Continuing Education Activity

Hyperthyroidism is a common thyroid disorder with multiple underlying etiologies. This disease is characterized by excess thyroid hormone production. Hyperthyroidism can be overt or subclinical. Overt hyperthyroidism is defined as low or suppressed thyroid stimulating hormone (TSH) levels with elevated triiodothyronine (T3) levels and/or elevated thyroxine (T4) levels. Hyperthyroidism is associated with significant short-term and long-term morbidity. Therefore, early recognition of this condition and timely instruction of appropriate therapy is critical. This activity reviews the etiology, presentation, evaluation, and management of hyperthyroidism and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Review the various etiologies that lead to a presentation of hyperthyroidism.
• Describe the presentation and expected examination findings when evaluating a patient with hyperthyroidism.
• Summarize the various treatment options available for hyperthyroidism, depending on specific etiology.
• Explain the importance of interprofessional team strategies for improving care coordination and communication to aid in prompt diagnosis of hyperthyroidism and improving outcomes in patients diagnosed with the condition.

Introduction

Hyperthyroidism is a common thyroid disorder. "Hyperthyroidism" defines a syndrome associated with excess thyroid hormone production.[1] It is a common misconception that the terms thyrotoxicosis and hyperthyroidism are synonyms. The term "thyrotoxicosis" refers to a state of excess thyroid hormone exposure to tissues.[1] Although hyperthyroidism can lead to thyrotoxicosis and can be used interchangeably, it is essential to note their differences. For the sake of simplicity, this review will cover a discussion of hyperthyroidism and thyrotoxicosis. Hyperthyroidism has multiple etiologies, clinical manifestations, and treatment modalities.

Hyperthyroidism can be overt or subclinical. Overt hyperthyroidism is defined as low or suppressed thyroid stimulating hormone (TSH) levels with elevated triiodothyronine (T3) levels and/or elevated thyroxine (T4) levels.[1] When T3 levels are elevated with low/suppressed TSH and normal T4 levels, this is called 'T3 toxicosis'.[2] Subclinical hyperthyroidism is low or suppressed TSH with normal T3 and T4 levels.[2] Both overt and subclinical hyperthyroidism are associated with significant long-term complications.[3][4][5][6][7]

Etiology

The three most common etiologies of hyperthyroidism include:

1. Graves disease (GD)
2. Toxic multinodular goiter (TMNG)
3. Toxic adenoma (TA)[1]

Other less common etiologies of hyperthyroidism:

1. Iodine-induced hyperthyroidism[8]
2. TSH (thyroid stimulating hormone)-secreting pituitary adenomas[9]
3. Conditions associated with high human chorionic gonadotrophin levels: choriocarcinomas and hydatiform moles in females and germ cell tumors in males[10]
4. Ectopic thyroid in struma ovarii (excess thyroid hormone production from ovarian teratomas)[11]
5. Extensive metastasis from functional differentiated thyroid carcinoma (follicular or papillary)[12]
6. Drug-induced thyroiditis: amiodarone, lithium, tyrosine kinase inhibitors, interferon-alpha, immune checkpoint inhibitor therapy[13][14][15][16][17]
7. Other thyroiditis: Hashitoxicosis, painless thyroiditis, painful subacute thyroiditis, suppurative thyroiditis, and Riedel thyroiditis[18][19]
8. Factitious thyroiditis (due to excess exogenous thyroid hormone: intentional or unintentional use)[10]

Graves disease is the most common cause of hyperthyroidism in the United States and most western countries.[20] As Graves disease is autoimmune in etiology, this form of hyperthyroidism tends to manifest itself in younger populations. In older adults and people living in regions of iodine deficiency, toxic multinodular goiter is the most common cause of hyperthyroidism.[21][22][23]

Factitious thyroiditis is thyrotoxicosis associated with inappropriate or excessive use of pharmaceutical thyroid hormone.[10] Due to a well-received side effect of weight loss, thyroxine has the potential for abuse. Any history of a hyperthyroid patient should include a medication list and an assessment of possible misuse (whether intentional or unintentional).

