The thyroid gland is a bilobed structure located in the anterior aspect of the trachea between the cricoid cartilage and the suprasternal notch. Each lobe of the thyroid connects via a thyroid isthmus. It is supplied via the superior thyroid artery which stems from the external carotid artery and the inferior thyroid artery, which is a branch of the thyrocervical trunk.
Histologically, the thyroid gland is surrounded by a thin, connective tissue covering that penetrates the gland and divides the thyroid gland into compartments. The thyroid gland is composed of spherical, polarized follicular cells that surround a gel-like, thyroglobulin-rich colloid. Thyroglobulin is the organic precursor for thyroid hormones and requires iodide to form thyroid hormone. Dietary iodine is transported into thyroid follicular cells via the sodium-iodide symporter after conversion to iodide via thyroid peroxidase enzyme. The process of iodide becoming incorporated into monoiodotyrosine (MIT) or diiodotyrosine (DIT) molecules is referred to as organification, and the process is relatively self-regulated. Low dietary iodide facilitated upregulation of the sodium-iodide symporter while high dietary iodide temporarily inhibits the organification process, a phenomenon known as the Wolff-Chaikoff effect. Iodide incorporation into the thyroid hormone precursors, MIT and DIT, is due to peroxidase enzyme. The organic coupling of one molecule of MIT with one molecule of DIT leads to the production of triiodothyronine (T3) while the coupling of 2 DIT molecules leads to thyroxine (T4).
The thyroid gland secretes thyroxine (T4) in response to thyroid-stimulating hormone (TSH) originating from the anterior pituitary gland. The secreted T4 is converted to a more potent and triiodothyronine (T3) via deiodinase enzymes. Most of the conversion of T4 to T3 takes places extrathyroidally, although the thyroid gland possesses the intrinsic ability for T3 production.
From a physiologic perspective, the hypothalamus releases thyrotropin-releasing hormone (TRH) in response to low circulating thyroid-stimulating hormone (TSH), T3 or T4. TRH promotes the anterior pituitary secretion of thyroid-stimulating hormone (TSH) which, in turn, promotes T4 secretion from the thyroid gland. T4 and T3 exert negative feedback control on both the hypothalamus and the anterior pituitary.
The term "hyperthyroidism" defines a syndrome associated with excess thyroid hormone production. It is a common misconception that the terms thyrotoxicosis and hyperthyroidism are synonyms of one another. The term "thyrotoxicosis" refers to a state of excess thyroid hormone exposure to tissues. Although hyperthyroidism can lead to thyrotoxicosis and can be used interchangeably, it is important to note the difference between the two.
In the United States and most western countries, Graves disease is the most common cause of hyperthyroidism. As Graves disease is autoimmune in etiology, this form of hyperthyroidism tends to manifest itself in younger populations. In the older demographic, toxic multinodular goiter is the most common cause of hyperthyroidism.
Although Graves disease and toxic multinodular goiter are the more common causes of hyperthyroidism, other causes of hyperthyroidism include iodine-induced hyperthyroidism (Jod-Basedow phenomenon), thyroid adenomas, de Quervain thyroiditis (subacute thyroiditis), postpartum thyroiditis, and factitious thyroiditis (thyrotoxicosis factitia).
Factitious thyroiditis is hyperthyroidism that is associated with inappropriate or excessive use of pharmaceutical thyroid hormone. Due to a well-received side effect of weight loss, thyroxine has the potential for abuse and any history of a hyperthyroid patient should include a medication list and an assessment of possible misuse (whether intentional or unintentional).
Other sources of hyperthyroidism include ectopic foci of thyroxine-secreting tissue. The more prevalent (although rare) form of this etiology is struma ovarii, consisting of ectopic and functional thyroid tissue (often compromising greater than 50% of total mass) in the ovary.
Amiodarone or other iodine-containing medications can induce iodine-associated hyperthyroidism or thyrotoxicosis. This iodine-induced hyperthyroidism is referred to as the Jod-Basedow phenomena (Jod is the German word for iodine).
