Hyperthyroidism

Thyroid Hormone Regulation

Functions of Thyroid Hormone

• Regulates cellular metabolism
• Facilitates development of the central nervous system (CNS)
• Important for normal growth, puberty, and protein synthesis

Hyperthyroidism

Hyperthyroidism is characterized by an excessive concentration of thyroid hormones in tissues, caused by increased synthesis, excessive release of preformed thyroid hormones, or an endogenous or exogenous extrathyroidal source.

Aetiology of Hyperthyroidism

Etiology and Pathogenesis of Hyperthyroidism

https://www.aafp.org/pubs/afp/issues/2016/0301/p363.html

Etiology	Mechanism
Most common causes
Graves disease	Autoimmune process in which antibodies stimulate the TSH receptor leading to overproduction of thyroid hormones
Painless or transient (silent) thyroiditis	Autoimmune destruction of thyroid tissue leading to a release of preformed thyroid hormones
Toxic adenoma (Plummer disease)	Somatic mutation in TSH receptor or Gs alpha gene in a thyroid nodule
Toxic multinodular goiter	Expansion of clonogenic cells with an activating TSH receptor mutation
Less common causes
Drug-induced thyroiditis	Overproduction of thyroid hormones (amiodarone-induced thyrotoxicosis type 1) or release of preformed thyroid hormones (amiodarone-induced thyrotoxicosis type 2, interferon alfa, interleukin-2, or lithium)
Hyperemesis gravidarum	High level of β-hCG stimulates TSH receptors
Postpartum thyroiditis	Variant of painless thyroiditis with the same mechanism, occurring after delivery
Subacute granulomatous (de Quervain) thyroiditis	Painful inflammation of the thyroid gland caused by viral infection, often with fever, triggering a release of preformed thyroid hormones
Rare causes
Factitious thyrotoxicosis	Surreptitious ingestion of thyroid hormones
Metastatic follicular thyroid cancer	Metastasis of functional follicular thyroid cancer
Struma ovarii	Ectopic thyroid tissue in ovarian dermoid tumor produces thyroid hormones
Trophoblastic tumor or a germ cell tumor	Tumor produces β-hCG, which stimulates thyroid TSH receptors
TSH-secreting pituitary adenoma	Tumor secreting large quantities of TSH, and not responding to thyroxine and triiodothyronine feedback

Common Causes

• Graves’ disease
• Toxic multinodular goiter
• Toxic adenoma
• Painless (silent) thyroiditis

(1) Graves’ Disease

• Most common cause of hyperthyroidism
• Female to male ratio: 5–10:1
• Peak onset: 40–60 years
• Diffuse, usually symmetrical goiter
• Associated with other autoimmune diseases (type 1 diabetes, rheumatoid arthritis, pernicious anemia, vitiligo)
• Autoimmune process where antibodies stimulate the TSH receptor, leading to overproduction of thyroid hormones
• Remission Potential: Graves’ disease can enter remission after a course of antithyroid medications, such as carbimazole or propylthiouracil (PTU), with about 30-50% achieving long-term remission after 12-18 months of therapy.
• Relapse Risk: High relapse rate (up to 50-70%); more likely in patients with a large goiter, high initial thyroid hormone levels, or persistent high levels of thyroid-stimulating immunoglobulins (TSI).

Pathophysiology

• Caused by TSH receptor antibodies (TSHR Ab, also known as TRAb)

Treatment

• Radioactive iodine or surgery
• Post-treatment: eventual development of hypothyroidism

Signs of Graves’ Disease

• Pre-tibial myxedema
• Acropachy (imitates the appearance of clubbing)
• Diffuse goiter with bruit
• Graves’ ophthalmopathy
  • Lid lag
  • Exophthalmous
  • Proptosis
  • Periorbital edema

Risk Factors

• Increased age of onset
• Duration of Graves’ hyperthyroidism
• Smoking

(2) Toxic Adenoma or Multinodular Goiter

• Second most common cause of hyperthyroidism
• Autonomously acting nodules from frequent replication of clonogenic cells leading to somatic activating mutation of TSH receptors
• Remission Potential: Unlike Graves’ disease, these conditions are typically not associated with remission when treated with antithyroid drugs. Medication primarily provides symptom control.

