Hypothyroidism

• Primary thyroid dysfunction and TSH feedback dysregulation: The thyroid gland produces thyroid hormones through iodine incorporation into tyrosine residues within thyroglobulin, catalyzed by thyroid peroxidase (TPO). T4 (80% of secretion) is then peripherally converted to the more biologically active T3 by deiodinases. When thyroid hormone production declines, the anterior pituitary responds to decreased negative feedback from free T4 and T3 by increasing TSH secretion—hence, markedly elevated TSH (typically >10 mIU/L) is the hallmark of primary hypothyroidism. This compensatory mechanism initially maintains near-normal hormone levels (subclinical hypothyroidism, where TSH is elevated but free T4 remains normal) but eventually decompensates as thyroid reserve diminishes, leading to overt hypothyroidism with elevated TSH and low free T4.

• Autoimmune destruction and chronic thyroiditis: In Hashimoto's thyroiditis (chronic autoimmune thyroiditis), the most common cause of hypothyroidism in iodine-sufficient areas, autoreactive T cells and B cells progressively infiltrate the thyroid, generating anti-TPO antibodies and anti-thyroglobulin antibodies that directly target critical enzymes and antigens involved in hormone synthesis and release. This lymphocytic infiltration gradually destroys thyroid follicles, reducing functional thyroid tissue volume and hormone-secreting capacity. The disease follows a chronic course with progressive fibrosis and replacement of glandular tissue by fibrous tissue, ultimately resulting in significant reduction in thyroid hormone synthesis. Genetic predisposition (HLA-DR3 and HLA-DR5 associations) combined with environmental triggers (infections, medications, radiation) initiates and perpetuates the autoimmune process.

• Metabolic consequences of thyroid hormone deficiency: Thyroid hormones are fundamental regulators of aerobic metabolism and mitochondrial oxidative phosphorylation through thyroid hormone receptors (TRα and TRβ) on nuclear DNA. Deficiency of these hormones causes a generalized decrease in basal metabolic rate, reducing energy expenditure, oxygen consumption, and heat production. At the cellular level, reduced T3-mediated activation of genes encoding enzymes in oxidative metabolism (such as cytochrome c oxidase, ATP synthase) and mitochondrial proteins decreases overall thermogenesis. This explains the cardinal manifestations of cold intolerance, fatigue, and weight gain. Additionally, impaired sympathetic nervous system responsiveness to catecholamines (due to reduced expression of β-adrenergic receptors on target tissues in the setting of low T3) manifests clinically as bradycardia, decreased cardiac contractility, and reduced peripheral vasoconstriction.

• Effects on lipid metabolism and cardiovascular function: Thyroid hormone promotes cholesterol catabolism and LDL receptor expression on hepatocytes; deficiency leads to accumulation of cholesterol and LDL particles, increasing atherogenic dyslipidemia. At the myocardial level, reduced T3 signaling decreases expression of sarcoplasmic reticulum calcium-ATPase (SERCA2a), impairing myocardial contractility and slowing both systolic and diastolic function. Diastolic dysfunction is particularly prominent, with prolonged isovolumetric relaxation time and reduced early diastolic filling. Reduced sympathetic tone decreases heart rate and cardiac output, contributing to diastolic dysfunction and reduced tissue perfusion. These cardiac effects increase risk of heart failure, especially in elderly patients with underlying coronary artery disease, and explain why hypothyroidism increases cardiovascular mortality 1.5- to 2-fold.

• Neuromuscular and cognitive dysfunction mechanisms: Thyroid hormones regulate synaptic plasticity, neurotransmitter synthesis, and myelination in the central and peripheral nervous systems. T3 deficiency impairs hippocampal long-term potentiation, reduces synthesis of dopamine and norepinephrine, and slows neuronal conduction velocity, manifesting clinically as cognitive slowing, depression, memory impairment, and delayed deep tendon reflexes with prolonged relaxation phase. In severe hypothyroidism, accumulation of glycosaminoglycans (hyaluronic acid and chondroitin sulfate) in interstitial spaces increases tissue edema and contributes to myxedema, the pathognomonic puffy, nonpitting edema of face, hands, and pretibial areas.

