests of the four extrathyroidal manifestations of GD.

TH in the thyrotoxic context

In all 22 patients with TH MRI confirmed the presence of the thymic enlargement detected by nUS. We eventually divided the GD group in two subgroups depending on the presence of TH. We found that some baseline characteristics (i.e., demographic and laboratory characteristics) significantly differed between the two subgroups (GD without TH vs GD with TH), among which are the following: age was lower in GD with TH [(30 (25–46) years vs 48 (35–58) in GD without TH, p 0.002]; prevalence of preexisting autoimmune diseases was higher in GD with TH (20% vs 14%, p 0.001); ft4 and ft3 levels were higher in GD with TH [48 (39–53) pmol/L vs 34 (29.4–52) pmol/L, p 0.003, and 18.9 (14–24) pmol/L vs 11.6 (8.3–17) pmol/L, p 0.005, respectively]; TgAb ratio (no/yes) was lower in GD with TH (0.67 vs 1.55, p 0.001) and TPOAb ratio (no/yes) was higher in GD with TH (1.0 vs 0.65, p 0.001); higher number of patients with abnormal ALT in GD with TH subgroup (70% vs 27%, p 0.001). Table 3 summarizes and compares the main characteristics of the two subgroups (GD without TH vs GD with TH).

GD-associated TH

In the 20 GD patients with TH, the median volume of thymus at MRI was 8.5 (7.5–11) mL. Median time of TH disappearance both at nUS and MRI was 12 (6–12) months. At the 6-month follow-up volume reduction rate (VRR) of TH was 60% (50–70.7%) and TH was not visible in six patients. At the 12-month follow-up, TH disappeared in other 12 patients. In 18 of 20 (90%) of cases, TH totally regressed within 12 months under biochemical and clinical euthyroidism through ATD therapy. In the remaining two GD patients TH gradually regressed at the 12- and 18-month follow-up and it disappeared 6 months after thyroid surgery (the latter was adopted after 18 months of ATD therapy). Figures  2 ,   3 depict how TH appear at nUS and MRI, respectively, and how TH was not evident after 6 months of ATD therapy in a 29-year woman with GD.

Representative case of GD-associated TH by nUS, at baseline ( a ) and after achieving stable euthyroidism ( b ). a 29-year-old woman with GD-associated TH: at diagnosis, thymus is sensibly enlarged in nUS transversal projection; b after 6 months of methimazole-based therapy under stable euthyroidism, the thymus parenchyma is not seen any more at nUS. TH thymic hyperplasia, GD Graves’ disease, nUS neck ultrasound

Representative case of GD-associated TH (the same patient of Fig.  2 ) evaluated by thoracic MRI, at baseline ( a ) and after achieving stable euthyroidism ( b ). a 29-year-old woman with GD-associated TH (the same patient of Fig.  2 ): at diagnosis, axial high-resolution T2 image demonstrated a well lobulated 50 mm (9.8 mL) soft tissue mass with homogeneous signal intensity in the mediastinal prevascular space extending superiorly to the level of the left brachiocephalic trunk (arrow), b that disappeared after 6 months of methimazole-based therapy under stable euthyroidism. TH, thymic hyperplasia; GD, Graves’ disease, MRI, magnetic resonance imaging

In ten out of the GD patients with TH TRAb disappeared (i.e., six cases and four cases at the 12-month and 18-month visits, respectively) in combination with the TH disappearance. On the contrary, in the other ten GD patients with TH TRAb did not disappear at the 18-month visit despite the disappearance of TH. Figure  4 shows the time-dependent decreasing trend of TRAb values and TH volumes in the 20 GD patients with TH under therapy determining biochemically and clinically euthyroidism.

Time-dependent decreasing trend of TRAb values (IU/L) and TH volumes (mL) in the 20 GD patients with TH under therapy determining stable euthyroidism TRAb thyrotropin receptor antibodies, TH thymic hyperplasia, GD Graves’ disease

Non-GD-associated TH

Two non-GD patients was found to have TH. One was a 32-year-old girl with TH of 6.5 mL without comorbidities and with silent thyroiditis, TgAb and TPOAb positivity, and negative TRAb. The other case was represented by a 37-year-old girl with TH of 5.8 mL without comorbidities and iatrogenic thyrotoxicosis secondary to T4 + T3 combination therapy for hypothyroidism due to Hashimoto's thyroiditis. In both patients, TH gradually disappeared along with return to normal thyroid function as demonstrated by serial nUS examinations and the 6-month follow-up MRI. In the patient with silent thyroiditis, the involution of TH occurred along with spontaneous achievement of euthyroidism, while in the thyrotoxic patient with T4 + T3 therapy TH disappeared after switching to T4 monotherapy and achievement of biochemical euthyroidism.

The knowledge of the relationship between the emerging extrathyroidal manifestations and GD is of paramount importance for proper diagnosis and therapeutic decision-making [ 7 , 8 , 9 ]. In hyperthyroidism, thymic enlargement can be the expression of thyrotoxicosis itself, or it more rarely indicates the coexistence of an independent autoimmune disease or a cancer [ 9 ]. It is necessary to be careful that the lack of familiarity about the association of TH with GD may result in an aggressive management including surgical intervention, along with its associated risks and costs [ 9 ].

