Thyroid Disorders

Autoimmune (most common in iodine-sufficient US)

• Hashimoto thyroiditis: cytotoxic T-cell destruction of follicles with anti-TPO/anti-thyroglobulin antibodies — the leading cause of primary hypothyroidism in the United States
• Graves disease: stimulating TSH-receptor antibodies (TSI/TRAb) drive unregulated hormone synthesis; the same antibody family drives orbitopathy and pretibial myxedema
• Postpartum thyroiditis: lymphocytic thyroiditis 2–12 months after delivery, classically thyrotoxic → hypothyroid → recovery phases

Nodular/autonomous

• Toxic multinodular goiter and toxic adenoma: somatic activating mutations of the TSH receptor or Gsα produce TSH-independent hormone output; typical of older patients with long-standing goiter

Destructive/inflammatory

• Subacute granulomatous (de Quervain) thyroiditis: post-viral, painful gland, preformed hormone leaks out
• Riedel and infiltrative disease (IgG4-related fibrosis, sarcoid, hemochromatosis): fibrous or infiltrative replacement of parenchyma

Iatrogenic and drug-related (modifiable)

• Iodine excess: Jod-Basedow thyrotoxicosis in autonomous nodules; Wolff-Chaikoff escape failure causing hypothyroidism
• Amiodarone: type 1 (iodine-load hyperthyroidism) vs type 2 (destructive thyroiditis); also a common cause of hypothyroidism
• Lithium (blocks hormone release), interferon-α, tyrosine kinase inhibitors, and immune checkpoint inhibitors (thyroiditis)
• Thyroidectomy, radioactive iodine, external-beam neck radiation
• Factitious/exogenous levothyroxine use

Central

• Pituitary or hypothalamic disease (macroadenoma, Sheehan syndrome, craniopharyngioma, hypophysitis) causing secondary hypothyroidism

Non-modifiable risk factors examiners plant in the stem

• Female sex and age — autoimmune thyroid disease is several times more common in women
• Family history and HLA associations; personal or family history of other autoimmune disease (type 1 diabetes, celiac disease, vitiligo, pernicious anemia, Addison disease in autoimmune polyglandular syndrome type 2)
• Down syndrome and Turner syndrome — the American Academy of Pediatrics recommends periodic thyroid function screening in Down syndrome
• Pregnancy and the postpartum year

Modifiable

• Cigarette smoking — strongest modifiable risk factor for Graves orbitopathy and for its worsening after radioiodine
• Iodine intake extremes — deficiency remains the leading global cause of hypothyroidism and goiter

Hypothalamic-Pituitary-Thyroid Axis

• TRH (thyrotropin-releasing hormone) from the hypothalamus stimulates the anterior pituitary to release TSH (thyroid-stimulating hormone)
• TSH binds to receptors on thyroid follicular cells, stimulating synthesis and release of T4 (80%) and T3 (20%)
• T4 is peripherally converted to active T3 in target tissues by deiodinase enzymes
• Negative feedback: T3 and T4 inhibit TRH and TSH release; free (not total) hormone levels provide the regulatory signal
• This axis maintains tight homeostatic control of thyroid hormone levels with a set point at TSH of 0.5-5 mIU/L

Hormone Synthesis and Metabolism

• Thyroid peroxidase (TPO) catalyzes iodination of tyrosine residues on thyroglobulin to form mono- and di-iodotyrosine
• These iodinated residues couple to form T3 and T4 within thyroglobulin storage granules
• T4 is more stable and circulates longer (half-life 7 days) than T3 (half-life 1.5 days)
• Approximately 99% of T3 and T4 bound to thyroid-binding globulin (TBG), transthyretin, and albumin; only ~1% exists as biologically active free hormone
• D1 and D3 deiodinases catalyze conversion of T4→T3 (activation) and T4→rT3 or T3→T2 (inactivation); D2 is crucial in CNS and pituitary

Major Pathophysiologic Categories

Hypothyroidism Mechanisms

• Primary hypothyroidism (95% of cases): thyroid gland failure due to autoimmune destruction (Hashimoto thyroiditis—TPO and thyroglobulin antibodies), iodine deficiency, medications (lithium, amiodarone, PTU), radioactive iodine, thyroidectomy, or infiltrative disease (lymphoma, sarcoidosis)
• Secondary hypothyroidism: TSH deficiency from pituitary disease or hypothalamic dysfunction (TRH deficiency); TSH will be low or inappropriately normal
• In primary hypothyroidism, TSH rises as a compensatory response to falling free T4; TSH is the most sensitive marker of early disease