The prevalence of hyperthyroidism is different according to the ethnic group while in Europe the frequency is affected by dietary intake of Iodine and some cases are due to autoimmune disease. Subclinical hyperthyroidism occurs more in women older than 65 than in men while overt hyperthyroidism rates are 0.4 per 1000 women and 0.1 per 1000 men and vary with age.
Any analysis of the global epidemiology of hyperthyroidism will delineate along the lines of iodine-sufficient regions and iodine-deficient regions. While iodine excess can lead to hyperthyroidism, iodine deficiency can lead to both hypothyroidism and hyperthyroidism.
Graves disease is typically seen in younger patients and is the most common cause of hyperthyroidism in that demographic. Toxic multifocal goiter is typically seen in older individuals and is the most common cause of hyperthyroidism in this respective demographic. Both Graves disease and toxic multifocal goiter have a female predilection and are typically seen in patients with pertinent family and personal medical histories.
The 1977 Whickham Survey was an evaluation of the spectrum of thyroid disorders in County Durham in northeastern England. Although the demographics of the Whickham Survey consisted of primary inhabitants of a community of northeastern England (and hence, poor extrapolation potential), the survey did show interesting results of hyperthyroidism. The Whickham Survey demonstrated a prevalence of hyperthyroidism in women approximately 10-times more than that of men (2.7% versus 0.23%).
The pathophysiology of hyperthyroidism depends on the particular variant of hyperthyroidism. In the case of Graves disease, the underlying cause is autoimmune, particularly the production of thyroid-stimulating immunoglobulins that bind to the TSH receptor and mimic the effects of TSH. Graves disease presents with 2 extra-thyroidal signs that are not typically seen in other forms of hyperthyroidism. The ophthalmopathy of Graves disease is characterized by the edema of retro-orbital tissues, thus causing anterior protrusion of the ocular globes. Pretibial myxedema is a plaque-like thickening of the skin anterior to the tibia due to infiltration of glycosaminoglycans in the dermis.
Toxic multinodular goiter presents with palpable thyroid nodules. It is the leading cause of hyperthyroidism, particularly in older populations. Toxic multinodular goiter leads to the production of excess thyroid hormone from autonomous ectopic tissue, thus leading to clinical thyrotoxicosis.
As opposed to toxic multinodular goiter which can present with multiple nodules, thyroid adenoma typically presents with a solitary papillary nodule that has the potential of causing hyperthyroidism. Hyperfunctioning thyroid adenomas can be distinguished from thyroid carcinomas by their clinical presentation. Thyroid hormone production by thyroid carcinomas is insufficient and cannot achieve thyroid hormone levels sufficient to cause overt hyperthyroidism. As a result, thyroid adenomas are generally benign.
Hyperthyroidism secondary to thyroiditis results in the transient increase in circulating thyroid hormone resulting from mechanical disruption of thyroid follicles. Subacute thyroiditis (DeQuervain thyroiditis) typically follows an acute infection, for example, upper respiratory infection. It is a granulomatous inflammatory process, resulting in an exquisitely tender thyroid gland. Painless thyroiditis is a form of hyperthyroidism, usually seen in postpartum stages. It is lymphocytic thyroiditis, and it can be distinguished from its subacute counterpart by the clinical history and palpation of the thyroid gland (which is non-tender in painless thyroiditis but painful in subacute thyroiditis).
Iodine-induced hyperthyroidism (Jod-Basedow phenomenon) is typically iatrogenic, resulting from administration of iodine-containing medications such as contrast media or amiodarone. 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. However, professionals believe that in patients with iodine-induced hyperthyroidism, areas of autonomous function permit excessive secretion of thyroid hormone in the presence of high iodide levels. Discontinuation of the offending agent typically results in resolution of the hyperthyroidism. Amiodarone-induced thyrotoxicosis has two types: type 1 and type 2. The distinction between the 2 subtypes is apparent from history, diagnostic findings, and treatment. Amiodarone-induced thyrotoxicosis, type 1 patients typically have pre-existing thyroid pathology, low RAI uptake, and increased thyroid parenchymal blood flow. The treatment is typically anti-thyroid medication. In contrast, amiodarone-induced thyrotoxicosis, type 2 patients may not have a history of previous thyroid disease. Diagnostics may show a relatively lower RAI uptake and decreased thyroid parenchymal blood flow. Treatment for the type 2 variant is typically steroids. While excess iodine exposure from amiodarone administration can result in hyperthyroidism, amiodarone itself can be directly cytotoxic, contributing to thyroid injury.
