# Lecture 5: Thyroid Disorders
## Unit 2.3: Endocrine System
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Describe the clinical features and diagnosis of hypothyroidism
2. Explain Hashimoto's thyroiditis and other causes of hypothyroidism
3. Describe the clinical features and diagnosis of hyperthyroidism
4. Explain Graves' disease pathophysiology and management
5. Describe other causes of thyrotoxicosis
6. Explain thyroid emergencies including myxedema coma and thyroid storm
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## Lecture Outline
### I. Hypothyroidism - Overview
Hypothyroidism represents a clinical state of insufficient thyroid hormone action at the tissue level, affecting virtually every organ system in the body. Understanding the classification, causes, and laboratory patterns allows clinicians to accurately diagnose and appropriately treat this common endocrine disorder.
The classification of hypothyroidism depends on the anatomic level of dysfunction. Primary hypothyroidism accounts for approximately 95% of all cases and results from intrinsic dysfunction of the thyroid gland itself. Secondary hypothyroidism arises from pituitary TSH deficiency, while tertiary hypothyroidism stems from hypothalamic TRH deficiency. Secondary and tertiary forms are often grouped together as "central hypothyroidism." A rare fourth category, peripheral hypothyroidism, involves tissue resistance to thyroid hormone action despite adequate hormone production.
Epidemiologically, hypothyroidism affects 4-5% of adults, with subclinical disease being more common than overt hypothyroidism. Women are affected 5-10 times more frequently than men, and prevalence increases with advancing age. These demographic patterns reflect the autoimmune etiology of most cases in iodine-sufficient populations.
The causes of primary hypothyroidism vary geographically and include both destructive and inhibitory processes. In iodine-sufficient regions, Hashimoto's thyroiditis (chronic lymphocytic thyroiditis) represents the most common cause, while iodine deficiency remains the leading cause worldwide. Iatrogenic causes include thyroidectomy, radioiodine therapy for hyperthyroidism or thyroid cancer, and external beam radiation to the neck. Several medications can induce hypothyroidism, including lithium (which inhibits thyroid hormone release), amiodarone (through iodine excess or destructive thyroiditis), and tyrosine kinase inhibitors used in cancer therapy. Infiltrative diseases such as amyloidosis and sarcoidosis may rarely destroy enough thyroid tissue to cause hypothyroidism. Transient hypothyroidism follows destructive thyroiditis including subacute thyroiditis and postpartum thyroiditis. Congenital hypothyroidism results from thyroid dysgenesis or defects in hormone synthesis (dyshormonogenesis).
Laboratory findings distinguish primary from central hypothyroidism through characteristic patterns. In primary hypothyroidism, TSH is elevated due to loss of negative feedback, while free T4 is decreased. Free T3 may be decreased or initially preserved through increased peripheral T4-to-T3 conversion and preferential thyroidal T3 secretion. In secondary or tertiary hypothyroidism, both TSH and free T4 are low, with TSH being inappropriately normal or low for the degree of free T4 reduction.
Panel A: Classification flowchart dividing hypothyroidism into primary (95%, thyroid gland dysfunction), secondary (pituitary TSH deficiency), and tertiary (hypothalamic TRH deficiency) forms. Panel B: Causes of primary hypothyroidism organized by category including autoimmune (Hashimoto thyroiditis), iodine deficiency, iatrogenic (surgery, RAI, radiation), medications (lithium, amiodarone, TKIs), and congenital. Panel C: Laboratory pattern in primary hypothyroidism showing elevated TSH with low free T4 due to loss of negative feedback. Panel D: Laboratory pattern in central (secondary/tertiary) hypothyroidism showing low or inappropriately normal TSH with low free T4.
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### II. Hypothyroidism - Clinical Features
The clinical manifestations of hypothyroidism reflect the widespread metabolic slowing that occurs when thyroid hormone action is deficient. Symptoms develop insidiously, often over months to years, and may be attributed to aging or other conditions before the diagnosis is established.
General symptoms of hypothyroidism relate to decreased basal metabolic rate and tissue-specific effects. Fatigue is nearly universal and often the presenting complaint. Cold intolerance results from decreased thermogenesis, with patients describing the need for extra blankets or higher thermostat settings. Weight gain is typically modest, usually 5-10 pounds, and reflects fluid retention and decreased metabolic rate rather than true adiposity. Constipation develops from decreased gastrointestinal motility. Depression and other mood changes are common, as are cognitive slowing and memory difficulties. The skin becomes dry due to decreased sebaceous gland activity, and hair loss occurs, classically including the lateral third of the eyebrows (Queen Anne's sign).
