Hyperthyroidism

Hyperthyroidism refers to the symptoms caused by excessive circulating thyroid hormones. It is typically caused by thyroid gland hyperactivity, the most common causes of which are Graves disease (most common), toxic multinodular goiter (MNG), and toxic adenoma. In rare cases, hyperthyroidism is caused by TSH-producing pituitary tumors (central hyperthyroidism), excessive production of β-hCG (gestational trophoblastic disease), or oral intake of thyroid hormones (factitious hyperthyroidism). Regardless of the cause, the most common symptoms of hyperthyroidism include fatigue, anxiety, heat intolerance, increased perspiration, palpitations, and significant weight loss despite increased appetite. Serological thyroid hormone assay confirms hyperthyroidism, while measurement of antithyroid antibodies, thyroid ultrasonography, and radioactive iodine uptake tests help identify the etiology. Management of any form of hyperthyroidism involves the initial control of symptoms with beta blockers and antithyroid drugs, followed by definitive therapy either with radioactive iodine ablation of the thyroid gland or surgery.

• Hyperfunctioning thyroid gland
  • Graves disease (∼ 60–80% of cases)
  • Toxic MNG (∼ 15–20% of cases)
  • Toxic adenoma (3–5% of cases)
  • TSH-producing pituitary adenoma (thyrotropic adenoma)
  • β-hCG-mediated hyperthyroidism (hydatidiform mole, choriocarcinoma)
  • Hashitoxicosis (see Hashimoto thyroiditis)
• Destruction of the thyroid gland
  • Thyroiditis (see subacute thyroiditis)
    • Subacute granulomatous thyroiditis (de Quervain thyroiditis)
    • Subacute lymphocytic thyroiditis (e.g., post-partum thyroiditis)
  • Drug-induced thyroiditis (e.g., amiodarone, lithium)
  • Contrast-induced thyroiditis (Jod-Basedow phenomenon)
  • Hashimoto thyroiditis
  • Radiation thyroiditis
  • Palpation thyroiditis: due to thyroid gland manipulation during parathyroid surgery.
• Exogenous hyperthyroidism
• Ectopic (extrathyroidal) hormone production
  • Struma ovarii
  • Metastatic follicular thyroid carcinoma

References:^[4][6][7]

• General
  • Heat intolerance
  • Excessive sweating because of increased cutaneous blood flow
  • Weight loss despite increased appetite
  • Frequent bowel movements (because of intestinal hypermotility)
  • Weakness, fatigue
  • Onycholysis
  • Infiltrative dermopathy, especially in the pretibial area (pretibial myxedema)
• Eyes
  • Lid lag; : caused by adrenergic overactivity, which results in spasming of the smooth muscle of the levator palpebrae superioris
  • Lid retraction; : “staring look”
  • Graves ophthalmopathy (exophthalmos, edema of the periorbital tissue)
• Goiter
  • Diffuse, smooth, nontender goiter; often audible bruit at the superior poles
  • Also seen in subacute thyroiditis, toxic adenoma, and toxic MNG
• Cardiovascular
  • Tachycardia
  • Palpitations, irregular pulse (due to atrial fibrillation/ectopic beats)
  • Hypertension with widened pulse pressure
    • Systolic pressure is increased due to increased heart rate and cardiac output.
    • Diastolic pressure is decreased due to decreased peripheral vascular resistance.
  • Cardiac failure: elderly patients often present with features of cardiac failure (e.g., pedal edema, exertional dyspnea).
  • Abnormal heart rhythms, including atrial fibrillation
  • Chest pain
• Musculoskeletal
  • Fine tremor of the outstretched fingers
  • Hyperthyroid myopathy
    • Predominantly affects individuals > 40 years of age
    • Proximal muscles are predominantly affected
    • Serum creatine kinase levels are most often normal
  • Osteopathy: osteoporosis due to the direct effect of T₃ on osteoclastic bone resorption , fractures (in the elderly)
• Endocrinological
  • Female: oligo/amenorrhoea, anovulatory infertility, dysfunctional uterine bleeding
  • Male: gynecomastia, decreased libido, infertility, erectile dysfunction
• Neuropsychiatric system
  • Anxiety
  • Emotional instability
  • Depression
  • Restlessness
  • Insomnia
  • Tremoulousness (results from the hyperadrenergic state)
  • Hyperreflexia