We eventually included a large cohort of new-onset and untreated thyrotoxic patients, roughly half with GD and half with non-GD thyrotoxicosis. As expected, several baseline characteristics differed between the two groups (GD vs non-GD), among which are the following: age was higher in non-GD group [ 4 ]; prevalence of preexisting autoimmune diseases was higher in GD group [ 22 ]; higher ALT and GGT serum levels and higher number of patients with abnormal ALT and/or GGT were found in GD group [ 7 ]; NEU, GO and GDerm were present only in GD patients, with prevalences consistent with that reported in the current literature (i.e., 4.9%, 26.2% and 1.6%, respectively) [ 1 , 5 , 8 ]. Moreover, we found 22 cases (i.e., almost 1 out 10 thyrotoxic patients) of TH initially detected by nUS and then confirmed and further explored by thoracic MRI. We had no case of TH detected by nUS which were not confirmed by thoracic MRI. The distribution of TH was different among the two groups: higher prevalence was found among GD patients (i.e., 20 cases, corresponding to more than 15% of the GD group) than in non-GD group (i.e., 2 cases, corresponding to more than 1% of the non-GD group). We expected that TH was more prevalent in the GD group, since we knew that the production of TRAb is a consequence of the impairment of self‐tolerance which occurs in the thymus [ 22 ] and that the thyroid stimulating hormone (TSH) receptor is also found in extrathyroidal human tissues, including the thymus [ 23 , 24 ] where it has been shown to be functional [ 24 , 25 ]. These figures lead us to claim that in the GD scenario there was a high chance to encounter thymic enlargement, while TH was exceptional but not inconceivable in non-GD thyrotoxic patients.

Compared to GO and the other extrathyroidal manifestations (i.e., ALBTs and NEU), TH was associated to a good accuracy and a high PPV in discriminating between Graves’ and non-Graves’ thyrotoxicosis. In practice, this meant that, since TH was common among GD patients (i.e., almost one out of 10 GD patients), when we found TH at nUS there was a high chance (more than 90%) that the thyrotoxic patients had GD. Therefore, in thyrotoxicosis scenario, the presence of TH could be firstly investigated by cervical US and regarded as an accurate manifestation to discriminate GD from non-GD patients. However, at nUS, the absence of TH does not exclude the presence of GD.

In patients with GD some features seemed to be important factors affecting the thymic appearance. Specifically, we found that GD patients with TH were younger, had higher prevalence of preexisting autoimmune diseases and higher ft4 and ft3 levels, compared to GD patients without TH. As thymic involution is primarily driven by age [ 26 ], in the GD scenario also thymic enlargement can be an age-related process. Moreover, it is well known that the development of TLH is associated with several other autoimmune diseases (i.e., myasthenia gravis, systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus, pemphigus, polymyositis, and Addison’s disease) [ 9 , 27 ], and this can be boosted by the coexistence of an excess of thyroid hormones in a background of thyroid autoimmunity. Yet, as reported for other extrathyroidal manifestations (i.e., GO, ALBTs, NEU) [ 2 , 7 , 8 ], it can be postulated also for TH that increasing thyroid hormones increase the probability of TH development. We also found in GD patients with TH a higher TgAb positivity and a lower TPOAb positivity compared to GD patients without TH [ 28 ]. Moreover, we found that abnormal ALT was more prevalent in GD patients with TH compared to GD patients without TH, which was in line with the fact that GD patients with TH also had higher ft4 and ft3 levels than GD patients without TH [ 7 ].

The pathogenesis of TH in the setting of GD is unclear but seems to involve a complex interplay of hormonal and immunological mechanisms [ 9 ]. All the 20 GD patients with TH did not have symptoms of thymic enlargement (i.e., chest discomfort, shortness of breath, pain). On the contrary, in the study by Haider et al. [ 9 ], 9 out of 13 cases of GD-associated thymic enlargement presented with symptoms of thymic enlargement, supporting that these in the context of GD do not appear to portend a higher risk for pathology warranting surgery. In GD patients, TH was larger than that found in non-GD patients and in nine out of ten cases TH disappeared after 12 months of ATD therapy with 60% of VVR at the 6-month visit. In the remaining 10% of GD cases, TH disappeared 6 months after surgery. However, also I-131 therapy can lead to involution of TH in patients with GD, as reported by Jingui et al. [ 29 ]. Imaging plays a crucial role in diagnosis and follow-up of patients with suspected thymic masses. MRI is a promising imaging modality to differentiate thymic enlargement because of high-contrast resolution and no radiation exposure. Recently, MRI has demonstrated better performance than CT for the assessment of thymic mass, especially in distinguishing thymic hyperplasia bringing out both qualitative and quantitative details [ 30 ]. To avoid ionizing radiation, especially for young patients which would undergo long periods of follow-up during therapy, we used MRI as an adequate alternative to CT. Other studies and case series demonstrated that GD-associated thymic enlargement typically regressed on radiological follow-up [ 9 , 14 , 23 ] providing reassurance of the benign nature of TH associated with GD. Our results are in line with these preexisting data, since they showed that the thymus regressed in all cases under euthyroidism and a high VRR of TH at the 6-month follow-up like that reported by Haider et al. [ 9 ] (i.e., 85%) was found. The benign nature of GD-associated TH was also suggested by a radiological study by Murakami et al. [ 23 ] who demonstrated a statistically significant decrease in mean thymic size and thymic density in 13 patients with GD, after 5–24 months of treatment with ATD. We found that TRAb disappearance was not necessary to have the TH disappearance, as demonstrated by the fact that in half of our cases TH totally regressed despite persistently positive TRAb levels.

In two non-GD patients with TgAb and TPOAb positivity, we detected TH. In both cases, baseline TRAb were negative, and TH disappeared after reaching normal thyroid function. Therefore, for the fact that TH can totally regress although TRAb positivity and the possibility to also encounter TH in non-GD patients with negative TRAb, we believe that in a background of thyroid autoimmunity excess thyroid hormone comes before TRAb to TH development/disappearance (i.e., reversible, and gross thymic enlargement).