Excessively high levels of chorionic gonadotropin as seen in cases of trophoblastic tumors can cause hyperthyroidism via weak activation of the TSH receptors. This etiology of hyperthyroidism, however, is considerably rare compared to the previously mentioned causes of hyperthyroidism.
History and Physical
Hyperthyroidism may manifest as weight loss despite an increased appetite, palpitation, nervousness, tremors, dyspnea, fatigability, diarrhea or increased GI motility, muscle weakness, heat intolerance, and diaphoresis. The signs and symptoms of thyroid hormone exposure to peripheral tissues reflect a hypermetabolic state. A patient with hyperthyroidism classically presents with signs and symptoms that reflect this state of increased metabolic activity. Common symptoms that a patient may report include unintentional weight loss despite unchanged oral intake, palpitations, diarrhea or increased frequency of bowel movements, heat intolerance, diaphoresis, and/or menstrual irregularities.
Physical examination of the thyroid may or may not reveal an enlarged thyroid (referred to as goiter). The thyroid may be diffusely enlarged, or one or more nodules may be palpated. The thyroid may be painless to palpation or extremely tender to even light palpation.
Thyroid stimulating hormone (TSH) is the initial diagnostic test of choice and is considered the best screening test for assessing pathology of the thyroid and for the monitoring of thyroid replacement therapy. Due to the negative feedback that T3 and T4 exert on the pituitary gland, elevated T3 and/or elevated T4 will cause decreased TSH production from the anterior pituitary gland. Abnormal TSH is often followed up with a measurement of free T4 and/or free T3. Concerns for an autoimmune process such as Graves' disease will warrant further evaluation by assessing serum levels of TSH-receptor antibodies.
TSH levels in the context of acute illness should be interpreted with more discretion as TSH levels are considerably more susceptible to the effects of illness.
Hyperthyroidism is a common etiology for atrial fibrillation, thus further workup with an ECG may be warranted, especially in a patient complaining of palpitations. Obtaining troponin levels is not routine unless the clinical presentation warrants further cardiac ischemic workup, for example, active chest pain, among others.
Radiological diagnostics such as chest x-rays serve little diagnostic utility in the management of hyperthyroidism. Diagnostics such as ultrasound are not useful in diagnosing hyperthyroidism, but the ultrasound findings of nodules could potentially determine an etiology.
Since a majority of cases of hyperthyroidism are due to Graves disease or toxic multinodular goiter, confirmation of the diagnosis can be made based on history, clinical findings, and palpating of the thyroid. In cases of diffuse goiter or no thyroid enlargement, a 24-hour radioactive iodine uptake (RAIU) is needed to distinguish between Graves disease and other hyperthyroidism etiologies. Radioactive iodine uptake is the percentage of iodine-131 retained by the thyroid after 24 hours. For the typical western diet, the normal range of RAIU is typically 10% to 30%.
Graves’ disease, toxic multinodular goiter, and thyroid adenoma are etiologies of hyperthyroidism with increased RAIU, reflecting an increased synthesis of thyroid hormone. Subacute thyroiditis, painless thyroiditis, iodine-induced hyperthyroidism, and factitious hyperthyroidism have decreased RAIU. Thyroiditis represents a disruption of the thyroid follicles with subsequent release of thyroid hormone. Since there is no increased synthesis of thyroid hormone, RAIU will be low in thyroiditis.
If RAIU is not available or is contraindicated, then measurement of thyroid receptor antibodies can be used as an alternative test for diagnosis of Graves disease.
A radioisotope thyroid scan is a diagnostic tool which utilizes technetium-99m pertechnetate as a radioactive tracer. The technetium-99m pertechnetate is taken up by the thyroid gland by the sodium-iodide symporter. The scan itself assesses the functional activity of thyroid nodules, classifying as either "cold" (hypofunctioning), "warm" (isofunctioning), or "hot" (hyperfunctioning). "Cold" nodules raise concern for potential malignancy due to ineffective uptake of iodide and synthesis of thyroid hormone typically seen in thyroid carcinomas.