Epidemiology

The prevalence of hyperthyroidism varies worldwide, based on dietary iodine content.[12] Hyperthyroidism is more common in women compared to men.[24] Other risk factors associated with the development of hyperthyroidism include smoking, iodine deficiency, iodine excess, selenium deficiency, genetic factors, and the use of certain drugs.[12] Graves disease is typically seen in younger patients and is the most common cause of hyperthyroidism in this demographic. The incidence of GD is highest between the age group of 30 to 50 years.[25] Toxic multifocal goiter is typically seen in older individuals and is the most common cause of hyperthyroidism in this demographic.[22] Graves disease and toxic multifocal goiter have a female predilection and are typically seen in patients with pertinent family and personal medical histories. Thyroid nodular disease is also more common in women than men by 5- to 15-fold.[26] Autoimmune thyroid disorders like Graves disease are more common in iodine-replete areas, and nodular thyroid diseases are more common in iodine-deficient areas.[12]

The 1977 Whickham Survey evaluated the spectrum of thyroid disorders in County Durham in northeastern England. The Whickham Survey demonstrated a prevalence of hyperthyroidism in women, approximately ten times more than that of men (2.7% versus 0.23%).[27] An incidence of 80 cases per 100,000 women was seen at the 20-year follow-up of the Whickham cohort.[28] The prevalence of hyperthyroidism in the United States was 1.3% in the general population, with 0.5% cases of overt hyperthyroidism and 0.7% cases of subclinical hyperthyroidism.[29] A meta-analysis found the prevalence of hyperthyroidism in Europe to be 0.75%.[24] The prevalence of overt hyperthyroidism is similar in China at 0.78%.[30] 

Amiodarone-induced thyrotoxicosis (AIT) is seen in about 6% of the individuals taking the medication in iodine-sufficient areas and about 10% in individuals taking the medication from iodine-deficient areas.[31][32]

Pathophysiology

The pathophysiology of hyperthyroidism depends on the particular variant of hyperthyroidism.

Graves Disease

This is an autoimmune process with antibodies against the TSH receptor. An interplay between genetic and environmental factors influences this autoimmune process. The antibodies stimulate the TSH receptor (TSHR), leading to increased production and release of thyroid hormones. The trophic effects on the thyroid also lead to the growth of the thyroid gland.[20] 

Toxic Multinodular Goiter

Pathogenesis of TMNG includes the initial phase of development of the nodular disease. This phase is prolonged and present for years before the nodules develop autonomy for thyroid hormone production. The somatic mutations involving the TSHR lead to constitutive activation of the cAMP signaling pathway, resulting the thyroid autonomy.[33] There is a correlation between the size of the nodules and the development of hyperthyroidism. In a previous study, about 93.7% of the patients who developed overt hyperthyroidism had a nodule size greater than 3 cm.[34]  

Toxic Adenoma

These are solitary nodules with autonomous thyroid hormone production due to somatic mutations in the TSHR

Iodine-Induced Hyperthyroidism (Jod-Basedow Phenomenon)

This is typically iatrogenic, resulting from excessive iodine intake through diet or administration of iodine-containing medications such as contrast media or amiodarone.[35][36] Individuals susceptible to this phenomenon include the ones residing in iodine-deficient regions, individuals with underlying thyroid nodular disease, or underlying occult GD or previously treated GD.[8] Hyperthyroidism develops about 2-12 weeks after exposure to excessive iodine.[37] As mentioned previously, the organification of iodide residues into precursor thyroid hormone molecules is relatively self-regulating. Excessive circulating iodide inhibits organification, a process known as the Wolff-Chaikoff effect. This autoregulation is escaped in the Jod-Basedow phenomenon leading to excess thyroid hormone in the presence of excess iodine/iodide.

Amiodarone-Induced Thyrotoxicosis

There are two subtypes of amiodarone-induced thyrotoxicosis (AIT): type 1 and type 2. Type 1 AIT leads to increased thyroid hormone production secondary to excess iodine exposure from amiodarone in the setting of pre-existing thyroid disease (as seen in the Jod-Basedow phenomenon).[38] The pre-existing thyroid disease is usually multinodular goiter or latent Graves disease. Type 2 AIT is destructive thyroiditis due to the direct toxic effects of amiodarone on the thyroid follicular cells.[39]

Thyroiditis results in the transient increase in circulating thyroid hormone resulting from inflammation or destruction of the thyroid follicular cells. Various etiologies of thyroiditis have this common pathophysiology but vary in their clinical presentations. The inflammation or destruction of the thyroid follicular cells can result from autoimmunity (Hashimoto's thyroiditis, painless sporadic thyroiditis, and painless postpartum thyroiditis) or the result of external factors (infections in painful subacute thyroiditis, suppurative thyroiditis, drug-induced thyroiditis).[19]