There are limitations of our study that warrant some caution. First, we talked of thymic hyperplasia although we did not have anatomopathological details [i.e., true thymic hyperplasia (TTH) or thymic lymphoid hyperplasia (TLH)] [ 31 ]. However, we are confident that in all our patients with TH, thymic enlargement corresponded to a benign and hyperplastic enlargement since we demonstrated that it promptly resolved under stable euthyroidism. Second, we do not know if TH can appear again when thyrotoxicosis is not controlled, since in our patients with TH euthyroidism was stably maintained throughout follow-up. Third, perhaps we underestimated the real prevalence of TH among thyrotoxic patients, since only gross thymic enlargement which was initially seen on nUS was further assessed by thoracic MRI [ 31 , 32 , 33 ]. In fact, it is well known that while TTH always manifests with an enlarged thymus gland [ 31 , 34 ], TLH is common histological evidence during thyroidectomy for thyrotoxicosis [ 32 , 33 ]. Fourth, since we excluded GD patients with uncontrolled hyperthyroidism, we could not explore the outcome of GD-associated TH in uncontrolled hyperthyroidism. However, it is reported that failure to achieve a euthyroid state may impair resolution of the GD-associated TH [ 9 , 14 ]. Fifth, we could not demonstrate the contingency of thymoma in patients with GD, since in all patients, the restoration of euthyroidism was accompanied by the disappearance of TH. However, thymoma in thyrotoxic context is very rare, considering that only three thymoma cases in anterior mediastinum and one cervical ectopic thymoma have been reported to date in patients with GD [ 17 ].

To the best of our knowledge, this is the first study allowing to calculate the prevalence of radiological GD-associated TH since it was based on a prospective cohort of unselected patients with GD. Moreover, this is the first study exploring the value of nUS as the first mean to detect TH and to reliably support the diagnosis of GD in the setting of new-onset thyrotoxicosis, also because in all cases, TH was confirmed by MRI. We cannot derive definitive conclusions regarding the debate as to whether TH represents the cause of GD or is a consequence of GD [ 9 ]. However, we believe that TH is mainly a consequence of hyperthyroidism due to GD [ 9 , 33 ]. Indeed, we demonstrated that in all cases, the achievement of stable biochemical euthyrodism determined the disappearance of TH. Moreover, we demonstrated that TH also can be present in non-GD thyrotoxicosis, and it can disappear along with euthyroidism restoration. Indeed, we found the presence of TH in two non-GD cases with TgAb and TPOAb positivity, and negative TRAb: one case of silent thyroiditis, similar to the only other case report to date by Torres Gomez and Garcia Gastro [ 35 ]; instead, to the best of our knowledge, for the first time, we showed the case of a patient with thyrotoxicosis secondary to T4 + T3 therapy, where TH disappeared after switching to T4 monotherapy and achievement of biochemical euthyroidism. Therefore, as demonstrated in animals [ 10 , 36 ], we postulate that administration of T3 can induce TH (i.e., TTH), and T3 levels may influence considerably thymic hyperplasia and involution.

In summary, it is important for clinicians to recognize the association of TH with thyrotoxicosis for proper diagnosis and therapeutic decision-making.

We found that TH could represent a novel ultrasound manifestation of thyrotoxicosis that must be sought to accurately discriminate between GD and non-GD thyrotoxicosis. In addition, since we demonstrated that TH resolved after restoring euthyroidism, our experience supports the evidence that a conservative and non-surgical approach for the diagnostic work‐up and initial management of thyrotoxicosis-associated TH should be carefully adopted.

Data availability

Some or all data sets generated during and/or analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank PNRR—ANTHEM (AdvaNced Technologies for HumancentrEd Medicine) project to regulate the scientific activity of the researcher Lorenzo Scappaticcio.

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Scappaticcio, L., Caruso, P., Di Martino, N. et al. Thymic hyperplasia is accurate to detect new-onset Graves’ hyperthyroidism and resolves after restoring euthyroidism. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02355-w

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SYSTEMATIC REVIEW article

Brain functional connectivity in hyperthyroid patients: systematic review.

• 1 Department of Biomedical Sciences, Madda Walabu University Goba Referral Hospital, Bale-Robe, Ethiopia
• 2 Department of Human Physiology, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
• 3 Department of Epidemiology and Biostatistics, Institute of Public Health, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
• 4 Department of Reproductive Health, Institute of Public Health, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia
• 5 Department of Anatomy, School of Medicine, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia

Introduction: Functional connectivity (FC) is the correlation between brain regions’ activities, studied through neuroimaging techniques like fMRI. It helps researchers understand brain function, organization, and dysfunction. Hyperthyroidism, characterized by high serum levels of free thyroxin and suppressed thyroid stimulating hormone, can lead to mood disturbance, cognitive impairment, and psychiatric symptoms. Excessive thyroid hormone exposure can enhance neuronal death and decrease brain volume, affecting memory, attention, emotion, vision, and motor planning.

Methods: We conducted thorough searches across Google Scholar, PubMed, Hinari, and Science Direct to locate pertinent articles containing original data investigating FC measures in individuals diagnosed with hyperthyroidism.

Results: The systematic review identified 762 articles, excluding duplicates and non-matching titles and abstracts. Four full-text articles were included in this review. In conclusion, a strong bilateral hippocampal connection in hyperthyroid individuals suggests a possible neurobiological influence on brain networks that may affect cognitive and emotional processing.

Systematic Review Registration: PROSPERO, CRD42024516216.