Toxic Adenoma (TA)

• Single nodule
• Female > male
• Onset: 30–50 years
• Slowly growing solitary thyroid nodule, usually >3 cm

Toxic Multinodular Goiter (TMNG)

• Multiple nodules
• Female > male
• Onset: 50+ years
• Nodular goiter often present for years

Treatment

• Remission rare without definitive treatment
• Radioactive iodine is first line
• Surgery for compressive symptoms, large goiter, coexisting thyroid cancer, or hyperparathyroidism
• Occasionally long-term low-dose carbimazole is required

(3) Thyroiditis

• Painless (usually autoimmune)
• Hashimoto’s thyroiditis: autoimmune destruction of thyroid tissue leading to a release of preformed thyroid hormones
• Often self-limiting and typically resolves within weeks to months.
• Relapse Risk: Relapses are uncommon, though some cases may recur, particularly if an autoimmune etiology (like Hashimoto’s thyroiditis progressing through hyperthyroid phases) is involved.

Variants

• Atrophic / Juvenile thyroiditis
• Postpartum thyroiditis
• Silent / Focal thyroiditis

Pathophysiology

• Anti-TPO generally positive
• Thyrotoxic for the first 1-2 months then hypothyroidism for 4-6 months
• Hypothyroidism usually permanent

Silent Thyroiditis/Painless Thyroiditis

• Anti-TPO generally elevated
• Thyrotoxicosis followed by hypothyroidism

(4) Postpartum Thyroiditis

• Occurs 1-6 months post-delivery
• Anti-TPO generally elevated
• usually self-limiting, resolves to normal thyroid function within 12-18 months
• Relapse is possible in subsequent pregnancies, and 20% possibility of permanent hypothyroidism

Management

• Beta-blocker for symptoms
• Thyroxine if the hypothyroid phase is prolonged, symptomatic, if breastfeeding, or attempting further pregnancies

(5) Transient Gestational Thyrotoxicosis

• High level of beta-hCG stimulates TSH receptors
• Often with hyperemesis gravidarum due to high levels of beta-hCG
• Usually resolves spontaneously during the pregnancy or shortly after delivery.

(6) Medications Induced Thyroiditis

• Medications such as lithium, interferon alfa, interleukin-2, and amiodarone
• Either thyrotoxicosis or hypothyroidism
• Often continues as long as the drug is taken
• Generally resolves once the offending drug (e.g., interferon, lithium, amiodarone) is stopped.

(7) Painful Thyroiditis (Viral Destruction)

• De Quervain thyroiditis: painful inflammation of the thyroid gland post-respiratory tract infection
• Often self-limiting with complete resolution within weeks to a few months.

Pathophysiology

• Destruction of thyroid follicles with release of stored thyroid hormone
• Female to male ratio: 5:1
• Peak onset: 20–60 years
• Thyrotoxicosis followed by hypothyroidism
• Resolves to normal thyroid function within 12-18 months
• 5% possibility of permanent hypothyroidism
• Anti-TPO low or absent
• Elevated inflammatory markers

Management

• Beta-blocker for symptoms
• Nonsteroidal anti-inflammatory drugs for thyroid pain
• Glucocorticoids for severe pain
• Thyroxine if the hypothyroid phase is prolonged or symptomatic

(8) Suppurative Thyroiditis

• Caused by bacteria mainly, but any infectious organism
• generally not associated with long-term hyperthyroidism and resolves after treatment of the infectious cause
• May cause severe illness

(9) Amiodarone-Induced Hyperthyroidism

• 3% of patients administered the drug due to iodine content
• May require prolonged treatment; some cases resolve after discontinuation of amiodarone, though this can be challenging due to its long half-life.
• High likelihood of persisting thyroid dysfunction or recurrence upon resumption of amiodarone.

