Topic Editor: Robert Giles, MBBS, BPharm

Review Date: 12/03/2012

Definition

Hyperthyroidism is the excess secretion of the thyroid hormones [thyroxine (T4) and triiodothyronine (T3)] from the thyroid gland. An excess of thyroid hormones causes thyrotoxicosis, a hypermetabolic state. Numerous diseases cause hyperthyroidism although the most common in the developed world is Graves disease.

Description

• Hyperthyroidism is a type of thyrotoxicosis caused by excess secretion of thyroid hormones from the thyroid gland
• Thyroid hormones act upon and regulate almost every cell and system in the body. Thus, patients with thyrotoxicosis exhibit a variety of clinical presentations depending on their age, length of illness, degree of hormone excess and presence of comorbidities
• Many clinicians mistakenly use the terms hyperthyroidism and thyrotoxicosis interchangeably. Thyrotoxicosis is a hypermetabolic state secondary to any cause. It may be due to excessive production and/or secretion of endogenous thyroid hormone, or excessive use of exogenous thyroid hormones
• Graves' disease is the most common cause of thyrotoxicosis followed by toxic multi nodular goiter, toxic adenoma and thyroiditis
• Hyperthyroidism may present as an overt or subclinical condition with signs and symptoms which differ only in magnitude
• Subclinical hyperthyroidism is found in patients with low or indiscernible serum thyroid stimulating hormone (TSH) levels, but with T3 and T4 within the normal range. It may progress to overt hyperthyroidism. Elderly patients with subclinical hyperthyroidism have an elevated risk of atrial fibrillation (Relative risk 1.16-1.41 depending on severity) while postmenopausal women may develop reduced bone mineral density
• Overt hyperthyroidism is characterized by higher levels of serum T3 than T4. This occurs as a result of increased secretion of T3 and increased conversion of T4 to T3 in peripheral tissues
• Thyroid storm is a rare life threatening thyrotoxicosis secondary to excessive release of thyroid hormone. It may be precipitated by an acute event such as surgery, trauma or infection. Patients may present with fevers, tachycardia, hypertension, agitation or seizures, and progress to shock

Epidemiology

Incidence/Prevalence

• The prevalence of hyperthyroidism in the US is approximately 1.2% (0.5% overt and 0.7% subclinical)
• Graves' disease accounts for 60-80% of cases
• Toxic multinodular goiter accounts for 5% of cases and may be 10-times more common in iodine-deficient areas

Age

• Hyperthyroidism occurs in all ages but most commonly among those aged 20 years
• Graves' disease mainly occurs in those aged 20 to 40 years
• Toxic multinodular goiter is the primary cause of hyperthyroidism in elderly patients

• Hyperthyroidism has an incidence in women of 1:1,000. It is 10 times less common in men

• Caucasians and Asians have a similar incidence of Graves' disease. African Americans have a lower incidence

• An interplay between genetics and the environment is implicated in autoimmune thyroid disease
• Development of Graves' disease has been linked with C4A gene deletion in HLA-B8 and HLA-DR3 antigens
• Autosomal-dominant inheritance is known to play a role in familial nontoxic multinodular goiter

• Coexisting autoimmune disorders
• Diabetes mellitus
• Female gender
• High iodine intake
• Iodide repletion following deprivation, particularly in toxic multinodular goiter
• Smoking
• Strong family history, particularly among maternal members

Etiology

• In Graves' disease autoimmune antibodies are produced against the TSH receptor antigen. Binding of these antibodies to the receptor mimics the effect of TSH and stimulates follicles to produce an excess of thyroid hormone. Unlike a normally regulated system there is no negative/suppressant feedback response
• Patients with Graves disease may also display numerous extrathyroidal manifestations such as ophthalmopathy, pretibial myxedema, acropachy (digital clubbing, digital swelling, periosteal reaction of bones in the extremities)
• Toxic adenomas are monoclonal tumors of benign origin capable of autonomously over secreting thyroid hormone
• Toxic solitary/multinodular goiter presents with single or multiple autonomous thyroid nodules which function to produce thyroid hormone
• Thyroiditis (although not specifically classified as hyperthyroidism) is a common cause of thyrotoxicosis. It is caused by inflammation of the thyroid tissue which results in the release of pre-formed thyroid hormone. Subacute thyroiditis often occurs following a viral infection and resolves spontaneously over months. Lymphocytic and postpartum thyroiditis cause transient elevation and sometimes depression of thyroid hormone levels. These conditions also resolve spontaneously
• Transient thyrotoxicosis may result from:
  • Thyrotoxicosis factitia (the excess ingestion of exogenous thyroid hormone)
  • Administration of iodinated compounds such as amiodarone or contrast media
• Tumors (e.g. metastatic thyroid cancer, struma ovarii, trophoblastic beta-HCG producing tumors) may rarely produce thyrotoxicosis