Introduction

Functional connectivity (FC) refers to the statistical correlation between the activities of different brain regions, typically observed through neuroimaging techniques such as functional magnetic resonance imaging (fMRI) ( Müller, 2013 ; Cao et al., 2022 ; Ursino et al., 2022 ). Studies of it aim to understand how different brain regions communicate and coordinate their activities during various cognitive processes or in different states ( Cao et al., 2022 ). Analyses of it have become increasingly important in neuroscience, offering valuable information about brain function, organization, and dysfunction. Researchers use these analyses to explore normal brain function, investigate neurological and psychiatric disorders, and assess the effects of interventions or treatments on brain connectivity patterns ( Wojtalik et al., 2018 ).

Hyperthyroidism is defined as a high serum level of free thyroxin (FT4) and/or triiodothyronin (T3) and a suppressed thyroid stimulating hormone (TSH) level ( Samuels, 2014 ; Ross et al., 2016 ). Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury ( Liu and Brent, 2018 ; Talhada et al., 2019 ). Thyroid hormones are essential for appropriate growth, reproduction, and regulation of energy metabolism, neuronal development, and cognitive and behavioral development ( Stasiolek, 2015 ; Taylor et al., 2018 ; Mathew et al., 2020 ). The mechanisms include the regulation of neuronal plasticity processes, stimulation of angiogenesis and neurogenesis, as we as modulating the dynamics of cytoskeletal elements, and intracellular transport processes ( Talhada et al., 2019 ).

It is clear that without optimal thyroid function, mood disturbance, cognitive impairment, and other psychiatric symptoms can emerge ( Lekurwale et al., 2023 ). In animal studies, changes in the release pattern of acetylcholine and monoamines have been found in the hippocampus and frontal cortex of experimentally induced hyperthyroid rats, along with associated functional changes ( Eslami-Amirabadi and Sajjadi, 2021 ). Particularly in severe cases, thyroid dysfunction can result in a variety of emotional and cognitive disorders, such as executive function deficiencies, depression, anxiety, and irritability ( Samuels, 2014 ; Stasiolek, 2015 ).

Related to the morphological changes of hyperthyroid individuals in the brain, exposure to excess thyroid hormones has been shown to enhance neuronal death and decrease brain volume ( Folkestad et al., 2020 ), which leads to more severe atrophy of the amygdala ( Wu et al., 2016 ; Eslami-Amirabadi and Sajjadi, 2021 ) and hippocampus ( Wu et al., 2016 ; Eslami-Amirabadi and Sajjadi, 2021 ; Quinlan et al., 2022 ). Hyperthyroid patients exhibited reduced grey matter volume in regions associated with memory, attention, emotion, vision, and motor planning ( Zhang et al., 2014 ).

The exploration of functional connectivity between brain regions is deemed essential to elucidate the neuropsychiatric symptoms associated with hyperthyroidism and the impact of elevated thyroid hormone levels on the adult brain ( Cao et al., 2022 ; Lekurwale et al., 2023 ). Thyroid hormones play a crucial role in functional connectivity under physiological conditions ( Schroeder and Privalsky, 2014 ). In the brain, T4 is converted to active T3 by type 2 deiodinase produced by glial cells, highlighting the importance of these hormones in brain development and function ( Fingeret, 2024 ). Studies revealed functional connectivity changes in hyperthyroid patients, an increase in functional connectivity in the rostral temporal lobes, which is integrated with the cognitive control network ( Göbel et al., 2020 ), lower amplitude of low-frequency fluctuations (ALFF) was found in the patients in the right posterior cingulate cortex, and increased functional connectivity in the bilateral anterior and posterior insula, and importantly, in the left anterior lobe of the cerebellum ( Göbel et al., 2020 ). Research has shown that thyroid hormone functions may play a crucial role in modulating functional connectivity in early-course schizophrenia, impacting cognition and functional outcomes ( George et al., 2023 ), resting-state brain network functional connectivity, and shedding light on the intricate relationship between thyroid function and brain network dynamics ( Li et al., 2022 ).

Despite the significance of certain brain regions in emotional and cognitive regulation, there is a notable gap in research pertaining to the interactions between and within these regions in hyperthyroid patients. This review highlights hyperthyroidism’s potential impact on connectivity between brain regions and improves our understanding of the functional connectivity of targeted regions.

Registration and protocol

This study protocol is registered with the International Prospective Register of Systematic Reviews website (PROSPERO; registration number CRD42024516216).

Eligibility criteria

Hyperthyroid patients: all patients who have elevated serum FT3 or FT4 levels, and decreased TSH levels ( Ross et al., 2016 ; Toyib et al., 2019 ).

Pre/post studies: one experimental session was performed before and one after the end of administration of medications or procedures to assess the impact of medications like anti-thyroid drugs, radioiodine therapy, beta blockers, and thyroidectomy on patients with hyperthyroidism ( Doubleday and Sippel, 2020 ).

We applied the PICO method as a selection criteria for articles:

Population : hyperthyroid patients.

Interventions: thyroid hormone thyroxin replacement therapies, for example, levothyroxine.

Study type : randomized controlled trials, case–control studies, and quasi-experimental studies.

Cases : hyperthyroid patients.

Control : healthy controls.

Outcomes : primary outcome– brain functional connectivity.

Outcome assessment time : There was no limit to the outcome assessment time.

Publication year and language : English-language literature, with publication year not limited. List of countries : all countries in the world.

Search strategy and selection criteria

Four databases– PubMed, Hinari, Science Direct, and Google Scholar– were used to identify studies about brain functional connectivity from the inception date to November 21, 2023. Using title, abstract, and keywords, we searched out the primary studies using the keywords selected: brain, connectivity, network, hyperthyroidism, and their synonyms using AND, OR, and NOT filters as described in Supplementary file 2 . This systematic review was prepared according to the instructions of the PRISMA guideline.