• Secondary/tertiary hypothyroidism mechanisms: When pituitary (secondary) or hypothalamic (tertiary) dysfunction reduces TSH secretion or thyrotropin-releasing hormone (TRH) production, respectively, thyroid hormone synthesis declines despite intact thyroid gland function. In these conditions, TSH levels are inappropriately low or normal (rather than markedly elevated), a critical diagnostic distinction. Central hypothyroidism accounts for <5% of cases but is clinically important because TSH cannot be reliably used to assess adequacy of replacement therapy in these patients.

• Hashimoto's thyroiditis (chronic autoimmune thyroiditis): Accounts for 90% of hypothyroidism in iodine-sufficient regions. Characterized by progressive autoimmune destruction of the thyroid gland. Strong female predominance (5-8:1); increased incidence in those with family history of autoimmune thyroiditis or other autoimmune conditions (type 1 diabetes, celiac disease, rheumatoid arthritis, lupus). Presents in subclinical form for years before progressing to overt hypothyroidism. Anti-TPO and anti-thyroglobulin antibodies are diagnostic but not pathogenic.

• Iodine deficiency: Leading preventable cause of hypothyroidism worldwide; endemic in areas with insufficient dietary iodine intake (parts of Africa, Southeast Asia, South America, Europe). Iodine is essential for thyroid hormone synthesis; deficiency leads to impaired T4 and T3 production despite adequate thyroid tissue mass initially (goitrous hypothyroidism). Can cause cretinism (severe developmental delay) if unaddressed in pregnancy and early childhood.

• Medications: Amiodarone (contains high iodine content; induces both hypothyroidism and hyperthyroidism via type I and II amiodarone-induced thyroiditis), propranolol (reduces T4-to-T3 conversion), interferon-alpha (triggers autoimmune thyroiditis), interleukin-2, lithium (inhibits thyroid hormone release and may trigger autoimmune thyroiditis), thionamides (PTU, methimazole; intentional suppression in hyperthyroidism), radioactive iodine (ablative), contrast agents (iodinated radiographic contrast), tyrosine kinase inhibitors (sunitinib, sorafenib), corticosteroids (high-dose, through multiple mechanisms). Risk increases with duration and cumulative dose.

• Thyroidectomy and radioactive iodine ablation: Intentional or accidental destruction of thyroid tissue. Radioactive iodine ablation is standard treatment for Graves' disease and toxic nodules; hypothyroidism develops in approximately 80% of patients by 10 years post-ablation. Partial thyroidectomy for goiter or malignancy may also result in insufficient remaining tissue to maintain euthyroid state.

• Thyroid infiltrative diseases: Sarcoidosis, amyloidosis, hemochromatosis, cystinosis, infiltrative lymphoma: rare but important causes. Infiltrating disease progressively destroys functional thyroid parenchyma. Hemochromatosis causes hypothyroidism through iron deposition in thyroid follicles and potential concurrent pituitary involvement.

• Radiation: External beam radiation to neck or mediastinum (prior malignancy treatment, lymphoma), radioactive iodine ablation. Damage to thyroid follicular cells is dose-dependent; higher doses increase risk and accelerate onset.

• Congenital hypothyroidism: Results from thyroid dysgenesis (aplasia, hypoplasia, ectopia; ~85% of congenital cases), dyshormonogenesis (defects in TPO, thyroglobulin synthesis, iodine transport; ~10-15%), or TSH receptor mutations. Congenital hypothyroidism occurs in ~1 in 2,000-4,000 live births and is detected through newborn screening programs (elevated TSH or low T4 on dried blood spots). Early detection and treatment prevent intellectual disability (formerly "cretinism").