History and Physical

Thyroid hormone has physiological effects on multiple organs system. As a result, the symptoms and signs of hyperthyroidism involve manifestations from multiple organ systems. Clinical manifestations are associated with a hyperadrenergic and hypermetabolic state. Common manifestations include unintentional weight loss (about 10% of patients can gain weight due to increased appetite), palpitations, tremors, heat intolerance, dyspnea on exertion, increased anxiety, irritability, fatigue, muscle weakness, increased frequency of bowel movements (some patients can have significant diarrhea), hair loss, loss of libido, and oligomenorrhea or amenorrhea in women.[20][40] 

Patients with subacute thyroiditis can present with significant anterior neck pain and fever. On physical examination, patients have tachycardia (some can present with atrial fibrillation), hypertension, tremors, warm and moist skin, hyperreflexia, and an anxious appearance. Some patients might have signs of heart failure.

Eye signs of lid lad or lid retraction can be seen in all causes of hyperthyroidism due to a hyperadrenergic state.[41] Eye symptoms and signs of "true orbitopathy' are only seen in patients with Graves disease. These include diplopia, excessive tearing, conjunctival injection, and orbital or retro-orbital pressure proptosis.[42][43] Other specific physical findings associated with Graves disease are pretibial myxedema (plaques of thick, scaly skin and swelling involving the anterior aspect of lower legs) and acropachy (soft-tissue swelling of the hands and clubbing of the fingers).[44][45][46]

Examining the thyroid will reveal a diffuse non-nodular enlargement of the thyroid in Graves disease; a diffuse non-symmetric nodular enlargement can be seen in toxic multinodular goiter, and a single large nodule can be palpated in cases of a toxic adenoma. An exquisitely tender thyroid can be noted in subacute thyroiditis.[47] 

Evaluation

When hyperthyroidism is suspected based on clinical features, the patient should undergo an initial evaluation with measurement of TSH, free T4, and total T3 to confirm the diagnosis. Figure 1 illustrates the diagnostic algorithm for hyperthyroidism. Patients with overt hyperthyroidism will have low/suppressed TSH levels with elevated free T4 and total T3 levels. Patients with mild/subclinical hyperthyroidism will have low/suppressed TSH with normal free T4 and total T3 levels. 'T3 toxicosis' is defined as low/suppressed TSH with normal T4 and elevated T3 levels.

Conditions that can interfere with the assessment of TSH include the presence of heterophile antibodies and high biotin intake due to interference with the assays.[48] Heterophile antibodies can lead to a false elevation in TSH levels. High-dose biotin supplementation (5 to 30 mg) can result in falsely low TSH with elevated free T4 levels in-vitro.[49]

After the diagnosis of hyperthyroidism has been confirmed, measurement of thyrotropin receptor antibody (TRAb) levels as an initial test for determining the etiology of hyperthyroidism has been shown to reduce the time to diagnosis and is more cost-effective.[50]. Elevated TRAb levels confirm the diagnosis of Graves disease. TRAb levels are measured using TBI or TBII (thyrotropin-binding inhibiting or thyrotropin-binding inhibitory immunoglobulin) assays and TSI (thyroid stimulating immunoglobulin) bioassays. The newer bioassay using the Immulite method for TSI measurement has a high sensitivity and specificity of 98% and 99.9%, respectively, for diagnosing GD.[51] TBII assays used for measuring TRAb levels also have a high sensitivity of 96-97% and specificity of 99% of the diagnosis of GD.[52]

If TRAb levels are normal, the patient should undergo a radioiodine thyroid uptake and scan using an I-123 isotope (enters the thyroid gland through the Na/I symporter). This test is contraindicated in pregnant and lactating women. A capsule containing an I-123 isotope is given a day before the scan is performed. The pattern of uptake of I-123 by the thyroid gland seen on the scan can help determine the diagnosis (see Figure 1). However, this test does not help differentiate between type 1 and type 2 amiodarone-induced thyrotoxicosis, as the uptake will be low in chronic amiodarone use.