Physical examination reveals characteristic signs of thyroid hormone deficiency. Bradycardia reflects decreased β-adrenergic responsiveness and direct effects on cardiac conduction. Delayed relaxation of deep tendon reflexes, particularly the ankle jerk, represents a classic finding where the relaxation phase is visibly prolonged. Periorbital edema and a puffy appearance result from accumulation of mucopolysaccharides (glycosaminoglycans) in subcutaneous tissues. This accumulation causes myxedema, the non-pitting edema characteristic of hypothyroidism, which differs from the pitting edema of heart failure or nephrotic syndrome. Macroglossia may develop from similar tissue infiltration. Hoarseness results from vocal cord edema. The thyroid may be enlarged (goiter) or atrophic depending on the underlying cause.
System-specific effects of hypothyroidism extend throughout the body. Cardiovascular manifestations include bradycardia, diastolic hypertension (from increased peripheral vascular resistance), and pericardial effusion, which rarely causes tamponade. Neurologic complications include carpal tunnel syndrome from tissue swelling and peripheral neuropathy. Musculoskeletal symptoms include myalgias and elevated creatine kinase, which may lead to misdiagnosis of primary muscle disease. Reproductive effects in women include menorrhagia (heavy menstrual bleeding) and infertility from anovulation. Metabolic consequences include hyperlipidemia (particularly elevated LDL cholesterol) and hyponatremia from impaired free water excretion.
The term myxedema specifically refers to the non-pitting edema caused by glycosaminoglycan accumulation in tissues. These hydrophilic molecules attract water, causing tissue swelling without the fluid mobility that characterizes pitting edema. Myxedematous changes affect the face, hands, and pretibial areas most prominently. In severe cases, myxedematous changes can affect all organs.
Panel A: Patient with characteristic hypothyroid features including periorbital puffiness, coarse hair, dull expression, bradycardia with low voltage ECG and prolonged QT, and delayed ankle reflex with extended relaxation phase. Panel B: Dermatologic and general manifestations including dry coarse skin, constipation, modest weight gain, and cold intolerance from decreased thermogenesis. Panel C: Non-pitting myxedema demonstration showing glycosaminoglycan accumulation in tissues contrasted with pitting edema of heart failure or nephrotic syndrome. Panel D: Systemic effects organized by organ system including cardiovascular (bradycardia, diastolic hypertension, pericardial effusion), neurologic (carpal tunnel, neuropathy), reproductive (menorrhagia, infertility), and metabolic (hyperlipidemia, hyponatremia).
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### III. Hashimoto's Thyroiditis
Hashimoto's thyroiditis (chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in iodine-sufficient populations and serves as the prototype of organ-specific autoimmune disease. Understanding its pathophysiology explains the clinical course and associated conditions.
The pathophysiology involves both humoral and cell-mediated autoimmune destruction of the thyroid gland. Antithyroid antibodies include anti-thyroid peroxidase (anti-TPO) antibodies, present in over 90% of patients, and anti-thyroglobulin (anti-Tg) antibodies, present in approximately 50%. While these antibodies are diagnostically useful, the primary destructive mechanism is T cell-mediated, with cytotoxic T lymphocytes directly attacking thyroid follicular cells. Histologically, the gland shows dense lymphocytic infiltration, germinal center formation, and Hürthle cell (oncocytic) metaplasia of the remaining follicular cells.
The clinical course of Hashimoto's thyroiditis typically progresses through phases. Early in the disease, some patients experience transient thyrotoxicosis (hashitoxicosis) as inflammatory destruction releases preformed thyroid hormone. This differs from true hyperthyroidism because the gland is not overproducing hormone. Progressive thyroid destruction leads to gradual hypothyroidism over months to years. The end stage may be either a goitrous form with a firm, rubbery, enlarged gland or an atrophic form with a small, fibrotic gland.
Hashimoto's thyroiditis associates with other autoimmune conditions, reflecting shared genetic susceptibility. Type 1 diabetes mellitus co-occurs frequently, as does celiac disease, which warrants consideration in patients with unexplained nutrient deficiencies. Pernicious anemia results from autoimmune gastritis affecting intrinsic factor production. Vitiligo reflects autoimmune melanocyte destruction. The combination of Hashimoto's thyroiditis and primary adrenal insufficiency (Addison's disease) constitutes Schmidt syndrome (autoimmune polyglandular syndrome type 2). These associations have important clinical implications for screening and monitoring.