Treatment / Management
Treatment of hyperthyroidism depends on the underlying etiology and can be divided into 2 categories: symptomatic therapy 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 blocker, such as verapamil, can be used as second-line therapy for patients who are beta blocker intolerant or have contraindications to beta-blocker therapy.
Transient forms of hyperthyroidism such as subacute thyroiditis or postpartum thyroiditis should be managed with symptomatic therapy alone as the hyperthyroidism in these clinical situations tends to be self-limiting.
There are 3 definitive treatments of hyperthyroidism, all of which predispose the patient to potential long-term hypothyroidism: radioactive iodine therapy (RAI), thionamide therapy, and subtotal thyroidectomy. Clinical assessment and monitoring of free T4 are imperative for patients who undergo any of these treatments. TSH-monitoring status after definitive therapy is of poor utility since TSH remains suppressed until the patient becomes euthyroid. Thus, TSH monitoring for thyroid status is not recommended immediately following definitive therapy.
The choice of which definitive treatment modality depends on the etiology. RAI therapy is considered the treatment of choice in almost all patients with Graves disease due to a high efficacy. Despite the relative safety and high efficacy, RAI is contraindicated in patients who are pregnant or patients who are breastfeeding.
In RAI therapy, radioactive iodine-131 is administered with subsequent destruction of thyroid tissue. A single dose is sufficient enough to control hyperthyroidism in a significant portion of patients, and the effects of other parts of the human body are essentially negligible due to the high thyroid uptake of the radioactive iodine-131. In a female patient of reproductive potential, it is highly recommended to obtain a beta-hCG to rule out pregnancy prior to initiation of RAI therapy. Any patient on a thionamide (methimazole or propylthiouracil) should be instructed to discontinue this therapy approximately 1 week prior to 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. Typically, patients are evaluated in 4- to 6-week intervals with increased time intervals for stable, plasma-free, T4 levels. Failure to achieve euthyroidism after RAI therapy may indicate either for repeat RAI therapy (for symptomatic hyperthyroidism) or the initiation of thyroxine therapy (for hypothyroidism).
RAI therapy involves the release of stored thyroid hormone, 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 potential exacerbation of cardiac disease.
Thionamide therapy is used as a definitive treatment for hyperthyroidism inpatient unwilling to undergo RAI therapy or have contraindications to RAI therapy, for example, allergy or pregnancy. Methimazole and propylthiouracil both inhibit thyroid hormone synthesis by thyroid peroxidase. Thyroid peroxidase is the enzyme responsible for the conversion of 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.
Establishment of a euthyroid status typically requires several months after initiation of thionamide therapy. Although methimazole and PTU are equally effective, methimazole is preferred due to 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 the management of gestational hyperthyroidism.
Side effects of thionamide therapy include agranulocytosis, hepatitis, vasculitis, and drug-induced lupus. Although these are rare side effects, patients should be warned about the potential for these side effects. Patients should also be advised to discontinue to the thionamide immediately and notify their physician if symptoms suggestive of agranulocytosis occur (fever, chills, rapidly progressive infection, sore throat, among others). Routine monitoring of leukocyte counts is not recommended when starting a patient on a thionamide due to the rapid onset of agranulocytosis. A baseline comprehensive metobolic panel (CMP) to assess hepatic status would not be unreasonable due to the potential for hepatitis.
Subtotal thyroidectomy is utilized for long-term control of hyperthyroidism. Preparation of the patient for a subtotal thyroidectomy includes pretreatment with methimazole to achieve a nearly euthyroid status. Supersaturated potassium iodide is then added on a daily basis approximately 2 weeks before surgery and discontinued postoperatively. Alternatively, atenolol can be started 1 to 2 weeks before surgery to reduce resting heart rate. Supersaturated potassium iodide is also dosed and discontinued postoperatively. The rationale behind these management plans is to reduce complications associated with perioperative exacerbation of hyperthyroidism.