• High Uptake/Normal
• Graves disease will have high or normal uptake in a diffuse pattern
• TMNG will have a high or normal uptake in a patch pattern
• TA will have a high or normal uptake with a solitary area of high uptake (corresponding to the known nodule) with low uptake in the remainder of the gland
• Low or Absent Uptake
• Any etiology of thyroiditis is associated with low or absent uptake (Na/I symporters are not functional in inflamed or destroyed thyroid follicular cells)
• Iatrogenic and factitious thyrotoxicosis

Thyroid ultrasound using the color doppler is another important test that can help determine the underlying etiology. Intrathyroidal arterial flow velocities are measured.[53] Increased (thyroid inferno) and normal flow are seen in Graves disease. Low flow is seen in thyroiditis.[53] This test can help differentiate between type 1 and type 2 amiodarone-induced thyrotoxicosis (AIT). The flow will be high or normal in type 1 AIT (hyperthyroidism due to underlying nodular thyroid disease or occult GD) and low in type 2 AIT (destructive thyroiditis).[54]

Treatment / Management

Treatment of hyperthyroidism depends on the underlying etiology and can be divided into symptomatic and definitive therapy. The symptoms of hyperthyroidism, such as palpitations, anxiety, and tremor, can be controlled with a beta-adrenergic antagonist such as atenolol. Calcium channel blockers, such as verapamil, can be used as second-line therapy for patients who are beta-blocker intolerant or have contraindications to beta-blocker treatment.[1]

This review will only discuss the treatment for the most common causes of hyperthyroidism: Graves disease, toxic multinodular goiter, and toxic adenoma in non-pregnant patients. 

Indications for treatment:

1. Overt hyperthyroidism
2. Subclinical hyperthyroidism with TSH <0.1 and age >65 years
3. Subclinical hyperthyroidism with TSH <0.1 and age <65 years with comorbidities (cardiovascular disease, osteoporosis, or symptomatic)
4. Subclinical hyperthyroidism with TSH <0.1 and age <65 years, if TSH still elevated after 3 to 6 months
5. Subclinical hyperthyroidism with TSH between 0.1-0.4 and age >65 years, if TSH still elevated after 3 to 6 months
6. Subclinical hyperthyroidism with TSH between 0.1-0.4 and age <65 years with comorbidities (cardiovascular disease, osteoporosis, or symptomatic), if TSH still elevated after 3-6 months

There are three definitive treatments for hyperthyroidism: radioactive iodine therapy (RAI), thionamide therapy, and subtotal thyroidectomy. The choice of which definitive treatment modality depends on the etiology, comorbidities, and patient preferences. Historically, radioactive iodine (RAI) has been the preferred treatment for managing Graves disease in the United States. Still, the trend is changing towards increased use of anti-thyroidal drugs (ATD).[55] ATDs have been the preferred treatment for Graves disease in most other countries.[1] 

Antithyroid Drugs (ATDs)

Thionamide drugs include methimazole, carbimazole (precursor of methimazole), and propylthiouracil. These drugs are competitive inhibitors of the thyroid peroxidase (TPO) enzyme, resulting in their ability to block thyroid hormone synthesis. Additionally, these drugs may have additional immunosuppressive effects, as shown by their ability to induce remission in patients with Graves disease.[56][57] Methimazole and propylthiouracil both inhibit thyroid hormone synthesis by thyroid peroxidase. Thyroid peroxidase is the enzyme responsible for converting dietary iodine into iodide. Propylthiouracil (PTU) also lowers peripheral tissue exposure to active thyroid hormone by blocking the extrathyroidal conversion of T4 to T3. Thionamide therapy has no permanent effect on thyroid function, and remission of hyperthyroidism is common in patients who discontinue thionamide therapy.

Attaining a euthyroid status typically requires several months after initiation of thionamide therapy. Although methimazole and PTU are equally effective, methimazole is preferred due to once-daily dosing and a relatively better safety profile. An exception to this recommendation is in pregnant patients, in which PTU is preferred. Methimazole is associated with an increased risk of congenital defects, and thus PTU is preferred in managing hyperthyroidism during pregnancy.