Diagnosis of Hashimoto's thyroiditis relies on characteristic laboratory and imaging findings. TSH is elevated in overt hypothyroidism, while free T4 is decreased or normal (subclinical hypothyroidism). Anti-TPO antibodies are positive in over 90% of patients and represent the most sensitive serologic marker. Anti-thyroglobulin antibodies are positive in approximately 50%. Thyroid ultrasound characteristically shows a heterogeneous, hypoechoic echotexture reflecting lymphocytic infiltration and fibrosis.
Panel A: Autoimmune mechanism showing T lymphocytes and B cells attacking thyroid follicular cells, with anti-TPO and anti-Tg antibody production, where T cell-mediated destruction is the primary destructive mechanism. Panel B: Histologic features including dense lymphocytic infiltration, germinal center formation, and Hurthle cell (oncocytic) metaplasia of remaining follicular cells. Panel C: Clinical progression timeline from early hashitoxicosis (transient thyrotoxicosis from inflammatory destruction) through progressive hypothyroidism to end-stage goitrous or atrophic disease. Panel D: Diagnostic criteria showing elevated TSH with decreased or normal free T4, anti-TPO antibodies positive in >90%, anti-Tg in ~50%, and heterogeneous hypoechoic ultrasound appearance.
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### IV. Hypothyroidism Treatment
Treatment of hypothyroidism aims to restore euthyroidism through thyroid hormone replacement, with levothyroxine (synthetic T4) as the standard of care. Proper dosing, administration, and monitoring ensure optimal outcomes while avoiding complications.
Levothyroxine represents the treatment of choice for hypothyroidism replacement therapy. As synthetic thyroxine, it provides a stable substrate for peripheral conversion to the active hormone T3, mimicking normal physiology. The typical full replacement dose is approximately 1.6 μg/kg/day, though individual requirements vary based on lean body mass, residual thyroid function, and absorption. Consistent timing is essential, with administration on an empty stomach (ideally 30-60 minutes before breakfast) to ensure reliable absorption. Several medications and supplements decrease levothyroxine absorption, including calcium supplements, iron preparations, and proton pump inhibitors, necessitating separated dosing.
Dosing considerations vary by patient population. Young, otherwise healthy patients can often begin full replacement doses immediately. However, elderly patients should start with lower doses (25-50 μg daily) and titrate slowly to avoid precipitating cardiac events. Patients with known or suspected coronary artery disease require particularly cautious initiation with doses as low as 12.5-25 μg daily, as increased metabolic demand from thyroid hormone can unmask or exacerbate cardiac ischemia. Pregnant women require increased doses, typically 25-30% above pre-pregnancy requirements, beginning early in pregnancy to meet the increased demands of maternal and fetal metabolism.
Monitoring thyroid function guides dose adjustment. TSH represents the primary monitoring parameter for primary hypothyroidism, with a target within the normal reference range (approximately 0.4-4.0 mIU/L). TSH should be measured 6-8 weeks after any dose change, as this interval allows TSH to reach a new steady state. Once stable on an appropriate dose, annual TSH monitoring is typically sufficient.
Special situations require modified management approaches. Subclinical hypothyroidism (elevated TSH with normal free T4) does not always require treatment. Current guidelines suggest treatment when TSH exceeds 10 mIU/L, when symptoms are present, or during pregnancy. Central hypothyroidism requires monitoring free T4 rather than TSH, targeting the upper half of the normal reference range, since TSH cannot reliably indicate adequate replacement. Myxedema coma, a medical emergency, requires intravenous levothyroxine (loading dose 200-400 μg followed by 50-100 μg daily) along with stress-dose glucocorticoids until adrenal insufficiency is excluded.
Panel A: Levothyroxine dosing guidelines showing full replacement 1.6 mcg/kg/day, with starting doses by population (healthy adults full dose, elderly 25-50 mcg, cardiac disease 12.5-25 mcg, pregnancy requires 25-30% increase). Panel B: Administration requirements including empty stomach timing (30-60 minutes before breakfast) and drug interactions requiring separated dosing (calcium, iron, PPIs). Panel C: Monitoring guidelines with TSH target in normal range, recheck timing 6-8 weeks after dose change then annual when stable, and special consideration for central hypothyroidism where free T4 guides management. Panel D: Subclinical hypothyroidism treatment decision showing treatment indicated when TSH >10 mIU/L, symptoms present, or during pregnancy, with observation acceptable for mild elevation without symptoms.
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### V. Hyperthyroidism - Overview
Hyperthyroidism refers to overproduction of thyroid hormone by the thyroid gland, while the broader term thyrotoxicosis describes excess thyroid hormone from any source. This distinction has important implications for diagnosis and treatment, as the approach differs based on underlying etiology.