[Outline]

• Definition
• Description
• Epidemiology
• Etiology

History

Cardiovascular

• Chest Pain
• Dyspnea
• Edema
• Palpitations

• Heat intolerance and sweating
• Hyperpigmented skin
• Rapid hair shedding causing diffuse hair loss and thinning
• Pruritis/hives (Graves' disease)
• Soft and loosened fingernails
• Unusually soft skin
• Warm and clammy skin

• Diarrhea / Hyperdefecation
• Dysphagia (secondary to goiter)
• Polyuria/ polydipsia
• Vomiting

• Poor diabetic control
• Weight loss

• Fatigue
• Hyperactivity
• Muscle weakness
• Tremor

• Eyelid lag
• Diplopia
• Proptosis
• Stare

• Anxiety
• Agitation
• Dysphoria / depression
• Irritability
• Nervousness
• Psychosis

• Gynecomastia
• Loss of libido
• Oligomenorrhea

Physical findings on examination

• Physical examination reveals thyroid enlargement in 90% of patients <50 years of age
• Signs of thyrotoxicosis include sinus tachycardia, atrial fibrillation, systolic hypertension, high cardiac output, profuse perspiration, erythema, sweating of palms, tremor, hyperkinesis, large-muscle weakness, hyperreflexia and soft, smooth skin
• Graves' disease can often be diagnostic clinically with hyperthyroidism confirmed on laboratory studies. Patients may present with a symmetrically enlarged goiter, ophthalmopathy (eyelid retraction or lag, periorbital edema and exophthalmos), pretibial myxedema and acropachy (digital clubbing, digital swelling, periosteal reaction of bones in the extremities)
• A goiter with single or multiple nodules may be present in toxic multinodular goiter
• In inflammatory subacute thyroiditis, patients may present with fever, neck pain, or recent viral infection

[Outline]

• History
• Physical findings on examination

Blood tests findings

• Thyroid function tests:
  • A complete thyroid panel evaluates the serum levels of TSH, Free T4, Free T3, Total T4 and Total T3.
  • TSH level is the first test which should be ordered upon suspicion of thyroid dysfunction (hyper/hypothyroidism). A normal result effectively rules out primary thyroid dysfunction. An abnormal result should be followed by further investigations to identify the cause of dysfunction and to directly measure thyroid hormone levels
  • A low/undetectable TSH level is diagnostic of thyrotoxicosis (rarely due to primary pituitary failure)
  • Rarely an elevated TSH (secondary to pituitary/hypothalamic disease) may cause hyperthyroidism
  • Total T3 and total T4 are measures of both protein-bound and unbound hormone concentrations. Most circulating hormone is bound to thyroxine-binding globulin (TBG). Thus, factors that alter concentration/binding of TBG may affect the utility of total T3/T4 assays
  • Free T3 and free T4 estimate the biologically active unbound (free) fraction of hormone and as such are not affected by fluctuations in TBG level or binding . Some laboratories are unable to directly measure free hormone levels and instead calculate values indirectly
  • Patients with T3 toxicosis have an elevated T3 with a normal T4 and low TSH. T3 toxicosis is commonly found in Graves' disease and toxic multinodular goiter
  • Thyroxine/triiodothyronine ratio may be used when radioactive iodine uptake testing is contraindicated or unavailable. T3/T4 ratio >20 is usually evident in Graves' disease and toxic nodular goiter
• Antibody testing:
  • TSH-binding inhibitor immunoglobulin assay (TBII) which detects circulating TSH-receptor antibodies is generally not needed to diagnose Graves' disease, but may be useful if radionuclide imaging is unavailable or contraindicated (e.g. pregnancy/breast feeding). It is also useful to predict the risk of thyrotoxicosis to the fetus or neonate when the mother is thyrotoxic
• Nonspecific laboratory findings include anemia, and elevation of Blood glucose, calcium, transaminases (ALT and AST), and alkaline phosphatase

