Definition and epidemiology
Hypothyroidism is a state of thyroid hormone deficiency that slows metabolic processes throughout the body. It is classified as:
- Primary hypothyroidism: thyroid gland failure (over 95% of cases)
- Secondary (central) hypothyroidism: pituitary TSH deficiency
- Tertiary hypothyroidism: hypothalamic TRH deficiency
It is further divided into overt (elevated TSH with low free T4, symptomatic) and subclinical (elevated TSH with normal free T4, often asymptomatic) disease.
Prevalence of overt hypothyroidism is approximately 1-2% in iodine-sufficient populations, with subclinical disease affecting up to 10% of adults, rising with age. Women are affected roughly 5-10 times more often than men. Hashimoto's thyroiditis is the leading cause worldwide where iodine intake is adequate, while iodine deficiency remains the leading cause globally.
- Primary hypothyroidism: high TSH, low free T4; central hypothyroidism: low/normal TSH, low free T4
- Hashimoto's thyroiditis is the most common cause in iodine-sufficient areas; anti-TPO antibodies are the key marker
- Delayed relaxation of deep tendon reflexes is a classic bedside finding
- Levothyroxine is first-line therapy; take on an empty stomach, separate from calcium and iron
- Myxedema coma presents with hypothermia, bradycardia, and altered mental status, treat as an emergency
- Subclinical hypothyroidism = elevated TSH with normal free T4, often asymptomatic
- In pregnancy, levothyroxine dose requirements increase and TSH targets are lower trimester-specifically
- Amiodarone and lithium are classic drug causes of hypothyroidism
Etiology and risk factors
Primary causes
- Hashimoto's (autoimmune) thyroiditis: most common cause in iodine-replete areas; associated with anti-TPO and anti-thyroglobulin antibodies
- Iatrogenic: post-thyroidectomy, post-radioactive iodine ablation, external neck irradiation
- Drug-induced: amiodarone, lithium, interferon-alpha, tyrosine kinase inhibitors, immune checkpoint inhibitors
- Iodine deficiency: leading global cause, especially in developing regions
- Subacute (de Quervain) thyroiditis: transient hypothyroid phase after initial hyperthyroid phase
- Postpartum thyroiditis: occurs within a year of delivery
- Congenital hypothyroidism: thyroid dysgenesis or dyshormonogenesis
Central causes
- Pituitary adenoma or pituitary surgery/radiation
- Sheehan syndrome (postpartum pituitary necrosis)
- Hypothalamic lesions
Risk factors
- Female sex
- Age over 60
- Family history of autoimmune thyroid disease
- Personal history of other autoimmune disease (type 1 diabetes, celiac disease, vitiligo)
- Down syndrome and Turner syndrome
- Prior neck irradiation or thyroid surgery
Pathophysiology
In Hashimoto's thyroiditis, lymphocytic infiltration of the thyroid gland leads to progressive follicular destruction mediated by both humoral (anti-TPO, anti-thyroglobulin antibodies) and cell-mediated immune mechanisms. Gradual loss of functional thyroid tissue reduces T4 and T3 output.
Reduced circulating thyroid hormone decreases negative feedback on the hypothalamic-pituitary axis, causing a compensatory rise in TRH and TSH, this is the basis of the elevated TSH seen in primary disease.
Systemically, thyroid hormone deficiency reduces basal metabolic rate, slows cardiac contractility and heart rate, decreases gut motility, and promotes accumulation of glycosaminoglycans in the dermis and other tissues, producing the non-pitting edema (myxedema) characteristic of severe disease. Reduced thermogenesis contributes to cold intolerance, and slowed CNS metabolism contributes to cognitive slowing and depression.
Clinical features
Onset is typically insidious, and symptoms are nonspecific, which can delay diagnosis.