References:^[6][10]

Overview of changes in hormone levels

	Overt hyperthyroidism	Subclinical hyperthyroidism
Basal TSH	↓ Or undetectable	↓
FT3	↑	Normal
FT4	↑ In 90% of cases	Normal

Laboratory studies

• Thyroid function tests
  • Test of choice: thyroid-stimulating hormone (TSH) levels
    • TSH is low/undetectable.
    • In pregnancy, levels of β-hCG (similar molecular structure to TSH) peak at the end of the first trimester, which leads to a decrease in serum TSH levels. However, FT₃/FT₄ levels are normal.
  • Free T₃ and free T₄ levels: Both are characteristically high.
• Serum thyroglobulin (Tg)
  • Indicated if exogenous hyperthyroidism is suspected
  • Characteristically low levels due to suppression of the production by the administered thyroid hormones
• Serum thyroid antibodies: if Graves disease/Hashimoto thyroiditis is suspected (see “Overview” in thyroid antibodies)
• Other: decreased total cholesterol, LDL, and HDL levels

Imaging

Thyroid ultrasound

Can be used to diagnose the underlying cause of hyperthyroidism (e.g., diffuse enlargement, solitary/multiple nodules, increased vascularity of the gland)

Thyroid scintigraphy

A nuclear medicine imaging technique that allows the structure and function of thyroid tissue to be visualized based on its selective uptake of radioactive iodine (RAI).

• Indications
  • If etiology of hyperthyroidism is uncertain or if physical examination suggests nodular thyroid disease
  • Identification of ectopic thyroid tissue (e.g., base of tongue masses, which could be lingual thyroid tissue or cases of struma ovarii)
  • Evaluation of thyroglossal cysts
• Contraindications: pregnant or breast-feeding women
• Interpretation of results
  • Only the functional part of the gland takes up RAI.
  • Normal thyroid tissue: normal-sized gland with diffuse uptake of RAI
  • Most common findings
    • Graves disease: enlarged gland with diffusely increased RAI uptake
    • Toxic MNG: multiple nodular areas, both cold and hot, resulting in an overall heterogeneous appearance
    • Toxic adenoma: a hot nodule
    • Factitious hyperthyroidism: no uptake of RAI since there is no thyroid gland hyperfunction

References:^[6][11][10]

Common differential diagnoses

• Neuropsychiatric symptoms: anxiety/panic disorders
• Hyperadrenergic symptoms: intoxication with anticholinergics; cocaine/amphetamine abuse; withdrawal syndromes
• Weight loss: diabetes mellitus, malignancy
• Cardiac symptoms: congestive cardiac failure