Radiographic findings

• Radioactive imaging
  • Radionuclide scans are used to identify the cause of thyrotoxicosis
  • Technetium-99m (Tc-99m) pertechnetate scintigraphy may preferred over radioactive iodine uptake because of a rapid turnover and lower radioactivity exposure
  • Radionuclide scans should be considered in a thyrotoxic patient without clinical features to definitively diagnose Graves' disease
  • The total uptake and pattern of uptake of radionuclide isotopes helps characterize each disease
  • Scans in Graves' disease usually reveal a diffuse increased uptake throughout the thyroid
  • A multinodular goiter usually demonstrates increased heterogeneous uptake
  • A solitary toxic nodule has a single focus of increased uptake
  • Subacute thyroiditis usually shows very little uptake
  • A palpable nodule without isotope uptake (cold nodule) is concerning for malignancy and should be biopsied
• Thyroid ultrasonography
  • Not generally required for the routine workup of thyrotoxic patients but may be useful when radioactive studies are contraindicated or not available
  • Helps detect thyroid nodules and goiters that are not easily evident on examination
  • May help differentiate Graves' disease from thyroiditis by quantitatively measuring blood flow

[Outline]

• Blood tests findings
• Radiographic findings

• Anxiety
• Carcinoid syndrome
• Delirium tremens
• Depression
• Diabetes mellitus
• Euthyroid hyperthyroxinemia
• Factitious thyrotoxicosis
• Heat stroke
• Hypothalamic stroke
• Hypothyroidism (may mimic apathetic hyperthyroidism)
• Malignancy
• Malignant hyperthermia
• Menopause
• Neuroleptic malignant syndrome
• Pheochromocytoma
• Pregnancy
• Sepsis
• Sympathomimetic ingestion

General treatment items

The treatment of hyperthyroidism involves symptom management followed by definitive therapy with either antithyroid medications, radioactive iodine or surgical thyroidectomy. All treatments are equally effective, with therapy individualized to the patient

• Antithyroid medications:
  • The thionamide antithyroid medications propylthiouracil (PTU) and methimazole are used to treat Graves disease
  • Thionamides major action is prevention of thyroid hormone synthesis by inhibiting thyroid peroxidase catalyzed reactions and interfering with the organification of iodine
  • 90% of patients taking antithyroid therapy are euthyroid within several weeks of therapy
  • 40% to 60% of patients achieve remission with prolonged therapy (12 to 18 months). The risk of relapse is >50%. There is little evidence to support the effectiveness of thionamides beyond 1to 2 years of treatment
  • Due to easier dosing and a better safety profile methimazole is the preferred antithyroid agent in all patients except those with:
    • Thyroid storm (PTU has an added effect of blocking deiodination of T4 to T3 which rapidly reduces serum T3 concentrations)
    • Previous allergy to methimazole
    • First trimester pregnancy (PTU has a lower risk of congenital abnormalities as compared with methimazole)
  • Initiate antithyroid drug therapy at the lowest possible dose
  • Thionamides have been associated with agranulocytosis and liver failure. Patients taking thionamides should undergo baseline blood testing and be aware of warning symptoms of hepatic and bone marrow failure
• Radioactive iodine:
  • Radioactive iodine (131I) is taken up by the thyroid gland in a manner similar to natural iodine and is concentrated in thyroid tissue. beta particle emission from 131I ablates the follicular cells leading to tissue destruction
  • 131I is the preferred treatment for Graves' disease, multinodular goiter, toxic adenoma in patients >40 years, and after failure of antithyroid therapy
  • The goal of 131I therapy is to render the patient euthyroid or hypothyroid. Approximately 80% to 90% of patients are rendered euthyroid within 8 weeks of the initial 131I dose
  • Antithyroid medication before 131I therapy may be considered in patients with severe thyrotoxicosis
  • The American Thyroid Association advocates radioactive iodine as a safe and highly effective intervention, assuming appropriate post-treatment care is taken
  • ¹³¹I therapy is contraindicated in pregnant women and lactating mothers due to the risk of damage to the fetus, and to breastfeeding infant's thyroid gland
  • ¹³¹I therapy may worsen ophthalmopathy in patients with Graves' disease if moderate – severe ophthalmopathy is pre-existing
• Thyroidectomy
  • Thyroidectomy is less popular with most patients, but is indicated in:
    • Active moderate-severe ophthalmopathy
    • Allergy to or non-compliance with medications
    • Large or obstructing goiters
    • Pregnancy or those desiring pregnancy in the immediate future
    • Refusal of radioactive iodine therapy
    • Severe hyperthyroidism in a child
  • Patients are usually rendered euthyroid using methimazole prior to the surgery
  • beta blockers and potassium iodide are also used prior to surgery.
  • Subtotal thyroidectomy is the most commonly performed procedure however there is a recurrence rate of 8% at 5 years
  • Total thyroidectomy has almost no risk of recurrence and is indicated when the possibility of recurrence is otherwise high, e.g., severe disease or large-sized goiters
  • Levothyroxine (weight-based dose) should be initiated in patients following thyroidectomy
  • Post-surgical complications may include recurrent laryngeal nerve injury, permanent hypoparathyroidism, transient hypocalcemia, hemorrhage, and infection
• Adjunctive therapy
  • beta blockers: beta blockers such as atenolol, metoprolol, and propranolol can provide immediate symptomatic relief to thyrotoxic patients by inhibiting adrenergic effects. They are often used in conjunction with surgery, radioactive iodine, and thionamide therapy to relieve tachycardia, tremor, sweating and anxiety in thyrotoxic patients
  • Glucocorticoids: Oral glucocorticoids are recommended for the management of Graves' ophthalmopathy, especially in smokers. Evidence suggests that the administration of glucocorticoids during radioactive iodine ablation can prevent exacerbation of the ophthalmopathy
  • Levothyroxine: Interventions aimed at treating hyperthyroidism may cause hypothyroidism and if so thyroid hormone will need to be replaced
  • Potassium iodide: Owing to its rapid reduction of thyroid hormone levels, it may be used in patients with thyroid storm, or to reduce thyroid vascularity prior to thyroidectomy