Data extraction

We developed a form to extract the suitable data, including the following details: (1) characteristics of the papers (authors, publication year, and country); (2) characteristics of the participants (sample size, age range, and drug use); (3) study design and measurement method; (4) method of analysis; and (5) results. Two authors (ET and LM) independently extracted the data, and disagreements were resolved by discussing with the third author (MG).

Identification of eligible studies

Figure 1 shows the result of our screening process. We identified 762 articles with our searching strategy. Duplicate articles ( n = 85) were excluded. The articles that according to title and abstract did not match the selection criteria ( n = 667) were also excluded. Finally, four articles out of 10 available full-text articles were included in this systematic review. The details of the excluded six articles are presented in Supplementary file S1 .

Figure 1 . PRISMA flow chart for selection of eligible articles.

Characteristics of included studies

The included studies were either case–control or quasi-experimental studies. The etiology of the disease in the three studies was Graves’ disease, and one drug-induced pre-and post-study. They were all small studies, with the largest sample size of 47. General characteristics of the studies, like the first author’s name, year of publication, country, sample size (case/control or pre-post), age range of participants, and drug use for the study, are shown in Table 1 , and the imaging method, study design, analysis method, and results are presented in Table 2 .

Table 1 . General characteristics of the studies included in this systematic review.

Table 2 . List of studies with their methods and results.

Reviewing the available evidence, we find significant changes in brain functional connectivity among hyperthyroid patients. These alterations imply that hyperthyroidism may impact brain networks neurobiologically. Studying connectivity patterns in healthy individuals and those with hyperthyroidism can help us understand disruptions in thyroid dysfunction networks, clarify cognitive and emotional symptoms in thyroid disorders, and guide future therapeutic interventions targeting neural circuits. In hyperthyroid patients, alterations in functional connectivity have been observed, particularly in regions associated with emotion regulation, memory, and cognitive processing ( Chen et al., 2021 ). Changes in FC observed in hyperthyroid patients can be attributed to several mechanisms and could explain the manifestations of different disorders.

Recent advancements in neuroimaging techniques have shed light on the intricate neural alterations accompanying this disorder ( Minnerop et al., 2018 ; Yen et al., 2023 ). Among these, changes in FC within the brain have emerged as a critical area of investigation. The observed connectivity between hyperthyroid patients and healthy controls suggests shared neural circuitry, potentially crucial for detecting the hippocampal memory system’s operation in humans ( Liu et al., 2017 ; Ma et al., 2022 ).

One of the central findings of the reviewed papers is the disruption in connectivity patterns involving the hippocampus and cingulate cortex. Zhang et al’s. (2014) study found that hyperthyroid individuals show weakened connectivity between the bilateral ACC and PCC and the hippocampi. This suggests that hyperthyroidism affects the limbic system, which is crucial for memory consolidation and emotional regulation. The alterations may indicate cognitive or mental disorders associated with the hippocampus and other brain areas ( Li et al., 2017 ; Yao et al., 2022 ). Hyper-connectivity patterns may affect the functional connectivity of the default mode network, potentially impacting episodic memory and self-representation ( Zanão et al., 2017 ; Staffaroni et al., 2018 ; Ursino et al., 2022 ). The direct effects of thyroid hormones on these brain regions contribute to their functional integrity and connectivity ( Biswas and Dey, 2014 ). Thyroid hormones have receptors in the cingulate cortices and hippocampi. T3 and T4 influence neurotransmitter systems such as glutamate ( Ritchie and Yeap, 2015 ; Zhu et al., 2022 ), and gamma-aminobutyric acid (GABA) ( Yi et al., 2014 ; Prisciandaro et al., 2021 ), which are crucial for synaptic transmission and neuronal plasticity in the cingulate cortices ( Prisciandaro et al., 2021 ). Alterations in thyroid hormone levels can disrupt the balance of excitatory and inhibitory neurotransmission, leading to changes in neural connectivity and function within the ACC and PCC and impairing hippocampal function, leading to deficits in memory consolidation, emotional processing, and spatial navigation ( Bavarsad et al., 2019 ).

Moreover, the correlation between FC strength and clinical variables provides valuable insights into the progression of the disease ( Zhang et al., 2014 ). A significant negative correlation was found between disease duration and FC strength between the hippocampi and cingulate cortices ( Zhang et al., 2014 ; Milton et al., 2022 ). This suggests that as the disease progresses, there is a decline in the integrity of neural circuits linking these regions ( Zhi et al., 2018 ; Johansson et al., 2023 ), due to adaptive changes or neuronal damage in hyperthyroid patients. In addition, chronic hyperthyroidism could lead to structural ( Zhang et al., 2014 ; Zhe et al., 2021 ; Duda et al., 2023 ; Xiong et al., 2023 ), and functional changes in the hippocampi and cingulate cortices, affecting their connectivity patterns. This is clinically important in identifying neuroimaging markers that can be used to track the progression of hyperthyroidism and assess the effectiveness of treatment interventions ( Clerc, 2020 ).