Differential diagnoses of hyperthyroidism
		Graves disease	Toxic multinodular goiter	Subacute granulomatous thyroiditis (de Quervain thyroiditis)	Subacute lymphocytic thyroiditis (silent thyroiditis)	Iodine-induced hyperthyroidism
Thyroid status		Acute to chronic hyperthyroidism	Chronic hyperthyroidism	Transient hyperthyroidism followed by features of hypothyroidism		Thyrotoxicosis in patients with a preexisting iodine-deficiency thyroid disorder
Epidemiology		Most common cause of hyperthyroidism in the US Peak incidence: 20–30 years of age ♀ > ♂ (8:1)	Peak incidence: > 50 years of age ♀ > ♂	Peak incidence: 30–50 years of age ♀ > ♂ (3:1)		More common in iodine-deficient regions
Causes		Autoimmune due to TSH receptor autoantibodies	Chronic iodine deficiency	Viral and mycobacterial infections causing damage to follicular cells	Postpartum thyroiditis Autoimmune diseases Drugs: α–interferon, lithium, amiodarone, interleukin–2, tyrosine kinase inhibitors	Iodine excess from diet, contrast, or amiodarone
Goiter	Consistency	Diffuse and smooth	Multinodular	Diffuse and firm		Depends on underlying thyroid disorder
	Pain	Painless	Painless	Painful	Painless	Painless
Other findings		Graves ophthalmopathy Pretibial myxedema	Nonspecific	↑ ESR Fever, malaise Possible history of upper respiratory tract infections a few weeks prior to the onset of subacute thyroiditis		Nonspecific
Thyroid function tests		↓/Undetectable TSH ↑ T3/T4	↓ TSH ↑ T3/T4	Thyrotoxic phase: ↓ TSH, ↑ T3/T4, and ↑ thyroglobulin Hypothyroid phase: ↑ TSH and ↓ T3/T4		↓ TSH ↑ T3/T4
Antibodies		↑ TRAbs, anti-TPO antibody, and anti-Tg	Absent	Anti-TPO antibody		Possible ↑ TRAb in patients with Graves disease
Iodine uptake on scintigraphy		Diffuse	Multiple focal areas of increased uptake	Reduced		Reduced
Pathologic findings		Diffuse hyperplasia and hypertrophy of follicular cells	Patches of enlarged follicular cells distended with colloid and flattened epithelium	Granulomatous inflammation, multinucleated giant cells on histology	Absence of germinal follicles, lymphocytic infiltration on histology	Depends on underlying thyroid disorder

Exogenous hyperthyroidism or factitious hyperthyroidism

• Definition: hyperthyroidism due to excessive intake of thyroid hormone
• Etiology
  • Intentional
    • Therapeutic: suppressive doses of thyroid hormones for thyroid cancer treatment
    • Patients with psychiatric disorders, like Munchausen syndrome
    • People who are trying to lose weight
  • Unintentional
    • Iatrogenic
    • Accidental ingestion (primarily in children)
    • Dietary supplement overdose
• Clinical features: symptoms of hyperthyroidism but no goiter
• Diagnostics
  • Low/undetectable TSH, high levels of T₄/T₃, low Tg levels
  • Low RAI uptake in scintigraphy
• Treatment
  • Taper and stop the exogenous thyroid hormone.
  • Beta blockers: if symptoms are severe
  • Cholestyramine: binds to T₃ and T₄ in the intestine and interrupts the enterohepatic circulation

References:^{[12][13][14][15][16] [17][18][19]}

The differential diagnoses listed here are not exhaustive.

Symptomatic therapy of thyrotoxicosis

• Beta blockers provide immediate control of symptoms.
  • Improve tachycardia, hypertension, tremor, and neuropsychiatric symptoms
  • In high doses, propranolol also decreases the peripheral conversion of T₄ to T₃ by inhibiting the 5'-monodeiodinase enzyme.
• Indication: all symptomatic patients
• Contraindications: : e.g., asthma, Raynaud phenomenon; for more information, see section “Contraindications” in beta blockers.
• Drugs used
  • Preferred drug: propranolol (nonselective)
  • Alternatives: atenolol, metoprolol (both have relative beta-1 selectivity), nadolol (nonselective), esmolol (IV administration)

Definitive therapy

There are currently three effective initial treatment options for Graves disease: antithyroid drugs, radioactive iodine ablation, and surgery. Toxic MNG and toxic adenoma (TA) are not generally treated with antithyroid drugs, but rather with ablation or surgery. Which form of therapy is chosen depends on the individual clinical situation and the patient preference.