• Central hypothyroidism (secondary/tertiary): Pituitary adenomas, pituitary surgery or radiation, hypophysitis, hypothalamic dysfunction (from tumors, CNS lymphoma, granulomatous diseases, trauma), genetic mutations affecting TSH or TRH synthesis or signaling. Accounts for <5% of hypothyroidism; TSH is low or inappropriately normal with low free T4.

• Genetic mutations: Rare autosomal recessive mutations in genes encoding TSHB (TSH-β subunit), TRHR (TRH receptor), PAX8, TSHR (TSH receptor), or thyroid peroxidase cause congenital hypothyroidism with variable inheritance patterns.

• Risk factors enhancing progression from subclinical to overt hypothyroidism: Female sex, advanced age, presence of anti-TPO antibodies (strongest predictor), baseline TSH >10 mIU/L, higher antibody titers. Approximately 2-5% of patients with subclinical hypothyroidism progress to overt disease annually if antibody-positive.

Cardinal manifestations reflect generalized reduction in metabolic rate, impaired thermogenesis, altered sympathetic responsiveness, and reduced cardiovascular output.

• Fatigue and weakness: Nearly universal symptom; results from decreased ATP production, mitochondrial dysfunction, and altered neurotransmitter metabolism (reduced dopamine, norepinephrine). Fatigue is often disproportionate to objective findings and improves dramatically with thyroid hormone replacement, distinguishing it from depression or systemic disease. Weakness is typically generalized, proximal, and associated with muscle stiffness (elevated creatine kinase occasionally present, leading to misdiagnosis as myositis).

• Cold intolerance: Highly characteristic; patient reports unusual sensitivity to cold environments despite normal ambient temperature perception in others. Reflects reduced non-shivering thermogenesis and decreased metabolic heat production. Often accompanied by request for extra blankets and heavy clothing.

• Weight gain and reduced appetite paradoxically coexisting: Despite reduced caloric intake, patients gain weight because basal metabolic rate decreases more dramatically than energy consumption; fat accumulation predominates. Some patients report anorexia, while others complain of increased appetite but still gain weight.

• Bradycardia and reduced cardiac output: Reflects reduced β-adrenergic responsiveness and decreased myocardial contractility. Resting heart rate often <60 bpm; exercise-induced tachycardia is blunted. May present as reduced exercise tolerance or dyspnea on exertion. Diastolic dysfunction is prominent; systolic dysfunction develops in severe/longstanding disease.

• Cognitive slowing, depression, and psychiatric manifestations: Patient reports difficulty concentrating, slowed thinking, memory impairment, and poor decision-making ability. Depression is common (present in 40% of patients) and may dominate clinical presentation, particularly in women and elderly patients. Psychosis ("myxedema madness") occurs rarely in severe, untreated disease. Cognitive symptoms are reversible with adequate replacement therapy, distinguishing them from primary psychiatric illness.

• Constipation: Results from reduced gastrointestinal motility secondary to decreased catecholamine responsiveness and metabolic slowdown. Often severe; may lead to functional obstruction in elderly patients if untreated. Responds promptly to thyroid hormone replacement.

• Hoarseness and voice deepening: Caused by vocal cord edema from myxedema; voice becomes coarse and hoarse. Results from glycosaminoglycan accumulation in tissues including laryngeal tissues. Resolves with treatment.

• Myxedema (nonpitting edema): Pathognomonic finding in moderate to severe hypothyroidism. Accumulation of hyaluronic acid and chondroitin sulfate in dermal and subcutaneous tissues produces characteristic puffy, thickened appearance of face (periorbital puffiness, broadened nose, thickened lips, macroglossia), hands, feet, and pretibial areas. Edema is nonpitting, does not blanch with pressure, and is typically accompanied by cool, dry, rough skin. More prominent in morning and decreases throughout day with gravity effects. Resolves slowly over weeks to months with thyroid hormone replacement.

• Dry skin and hair changes: Reduced sebaceous gland activity and increased keratinization produce dry, rough, cool skin with reduced sweating capacity. Hair becomes coarse, brittle, and sparse, with loss of outer one-third of eyebrows (loss of lateral eyebrows—highly characteristic). Nail growth slows; nails become brittle and develop horizontal ridges (Beau's lines).