Medications indicated with specific doses

Antithyroid drugs

• Methimazole
  • Adult dosing
  • Pediatric dosing
• Propylthiouracil
• Adult dosing
• Pediatric dosing

• sodium iodide I-131
  • Adult dosing

• Levothyroxine [Oral]
  • Adult dosing
  • Pediatric dosing

• Atenolol
  • Adult dosing
  • Pediatric dosing
• Metoprolol [Oral]
  • Adult dosing
  • Pediatric dosing
• Propranolol [Oral]
  • Adult dosing
  • Pediatric dosing

• Potassium iodide
  • Adult dosing:
  • Pediatric dosing

Dietary or Activity restrictions

• No specific dietary restriction is recommended; however, patients should be advised to avoid iodine containing expectorants, radiographic contrast dyes, seaweed tablets, and health supplements
• An adequate caloric intake is recommended to prevent weight loss
• Young, healthy patients with hyperthyroidism and no other cardiopulmonary comorbidities are not required to restrict their physical activity

Disposition

Admission Criteria

• Impaired vision secondary to ophthalmopathy
• Intravenous drugs required to maintain heart rate
• Serious cardiovascular manifestations such as congestive heart failure (CHF), atrial fibrillation, or angina
• Severely symptomatic
• Thyroid storm

• Patients with good symptom control and response to oral medications may be discharged

[Outline]

• General treatment items
• Medications indicated with specific doses
• Dietary or Activity restrictions
• Disposition

Monitoring

• TSH measurement in patients being treated for hyperthyroidism should be repeated after a minimum of 3 months as there may be prolonged suppression of pituitary TSH. Free thyroxine levels should be measured to assess thyroid status during this time
• Patients receiving antithyroid medications should have thyroid function tests every 4-8 weeks until euthyroid levels are achieved with a focus on utilization of minimal doses of thionamides
• White blood cell count should be checked in all patients taking thionamides who develop fever and pharyngitis to aid the early detection of agranulocytosis. Thionamides may cause transient elevations of serum transaminases; LFTs should be monitored
• Therapeutic response to radioiodine treatment can be measured by observing the patients clinical features, gland size and thyroid function tests. Following therapy, patients should be monitored for relapse or hypothyroidism. Thyroid function tests should be carried out at 6 weeks, 12 weeks, 6 months, and annually thereafter once the patient is euthyroid

Complications

Complications of hyperthyroidism

• Atrial fibrillation
• Bone mineral loss
• CHF
• Dermopathy
• Endothelial dysfunction
• Obesity and insulin resistance following treatment
• Pulmonary hypertension
• Recurrent hyperthyroidism
• Visual impairment due to Graves' ophthalmopathy

Complications of thyroidectomy

• Hypoparathyroidism
• Hypothyroidism
• Laryngeal nerve damage
• Permanent vocal cord palsy

• Postablation hypothyroidism, particularly in Graves' disease

• Acute inflammatory hepatitis (rare)
• Agranulocytosis
• Aplastic anemia (rare)
• Leukopenia
• Lupus-like syndrome (rare)
• Polyarthritis syndrome
• Reversible cholestasis due to methimazole
• Thrombocytopenia (rare)
• Vasculitis (rare)