Hyperthyroidism Mechanisms

• Graves disease (70% of hyperthyroidism cases): autoimmune IgG antibodies bind and activate TSH receptors on thyroid cells, stimulating hormone synthesis and release independently of TSH
• Toxic multinodular goiter and toxic adenoma: autonomous thyroid tissue produces hormone without TSH stimulation
• Thyroiditis (acute phase): inflammatory destruction of follicles releases preformed hormone into circulation; TSH is suppressed, but thyroid cannot synthesize new hormone
• Exogenous thyroid hormone excess: iatrogenic or intentional overdose

Autoimmune Mechanisms (Hashimoto's and Graves')

• Loss of self-tolerance leads to T cell and B cell responses against TPO, thyroglobulin, and TSH receptor
• Infiltration of thyroid by CD4+ and CD8+ T cells and B cells producing pathogenic antibodies
• Hashimoto's characterized by Th1-mediated response and progressive destruction; Graves' characterized by Th2-mediated response with TSH receptor-activating antibodies
• Strong genetic predisposition (HLA-DR3, HLA-DR4 in Graves'; HLA-DR3, HLA-DR5 in Hashimoto's) with environmental triggers (infections, stress, pregnancy)

Hypothyroidism

• Constitutional symptoms: fatigue, lethargy, weakness, inability to tolerate cold, weight gain despite poor appetite, dry skin and hair, hair loss
• Neuropsychiatric: bradykinesia, slowed speech, depression, poor concentration, memory impairment, dementia in severe cases
• Metabolic: slowed gastrointestinal transit causing constipation, decreased heart rate (bradycardia), decreased blood pressure, decreased cardiac contractility
• Physical exam findings: myxedema (non-pitting edema from hyaluronic acid deposition in dermis and subcutaneous tissue affecting face, hands, and pretibial areas), thickened skin, husky voice, delayed deep tendon reflexes with prolonged relaxation phase ("hung-up" reflexes), macroglossia
• Goiter: may or may not be present depending on etiology; more common in Hashimoto's and iodine deficiency
• Menstrual abnormalities: menorrhagia, anovulation, infertility
• Myxedema coma: life-threatening presentation with severe hypothermia, altered mental status, seizures, bradycardia, hypoventilation; occurs with prolonged untreated severe hypothyroidism

Hyperthyroidism

• Constitutional symptoms: heat intolerance, excessive diaphoresis, weight loss despite increased appetite, nervousness, tremor, palpitations
• Cardiovascular: tachycardia at rest and with exertion, widened pulse pressure, systolic flow murmur, atrial fibrillation (risk increases with age and is a serious complication), increased contractility
• Neuropsychiatric: anxiety, irritability, insomnia, hyperreflexia, tremor (fine, rapid, best seen with hands outstretched), eye contact aversion, difficulty concentrating
• Gastrointestinal: hyperdefecation (not truly diarrhea, but increased frequency), nausea, weight loss
• Physical exam: warm, moist skin, lid lag and stare (from sympathetic overstimulation), tachycardia
• Graves disease-specific findings:
• Exophthalmos (proptosis): caused by lymphocytic infiltration and expansion of extraocular muscles and orbital fat; may cause compressive optic neuropathy or corneal ulceration (thyroid eye disease or Graves ophthalmopathy)
• Lid lag: eyelid fails to descend smoothly with downward gaze due to sympathetic stimulation of Müller muscle
• Pretibial myxedema: non-pitting edema over anterior shins (similar pathophysiology to hypothyroid myxedema but paradoxically occurs with hyperthyroidism)
• Thyroid acropachy: clubbing of fingers and toes (rare)
• Thyroid storm: life-threatening hypermetabolic state with high fever (>39°C), severe tachycardia, altered mental status, seizures, coma, precipitated by stress, infection, or abrupt iodine administration in untreated hyperthyroidism

Important Clinical Pearls

• Subclinical hypothyroidism: elevated TSH with normal free T4; many remain asymptomatic but progress at ~5% per year; treatment controversial but increasingly recommended, especially if TSH >10 or TPO antibodies present
• Subclinical hyperthyroidism: suppressed TSH with normal free T4; associated with atrial fibrillation risk and bone loss; should be treated if TSH <0.1 or symptoms present
• Symptoms of thyroid disease overlap significantly with psychiatric, cardiovascular, and metabolic disorders; TSH should be checked liberally in patients with compatible presentations
• Pregnancy considerations: both hyperthyroidism and hypothyroidism increase miscarriage and adverse fetal outcomes; TSH target is lower in pregnancy (0.1-2.5 mIU/L in first trim