Beyond hippocampal-cingulate alterations, hyperthyroidism is also associated with changes in FC involving regions crucial for cognitive processing and emotional regulation ( Göttlich et al., 2015 ). Increased degree centrality was observed in temporal regions, including the right inferior temporal gyrus, left middle temporal gyrus, right middle temporal gyrus, and left middle temporal pole. Additionally, there was a significant increase in FC within the bilateral temporal poles and left middle temporal gyrus ( Göttlich et al., 2015 ; Zhang et al., 2018 ), indicating heightened connectivity within temporal regions. Notably, the left temporal pole exhibited stronger connections with various regions, including the dACC, ITG, and frontal gyrus, underscoring the widespread impact of hyperthyroidism on functional brain networks. Degree centrality refers to the number of connections a node (brain region) has with other nodes in the network ( Yoo et al., 2017 ; Jia et al., 2019 ). The heightened degree centrality indicates increased functional connectivity and communication within these temporal regions. This indicates increased synchronization and information exchange within these regions ( Csató, 2017 ; Lorenzini et al., 2022 ). The study suggests that hyperthyroid patients’ cognitive deficits may be linked to disrupted functional coordination within the default mode network (DMN), emphasizing the significance of interhemispheric connectivity ( Zhi et al., 2018 ; Berron et al., 2020 ; Wang et al., 2023 ).

Conversely, decreased ALFF was noted in regions such as the posterior cingulate gyrus and bilateral inferior parietal gyrus ( Zhang et al., 2018 ), suggesting reduced neural activity. In association with this, Milton et al.’s ROI-based functional connectivity analysis reveals changes in connectivity patterns in the inferior parietal gyrus and posterior cingulate gyrus, indicating complex regional dynamics ( Uddin et al., 2009 ). Additionally, disruptions in FC were observed in cerebellar-frontal circuits, with decreased connectivity between the left PLC and MTG within the attention network ( Li et al., 2017 ). Besides its motor coordination ability, the cerebellum increasingly recognized for its role in cognitive functions, including attention ( Li et al., 2017 ; Liu et al., 2017 ; Yao et al., 2022 ). Dysfunction within the cerebellum and frontal regions impairs the coordination and modulation of attention networks ( Arif et al., 2020 ). Damage to the tract and disruptions in neuronal synchronization between the cerebellum and frontal cortex may contribute to decreased functional connectivity ( Wang et al., 2023 ). Cognitive ability is affected by reduced connectivity between cortical regions, particularly the prefrontal cortex, and sub-cortical regions in schizophrenia ( Sheffield and Barch, 2016 ), bipolar disease ( Ursino et al., 2022 ), depression ( Liu et al., 2020 ), traumatic brain injury ( Morelli et al., 2021 ; Nakuci et al., 2021 ), stroke ( Wang et al., 2023 ), and functional seizure ( Foroughi et al., 2020 ).

Taken together, these findings highlight the complex nature of the brain changes linked to hyperthyroidism. The dysregulation of thyroid hormones affects multiple pathways and mechanisms within the brain, leading to diverse neurological manifestations. This complexity underscores the need for a comprehensive understanding and management of the neurological aspects of hyperthyroidism. The findings open the door for additional research into the functional implications of these connectivity changes and how they might impact the mental and emotional health of hyperthyroid patients, in addition to expanding our understanding of the brain mechanisms underlying thyroid dysfunction ( Ritchie and Yeap, 2015 ; Eslami-Amirabadi and Sajjadi, 2021 ). Combining these many viewpoints allows for a more thorough understanding of the complex relationship between thyroid function and brain connections.

Limitations

This systematic review had some limitations.

• The exploration of functional connectivity in neuroscience has encountered limitations, with a paucity of comprehensive studies on the intricate networks that govern brain function. To advance our understanding of the dynamic relationships between distinct brain regions, there is a pressing need for more extensive studies on brain functional connectivity in patients with hyperthyroidism.

• A significant limitation frequently encountered in research is the small sample size. Small sample sizes can magnify individual differences and chance variations, making it challenging to draw robust conclusions or to establish the true effect of an intervention or phenomenon. The studies included in this review had a small sample size, with a minimum of 13 and a maximum of 46.

• All studies used fMRI as the imaging technique. It has limitations compared to other connectivity techniques, including lower temporal resolution (vs. EEG/MEG), sensitivity to motion artifacts, and reliance on blood flow measurement. Techniques like EEG and MEG offer better temporal resolution.

Conclusion and recommendation

In conclusion, research on brain functional connectivity among patients with hyperthyroidism suggests a potential neurobiological impact of hyperthyroidism on intricate brain networks. This study found strong bilateral hippocampal connectivity across various brain regions, suggesting a fundamental neural network. Alterations in connectivity patterns suggest a potential hub role in hyperthyroid states, affecting cognitive and emotional processing. These findings highlight the complex nature of brain changes linked to hyperthyroidism and suggest the need for further investigations into the functional effects of these connectivity alterations on mental and emotional well-being.

We suggest exploring how changes in connectivity affect thinking and emotions in hyperthyroidism patients to help develop better mental health treatments. Furthermore, given the recognized challenge of small sample sizes in research, it is advisable for future studies to strive for larger and more representative samples to enhance the reliability and generalizability of the findings. Additionally, researchers should consider diversifying imaging techniques beyond fMRI to overcome its limitations such as lower temporal resolution and susceptibility to motion artifacts.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary material , further inquiries can be directed to the corresponding author.

Author contributions

ET: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. MG: Conceptualization, Data curation, Methodology, Supervision, Writing – original draft, Writing – review & editing. DeA: Conceptualization, Data curation, Methodology, Writing – original draft, Writing – review & editing. DaA: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. LM: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnins.2024.1383355/full#supplementary-material

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Keywords: brain, fMRI, functional connectivity, hyperthyroid, resting-state fMRI

Citation: Tesfaye E, Getnet M, Anmut Bitew D, Adugna DG and Maru L (2024) Brain functional connectivity in hyperthyroid patients: systematic review. Front. Neurosci . 18:1383355. doi: 10.3389/fnins.2024.1383355

Received: 07 February 2024; Accepted: 05 April 2024; Published: 24 April 2024.