(10) Rare Causes

• TSH secreting pituitary tumors
• Ovarian struma (ovarian teratoma with thyroid tissue)

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FEATURES

Symptoms 

• Adrenergic
  • Palpitations
  • Anxiety
  • Tremor
  • Jitteriness
  • Heat intolerance
  • Hyperdefecation (not diarrhea)
• Cardiovascular
  • Dyspnea
  • Orthopnea
• Cutaneous
  • Sensation of skin changes (may be reported by patient)
• Hypermetabolism
  • Weight loss despite increased appetite
  • Fever (especially in thyroid storm)
• Neuromuscular
  • Muscle weakness (patient-reported fatigue or difficulty climbing stairs)
• Neuropsychiatric
  • Anxiety
  • Insomnia
• Ocular
  • Increased lacrimation
  • Photophobia
  • Grittiness or foreign body sensation
  • Sensitivity to wind or smoke

Signs

• Adrenergic
  • Tachycardia
  • Lid lag
  • Stare
  • Diaphoresis
• Cardiovascular
  • Tachycardia
  • Irregular pulse (e.g., atrial fibrillation)
  • Peripheral edema (in heart failure)
• Cutaneous
  • Onycholysis (Plummer nails)
  • Patchy/generalized hyperpigmentation (esp. face and neck)
  • Pretibial myxedema (Graves-specific)
  • Thyroid acropachy (Graves-specific)
  • Patchy vitiligo (Graves-associated)
• Neuromuscular
  • Brisk peripheral reflexes with accelerated relaxation phase
  • Proximal muscle weakness
• Neuropsychiatric
  • Pressured speech
  • Psychosis (if severe)
• Ocular
  • Exophthalmos (Graves-specific)
  • Periorbital edema
  • Incomplete eyelid closure during sleep
  • Diplopia
  • Blurred vision
  • Reduced color perception

• Nb: elderly present w fewer/atypical s/s, ie: AF, CCF, confusion

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INVESTIGATIONS

• TSH is firstline test.
  • If reduced, then measure free T3 and T4. 
  • Raised free T3 and/or T4 confirms thyrotoxicosis.
• If Graves disease is suspected
  • measure TSHRAb. 
• If thyroiditis is suspected,
  • measure anti-TPO and/or anti-TG to look for autoimmune cause. 
• Radionuclide thyroid scan is indicated if the cause of the thyrotoxicosis is not obvious.

• For patients with reduced TSH but normal T3 and T4, consider subclinical hyperthyroidism and non-thyroid causes (see diagram). 

• Investigation of subclinical hyperthyroidism is controversial with no consensus guidelines. 

• Journal in IJEM suggests repeating TSH in 3-12 months if 0.1<TSH<LLN; and investigate and manage as per thyrotoxicosis if TSH<0.1. 
• Low threshold of treatment in elderley patients or those at risk of osteopenia / AF etc.

	Thyroperoxidase autoantibodies	Thyroglobulin autoantibodies	TSH receptor antibody (TRAb)
General population	8–27% (11% without history of thyroid disease in Australia	5–20% (5% without history of thyroid disease in Australia)	1–2% (significance of these positive values remains to be determined)
Graves disease	50–80%	50–70%	90–99%†
Chronic autoimmune thyroiditis	90–100%	80–90%	10–20%

Condition	TSH	Total T₄	Free T₄	Total T₃
Overt hyperthyroidism	Suppressed	Elevated ↑	Elevated ↑	Elevated ↑
Subclinical hyperthyroidism*	Suppressed or low ↓	Normal	Normal	Normal
TSH-secreting pituitary adenoma	Normal or elevated ↑	Elevated ↑	Elevated ↑	Elevated ↑
Estrogen excess	Normal	Elevated ↑	Normal	Elevated ↑
Nonthyroidal illness syndrome	Low ↓	Normal or mildly decreased	Normal	Low ↓ (and reverse T₃ is elevated)
Glucocorticoid and/or dopamine therapy	Low ↓	Normal	Normal	Normal

Notes:

• Suppressed TSH = < 0.1 mIU/mL; Low TSH = 0.1–0.4 mIU/mL
• T₃ = Triiodothyronine
• T₄ = Thyroxine
• TSH = Thyroid-stimulating hormone
• *Subclinical hyperthyroidism does not refer to the absence of signs and symptoms.

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Treatment

General Management

All patients with thyrotoxicosis, where thyroiditis is unlikely or has been excluded, should be referred to an endocrinologist.

Symptomatic Treatment

• Symptoms of thyrotoxicosis often respond to beta-blockers or non-dihydropyridine calcium channel blockers (CCB).