• Hypertension: Occurs in 20-30% of hypothyroid patients; mechanism involves increased peripheral vascular resistance and increased systemic vascular resistance despite reduced cardiac output. Diastolic hypertension predominates. Hypertension may improve partially or completely with thyroid hormone replacement, particularly in newly diagnosed hypothyroidism.

• Menstrual abnormalities: Anovulation and prolonged cycles are common in premenopausal women due to altered GnRH pulsatility and impaired FSH responsiveness. Menorrhagia (heavy menstrual bleeding) occurs due to alteration in coagulation factors. Infertility may result from anovulation.

• Delayed relaxation phase of deep tendon reflexes: Highly characteristic physical exam finding. Ankle jerks demonstrate prolonged relaxation phase (slow return to baseline after contraction), which can be quantified by measuring reflex relaxation time (normal <400 ms; prolonged in hypothyroidism). This reflects slowed muscle relaxation due to impaired calcium reuptake by sarcoplasmic reticulum.

• Physical exam findings of myxedema: Puffy, expressionless face with periorbital edema, broadened nose, thickened lips, and macroglossia. Skin is cool (due to decreased peripheral blood flow), dry, rough, and may be scaly. Loss of lateral eyebrows is characteristic. Hands and feet are swollen, cool, and may appear cyanotic. Ascites may develop in severe cases. General demeanor reflects cognitive slowing: delayed speech, poverty of thought, decreased spontaneity.

• Important clinical variants and presentations: (1) Subclinical hypothyroidism: Elevated TSH with normal free T4; asymptomatic or with minimal symptoms. Risk factors for progression to overt disease include anti-TPO antibody positivity and higher baseline TSH. Treatment is debated but increasingly recommended in symptomatic patients, those >65 years, or those with TSH >10 mIU/L. (2) Hypothyroidism in elderly patients: Presentation is often atypical and subtle; fatigue and cognitive slowing may be attributed to aging or dementia rather than thyroid disease. Cardiovascular manifestations (heart failure exacerbation, atrial fibrillation worsening, angina) may be the presenting sign. Sensitivity to thyroid hormone replacement is increased; risk of iatrogenic hyperthyroidism and associated atrial fibrillation is higher. (3) Myxedema coma: Severe, life-threatening form of hypothyroidism (discussed in COMPLICATIONS section); presents with altered mental status, severe hypothermia, hypoventilation, and hypot

Step 1 — screening test

• Serum TSH: the single most sensitive initial test for suspected primary hypothyroidism, because the log-linear pituitary response amplifies small decrements in free T4 into large TSH changes. The American Thyroid Association (ATA) and AACE endorse TSH as the first-line test in ambulatory patients with intact pituitary function.

Step 2 — confirm and localize

• Free T4: added whenever TSH is abnormal, or ordered with TSH from the outset when central disease is suspected (known pituitary disease, other hormone deficiencies, visual field loss).
• Overt primary hypothyroidism: an elevated TSH of any magnitude together with a low free T4. Many patients present with TSH above 10 mIU/L, but that figure is not a diagnostic requirement — it is the threshold used to decide on treating subclinical disease. A TSH of 7 mIU/L with a frankly low free T4 is still overt hypothyroidism.
• Subclinical hypothyroidism: TSH elevated, free T4 normal; persistence above 10 mIU/L on repeat testing is the value that drives the ATA/AACE treatment recommendation.
• Central (secondary/tertiary): free T4 low with TSH low or inappropriately normal — the trap is a "normal" TSH. Pursue pituitary MRI and screen the other axes, especially cortisol.
• **Nonthyroidal illness (euthyroid sick syndrome)**: low T3, variable TSH, elevated reverse T3 in a hospitalized patient — defer testing until recovery.
• Total T3 is not useful for diagnosing hypothyroidism; it is preserved until late by preferential T3 secretion and deiodinase upregulation.