Antithyroid drugs (ATDs)

• Antithyroid drugs can effectively render a patient euthyroid; 20–75% of patients achieve permanent remission after 1–2 years of treatment. Some patient groups have a higher likelihood of remission than others.
• Indications
  • Patients with high likelihood of remission (e.g., small goiter, negative or low TRab titer, women)
  • Active Graves ophthalmopathy
  • Children age ≤ 5 years
  • Pregnancy
  • Thyroid storm
  • Patient preference
  • Patients who need rapid disease control before further treatment, e.g., achievement of euthyroid state prior to surgery
  • Patients with an inability to follow radiation safety regulations
• Contraindications: history of adverse reactions to ATD
• Adverse effects: See antithyroid drugs.
• Drugs used
  • Methimazole
    • Drug of choice, except during the first semester of pregnancy
  • Propylthiouracil
    • Drug of choice in the first trimester of pregnancy and in thyroid storm
    • Alternative drug for patients who are allergic to methimazole or do not tolerate it

Radioactive iodine ablation (RAIA)

• Definition: destruction of thyroid tissue using radioactive iodine (iodine 131) through a sodium/iodine symporter
• Technical background: Radioactive ¹³¹I emits both gamma rays and beta rays
  • Gamma rays: diagnostic effect
  • Beta rays: therapeutic effect
• Indications
  • High surgical risk; limited life-expectancy
  • Liver disease
  • Major adverse reaction to ATDs
  • Previous operations or radiation of the neck
  • No access to a high-volume thyroid surgeon
  • Failure to achieve euthyroidism with ATDs
  • Patient preference
  • Patients with congestive heart failure, right heart failure, pulmonary hypertension, or periodic hypokalemic paralysis
  • Recommended especially for TMNG and toxic adenoma patients with high nodular radioactive iodine uptake
• Contraindications
  • Pregnant/breastfeeding women
  • Children < 5 years
  • Confirmed or suspected thyroid malignancy
  • Patients with moderate to severe Graves ophthalmopathy (GO)
• Procedure
  • Pre-treatment methimazole: in patients who are at high risk for complications due to worsening of hyperthyroidism
    • For 4–6 weeks to rapidly achieve a euthyroid state; must be discontinued 2–3 days before RAIA is begun
    • Young or middle-aged patients with mild to moderate symptoms of hyperthyroidism who undergo RAIA do not routinely require pretreatment with methimazole.
  • Avoidance of excess iodine for 7 days prior to RAIA
  • Single oral dose of (¹³¹I) → isotope uptake by thyroid gland → emission of β-radiation that slowly destroys the thyroid tissue
• Post-procedural care
  • Patients with Graves disease become hypothyroid after RAI ablation and require life-long thyroid hormone replacement.
• Complications
  • Early
    • Gastritis
    • Sialadenitis
      • Prophylaxis: suck on sour candies, drink lemon juice, drink plenty of fluids
    • Hypothyroidism
      • Surveillance, thyroxine substitution
  • Late
    • Radiation-induced thyroiditis
    • Secondary malignancy or leukemia (risk of ∼ 1%)
    • Sicca syndrome with dry mouth (xerostomia)
    • In the case of (disseminated) lung metastases: pulmonary fibrosis

Thyroid surgery

• Surgery is rarely indicated
• Indications
  • Large goiters (≥ 80 g) or obstructive symptoms
  • Confirmed or suspected thyroid malignancy
  • Moderate to severe active Graves ophthalmopathy
  • Women planning to become pregnant in the next < 6 months
  • Large thyroid nodules
  • Patient preference
  • Access to a high-volume thyroid surgeon
  • Recommended especially for TMNG and TA patients with concomitant hyperparathyroidism, insufficient RAIA, or retrosternal extension
• Contraindications
  • Severe comorbidities that influence surgical risk
  • First and third trimester of pregnancy
• Procedure
  • See “procedure/application” in thyroid surgery.
  • For Graves disease: near total thyroidectomy
• Precautions
  • Antithyroid drugs and beta blockers are given preoperatively for at least 4–8 weeks.
  • Oral potassium iodide administered preoperatively for 10 days (Wolff-Chaikoff effect)
• Postprocedural care
  • Management of calcium levels: measurement of serum calcium and intact parathyroid hormone levels
  • Weaning of beta blockers

References:^{[6][13][20][21][22][23][24][25][26]}

Thyroid storm (thyrotoxic crisis)