• Doses:
• ATA (Americal Thyroid Association) guidelines provide a rough guide for the initial dose of methimazole based on free T4 levels [1]
• Free T4 1-1.5 times upper limit of normal: Start methimazole 5-10 mg daily
• Free T4 1.5-2.0 times the upper limit of normal: Start methimazole 10-20 mg daily
• Free T4 2.0-3.0 times the upper limit of normal: Start methimazole 30-40 mg daily
• PTU is administered in 2-3 doses per day due to its shorter duration of action. The initial dose of 5-150 three times daily is chosen based on the severity of hyperthyroidism. Once the disease is controlled, the dose can be decreased to a maintenance dose of 50 mg 2 to 3 times daily.
• Monitoring: TSH levels remain suppressed for almost six months in patients with Graves disease, so evaluation of free T4 and/or total T3 levels should be done every 4 to 6 weeks. 
• Pregnancy: Propylthiouracil is the preferred drug in the first trimester, associated with lower incidence and severity of embryopathy than methimazole.[58][59] The treatment can be switched to methimazole after 16 weeks of gestation.
• Drug conversions:
• 10 mg of carbimazole is converted to approximately 6 mg of methimazole [1]
• An equivalent dosage ratio of propylthiouracil to methimazole is 20:1. This ratio is recommended for dose conversions when switching between these agents.[60]

These drugs should be continued for at least 12-18 months. TRAb should be assessed at that time to evaluate for remission. If TRAb levels are normal, then thionamide therapy can be discontinued. If TRAb levels are still elevated, the patient remains at high risk for relapse if medication is stopped. Other factors associated with lower remission rates: male gender, smoking, large goiters, higher TRAb titers at the time of diagnosis, presence of orbitopathy, and the need for a high dose of thionamides to maintain euthyroidism.[20]

An older study from the United States showed a 20-30% remission rate for Graves disease using thionamides.[61] European and Japanese populations noted higher remission rates of 50-60%.[62][63][64]

Radioactive Iodine (RAI)

RAI (using I-131 isotope) can be the preferred therapy in most patients, especially the ones with high-risk comorbidities who are at high risk for surgery and need definitive management. Patients who have contraindications for the use of thionamides should also undergo RAI. This procedure should be avoided in patients planning a pregnancy in the six months due to the risk of inducing hypothyroidism in the fetus. RAI is also contraindicated in lactating women. Patients will a history of moderate to severe Graves orbitopathy should not undergo treatment with RAI due to the risk of worsening eye disease. Patients with underlying thyroid malignancies should not undergo RAI. 

Radioactive iodine-131 leads to the destruction of thyroid follicular cells. In a female patient of reproductive age, it is highly recommended to obtain a beta-hCG to rule out pregnancy before initiation of RAI therapy. Patients on a thionamide (methimazole or propylthiouracil) should be instructed to discontinue this therapy approximately one week before RAI therapy since thionamide administration can interfere with the therapeutic benefit of RAI therapy. Several months are typically needed status post-RAI therapy to achieve euthyroid status.

• Graves disease
• A single fixed dose of 10-15 mCi (370-555 MBq) is sufficient to render a patient with GD hypothyroid. Doses of RAI can be calculated using the size of the thyroid gland and the uptake of RAI. Cure rates are higher with higher doses, up to 85%.[65][66] 
• Toxic multinodular goiter
• A single dose of 15 mCi is usually sufficient.[67] A calculated dose of 150-200 microCi (5.5-7.4 MBq) per gram of thyroid tissue can be used, corrected for 24-hour radioactive iodine uptake. Cure rates are 55% at three months and 80% at six months.[68] Long-term studies have shown that the risk of hypothyroidism after RAI for TMNG is 3-5% by one year, 16% by five years, and 64% by 24 years.[69][70][71]
• Toxic adenoma
• A single fixed of 10-20 mCi (370-740 MBq) is usually sufficient. The dose can also be calculated based on nodule size: 150-200 microCi (5.5-7.5 MBq).[72] Long-term studies have shown that the risk of hypothyroidism after RAI for TA is 8% in 1 year and 60% in 20 years.[73]

Typically, patients with GD are evaluated in 4 to 6-week intervals with an assessment of TSH, free T4, and total T3 levels. The monitoring should continue for another six months or till the patient becomes hypothyroid and is on a stable dose of levothyroxine. Failure to achieve euthyroidism after RAI therapy may indicate the need for either repeat RAI therapy (for symptomatic hyperthyroidism) or the initiation of thyroxine therapy (for hypothyroidism).

RAI therapy involves the release of stored thyroid hormone due to the destruction of thyroid follicular cells, leading to transient hyperthyroidism. This is generally well tolerated, although this transient hyperthyroidism is of concern in patients with significant cardiac disease. For patients with cardiac disease, pretreatment with a thionamide to deplete the stored hormone is recommended to avoid the potential exacerbation of the cardiac disease. In addition, the use of beta-blocker therapy is also essential in these patients to minimize beta-adrenergic symptoms.