Step 1 — screening test

• Serum TSH: the single most sensitive initial test because of the log-linear amplification of TSH in response to small free T4 changes. Order TSH first in any suspected thyroid disorder; the USPSTF gives an I statement (insufficient evidence) for screening asymptomatic nonpregnant adults, so testing is case-finding, not screening

Step 2 — free T4 (± total or free T3) to localize the lesion

• High TSH, low free T4: overt primary hypothyroidism
• High TSH, normal free T4: subclinical hypothyroidism
• Low/undetectable TSH, high free T4 or T3: overt thyrotoxicosis (T3 toxicosis if only T3 is elevated — think early Graves or toxic adenoma)
• Low or inappropriately normal TSH with low free T4: central hypothyroidism — image the pituitary and evaluate other axes
• High TSH with high free T4: think assay interference, TSH-secreting adenoma, or thyroid hormone resistance

Step 3 — establish etiology

• Anti-TPO antibodies: confirm Hashimoto thyroiditis and predict progression from subclinical to overt disease
• TRAb/TSI: confirms Graves when the diagnosis is not clinically obvious, and is the ATA-recommended test in pregnancy (transplacental antibody predicts fetal/neonatal Graves)
• Radioactive iodine uptake and scan (the classic discriminator when TRAb is unavailable or negative):
• Diffusely increased uptake — Graves
• Focal hot nodule with suppressed background — toxic adenoma; patchy — toxic multinodular goiter
• Near-zero uptake — thyroiditis, exogenous hormone, or iodine load. Distinguish with thyroglobulin: low in factitious ingestion, high in destructive thyroiditis
• Ultrasound with color Doppler: first-line for nodules and goiter, and separates amiodarone-induced thyrotoxicosis type 1 (increased vascularity) from type 2 (absent flow)

Nodule work-up

• Risk-stratify by ACR TI-RADS or the ATA sonographic pattern system, then FNA by size threshold; cytology is reported by the Bethesda System for Reporting Thyroid Cytopathology

Named scoring system

• Burch-Wartofsky Point Scale quantifies likelihood of thyroid storm (temperature, CNS, GI-hepatic, cardiovascular, atrial fibrillation, precipitant); storm is a clinical diagnosis, not a lab value

Immediate stabilization — thyroid storm (emergency, ATA 2016 sequence)

• Beta blocker: propranolol — controls adrenergic symptoms and partially blocks T4→T3 conversion; use esmolol if titration/reversal is needed
• Thionamide: propylthiouracil preferred in storm because it also inhibits peripheral deiodination
• Iodine (SSKI or Lugol solution) given at least one hour after the thionamide, exploiting the Wolff-Chaikoff effect to block hormone release; giving iodine first fuels new hormone synthesis
• Glucocorticoid: hydrocortisone — blocks T4→T3 conversion and covers relative adrenal insufficiency
• Cooling, volume resuscitation, and treatment of the precipitant. Avoid aspirin — it displaces T4 from TBG and raises free hormone

Immediate stabilization — myxedema coma (emergency)

• IV levothyroxine (some add liothyronine), with IV hydrocortisone given first or concurrently until adrenal insufficiency is excluded, plus passive rewarming and ventilatory support

Hypothyroidism, first-line

• Levothyroxine (T4) monotherapy is the ATA 2014 standard; combination T4/T3 and desiccated thyroid extract are not routinely recommended
• Take on an empty stomach, separated from calcium, iron, and PPIs; recheck TSH after about six weeks
• Start at low dose in the elderly and in coronary disease to avoid precipitating angina or arrhythmia
• In pregnancy, requirements rise — ATA 2017 advises an early dose increase and trimester-specific TSH targets

Hyperthyroidism, three definitive options (ATA 2016 — all acceptable, choice is shared)

• Thionamides: methimazole is first-line for nearly all patients; PTU is reserved for first-trimester pregnancy, storm, and methimazole intolerance because of its black-box hepatotoxicity
• Radioactive iodine ablation: convenient and definitive; contraindicated in pregnancy and lactation, and avoided in moderate-to-severe active Graves orbitopathy (may worsen it — steroid prophylaxis if used in smokers/mild eye disease)
• Total thyroidectomy: preferred for large compressive goiter, suspected malignancy, severe orbitopathy, or pregnancy failing medical therapy; pretreat with thionamide ± iodine to render euthyroid
• Adjunct beta blockers for symptom control in all thyrotoxicosis, including thyroiditis, which is otherwise self-limited and needs no thionamide