The causes of hyperthyroidism and thyrotoxicosis span several mechanisms. Graves' disease is the most common cause of hyperthyroidism, accounting for 70-80% of cases, and results from thyroid-stimulating antibodies that activate the TSH receptor. Toxic multinodular goiter occurs when autonomous nodules develop the capacity for independent hormone production, typically in the setting of longstanding iodine deficiency. A toxic adenoma (Plummer disease) represents a single autonomous nodule producing excess hormone. Thyroiditis causes thyrotoxicosis through release of preformed hormone from damaged follicular cells rather than overproduction—this is a destructive process distinct from true hyperthyroidism. Iodine-induced thyrotoxicosis (Jod-Basedow phenomenon) occurs when excess iodine triggers hormone production in a previously iodine-deficient gland with autonomous nodules. Exogenous thyrotoxicosis results from intentional or inadvertent thyroid hormone ingestion. Rare causes include TSH-secreting pituitary adenomas (characterized by elevated rather than suppressed TSH) and hCG-mediated thyrotoxicosis from gestational trophoblastic disease, where the structural similarity between hCG and TSH allows hCG to weakly stimulate the TSH receptor.
Laboratory findings help distinguish among the causes of thyrotoxicosis. In all forms of primary hyperthyroidism and thyrotoxicosis (except TSH-secreting adenoma), TSH is suppressed due to negative feedback. Free T4 and T3 are elevated. Radioactive iodine uptake (RAIU) provides critical diagnostic information: Graves' disease shows elevated diffuse uptake, toxic nodules show elevated focal uptake (hot nodules), while thyroiditis and exogenous thyrotoxicosis show low or absent uptake because the gland is either damaged or suppressed. The TSH-secreting adenoma uniquely shows elevated or inappropriately normal TSH with elevated thyroid hormones and elevated RAIU.
Panel A: Definition distinguishing hyperthyroidism (thyroid gland overproduction) from thyrotoxicosis (excess thyroid hormone from any source including exogenous or destructive processes). Panel B: Causes organized by mechanism including autoimmune (Graves disease 70-80%), autonomous (toxic MNG, toxic adenoma), destructive (thyroiditis), exogenous, and rare (TSH-secreting adenoma, hCG-mediated). Panel C: Thyroid scan patterns showing Graves disease (diffuse increased uptake), toxic nodule (focal hot nodule with suppressed background), and thyroiditis (absent uptake because gland cannot trap iodine). Panel D: Laboratory values for each condition showing TSH suppression in all primary forms except TSHoma, with elevated T4/T3, and RAIU distinguishing overproduction (elevated) from destruction (low/absent).
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### VI. Hyperthyroidism - Clinical Features
The clinical manifestations of hyperthyroidism reflect the widespread acceleration of metabolism and enhanced sensitivity to catecholamines. Symptoms typically develop over weeks to months, though presentation can be more acute with thyroid storm or more indolent in elderly patients.
General symptoms of hyperthyroidism relate to increased metabolic rate and sympathetic activation. Heat intolerance occurs due to increased thermogenesis, with patients preferring cooler environments. Weight loss despite increased appetite is characteristic, reflecting the caloric cost of hypermetabolism. Palpitations result from both increased heart rate and enhanced awareness of cardiac activity. A fine postural tremor affects the outstretched hands. Anxiety, irritability, and emotional lability reflect central nervous system effects. Increased sweating accompanies the elevated metabolic rate. Diarrhea or increased stool frequency results from enhanced gastrointestinal motility. Despite hyperactivity, fatigue is paradoxically common, possibly reflecting muscle catabolism or sleep disturbance.
Physical examination reveals characteristic signs of thyroid hormone excess. Resting tachycardia is typical, and atrial fibrillation develops in 10-15% of patients, particularly the elderly. A fine tremor is evident with arms extended and fingers spread. The skin is warm and moist due to increased peripheral blood flow and sweating. Hyperreflexia with brisk, quick deep tendon reflexes contrasts with the delayed relaxation of hypothyroidism. Lid lag describes the phenomenon where the upper eyelid fails to follow the eyeball during slow downward gaze, reflecting increased sympathetic tone to the levator palpebrae muscle. A thyroid stare results from similar sympathetic overactivity. Goiter characteristics vary by cause.
