What is the pathophysiology, clinical presentation, diagnosis, and treatment of hyperthyroidism?

Hyperthyroidism: A Comprehensive Teaching Guide for Postgraduate Endocrinology

Pathophysiology

Hyperthyroidism results from excessive thyroid hormone synthesis, excessive release of preformed hormones, or extrathyroidal sources, with distinct mechanisms depending on the underlying etiology. 1

Mechanisms by Etiology

Graves' Disease (70% of cases):

• Autoantibodies bind to and stimulate the TSH receptor, causing sustained autonomous thyroid overactivity 2, 3
• These TSH-receptor antibodies drive continuous hormone production independent of normal feedback mechanisms 4
• Global prevalence: 2% in women, 0.5% in men 4

Toxic Nodular Goiter (16% of cases):

• Somatic activating gain-of-function mutations cause autonomous hyperfunctioning of localized thyroid areas 3, 5
• Includes both toxic multinodular goiter (TMNG) and toxic adenoma (TA) 5
• These nodules produce thyroid hormone independently of TSH stimulation 2

Destructive Thyroiditis (3% of cases):

• Passive release of preformed thyroid hormones from damaged follicles 1
• Includes subacute granulomatous thyroiditis and painless (silent) thyroiditis 3
• Clinical presentation mimics other causes despite different mechanism 1

Drug-Induced (9% of cases):

• Amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors 3
• Can cause either increased synthesis (type 1) or destructive release (type 2) 5

Cardiovascular Pathophysiology

The cardiovascular system undergoes profound changes:

• Decreased systemic vascular resistance with increased cardiac output 6, 7
• Tachycardia and potential pulmonary artery hypertension 6
• In severe, long-standing cases: heart failure despite typically increased contractility, particularly with persistent tachycardia or rapid atrial fibrillation 6, 7

Clinical Presentation

Cardinal Symptoms

Neuropsychiatric manifestations:

• Tremors, nervousness, anxiety, hyperactivity, and insomnia 6

Cardiovascular symptoms:

• Tachycardia, hypertension, palpitations 6
• Atrial fibrillation (more common in hyperthyroid patients) 6

Metabolic and dermatologic features:

• Excessive sweating, heat intolerance, hair loss 6
• Unintentional weight loss, diarrhea 4

Physical Examination Findings

Graves' Disease-specific signs:

• Diffusely enlarged thyroid gland (goiter) 6, 4
• Ophthalmopathy: stare or exophthalmos 4
• Thyroid bruit (diagnostic of Graves' disease, warrants early endocrine referral) 8
• Physical examination findings of ophthalmopathy are diagnostic and should prompt early endocrine referral 8

Toxic Nodular Disease:

• Symptoms from local compression: dysphagia, orthopnea, voice changes 4
• Palpable nodules on examination 4

High-Risk Populations Requiring Vigilant Screening

Screen aggressively in:

• Elderly patients 6
• Post-partum women 6
• Patients with high radiation exposure (>20 mGy) 6
• Patients with Down syndrome (symptoms may overlap with syndrome features) 6

Life-Threatening Complications

Thyroid storm:

• Rare but life-threatening emergency in untreated hyperthyroidism 6

Cardiovascular death:

• Chief cause of mortality after treatment, especially in patients over 50 years 6, 7

Pregnancy complications:

• Severe preeclampsia, preterm delivery, heart failure 6

Diagnosis

Initial Laboratory Approach

Measure serum TSH first—it has >98% sensitivity for detecting thyroid dysfunction. 6

Interpretation algorithm:

TSH <0.1 mIU/L (suppressed):

• Measure free T4 (FT4) and total T3 or free T3 to confirm diagnosis and determine severity 6
• Repeat measurement along with FT4 and T3 within 4 weeks 6
• If cardiac symptoms or arrhythmias present, test more urgently 6

TSH 0.1-0.45 mIU/L (low but not suppressed):

• May indicate subclinical hyperthyroidism 6
• Repeat for confirmation 6
• If patient has atrial fibrillation, cardiac disease, or serious medical conditions: repeat within 2 weeks 6
• Without risk factors: repeat within 3 months 6
• If TSH remains abnormal but stable: monitor at 3-12 month intervals 6

Establishing Etiology

After confirming biochemical hyperthyroidism, determine the underlying disease:

First-line tools:

• TSH-receptor antibodies (positive in Graves' disease) 3, 5
• Thyroid peroxidase antibodies 3
• Thyroid ultrasonography (size, vascularity, nodule characteristics) 3, 5

Consider TSH receptor antibody testing if clinical features suggest Graves' disease (ophthalmopathy, T3 toxicosis). 8

Thyroid scintigraphy indications:

• Recommended if thyroid nodules present or etiology unclear 4, 5
• Use radioiodine or 99mTc-pertechnetate 5

Specific scintigraphic patterns:

• Graves' disease: Diffusely increased uptake 5
• TMNG: Multiple areas of increased uptake with suppressed background 5
• Toxic adenoma: Single focus of increased uptake with suppressed background 5
• Destructive thyroiditis: Decreased or absent uptake 5

For amiodarone-induced hyperthyroidism:

• 99mTc-sestamibi scintigraphy differentiates type 1 from type 2 5

Radioiodine uptake test:

• Provides information for planning radioiodine therapy 5

Evaluating for Complications

Cardiovascular assessment:

• Screen for atrial fibrillation 6
• Evaluate for pulmonary artery hypertension and right ventricular dilatation 6
• Assess for heart failure in severe, long-standing cases 6

Bone health:

• Consider bone mineral density testing in postmenopausal women with prolonged subclinical hyperthyroidism (increased risk for bone loss) 6

Critical Pitfalls to Avoid

False positives:

• Severe non-thyroid illness can cause false positive TSH results 6

Prevalence considerations:

• Subclinical hyperthyroidism is more common than overt disease in primary care populations 6

Iodine-induced hyperthyroidism:

• Patients with known nodular thyroid disease may develop overt hyperthyroidism when exposed to excess iodine (radiographic contrast agents) 6

Treatment

Immediate Symptomatic Management

Initiate beta-blockers promptly in all patients to control heart rate, reduce tremors, and mitigate cardiovascular complications. 6, 7

Beta-blocker specifics:

• Use atenolol or propranolol 8, 6, 7
• Goal: lower heart rate to nearly normal 6, 7
• Improves tachycardia-mediated ventricular dysfunction 6, 7
• Provides rapid improvement in cardiac and neurological symptoms while definitive treatment takes effect 7

Definitive Treatment Options

Three recognized modalities exist: antithyroid drugs, radioactive iodine, and surgery—all effective but none offers absolute cure. 2

Treatment by Etiology

Graves' Disease:

Antithyroid drugs (methimazole or propylthiouracil):

• Prescribed for 12-18 months with view to inducing long-term remission 2, 3
• Recurrence occurs in approximately 50% after standard course 3
• Risk factors for recurrence: age <40 years, FT4 ≥40 pmol/L, TSH-binding inhibitory immunoglobulins >6 U/L, goiter size ≥WHO grade 2 3
• Long-term treatment (5-10 years) associated with fewer recurrences (15%) compared to short-term treatment 3
• Often given short-term to render patient euthyroid before radioiodine or thyroidectomy 2

Radioactive iodine ablation:

• Most widely used treatment in the United States 1
• Well tolerated; only long-term sequela is risk of radioiodine-induced hypothyroidism 2
• Goal in Graves' disease: induce hypothyroidism (readily treatable with thyroid hormone replacement) 5
• Can be used in all age groups except children 2
• Avoid in pregnancy and lactation; avoid pregnancy for 4 months post-administration 2
• May cause deterioration in Graves' ophthalmopathy; corticosteroid cover may reduce this risk 2
• Dosimetric estimates based on thyroid volume and radioiodine uptake guide 131I-activity selection 5

Surgery (subtotal or near-total thyroidectomy):

• Limited but specific roles 2
• Rarely used unless radioiodine refused or large goitre causing neck compression symptoms 2
• Goal: cure underlying pathology while leaving residual tissue to maintain euthyroidism 2

Toxic Nodular Goiter (TMNG and TA):

Radioiodine is the treatment of choice. 2, 5

• Goal: achieve euthyroid status (not hypothyroidism as in Graves') 5
• Antithyroid drugs will not cure toxic nodular goiter 2

Surgery:

• Alternative to radioiodine 2

Radiofrequency ablation:

• Rarely used 3

Destructive Thyroiditis:

Observation or supportive care for mild cases. 4

• Thyroiditis is self-limited; initial hyperthyroidism generally resolves in weeks with supportive care 8
• Most often progresses to primary hypothyroidism or occasionally returns to normal 8
• Beta-blockers for symptomatic relief 8
• Hydration and supportive care 8
• Steroids only in severe cases 3

Treatment by Severity (Immune Checkpoint Inhibitor-Induced Framework Applicable to All Causes)

Grade 1 (Asymptomatic or mild symptoms):

• Continue treatment if applicable 8
• Beta-blocker for symptomatic relief 8
• Close monitoring of thyroid function every 2-3 weeks to catch transition to hypothyroidism 8
• For persistent thyrotoxicosis (>6 weeks): endocrine consultation for additional workup 8

Grade 2 (Moderate symptoms, able to perform ADL):

• Consider holding causative treatment until symptoms return to baseline 8
• Endocrine consultation 8
• Beta-blocker for symptomatic relief 8
• Hydration and supportive care 8
• For persistent thyrotoxicosis (>6 weeks): refer to endocrinology for additional workup and possible medical thyroid suppression 8

Grade 3-4 (Severe symptoms, life-threatening, unable to perform ADL):

• Hold causative treatment until symptoms resolve 8
• Endocrine consultation for all patients 8
• Beta-blocker 8
• Hydration and supportive care 8
• Consider hospitalization; inpatient endocrine consultation can guide use of additional therapies including steroids, SSKI, or thionamide (methimazole or propylthiouracil) and possible surgery 8

Subclinical Hyperthyroidism

Treatment recommended for patients at highest risk of osteoporosis and cardiovascular disease:

• Age >65 years 4
• Persistent serum TSH <0.1 mIU/L 4

Special Populations

Pregnancy:

• Hyperthyroidism increases risk of severe preeclampsia, preterm delivery, heart failure 6
• Avoid radioiodine 2
• Use antithyroid drugs with caution (propylthiouracil preferred in first trimester) 2

Patients over 50 years:

• Prompt recognition and management of cardiac manifestations crucial (cardiovascular complications are chief cause of death) 6, 7

Persistent or symptomatic hypothyroidism developing after hyperthyroidism:

• Treat with thyroid hormone replacement 8

Treatment Side Effects

Radioiodine therapy:

• Early: typically mild thyroid pain (manage with NSAIDs) 5
• Delayed: hypothyroidism, minimal risk of radiation-induced malignancies 5

Prognosis and Mortality

Hyperthyroidism is associated with increased mortality. 4, 3

Prognosis may be improved by rapid and sustained control of hyperthyroidism. 3

Untreated hyperthyroidism causes:

• Cardiac arrhythmias, heart failure 4
• Osteoporosis 4
• Adverse pregnancy outcomes 4

Global prevalence:

• Overt hyperthyroidism: 0.2-1.4% worldwide 4
• Subclinical hyperthyroidism: 0.7-1.4% worldwide 4
• Overall affects 2.5% of adults worldwide 4