Complications of subtotal thyroidectomy include hypothyroidism due to the decreased secretory potential of T4. Hypothyroidism remains the most common complication associated with subtotal thyroidectomy. The proximity of the parathyroid glands to the thyroid gland can result in removal of parathyroid glands along with thyroid tissue, resulting in hypoparathyroidism. Due to the risk of iatrogenic injury to the recurrent laryngeal nerve, vocal cord paralysis is also a complication of subtotal thyroidectomy. All of these complications should be discussed with the patient, and the discussion should be documented.
Hyperthyroidism presents with rather nonspecific signs and symptoms such as palpitations, increased frequency of bowel movements, weight loss, among others. Other pathologies should be ruled out as possible explanations of the patient’s symptomatology.
For etiologies of hyperthyroidism, differential diagnosis 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 be indicative of DeQuervain thyroiditis (subacute thyroiditis). Palpation of a single thyroid nodule is likely thyroid adenoma, and palpation of multiple thyroid nodules is strongly indicative of toxic multinodular goiter.
Other differential diagnoses include euthyroid hyperthyroxinemia (a condition in which serum total T4 and T3 are elevated, but the TSH level is within normal limits) and struma ovarii.
Pertinent Studies and Ongoing Trials
Some question the addition of supplemental selenium has any effect on hyperthyroidism associated with Graves disease. One 2017 double-blinded, the placebo-controlled study utilized 2 treatment arms: methimazole plus 300 mcg per day of oral selenium versus methimazole plus placebo. Although the study concluded supplemental selenium did not affect response or recurrence of Graves disease, the study itself lacked sufficient data to be statistically meaningful, likely due to small sample size in both the intervention arm and the control arm. An additional 2017 study regarding the same topic of selenium as a possible adjuvant failed to show any efficacy in supplemental selenium in short-term control of hyperthyroidism.
Hyperthyroidism secondary to Graves disease or toxic multinodular goiter has an overall, positive prognosis due to high success rates of definitive treatment and efficacy of symptom management. As with any disease, the prognosis of particular disease pathology is patient-oriented and reflects management, response to therapy, and compliance with prescribed treatments.
Untreated or unmanaged hyperthyroidism can lead to an extreme case of hyperthyroidism referred to as thyroid storm. Reflecting the hypermetabolic state of hyperthyroidism, the patient experiencing thyroid storm will present with tachycardia, increased GI motility, diaphoresis, anxiety, and fever. Thyroid storm is a potentially life-threatening complication of hyperthyroidism, thus requiring immediate attention. Management for thyroid storm or a high degree of suspicion of thyroid storm should include thionamide therapy (methimazole or propylthiouracil). PTU, in particular, is useful due to its inhibition of peripheral T4 to T3 conversion. Beta blockade can also be utilized in symptom management.
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 educated on the signs and symptoms of extreme hyperthyroidism (thyroid storm).
Pearls and Other Issues
Acute coronary syndrome (ACS) may be complicated with 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%.
Pregnancy and concurrent thyroid pathology can pose a medical management challenge. 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. 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. 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 2 variants of neonatal thyrotoxicosis: autoimmune mediated and non-autoimmune-mediated. Autoimmune fetal hyperthyroidism involves the transplacental passage of TSH receptor-stimulating antibodies. The hyperthyroidism is typically 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). As opposed to the autoimmune etiology, the non-autoimmune variant is permanent, long persisting after birth.
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 a poor quality of life. Because there are many cause of hyperthyroidism, the condition is best managed by an interprofessional team.
The primary care providers including the nurse practitioner 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 mat 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, but the presence of thyroid storm may warrant consultation with an endocrinologist and possible admission to the intensive care unit due to potentially life-threatening complications such as tachycardia and hypertensive crisis. Nurses involved with patient care should be vigilant about the signs and symptoms of thyroid storm.
As mentioned previously, 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. Incorporating a mandatory pregnancy test as part of 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, life long treatment with levothyroxine is required.
The interprofessional team must communicate with other members to ensure that the patient is receiving the current standard of care treatment.
(Click Image to Enlarge)
The Hypothalamus-Pituitary-Thyroid Axis.
Contributed by M. Philip Mathew, DO
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