System-specific effects of hyperthyroidism affect multiple organs. Cardiovascular consequences include atrial fibrillation, high-output heart failure, and angina from increased myocardial oxygen demand. Neuromuscular effects include proximal myopathy with weakness and, rarely in Asian patients, thyrotoxic periodic paralysis. Bone effects include accelerated turnover leading to osteoporosis, with increased fracture risk in postmenopausal women. Reproductive manifestations include oligomenorrhea in women and gynecomastia in men from increased aromatization of androgens. Metabolic effects include glucose intolerance and mild hypercalcemia.
Panel A: Patient with characteristic hyperthyroid features including anxious expression, visible fine tremor at extended hands, perspiration, tachycardia (with potential AF on ECG), and lid lag during downward gaze. Panel B: General manifestations including heat intolerance, weight loss despite increased appetite, warm moist skin, and paradoxical fatigue despite hyperactivity. Panel C: Cardiovascular effects including atrial fibrillation (10-15% especially elderly), high-output heart failure, and angina from increased myocardial oxygen demand. Panel D: System-specific effects showing neuromuscular (proximal myopathy, thyrotoxic periodic paralysis), bone (osteoporosis from accelerated turnover), reproductive (oligomenorrhea in women, gynecomastia in men), and metabolic (glucose intolerance, mild hypercalcemia).
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### VII. Graves' Disease
Graves' disease is the most common cause of hyperthyroidism and represents an autoimmune disorder characterized by thyroid-stimulating antibodies. Understanding its unique pathophysiology explains the distinctive extra-thyroidal manifestations that distinguish it from other causes of hyperthyroidism.
The pathophysiology centers on autoantibodies against the TSH receptor (TRAb, also called thyroid-stimulating immunoglobulin or TSI). These antibodies bind to and activate the TSH receptor, triggering continuous stimulation of thyroid hormone synthesis and secretion independent of TSH. The elevated thyroid hormone levels suppress TSH through negative feedback, but the antibodies continue to stimulate the gland regardless of TSH suppression. The thyroid gland undergoes diffuse hyperplasia in response to the chronic stimulation.
Graves' disease is distinguished by three extra-thyroidal manifestations not seen in other causes of hyperthyroidism. Graves' ophthalmopathy (thyroid eye disease) results from TRAb cross-reacting with TSH receptors expressed on orbital fibroblasts, triggering inflammation and glycosaminoglycan deposition. Pretibial myxedema (thyroid dermopathy) involves similar glycosaminoglycan deposition in the skin, typically over the anterior shins, creating raised, waxy, orange-peel textured plaques. Thyroid acropachy, the rarest manifestation, produces digital clubbing and periosteal new bone formation.
Graves' ophthalmopathy affects the majority of patients with Graves' disease to varying degrees, though only 5-10% develop severe disease. Clinical features include proptosis (exophthalmos) from increased orbital contents, periorbital edema, lid retraction giving a startled appearance, and diplopia from extraocular muscle involvement. Exposure keratitis may develop when the lids cannot fully close, risking corneal damage. Optic neuropathy from compression represents a sight-threatening emergency requiring urgent intervention. The ophthalmopathy may precede, accompany, or follow the hyperthyroidism and does not always correlate with thyroid function status.
Diagnosis of Graves' disease relies on clinical and laboratory findings. TSH is markedly suppressed, and free T4 and T3 are elevated. TRAb is positive in over 95% of patients and provides diagnostic confirmation. Radioactive iodine uptake is elevated with diffuse, homogeneous uptake throughout the gland, distinguishing Graves' from nodular disease.
Panel A: Autoimmune mechanism showing B cells producing TSH receptor antibodies (TRAb/TSI) that bind and continuously activate the TSH receptor, causing thyroid stimulation independent of TSH with downstream Gs-cAMP signaling. Panel B: Graves ophthalmopathy showing orbital cross-section with enlarged extraocular muscles and increased retro-orbital fat from TRAb cross-reacting with orbital fibroblast TSH receptors, causing proptosis and lid retraction. Panel C: Pretibial myxedema showing waxy, raised plaques with orange-peel texture over anterior shins from glycosaminoglycan deposition, plus thyroid acropachy with digital clubbing and periosteal new bone formation. Panel D: Diagnostic criteria showing suppressed TSH with elevated T4/T3, TRAb positive in >95%, and diffuse homogeneous elevated radioactive iodine uptake pattern distinguishing from nodular disease.
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### VIII. Hyperthyroidism Treatment
Treatment of hyperthyroidism aims to normalize thyroid hormone levels and address the underlying cause. Three primary treatment modalities exist—antithyroid drugs, radioactive iodine, and surgery—with selection based on cause, patient factors, and preferences. Beta-blockers provide adjunctive symptomatic control.