• Definition: an acute exacerbation of hyperthyroidism that results in a life-threatening hypermetabolic state
• Etiology
  • Iatrogenic
    • Thyroid surgery
    • RAI ablation
    • Discontinuation of antithyroid medication
  • Stress-related catecholamine surge
    • Surgery
    • Anesthesia induction
    • Labor
    • Sepsis
• Clinical features
  • Hyperpyrexia with profuse sweating
  • Tachycardia (> 140 beats/minute) and (possibly severe) arrhythmia (e.g., atrial fibrillation), hypertension (with wide pulse pressure), congestive cardiac failure
  • Severe nausea, vomiting, diarrhea, possibly jaundice
  • Severe agitation and anxiety, delirium and psychoses, seizures, coma
  • Low/undetectable TSH, elevated free T₃/T₄
  • Possible increase of liver function tests
• Treatment
  • General measures
    • Intensive care monitoring with fluid and electrolyte substitution
    • Treatment of hyperthermia: ice packs, cooling blankets, and antipyretics (e.g., acetaminophen)
    • Treatment of the underlying condition
  • Beta blockers (propranolol) should be promptly started.
  • Antithyroid drugs ^[26]
    • First-line: propylthiouracil
    • Second-line: methimazole
  • Potassium iodide/Lugol iodine: clinical effect is due to the decrease of T₄ production in response to iodine load (Wolff-Chaikoff effect)
  • Glucocorticoids: IV hydrocortisone/dexamethasone
  • Plasmapheresis: as a life-saving treatment, rarely needed

Treat thyroid storm with PROverbial PROficiency and POetic GLUttony: PROpanolol, PROpylthiouracil, POtassium iodide, and GLUcocorticoids.

In the event of simultaneous heart failure, the administration of beta blockers may worsen hemodynamics and is therefore contraindicated!

References:^[13][27]

We list the most important complications. The selection is not exhaustive.

Hyperthyroidism in pregnancy

• Epidemiology: Hyperthyroidism is rare in pregnancy (< 0.5% of cases).
• Etiology: Graves disease and β-hCG-mediated hyperthyroidism are the most common causes.
• Pathogenesis
  • β-hCG molecule has a similar structure to that of the TSH molecule.
  • β-hCG binds to TSH receptors of the thyroid gland → thyroid stimulation → hyperthyroidism
• Clinical features
  • Graves disease: signs of hyperthyroidism, ophthalmopathy
  • β-hCG-mediated hyperthyroidism can cause:
    • Subclinical hyperthyroidism
    • Overt (severe) hyperthyroidism in cases of hydatidiform moles/choriocarcinoma (see gestational trophoblastic disease)
• Diagnosis: same as in non-pregnant patients, but thyroid scintigraphy is contraindicated
• Treatment
  • Propylthiouracil , methimazole
  • Beta blockers
  • Surgery: if medication cannot be tolerated; safest in second trimester
• Complications: : If left untreated → miscarriage, stillbirth, pre-eclampsia, premature labor, cardiac failure, low birth weight, neonatal hyperthyroidism (see below).

Suspect a molar pregnancy or choriocarcinoma if severe hyperthyroidism manifests during pregnancy!

Neonatal hyperthyroidism

• Occurs in ∼ 5% of babies born to mothers with Graves disease
• Etiology: transplacental passage of maternal TRAbs
• Clinical features
  • Hyperthyroidism: irritability, restlessness, tachycardia, diaphoresis, hyperphagia, poor weight gain, diffuse goiter (can cause tracheal compression), microcephaly (due to craniosynostosis)
  • May arise directly after birth or delayed up to 10 days later as a result of transplacental maternal antithyroid medication (including propylthiouracil or carbimazole)
• Treatment
  • Neonatal Graves disease resolves within 1–3 months
  • Infants with symptomatic hyperthyroidism: methimazole and propranolol
• Complications: Untreated symptomatic hyperthyroidism in infants can cause cardiac failure and intellectual disability.

References:^[28][29]