Step 3 — establish etiology

• Anti-TPO antibodies: confirm Hashimoto's thyroiditis and predict progression from subclinical to overt disease. Ultrasound is not required for diagnosis and is reserved for nodule or compressive symptoms.

Supporting laboratory findings

• Hyponatremia (impaired free-water excretion), elevated creatine kinase (myopathy), hypercholesterolemia/high LDL (reduced hepatic LDL-receptor expression), macrocytic anemia, and hyperprolactinemia from TRH-driven lactotroph stimulation.

Special settings

• Newborn screening: mandatory US dried-blood-spot TSH/T4 testing; treatment must begin within the first weeks of life to preserve neurodevelopment.
• Myxedema coma is a clinical diagnosis made at the bedside; the Popoveniuc diagnostic score (thermoregulatory, CNS, cardiovascular, GI, metabolic components plus a precipitant) is sometimes cited, but treatment must never await confirmatory labs.

Immediate stabilization (myxedema coma — emergency)

• IV levothyroxine (loading dose then daily maintenance), with some centers adding liothyronine (T3) given impaired peripheral deiodination in critical illness.
• Empiric IV glucocorticoid (hydrocortisone) before or with thyroid hormone, because unrecognized coexisting adrenal insufficiency plus accelerated cortisol clearance precipitates adrenal crisis.
• Supportive ICU care: passive external rewarming (active rewarming causes vasodilatory collapse), ventilatory support for CO₂ retention, cautious free-water restriction for hyponatremia, and treatment of the precipitant (infection, cold exposure, sedatives).

First-line therapy (outpatient)

• Levothyroxine (synthetic T4) is the treatment of choice per the ATA; its long half-life allows once-daily dosing and stable T3 generation via peripheral deiodinases. Full replacement in healthy adults is approximately 1.6 mcg/kg/day.
• Start low and titrate — roughly 12.5–25 mcg/day — in the elderly and in known coronary disease, since abrupt restoration of metabolic rate and β-adrenergic sensitivity can unmask angina or arrhythmia.
• Administration counseling: empty stomach, 30–60 minutes before food; separate dosing from coffee, soy products, calcium, iron, PPIs, and bile-acid sequestrants, all of which reduce absorption or bioavailability.
• Malabsorption raises the requirement: celiac disease (frequently coexisting, given the shared autoimmune predisposition noted earlier), atrophic gastritis/H. pylori-related hypochlorhydria, and bariatric surgery all reduce levothyroxine absorption — reconsider these when the dose needed seems unexpectedly high or TSH will not normalize.
• Recheck TSH in about 6–8 weeks after any dose change (the pituitary-thyroid axis needs that long to re-equilibrate), then annually.

Special populations and escalation

• Pregnancy: requirements rise early; ATA recommends increasing the pre-pregnancy dose (commonly by about 30%) as soon as pregnancy is confirmed, with trimester-specific TSH targets. Levothyroxine is safe and mandatory — untreated maternal hypothyroidism impairs fetal neurodevelopment.
• Central hypothyroidism: titrate to free T4 in the upper-normal range, not TSH, and always exclude/treat adrenal insufficiency first.
• Subclinical disease: ATA/AACE favor treating when TSH is persistently >10 mIU/L; individualize for lower values based on symptoms, anti-TPO positivity, pregnancy, or young age.

Not recommended

• Desiccated thyroid extract and routine T4/T3 combination therapy are not endorsed by the ATA (supraphysiologic T3 peaks, unstable ratios).
• Levothyroxine for obesity or fatigue in euthyroid patients — iatrogenic thyrotoxicosis without benefit.