Surgery

Preferred in women planning a pregnancy in less than six months, presence of active Graves orbitopathy, patients who experience significant adverse effects with the use of thionamides, when thyroid malignancy is suspected, presence of large compressive goiters, and the presence of co-existing hyperparathyroidism needing surgery. The surgical option should be avoided in patients with significant comorbidities deemed high-risk for undergoing surgery.

Euthyroidism should be achieved before surgery with the use of thionamides. Preoperative SSKI (saturated solutions of potassium iodide), KI (potassium iodide), or Lugol's iodine should be used in patients with Graves disease and TMNG to decrease gland vascularity and decrease intraoperative blood loss.[74][75] 

• Graves disease: Near-total or total thyroidectomy is the surgical procedure of choice in patients with Graves disease, with excellent cure rates. The risk of remission or disease persistence with total thyroidectomy is almost 0% versus 8% with sub-total thyroidectomy after five years.[76][77][78]
• Toxic multinodular goiter: Surgical option of choice is near-total or total thyroidectomy to avoid recurrences.[79][80]
• Toxic adenoma: Preferred surgical option is ipsilateral thyroid lobectomy or isthmusectomy, with excellent cure rates and a risk of the treatment failure rate of less than 1%.[81]

After patients undergo near-total or total thyroidectomy, they should be started on weight-based levothyroxine replacement therapy (0.8 mcg/lb or 1.6 mcg/kg). Lower doses should be used in the elderly, especially in patients with a history of cardiovascular disease or arrhythmia.

Differential Diagnosis

Hyperthyroidism presents with relatively nonspecific signs and symptoms such as palpitations, increased frequency of bowel movements, and weight loss, among others. Therefore, other pathologies should be ruled out as possible explanations for the patient’s symptomatology.

For etiologies of hyperthyroidism, differential diagnoses can be made based on the physical findings of the thyroid gland. Palpation of a normal thyroid gland in the context of hyperthyroidism can be due to Graves disease, painless thyroiditis, or factitious hyperthyroidism (thyrotoxicosis factitia). Graves disease can also present as a non-tender, enlarged thyroid.

Palpation of a tender enlarged thyroid may indicate De Quervain thyroiditis (subacute thyroiditis). Palpation of a single thyroid nodule is likely indicative of thyroid adenoma, and palpation of multiple thyroid nodules strongly indicates toxic multinodular goiter.

Other differential diagnoses include euthyroid hyperthyroxinemia (in which serum total T4 and T3 are elevated, but the TSH level is within normal limits) and struma ovarii.

Toxicity and Adverse Effect Management

Antithyroid drugs or thionamides are associated with rare but serious adverse effects of agranulocytosis, hepatotoxicity, and vasculitis. Hepatotoxicity is more common with the use of propylthiouracil (2.7%) than methimazole (0.4%).[82] Hepatotoxicity due to methimazole is more likely to be cholestatic, while hepatotoxicity due to PTU is more likely to be hepatocellular.[83] Hematological complications have an incidence of 0.1-0.15% with the use of PTU or methimazole. Of these patients, 89% had agranulocytosis, and 11% had pancytopenia or aplastic anemia.[84] Patients taking PTU and rarely methimazole can develop p-ANCA (anti-neutrophil cytoplasmic antibody) positive small vessel vasculitis.[85] Up to 40% of those taking PTU can develop c-ANCA positivity, but very few develop vasculitis.[86][87] These medications are also associated with the development of drug-induced lupus.[88][89] Few cases of hypoglycemia secondary to autoimmune insulin syndrome have been reported using methimazole.[90][91]

If patients develop an acute febrile illness with symptoms of pharyngitis, they should get blood work done to check complete blood cell counts along with differentials to rule out the development of agranulocytosis. Liver function tests should be assessed in patients who develop a pruritic rash, abdominal pain or bloating, anorexia, nausea, vomiting, fatigue, jaundice, light-colored stool, or dark urine.

The most common complications following total or near-total thyroidectomy include hypocalcemia due to hypoparathyroidism in less than 2% of cases (can be transient or permanent), recurrent or superior laryngeal nerve paralysis in less than 2% of cases (can be temporary or permanent), hemorrhage, and complications related to anesthesia.[92][93][94]

Prognosis

Hyperthyroidism secondary to Graves disease or toxic multinodular goiter has overall good outcomes due to high success rates of definitive treatment and efficacy of symptom management. However, as with any disease, the prognosis of particular disease pathology is patient-oriented and reflects management, response to therapy, and compliance with prescribed treatments.