Emergencies

• Thyroid storm: decompensated thyrotoxicosis triggered by surgery, infection, parturition, or iodine load; fever, delirium, tachyarrhythmia, and high-output heart failure. Mortality is substantial even with treatment
• Myxedema coma: hypothermia, hypoventilation with CO2 retention, hyponatremia (impaired free-water excretion), bradycardia, and obtundation in a decompensated hypothyroid patient — frequently precipitated by cold exposure, sedatives, or infection

Complications of untreated hyperthyroidism

• Atrial fibrillation and thromboembolism: shortened atrial refractoriness and increased automaticity; the risk applies to subclinical disease as well and rises with age
• Osteoporosis and fragility fracture: thyroid hormone accelerates bone remodeling with net resorption
• Graves orbitopathy: retro-orbital glycosaminoglycan deposition; compressive optic neuropathy (loss of color vision, afferent pupillary defect) and corneal ulceration from exposure are sight-threatening emergencies
• Thyrotoxic periodic paralysis: intracellular potassium shift with sudden proximal weakness, classically in Asian men

Complications of untreated hypothyroidism

• Atherogenic dyslipidemia (reduced LDL-receptor expression), pericardial effusion, and reversible diastolic hypertension
• Obstetric: miscarriage, preeclampsia, preterm birth; untreated maternal/congenital hypothyroidism causes irreversible neurodevelopmental injury (cretinism) — the rationale for universal newborn screening
• Primary thyroid lymphoma: rare but classically arises in a Hashimoto gland that enlarges rapidly

Treatment-related

• Thionamide agranulocytosis: idiosyncratic; fever and sore throat mandate stopping the drug and obtaining a CBC with differential — do not simply treat as pharyngitis
• PTU hepatotoxicity (black-box, can be fulminant) and ANCA-associated vasculitis
• Methimazole embryopathy in first-trimester exposure (aplasia cutis, choanal/esophageal atresia)
• Post-thyroidectomy: recurrent laryngeal nerve injury (hoarseness; bilateral injury causes stridor), hypoparathyroidism with perioral numbness, Chvostek and Trousseau signs and prolonged QT, and expanding neck hematoma causing airway compromise
• Radioiodine: near-inevitable permanent hypothyroidism and possible worsening of orbitopathy
• Levothyroxine over-replacement: iatrogenic subclinical hyperthyroidism with atrial fibrillation and bone loss

• TSH is always the first step: in a stem describing fatigue, weight change, or new atrial fibrillation, the single best next step is a serum TSH, then free T4 to grade severity
• Low uptake thyrotoxicosis is the classic discriminator: thyrotoxic symptoms with near-zero radioiodine uptake means thyroiditis, exogenous hormone, or iodine load — never Graves. Add thyroglobulin: suppressed in factitious ingestion, elevated in destructive thyroiditis. The distractor is reflexively starting methimazole, which does nothing for released preformed hormone; give a beta blocker instead
• Order matters in thyroid storm: thionamide before iodine. Iodine given first supplies substrate and worsens the storm
• PTU only in three settings: first-trimester pregnancy, thyroid storm, and methimazole intolerance. Otherwise methimazole, because of PTU's black-box hepatotoxicity (ATA 2016). Remember the mirror trap — methimazole is the teratogen (aplasia cutis), PTU is the hepatotoxin
• Fever and sore throat on a thionamide = agranulocytosis until proven otherwise: stop the drug and get a CBC with differential. This is the most frequently tested drug-toxicity vignette in endocrinology
• Radioactive iodine is absolutely contraindicated in pregnancy and lactation, and is avoided in moderate-to-severe active Graves orbitopathy; smoking is the modifiable risk factor that worsens eye disease
• Hashimoto associations: anti-TPO antibodies, Hürthle cells and germinal centers on histology, other autoimmune disease, and rapid painless gland enlargement suggesting primary thyroid lymphoma
• Painful tender goiter after a viral URI with elevated ESR is subacute (de Quervain) thyroiditis — self-limited, treat with NSAIDs (glucocorticoids if severe), not thionamides
• In pregnancy, hCG cross-stimulates the TSH receptor and can suppress TSH physiologically in the first trimester; do not misread transient gestational thyrotoxicosis with hyperemesis as Graves — check TRAb and look for orbitopathy
• Myxedema coma: give hydrocortisone before or with levothyroxine; thyroid hormone alone can precipitate adrenal crisis