Reviewed by:

Copyright © 2024 Tesfaye, Getnet, Anmut Bitew, Adugna and Maru. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ephrem Tesfaye, [email protected]

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Hyperthyroidism: Case Study Analysis Case Study

System identification, normal functioning of identified system, alterations in normal function, labs, tests, medications, and/or other treatments, appropriate nursing interventions.

Based on the symptoms of EB, as well as her test results, it can be assumed that the patient is suffering from hyperthyroidism, which is a condition of hyperthyroidism. Hyperthyroidism is characterized by such symptoms as weight loss while maintaining appetite, heart palpitations, nervousness, irritability, hand tremors, excessive sweating, menstrual irregularities, fever, diarrhea, enlarged thyroid gland, fatigue, muscle weakness, insomnia, blurred vision, and exophthalmos. EB has most of them, including enlargement of the visible part of the eyeballs, increased heart rate and blood pressure, hand tremors, weight loss, anxiety, and trouble sleeping.

Wijesinghe (2020) affirms that the symptoms of hyperthyroidism can be disguised as various diseases of cardiovascular, nervous, digestive, and other organ systems. Thus, the identification of this syndrome is not always an easy task. Although EB has some cardiovascular disorders, including tachycardia and hypertension, this is not indicative of cardiac disease. This fact is also confirmed by the normal level of troponin and the absence of blockage of the coronary artery.

Moreover, abnormal levels of thyroid hormones, which support metabolic processes in the human body, speak in support of hyperthyroidism. A change in their concentration in the blood leads to a digestive disorder and disrupts the work of the cardiovascular and nervous systems. EB has an increase in T3 to 7.8 pmol/L when 2.0 to 7.0 pmol/L is normal. Triiodothyronine (T3) and thyroxine (T4) – reflect the total amount of hormones synthesized by the thyroid gland. According to Taylor et al. (2018), their level is usually increased with hyperthyroidism. T4 total may remain normal in asymptomatic forms of hyperthyroidism. Moreover, hyperthyroidism is characterized by a reduced level of TSH with normal values of thyroxine (T4). This is precisely what is observed in EB when TSH, although normal, is at its lowest limit, and T4 is normal.

The thyroid gland is located on the neck under Adam’s apple and has the shape of a butterfly. It consists of two lobes connected by an isthmus, and its size is no larger than a walnut. The work of the thyroid gland depends on iodine, which enters the body with food. Thyroid hormones that regulate metabolism are synthesized from it.

The thyroid gland plays a vital role in the functioning of the body. It produces hormones, thyroxine (T4) and triiodothyronine (T3), which, released directly into the blood, affect all cells and tissues of the body, which influence the functions of all organs and systems. Specifically, thyroid hormones regulate metabolic rate, appetite, glucose breakdown and uptake by cells, nutrient absorption and intestinal motility, fat breakdown, cholesterol levels, heart rate and strength, respiratory rate, cellular oxygen consumption, blood flow, body temperature, and calcium in the body.

The body has a mechanism that allows it to maintain an almost constant level of thyroid hormones in the blood. This system is controlled by thyroid-stimulating hormone (TSH), which is produced by the part of the brain, the pituitary gland. This hormone performs the function of stimulating the thyroid gland and inducing the production of thyroid hormones (T4, T3).

If the thyroid gland does not produce enough hormones, then the metabolic processes in the body slow down, and hypothyroidism develops. On the contrary, if there is more thyroid hormone than necessary, the metabolism increases, and the opposite state of hypothyroidism develops – hyperthyroidism. Doenges et al. (2019) note that hyperthyroidism is a common pathology that leads to severe complications that can significantly reduce a person’s quality of life. An increase in the level of thyroid hormones in the blood accelerates metabolic processes in the body and hurts almost all organ systems.

The cardiovascular system is one of the main targets of the action of thyroid hormones. According to Khan et al. (2020), thyroid dysfunction is associated with higher morbidity and mortality from cardiovascular disease. Moreover, even fluctuations in thyroid hormone levels within normal limits may be associated with the risk of adverse cardiovascular events. Hyperthyroidism affects the cardiovascular system, which can be manifested by bradycardia, increased diastolic blood pressure, tachycardia, and fluid in the pericardium. The patient does not tolerate physical activity, and there is a violation of the heart rhythm.

However, the effects are reversible. Lane et al. (2020) note that the signs of arrhythmia are completely cured after the elimination of hyperthyroidism. In this regard, the timely detection of thyroid diseases is the key to successful treatment, leading to an increase in the quality of life.

When hyperthyroidism is suspected, the patient has prescribed an ultrasound of the thyroid gland to determine the size and structure of the gland, the nature of pathological changes, and the number and size of nodes. When visualizing nodes and focal formations in the thyroid gland, an ultrasound of the thyroid gland with elastography is prescribed, as well as a biopsy of the formation if a malignant process is suspected. Furthermore, tests such as CBC, the total protein test, blood glucose test, cholesterol test, a calcium blood test, Serum Calcitonin, Iodine Uptake Scan, and Thyroid Scan are helpful. In a clinical blood test, an increase in the level of leukocytes, ESR can be observed, which may indirectly indicate an inflammatory process in the tissues of the thyroid gland (Wijesinghe, 2020). In hyperthyroidism, the levels of total protein, glucose, and cholesterol may be reduced, and the amount of calcium may increase. With hyperfunction of the thyroid gland, the amount of calcitonin in the serum may also increase.

An Iodine Uptake Scan is done to check thyroid function when thyroid function blood tests show that a person may have an overactive thyroid. This test measures thyroid function by determining how much iodine is absorbed by the thyroid gland. Lane et al. (2020) note that high absorption of radioactive iodine indicates that the thyroid gland produces too much thyroxine. The most likely cause is either Graves’ disease or hyperfunctioning thyroid nodules. If the patient has hyperthyroidism and low absorption of radioactive iodine, this indicates that thyroxine stored in the gland is entering the bloodstream, which may indicate thyroiditis.