Complications

Untreated or unmanaged hyperthyroidism can lead to an extreme case of hyperthyroidism, referred to as a thyroid storm. Reflecting the hypermetabolic state of hyperthyroidism, the patient experiencing thyroid storm will present with tachycardia, increased GI motility, diaphoresis, anxiety, fever, and manifestations of multiple organ dysfunction. Thyroid storm is a potentially life-threatening complication of hyperthyroidism, thus requiring immediate attention. The mortality rate is high in individuals more than 60 years of age, of about 16%.[95] 

Prolonged untreated or undertreated hyperthyroidism is associated with an increased risk of acute cardiovascular events, atrial fibrillation, ischemic stroke, osteoporosis, infertility, abnormalities of menstrual cycles, and mortality.[96][97][98][99] Subclinical hyperthyroidism has been associated with an increased risk of arrhythmias such as atrial fibrillation, osteoporosis, hip fractures, and mortality.[100][2][101]

Deterrence and Patient Education

Patient education regarding hyperthyroidism is similar to other diseases. Patients should be educated on the importance of compliance with therapy and on the signs and symptoms of extreme hyperthyroidism (thyroid storm).

Pearls and Other Issues

Acute coronary syndrome (ACS) may be complicated by thyroid dysfunction. A recent study has shown that thyroid dysfunction is seen in up to 23.3% of patients with coronary artery disease and both overt and subclinical hyperthyroidism in 2.5%.[102]

Pregnancy and concurrent thyroid pathology can pose medical management challenges. PTU is recommended in pregnant women presenting with hyperthyroidism due to methimazole’s association with congenital defects. Close monitoring is recommended with PTU administration, as overcorrection can potentially cause fetal hypothyroidism. The thyroid hormone is particularly important due to its role in fetal neurodevelopment. Recent literature indicates that previously recommended TSH cutoffs in pregnant women lead to overcorrection of thyroid disease in pregnant patients.[103] As fetal exposure to thyroid hormone plays a significant role, careful monitoring and close supervision are warranted.

Neonatal thyrotoxicosis results from fetal tissue exposure to excessive thyroid hormone. There are typically two variants of neonatal thyrotoxicosis: autoimmune-mediated and non-autoimmune-mediated. Autoimmune fetal hyperthyroidism involves the transplacental passage of TSH receptor-stimulating antibodies. Hyperthyroidism is usually transient as symptoms cease 5 to 6 months after birth following clearance of maternal antibodies. Non-autoimmune fetal hyperthyroidism is associated with an activating mutation of either the TSH receptor or the GNAS gene (leading to McCune-Albright syndrome). Unlike the autoimmune etiology, the non-autoimmune variant is permanent, long persisting after birth.[104]

Enhancing Healthcare Team Outcomes

Except for thyroid storm, hyperthyroidism in itself is rarely life-threatening but can pose a significant burden on a patient’s day-to-day routine. Hyperthyroidism can present with many symptoms and, if not managed, can lead to poor quality of life. Because there are many causes of hyperthyroidism, the condition is best managed by an interprofessional team.

Primary care clinicians should educate patients on the importance of medication compliance. In addition, the patient should be informed by the pharmacist that certain products like contrast dyes, expectorants, food supplements, and seaweed tablets may contain high levels of iodine and interfere with therapy.

Inpatient management of a patient with hyperthyroidism does not always necessarily require consultation with an endocrinologist. Still, thyroid storm strongly warrants consultation with an endocrinologist and possible admission to the intensive care unit due to potentially life-threatening complications such as tachycardia and hypertensive crisis. Therefore, nurses and physician assistants involved with patient care should be vigilant about the signs and symptoms of thyroid storm.

As mentioned, any consideration of RAI therapy in a female of reproductive potential should follow a negative beta-hCG, as pregnancy is an absolute contraindication to RAI therapy. Therefore, incorporating a mandatory pregnancy test into an overall care plan would help avoid potentially damaging radiation exposure.

Patients with Graves disease will need an ophthalmology consult. For those who undergo thyroidectomy, lifelong treatment with levothyroxine is required. Pharmacists must review prescriptions, check for drug interactions, and educate patients.

The interprofessional team must communicate with other members to ensure the patient receives the current standard of care treatment.