Treatment of Thyroiditis

• The disease is self-limiting; treatment is usually symptomatic and supportive.
  • Beta-blockers: to control symptoms.
  • NSAIDs: for pain management.
  • Steroids: Thyroid storm, eye disease, Dexamethasone 4 mg BD
  • Thyroxine: required if the patient becomes hypothyroid.

Specific Treatments:

Antithyroid Medications

Goal of Therapy

• Induce euthyroidism (normal thyroid function).
• Aim for remission after 12–18 months of continuous therapy.

Efficacy & Duration

• 30–50% of patients may achieve long-term remission.
• Relapse is possible; influenced by:
  • Severity of initial hyperthyroidism
  • Presence of goiter
  • Thyroid-stimulating antibody levels

Definitive Options if Relapse

eTG:

Option	Indication	Notes
12–18 months of antithyroid drugs then withdraw	Mild Graves	TSH-R ab normalization predicts remission
Long-term antithyroid drugs	Persistent mild Graves, poor surgical candidates	Monitor closely
Radioiodine	Older pts, toxic nodules, large goitre	Stop carbimazole 3–7 days before
Thyroidectomy	Large obstructive goitre, cancer, pregnancy planning	Needs preop euthyroid state

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Carbimazole (CBZ)

eTG:

Severity	Dose	Frequency
Severe	30–45 mg/day	in 2–3 divided doses
Mild–Mod	10–20 mg/day	in 2–3 divided doses
Maintenance	Often 5–15 mg/day	once daily

• Preferred antithyroid drug due to long half-life.
• Review thyroid function after 4 weeks to avoid hypothyroidism.
• Cease after 12–18 months if euthyroid.
• Remission rate: ~50%
• 5–20% may develop hypothyroidism later due to:
  • Autoimmune thyroiditis
  • TSH receptor blocking antibodies

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Propylthiouracil (PTU)

eTG:

Severity	Dose	Frequency
Severe	300–450 mg/day	in 2–3 divided doses
Mild–Mod	100–200 mg/day	in 2–3 divided doses
Thyroid storm	200 mg	every 4–6 hours

• Preferred in:
  • Pregnancy
  • Thyroid storm
  • Carbimazole intolerance
• Consider withdrawal in mild Graves’ disease once euthyroidism achieved
• Do not use in children due to hepatotoxicity
• Side effects:
  • Common: GI upset, rash, arthralgia
  • Serious:
    • Agranulocytosis (early months; suspend drug if infection symptoms)
    • ANCA vasculitis (more common with PTU)
    • Hepatitis:
      • PTU → hepatocellular
      • CBZ → cholestatic

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BETA BLOCKERS (Symptomatic relief)

eTG:

Medication	Dose	Notes
Propranolol Most experience; fast	10–40 mg BD–QID	Up to 160 mg/day
Atenolol Once daily option	25–50 mg daily	Once daily convenient
Child	Propranolol 0.5–1 mg/kg/day	In 3–4 doses
If beta blockers contraindicated	Use diltiazem 60 mg QID

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Radioactive Iodine (RAI)

• Oral therapy targeting thyroid tissue → cellular necrosis.
• Cure rate: ~81%
• Adverse effects:
  • post-treatment ~10% transient radiation thyroiditis (painful, worsens thyrotoxicosis)
  • Causes hypothyroidism
  • Can worsen Graves’ ophthalmopathy → may need steroid cover
• Pregnancy considerations:
  • Avoid pregnancy for 6 months (women)
  • Avoid fathering for 4 months (men)

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Surgery (Thyroidectomy)

• Provides rapid symptom control
• Risks:
  • Laryngeal nerve injury (~1%)
  • Hypoparathyroidism (~2%)

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Graves’ Ophthalmopathy

• Management:
  • Local lubricants
  • Corticosteroids
  • Orbital radiation
  • Surgery (e.g., decompression)
• Smoking cessation is essential (smoking worsens disease severity)

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Toxic Multinodular Goitre (MNG) / Toxic Adenoma

• First-line: Radioactive iodine (RAI)
• Second-line: Surgery (especially if large/compressive goiter)

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Amiodarone-Induced Hyperthyroidism