A thyroid Scan will show how iodine accumulates in the thyroid gland. This test is done to evaluate thyroid nodules or goiters and look for the cause of an overactive thyroid. Normal test results will show that the thyroid is the standard size, shape, and location (Doenges et al., 2019). This is a solid gray color in a computer image with no darker or lighter areas. Abnormal results will show darker or lighter nodules that absorb more or less iodine. Darker nodules absorb more iodine; they may be overactive and may be the cause of an overactive thyroid.

Furthermore, such tests as antibodies to TSH receptors, thyroperoxidase, and thyroglobulin may be prescribed. Antibodies to TSH receptors are protective proteins of the immune system that, in pathology, are produced to receptors located on thyroid cells, stimulating the production of T3 and T4. In turn, thyroperoxidase is an enzyme responsible for the activation of the iodine molecule and its inclusion in the synthesis of thyroid hormones. According to Doenges et al. (2019), an increase in the production of such antibodies speaks in favor of an autoimmune process. Thyroglobulin is a protein from which thyroid hormones are formed. An increase in their titer may also indicate favor of an autoimmune lesion.

Treatment consists of antithyroid drugs, such as methimazole (tapazole) and propylthiouracil, and radioactive iodine drugs, which suppress the overactive thyroid gland. Also, as a symptomatic treatment, B-blockers can be used to relieve symptoms of hyperthyroidism, such as tremors, heart palpitations, and palpitations. For the treatment of eye manifestations in the initial stages, moisturizing eye drops are used.

Moreover, it is recommended to balance nutrition according to BJU and introduce foods rich in vitamins A, B, and C and minerals into the diet. Diet and hydrotherapy help not only in the prevention of hyperthyroidism but also in the rehabilitation of patients after treatment. Refusal of bad habits, walks in the fresh air, and emotional stability will help maintain health not only in the endocrine system, but throughout the body.

Nursing interventions in hyperthyroidism should be aimed at all links in the pathogenesis of the disease and be carried out taking into account the type of disease, the severity of the course, the main symptoms, the state of compensation, the side effects of pharmacotherapy, and possible complications in order to prevent them. Gulanick and Myers (2021) assert that the nurse ensures that the patient complies with the motor and nutritional regimen prescribed by the doctor, the timely and correct intake of drugs and the control of their side effects, control of blood pressure, respiratory rate, heart rate, and preparing the patient for laboratory and instrumental studies.

Since EB has the adverse cardiovascular consequences of hyperthyroidism, the nurse should pay special attention to these conditions. Blood pressure monitoring, assessment of pulse and heart rate, and control of chest pain are necessary. Because EB has experienced weight loss, daily weight monitoring and a balanced diet are essential. The nurse should encourage the patient to eat and offer high-calorie foods that are easy to digest. In the case of prescribing drugs, it is necessary to administer them in the indicated dosage and form. Because EB suffers from anxiety and has trouble sleeping, the nurse needs to watch for behaviors that indicate levels of anxiety. Moreover, the nurse should reduce external stimuli, including being placed in a quiet room, providing soft, soothing music, reducing bright lights, and reducing the number of people in contact with the patient.

The nurse should conduct a detailed conversation with the patient and her relatives about the causes and symptoms of the disease. Recommend popular literature on lifestyle with this disease. Conduct a conversation about the need for strict adherence to diet, behavior, and use of drugs, their therapeutic and side effects.

Doenges, M. E., Moorhouse, M. F., & Murr, A. C. (2019). Nursing care plans: Guidelines for individualizing client care across the life span (10 th ed.). F.A. Davis.

Gulanick, M. & Myers, J. L. (2021). Nursing care plans: Diagnoses, intervention, & outcomes (10 th ed.). Mosby.

Khan, R., Sikanderkhel, S., Gui, J., Adeniyi, A. R., O’Dell, K., Erickson, M., Malpartida, J., Mufti, Z., Khan, T., Mufti, H., Al-Adwan, S. A., Alvarez, D., Davis, J., Pendley, J., & Patel, D. (2020). Thyroid and cardiovascular disease: A focused review on the impact of hyperthyroidism in heart failure. Cardiology Research, 11 (2), 68–75. Web.

Lane, L. C., Cheetham, T. D., Perros, P., & Pearce, S. H. (2020). New therapeutic horizons for Graves’ hyperthyroidism. Endocrine Reviews, 41 (6), 873-884.

Taylor, P. N., Albrecht, D., Scholz, A., Gutierrez-Buey, G., Lazarus, J. H., Dayan, C. M., & Okosieme, O. E. (2018). Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews Endocrinology, 14 (5), 301-316.

Wijesinghe, S. (2020). 101 primary care case studies: A workbook for clinical and bedside skills . Springer Publishing Company.

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Various Manifestations of Hyperthyroidism in an Ambulatory Clinic: Case Studies

This study reviews five cases of women with hyperthyroidism, three black women and two Hispanic women. Initially, two patients presented with voice changes, weight loss, and increased appetite. Only two patients presented with classical symptoms of hyperthyroidism. Examination showed all patients had diffusely enlarged thyroids and exaggerated reflexes. Two patients showed Graves' opthalmopathy.

These cases document the variety of presentations of hyperthyroidism. Hence, a high index of suspicion must exist for this disease, even in the absence of a number of the classical manifestations of hyperthyroidism. When patients present to primary care centers with a constellation of symptoms, an examination of the thyroid gland is essential.

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (558K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References .

Selected References

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