Emergencies

• Myxedema coma: decompensated severe hypothyroidism, usually in an elderly woman with an infection, cold exposure, or sedative/opioid exposure. Mechanism is failure of thermogenesis plus blunted hypoxic/hypercapnic ventilatory drive. Signaled by hypothermia, altered mental status, hypoventilation with hypercapnia, hypotension, bradycardia, and hyponatremia. High mortality; treat empirically.
• Adrenal crisis after starting levothyroxine: thyroid hormone accelerates hepatic cortisol clearance; in undiagnosed adrenal insufficiency (e.g., polyglandular autoimmune syndrome type 2, hypopituitarism) this precipitates hypotension and shock. Give glucocorticoid first when coexisting adrenal disease is possible.
• Precipitation of angina or MI: restoring metabolic demand and heart rate in a patient with fixed coronary stenoses. Signaled by new chest pain during dose escalation — slow the titration.

Disease complications

• Atherogenic dyslipidemia and accelerated atherosclerosis: reduced hepatic LDL-receptor expression raises LDL; hypothyroidism should be excluded before labeling a hyperlipidemia as primary.
• Diastolic dysfunction, heart failure, and pericardial effusion: impaired SERCA2a-mediated calcium reuptake plus glycosaminoglycan-rich effusion; low-voltage ECG and enlarged cardiac silhouette are clues. Tamponade is rare because the effusion accumulates slowly.
• Obstetric and fetal complications: anovulatory infertility, miscarriage, preeclampsia, and — in untreated maternal or congenital disease — irreversible intellectual disability (cretinism).
• Neuromuscular: hypothyroid myopathy with elevated CK, carpal tunnel syndrome and other entrapment neuropathies from mucopolysaccharide deposition, and obstructive sleep apnea from macroglossia.
• Hyponatremia from impaired free-water clearance; megacolon/adynamic ileus from GI hypomotility.
• Pituitary thyrotroph hyperplasia with hyperprolactinemia: chronic TRH drive can enlarge the sella and cause galactorrhea, mimicking a prolactinoma — it regresses with levothyroxine.
• Primary thyroid lymphoma: rare but the classic association with long-standing Hashimoto's; suspect with a rapidly enlarging goiter.

Overtreatment complications

• Iatrogenic thyrotoxicosis (suppressed TSH): atrial fibrillation, especially in the elderly, and accelerated bone loss/osteoporosis in postmenopausal women.

• TSH is the single best next step in any stem with fatigue, cold intolerance, weight gain, constipation, or unexplained hyperlipidemia. Add free T4 only to confirm and to stage overt versus subclinical disease.
• A low free T4 with a "normal" TSH is central hypothyroidism, not a normal thyroid. The examiners' follow-up is pituitary MRI plus assessment of the other axes — and never titrating replacement by TSH in these patients.
• Delayed relaxation phase of the ankle reflex and loss of the lateral third of the eyebrows are the two physical-exam buzzwords; anti-TPO antibodies are the serologic buzzword for Hashimoto's.
• Give hydrocortisone before (or with) levothyroxine whenever adrenal insufficiency is possible — in myxedema coma and in hypopituitarism. This is the most commonly tested sequencing question in the topic.
• In pregnancy, increase the levothyroxine dose promptly (ATA guidance); the distractor is holding or lowering therapy out of misplaced fetal-safety concern. Maternal T4 crosses the placenta and is essential for fetal neurodevelopment in the first trimester, before the fetal thyroid is functional; TSH does not cross. Levothyroxine is safe in pregnancy and the dose should be increased promptly (~30%, often operationalized as two extra tablets per week) once pregnancy is confirmed.
• Start low in the elderly and in coronary disease (12.5–25 mcg/day). The classic vignette is new angina or atrial fibrillation after full weight-based replacement was started in an 80-year-old.
• Suppressed TSH on therapy = overtreatment, and the harms tested are atrial fibrillation and osteoporosis, not symptom relief.
• Recheck TSH at about 6–8 weeks after a dose change — rechecking at 1–2 weeks is a favorite wrong answer because the axis has not re-equilibrated.
• Distractors to avoid: ordering T3 to diagnose hypothyroidism; treating euthyroid sick syndrome in an ICU patient; prescribing desiccated thyroid or T4/T3 combinations, which the ATA does not endorse; and attributing a rapidly enlarging goiter in Hashimoto's to worsening thyroiditis rather than primary thyroid lymphoma.