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

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 

Signs = warm moist skin, tremor, tachycardia, wide pulse pressure, hyperreflexia, proximal muscle weakness, goiter, rash, lid lag, lid retraction

• 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
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%

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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: for more severe cases.
  • Thyroxine: required if the patient becomes hypothyroid.

Specific Treatments:

Graves’ Disease

Antithyroid Medications:

• Goal of Therapy: The primary goal of using antithyroid medications is to induce a state of euthyroidism (normal thyroid function) and ideally achieve remission. This is typically achieved after a period of 12-18 months of continuous therapy.
• Treatment Duration: Studies suggest that around 30-50% of patients may achieve long-term remission after a course of antithyroid drugs.
• Relapse Rates: While some patients may remain in remission after stopping antithyroid drugs, there is a risk of relapse. Factors influencing the likelihood of relapse include the severity of the initial hyperthyroidism, presence of goiter, and levels of thyroid-stimulating antibodies.
• Alternative Definitive Treatments: If relapse occurs, alternative longer-term solutions such as radioiodine therapy or thyroidectomy (surgical removal of the thyroid) are considered. These options are definitive treatments and eliminate the need for prolonged antithyroid drug use.

• Carbimazole: Preferred choice.
  • Can be given once daily due to its longer half-life.
  • Starting dose: 10–30 mg/day in 2–3 divided doses depending on the severity of thyrotoxicosis.
  • Four weeks following initiation of therapy, clinical review with repeat thyroid function tests should be undertaken to avoid hypothyroidism.
  • Tapered to a maintenance dose (usually carbimazole 2.5–10 mg) and ceased after 12–18 months of therapy.
  • 50% of patients achieve long-term remission.
  • 5–20% of patients in remission eventually develop hypothyroidism due to autoimmune thyroiditis or the presence of TSH receptor blocking antibodies.
• Propylthiouracil (PTU):
  • Preferred in pregnancy and in the treatment of thyroid storm.
• mild Graves’ disease, a trial of discontinuation may be done once the patient achieves euthyroidism, given the balance of benefit-risk in continued drug therapy.

Side Effects:

• Common: GI disturbances, rash, arthralgia.
• Serious:
  • Agranulocytosis: Usually occurs in the first 3 months of therapy but can occur at any time. More common with carbimazole. If patients develop fevers, sore throat, or infectious symptoms, they should suspend therapy and obtain urgent FBC.
  • ANCA vasculitis: More common with PTU.
  • Hepatitis: PTU – hepatocellular; CBZ – cholestatic.

Radioactive Iodine (RAI):

• Oral administration of RAI leads to its transport into thyroid cells, causing cellular death and necrosis. Cure rates of up to 81%.
• 10% of patients may experience transient radiation thyroiditis with painful thyroid and worsening of thyrotoxicosis symptoms.
• Women are advised to avoid pregnancy for 6 months following treatment; men are advised not to impregnate for 4 months following treatment.
• RAI can exacerbate Graves’ ophthalmopathy, requiring steroid cover.

Surgery:

• Thyroidectomy leads to rapid control of symptoms.
• Risks include laryngeal nerve damage (1%) and hypoparathyroidism (2%).

Graves’ Eye Disease

• Treatments include local measures, corticosteroids, orbital radiation, and surgery.
• All patients should be advised to quit smoking, as it can worsen Graves’ ophthalmopathy.

Toxic Multinodular Goiter (MNG) or Toxic Adenoma

• RAI: First-line treatment.
• Surgery: Second option, particularly for large compressive goiters.

Amiodarone-Induced Hyperthyroidism

• Early specialist referral.
• Cease amiodarone.
• Treatment includes anti-thyroid medications +/- steroids +/- thyroidectomy.