[Outline]

• Monitoring
• Complications

Prevention

• There is no known prevention for thyroid disease however given the increased prevalence of toxic multi nodular goiter in countries deficient in iodine intake, it is important to ensure adequate intake of iodine to prevent the development thyroid disease

Prognosis

• Most patients have a good prognosis if treated promptly
• Patients may present with cardiac, and neuropsychiatric complications, often requiring hospital admission
• There is an increased risk of all-cause mortality from cardiovascular/cerebrovascular diseases, and hip fractures due to bone mineral density loss
• Subclinical hyperthyroidism was not found to increase the risk of all-cause or cardiovascular mortality
• Treatment of hyperthyroidism may make patients susceptible to obesity and insulin resistance
• Hyperthyroidism may also lead to endothelial dysfunction which is an independent risk factor for thromboembolism

Associated conditions

• Autoimmune diseases
• Down syndrome
• Iodine deficiency

Pregnancy/Pediatric effects on condition

• Gestational hyperthyroidism is a mild biochemical derangement that may be seen in normal first trimester pregnancies secondary to beta-hCG mediated TSH suppression. It is generally benign and requires no treatment
• Untreated hyperthyroidism during pregnancy may result in serious adverse maternal, fetal, and neonatal outcomes
• Adverse maternal outcomes include spontaneous abortion, pregnancy-induced hypertension, heart failure, premature labor, placental abruption and thyroid storm
• Adverse fetal and neonatal outcomes include fetal growth impairment, preterm birth, stillbirth, low birth weight, hyper/hypothyroidism and goiter
• Subclinical hyperthyroidism has not been found to adversely affect pregnancy outcomes
• Graves' hyperthyroidism has a higher likelihood of relapse both during pregnancy and for the year following delivery
• PTU is the preferred drug during the first trimester of pregnancy following which patients should be switched to methimazole. Treatment with the lowest effective dose is recommended
• Treatment with radioiodine is absolutely contraindicated during pregnancy and lactation. Thyroidectomy is preferable if intolerance to PTU occurs
• Continued monitoring of thyroid function following parturition is recommended until the patient becomes euthyroid

Synonyms/Abbreviations

• Antithyroid drugs (ATDs)
• Hyperthyroidism
• Propylthiouracil (PTU)
• Thyroid stimulating hormone (TSH)
• Thyrotoxicosis
• Thyroxine (T4)
• Triiodothyronine (T3)

ICD-9-CM

• 242.0 Toxic diffuse goiter with mention of thyrotoxic crisis or storm
• 242.90 Thyrotoxicosis without mention of goiter or other cause without mention of thyrotoxic crisis or storm (includes hyperthyroidism, not otherwise specified) Hyperthyroidism (Graves' Disease)
• 242.91 Thyrotoxicosis without mention of goiter or other cause with mention of thyrotoxic crisis or storm Hyperthyroidism (Graves' Disease)
• 648.1 Thyroid dysfunction (as a complication of pregnancy, childbirth & puerperium)
• 775.30 Neonatal thyrotoxicosis

ICD-10-CM

• E05.00 Thyrotoxicosis with diffuse goiter without thyrotoxic crisis or storm
• E05.01 Thyrotoxicosis with diffuse goiter with thyrotoxic crisis or storm
• E05.10 Thyrotoxicosis with toxic single thyroid nodule without thyrotoxic crisis or storm
• E05.11 Thyrotoxicosis with toxic single thyroid nodule with thyrotoxic crisis or storm
• E05.20 Thyrotoxicosis with toxic multinodular goiter without thyrotoxic crisis or storm
• E05.21 Thyrotoxicosis with toxic multinodular goiter with thyrotoxic crisis or storm
• E05.30 Thyrotoxicosis from ectopic thyroid tissue without thyrotoxic crisis or storm
• E05.31 Thyrotoxicosis from ectopic thyroid tissue with thyrotoxic crisis or storm
• E05.80 Other thyrotoxicosis without thyrotoxic crisis or storm
• E05.81 Other thyrotoxicosis with thyrotoxic crisis or storm
• E05.90 Thyrotoxicosis, unspecified without thyrotoxic crisis or storm
• E05.91 Thyrotoxicosis, unspecified with thyrotoxic crisis or storm
• P72.1 Transitory neonatal hyperthyroidism

[Outline]

• Prevention
• Prognosis
• Associated conditions
• Pregnancy/Pediatric effects on condition
• Synonyms/Abbreviations
• ICD-9-CM
• ICD-10-CM

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