The treatment options for hyperthyroidism each have distinct roles. Antithyroid drugs are often used first-line, particularly in young patients with Graves' disease, because they offer the possibility of remission without thyroid destruction. Radioactive iodine provides definitive treatment and is commonly used in the United States. Surgery is indicated for large goiters causing compressive symptoms, concurrent suspicious nodules, significant ophthalmopathy (where RAI may worsen eye disease), and in the second trimester of pregnancy when antithyroid drugs cannot be used or have failed. Beta-blockers control adrenergic symptoms while awaiting definitive treatment.
Antithyroid drugs (thionamides) include methimazole and propylthiouracil (PTU). Methimazole is preferred due to once-daily dosing, more favorable side effect profile, and more consistent potency. PTU is specifically indicated in the first trimester of pregnancy (due to lower teratogenicity) and in thyroid storm (because it additionally blocks peripheral T4-to-T3 conversion). Both drugs work primarily by inhibiting thyroid peroxidase, blocking the organification of iodine and coupling of iodotyrosines. Common side effects include rash and gastrointestinal upset. Serious complications include agranulocytosis (occurring in about 0.3% of patients) and hepatotoxicity, necessitating patient education about warning symptoms.
Radioactive iodine (I-131) therapy delivers targeted radiation to thyroid tissue, causing gradual destruction over weeks to months. Most patients eventually develop hypothyroidism requiring lifelong levothyroxine replacement. Contraindications include pregnancy, breastfeeding, and inability to follow radiation safety precautions. In patients with Graves' ophthalmopathy, RAI may worsen eye disease, and prophylactic glucocorticoids should be considered for those with mild-to-moderate active ophthalmopathy.
Thyroidectomy offers immediate, definitive treatment. Indications include large goiters, suspicious nodules, severe ophthalmopathy, pregnancy (second trimester), and patient preference. Complications include hypoparathyroidism from parathyroid gland injury and recurrent laryngeal nerve damage causing hoarseness or vocal cord paralysis.
Graves' ophthalmopathy treatment is graded by severity. Mild disease responds to supportive measures including artificial tears, sunglasses, and nighttime taping of lids. Moderate-to-severe active disease is treated with intravenous glucocorticoids or teprotumumab (an IGF-1 receptor inhibitor). Sight-threatening optic neuropathy requires urgent surgical decompression.
Panel A: Antithyroid drugs (thionamides) showing methimazole as preferred (once daily, better side effect profile) and PTU for first trimester pregnancy and thyroid storm, with TPO inhibition mechanism and warnings about agranulocytosis (0.3%) and hepatotoxicity. Panel B: Radioactive iodine (I-131) therapy showing targeted thyroid tissue destruction, most patients developing hypothyroidism requiring levothyroxine, and contraindications (pregnancy, breastfeeding) with ophthalmopathy considerations. Panel C: Thyroidectomy indications including large goiter, suspicious nodules, severe ophthalmopathy, pregnancy (second trimester), with risks of hypoparathyroidism and recurrent laryngeal nerve injury. Panel D: Graves ophthalmopathy management by severity showing mild (supportive with artificial tears, sunglasses), moderate-severe (IV glucocorticoids, teprotumumab), and sight-threatening optic neuropathy (urgent surgical decompression).
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### IX. Thyroiditis
Thyroiditis encompasses a group of inflammatory thyroid disorders with distinct etiologies and clinical courses. Understanding the different types allows appropriate diagnosis and management, particularly recognizing when antithyroid drugs are inappropriate because the gland is releasing stored hormone rather than overproducing.
The types of thyroiditis vary in presentation, duration, and outcome. Hashimoto's thyroiditis represents chronic autoimmune thyroiditis leading to eventual hypothyroidism. Subacute thyroiditis (de Quervain's or granulomatous thyroiditis) is a painful inflammatory condition typically following viral illness. Silent (painless) thyroiditis is an autoimmune variant causing transient thyrotoxicosis. Postpartum thyroiditis occurs 3-6 months after delivery with similar autoimmune pathophysiology. Drug-induced thyroiditis results from medications such as amiodarone and immune checkpoint inhibitors. Suppurative thyroiditis is a rare bacterial infection requiring drainage and antibiotics.