Type	Pathophysiology	Treatment
Type 1	Iodine-induced hormone synthesis	Antithyroid drugs
Type 2	Destructive thyroiditis	Glucocorticoids
Mixed/unclear	Empirical dual therapy	Both PTU + prednisolone

• Early specialist referral required
• Cease amiodarone
• Treatment options:
  • Antithyroid drugs ± steroids
  • Consider thyroidectomy if severe

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Pregnancy

Doses: Use lowest effective dose to keep FT4 in upper trimester-specific reference range

Before conception: Achieve remission; switch carbimazole → PTU

1st trimester: PTU preferred (lower teratogenicity)

2nd trimester onwards: Switch back to carbimazole (lower hepatotoxicity)

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POSTPARTUM AND SPORADIC THYROIDITIS

• Features: Transient hyper → hypo phases; no uptake on scan
• Tx:
  • Beta blockers during hyperthyroid phase
  • Levothyroxine if symptomatic during hypo phase or if planning pregnancy/breastfeeding

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Benefits and Risks of Graves Disease Treatment Options

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Treatment Options	Benefits	Risks
Antithyroid medication (Methimazole [Tapazole] or Propylthiouracil)	– No exposure to radiation or surgical risks – No permanent hypothyroidism – Propylthiouracil is safe in the first trimester of pregnancy	– Agranulocytosis, hepatotoxicity (especially with propylthiouracil), rash – Methimazole can cause aplasia cutis and other birth defects in first trimester
Radioactive iodine ablation	– No exposure to adverse effects of medications or surgical risks – Treatment of choice in the U.S.	– Aggravation of Graves orbitopathy (esp. in smokers) – Permanent hypothyroidism (most patients) – Radiation exposure – Failure if dose insufficient – Recurrence possible even after treatment – Contraindicated in pregnancy
Thyroidectomy	– No exposure to adverse effects of antithyroid drugs or radiation – Little chance of Graves recurrence	– General anesthesia risk – Risk of recurrent laryngeal nerve injury (hoarseness if unilateral, respiratory distress if bilateral) – Risk of parathyroid damage causing permanent hypoparathyroidism

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Sources:
Abraham P et al., Eur J Endocrinol. 2005;153(4):489–498.
Bartalena L. Nat Rev Endocrinol. 2013;9(12):724–734.
Cappelli C et al., Eur J Radiol. 2008;65(1):99–103.
Nakamura H et al., J Clin Endocrinol Metab. 2007;92(6):2157–2162.

Treatment of Thyroid Storm

Thyroid storm = life-threatening thyrotoxicosis + systemic decompensation (e.g. delirium, CHF, hyperpyrexia, hypotension).

Supportive Treatment

• Airway maintenance
• Oxygen
• IV fluids
• Cooling blanket (avoid salicylates, as they increase free T₄ and free T₃ levels)

Inhibit T₄ and T₃ Synthesis

• Propylthiouracil (PTU)
  • preferred due to T4→T3 inhibition
  • Route: Oral, rectal, or nasogastric tube
  • Dose: 200 mg Q4–6H PO

Inhibit T₄ and T₃ Release

• Saturated solution of potassium iodide
  • Dose: 5 drops orally every 6 hours
  • Start at least 1 hour after antithyroid agent administration

Heart Rate Control

• Esmolol
  • Route: IV
  • 250–500 mcg/kg IV loading → 50–100 mcg/kg/min infusion
• Propranolol
  • Route: Oral
  • Dose: 60 to 80 mg every 4 hours
• Metoprolol
  • Route: IV
  • Dose: 5 to 10 mg every 2 to 4 hours
• If β-blockers contraindicated → Diltiazem
  • Route: IV
  • Dose: 0.25 mg/kg over 2 minutes, then 10 mg/hr IV infusion
  • Oral alternative: 60 to 90 mg every 6 to 8 hours

Inhibit T₄ to T₃ Conversion

• Dexamethasone:
  • 4 mg IV/PO 12-hourly
• Hydrocortisone
  • Dose: 100 mg IV every 8 hours
  • Also suppresses autoimmune process in Graves disease

Treat Precipitating Cause

Source: Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. 2006;35(4):663–686.