Subacute (de Quervain's) thyroiditis typically follows upper respiratory infection and presents with anterior neck pain that may radiate to the jaw or ears. The triphasic clinical course begins with a thyrotoxic phase lasting 2-8 weeks as inflammation releases stored thyroid hormone. Patients experience systemic symptoms including fever, fatigue, and myalgias along with typical thyrotoxic symptoms. Laboratory findings include markedly elevated ESR and CRP, suppressed TSH, elevated free T4, and very low radioactive iodine uptake (the inflamed gland cannot trap iodine). A hypothyroid phase of 4-8 weeks may follow as hormone stores are depleted before the gland recovers. Most patients eventually return to normal function. Treatment is supportive, with NSAIDs or glucocorticoids for pain, and beta-blockers for thyrotoxic symptoms. Antithyroid drugs are contraindicated because the gland is not overproducing hormone.
Postpartum thyroiditis affects 5-10% of pregnancies and shares autoimmune pathophysiology with Hashimoto's thyroiditis. Anti-TPO antibodies are often positive. The clinical course typically begins with thyrotoxicosis 1-4 months postpartum, followed by hypothyroidism at 4-8 months, with recovery by 12 months. However, 20-30% of affected women develop permanent hypothyroidism requiring ongoing levothyroxine. The condition recurs in subsequent pregnancies.
Amiodarone-induced thyroid disease deserves special attention given amiodarone's high iodine content and direct thyroid toxic effects. Two types of amiodarone-induced thyrotoxicosis (AIT) exist: Type 1 represents iodine-induced hyperthyroidism (Jod-Basedow effect) in patients with underlying thyroid abnormality, while Type 2 represents destructive thyroiditis from the drug's direct toxic effects. Distinguishing between types is often difficult but important for treatment selection. Amiodarone also commonly causes hypothyroidism, occurring more frequently than thyrotoxicosis.
Panel A: Thyroiditis comparison table showing type (subacute, silent, postpartum, drug-induced), cause (viral, autoimmune, medications), pain status (painful vs painless), duration, and radioactive iodine uptake pattern (low/absent in all destructive forms). Panel B: Subacute (de Quervain) thyroiditis triphasic course showing thyrotoxic phase (2-8 weeks with hormone release), hypothyroid phase (4-8 weeks with depleted stores), and recovery, with treatment being NSAIDs/steroids for pain and beta-blockers for symptoms (antithyroid drugs contraindicated). Panel C: Postpartum thyroiditis timeline showing thyrotoxicosis at 1-4 months postpartum, hypothyroidism at 4-8 months, recovery by 12 months (though 20-30% develop permanent hypothyroidism), with anti-TPO antibodies often positive. Panel D: Amiodarone-induced thyroid disease comparing Type 1 (iodine-induced hyperthyroidism in underlying thyroid abnormality) versus Type 2 (destructive thyroiditis from direct drug toxicity), with treatment implications for each type.
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### X. Thyroid Emergencies
Thyroid emergencies represent life-threatening extremes of thyroid dysfunction requiring immediate recognition and aggressive management. Myxedema coma and thyroid storm carry high mortality even with appropriate treatment.
Myxedema coma represents the end-stage of severe, decompensated hypothyroidism and constitutes a medical emergency. Despite the name, patients may not be comatose, and the term describes severe hypothyroidism with altered mental status. Precipitating factors include infection (most common), cold exposure, medications (sedatives, anesthetics), surgery, and trauma. The syndrome develops in patients with longstanding untreated or undertreated hypothyroidism who experience an additional physiologic stress. Mortality remains 30-60% even with treatment.
Clinical features of myxedema coma reflect severe metabolic depression. Hypothermia is characteristic, with core temperatures potentially below 35°C. Hypotension occurs due to decreased cardiac output and peripheral vasoconstriction. Hypoventilation leads to hypercapnia and respiratory acidosis. Hyponatremia results from impaired free water excretion and inappropriate ADH secretion. Altered mental status ranges from confusion to frank coma.
Treatment of myxedema coma requires simultaneous hormone replacement and supportive care. Intravenous levothyroxine is administered as a loading dose of 200-400 μg followed by 50-100 μg daily—oral medication cannot be reliably absorbed in this setting. Some protocols add intravenous T3 for more rapid effect, though this remains controversial. Stress-dose glucocorticoids (hydrocortisone 100 mg IV every 8 hours) are empirically administered until concomitant adrenal insufficiency is excluded, as hypothyroidism and adrenal insufficiency may coexist in autoimmune polyglandular syndrome. Supportive measures include passive rewarming (active rewarming can precipitate cardiovascular collapse), mechanical ventilation if needed, vasopressors for hypotension, and treatment of any precipitating illness.
Thyroid storm is a life-threatening exacerbation of thyrotoxicosis characterized by fever, cardiovascular decompensation, and altered mental status. Precipitating factors include surgery (particularly thyroid surgery in unprepared patients), infection, trauma, iodine load (contrast agents), and childbirth. Mortality ranges from 10-30% even with treatment.
Clinical features of thyroid storm include high fever (typically >104°F/40°C), marked tachycardia (often with atrial fibrillation), altered mental status (agitation, delirium, psychosis, coma), vomiting and diarrhea, and cardiovascular collapse. The Burch-Wartofsky point scale provides a scoring system for diagnosis, with scores above 45 highly suggestive of thyroid storm.
Treatment of thyroid storm employs multiple medications in a specific sequence. PTU is preferred over methimazole because it blocks both synthesis and peripheral T4-to-T3 conversion. Iodine (potassium iodide or Lugol's solution) is given one hour after PTU to block hormone release via the Wolff-Chaikoff effect—giving iodine first could paradoxically worsen thyrotoxicosis. Beta-blockers control adrenergic symptoms, with propranolol preferred because it also inhibits T4-to-T3 conversion. Glucocorticoids reduce T4-to-T3 conversion and provide adrenal support. Cooling measures address hyperthermia, and the precipitating factor must be identified and treated.
Panel A: Myxedema coma clinical features including hypothermia (<35C), hypotension, hypoventilation with hypercapnia, hyponatremia, and altered mental status, with precipitants (infection, cold exposure, sedatives, surgery). Panel B: Myxedema coma treatment protocol showing IV levothyroxine loading dose 200-400 mcg followed by 50-100 mcg daily, stress-dose hydrocortisone 100 mg IV q8h until adrenal insufficiency excluded, and supportive care (passive rewarming, mechanical ventilation, vasopressors). Panel C: Thyroid storm clinical features including high fever (>104F/40C), marked tachycardia with frequent AF, altered mental status, vomiting/diarrhea, and cardiovascular collapse, with Burch-Wartofsky scoring system. Panel D: Thyroid storm treatment sequence showing 1) PTU (blocks synthesis and peripheral conversion), 2) iodine one hour after PTU (blocks release), 3) beta-blocker preferably propranolol, 4) glucocorticoids, 5) cooling measures, 6) identify and treat precipitant.
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## Summary
Hypothyroidism is characterized by elevated TSH and decreased free T4, presenting with fatigue, cold intolerance, and weight gain. The most common cause in iodine-sufficient regions is Hashimoto's thyroiditis, an autoimmune disorder marked by anti-TPO antibodies and lymphocytic thyroid infiltration. Treatment with levothyroxine requires cautious initiation in elderly and cardiac patients with dose titration guided by TSH monitoring.
Hyperthyroidism presents with suppressed TSH and elevated free T4, manifesting as heat intolerance, weight loss, and palpitations. Graves' disease is the most common cause, characterized by TSH receptor antibodies and unique extra-thyroidal features including ophthalmopathy, pretibial myxedema, and acropachy. Treatment options include antithyroid drugs (with methimazole preferred except in first trimester pregnancy and thyroid storm), radioactive iodine, and surgery, with beta-blockers providing symptomatic relief.
Thyroiditis represents a group of inflammatory conditions causing transient thyrotoxicosis through hormone release rather than overproduction. Low radioactive iodine uptake distinguishes thyroiditis from true hyperthyroidism, and antithyroid drugs are contraindicated. Most forms are self-limited, though postpartum thyroiditis may progress to permanent hypothyroidism.
Thyroid emergencies require immediate recognition and treatment. Myxedema coma presents with hypothermia, hypotension, and altered mental status, treated with intravenous thyroid hormone and supportive care. Thyroid storm presents with high fever, marked tachycardia, and altered mental status, treated with a specific sequence of PTU, iodine, beta-blockers, and glucocorticoids.
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## Key Terms
| Term | Definition |
|------|------------|
| Hashimoto's thyroiditis | Autoimmune destruction of the thyroid gland characterized by lymphocytic infiltration and antithyroid antibodies |
| Graves' disease | Autoimmune hyperthyroidism caused by TSH receptor-stimulating antibodies |
| Thyrotoxicosis | Clinical syndrome of excess thyroid hormone from any cause |
| TRAb | TSH receptor antibodies; also called thyroid-stimulating immunoglobulin (TSI) |
| Thionamides | Antithyroid drugs (methimazole, propylthiouracil) that inhibit thyroid hormone synthesis |
| Radioactive iodine | I-131 therapy that destroys thyroid tissue for definitive treatment of hyperthyroidism |
| Myxedema coma | Life-threatening decompensated hypothyroidism with altered mental status |
| Thyroid storm | Life-threatening exacerbation of thyrotoxicosis with fever and cardiovascular decompensation |
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