General and metabolic
- Fatigue, weight gain despite poor appetite
- Cold intolerance
- Constipation
Skin, hair, and face
- Dry, coarse skin
- Hair thinning and loss
- Periorbital puffiness
- Non-pitting edema (myxedema) in severe disease
Neuropsychiatric
- Depression, cognitive slowing, memory impairment
- Delayed relaxation phase of deep tendon reflexes (classic exam finding)
Cardiovascular
- Bradycardia
- Diastolic hypertension
- Pericardial effusion in severe disease
Reproductive and other
- Menstrual irregularities, especially menorrhagia
- Infertility
- Hoarse voice
- Carpal tunnel syndrome
Myxedema coma (rare, severe)
- Hypothermia, altered mental status, bradycardia, hypoventilation
- A medical emergency with significant mortality, often precipitated by infection, cold exposure, or sedative use in a patient with undiagnosed or undertreated hypothyroidism
Diagnosis
Initial test
- Serum TSH: the most sensitive screening test for primary thyroid dysfunction
Confirmatory and localizing tests
| Pattern | TSH | Free T4 | Interpretation |
|---|---|---|---|
| Overt primary hypothyroidism | High | Low | Thyroid gland failure |
| Subclinical hypothyroidism | High | Normal | Early/mild thyroid failure |
| Central hypothyroidism | Low or inappropriately normal | Low | Pituitary/hypothalamic cause |
Additional workup
- Anti-TPO (anti-thyroid peroxidase) antibodies: confirm autoimmune (Hashimoto's) etiology
- Anti-thyroglobulin antibodies: supportive, less sensitive
- Lipid panel: often shows elevated LDL
- CBC: may show normocytic or macrocytic anemia
- Thyroid ultrasound: not routinely required unless a nodule or goiter is palpated
- Pituitary MRI: considered if central hypothyroidism is suspected
Universal screening in asymptomatic adults is not recommended by most major guidelines; targeted screening is favored in high-risk groups (pregnancy, older women, autoimmune disease, strong family history).
Differential diagnosis
- Depression: overlapping fatigue and cognitive slowing; distinguished by normal TSH
- Chronic fatigue syndrome: diagnosis of exclusion, normal thyroid function
- Anemia: fatigue and pallor, normal thyroid panel
- Nephrotic syndrome: periorbital edema can mimic myxedema facies, but proteinuria and normal TSH distinguish it
- Euthyroid sick syndrome (non-thyroidal illness): low T3/T4 with normal or low TSH in acutely ill patients, resolves with recovery
- Obstructive sleep apnea: fatigue and weight gain overlap, confirmed by sleep study
- Central hypothyroidism: distinguished from primary disease by low/normal TSH with low free T4
Management
First-line therapy
- Levothyroxine (synthetic T4) is the standard of care across US (ATA), European (ETA), and most international guidelines
- Dosing is weight-based and titrated to clinical response and laboratory targets
- Taken on an empty stomach, separated from calcium, iron, and proton pump inhibitors, which impair absorption
FDA Black Box Warning: Thyroid hormones, including levothyroxine, should not be used for the treatment of obesity or for weight loss in euthyroid patients. Large doses in euthyroid individuals can cause serious or life-threatening toxicity, particularly when used with sympathomimetic amines for weight reduction.
Monitoring
- Recheck TSH approximately 4-6 weeks after dose initiation or change
- In primary hypothyroidism, titrate to a normal TSH; in central hypothyroidism, titrate using free T4 since TSH cannot be used as a feedback marker
- Once stable, monitor annually or with symptom change
Special situations
- Pregnancy: dose requirements increase early in pregnancy; target TSH is lower than in non-pregnant adults per trimester-specific ranges; monitor more frequently
- Subclinical hypothyroidism: treatment is generally considered when TSH is markedly elevated (commonly cited threshold above 10 mIU/L), when the patient is pregnant or trying to conceive, or when symptomatic with positive thyroid antibodies; guidelines vary on treating milder elevations
- Elderly patients: start with lower doses and titrate more cautiously due to cardiac risk
- Myxedema coma: medical emergency requiring IV levothyroxine (sometimes combined with IV liothyronine), stress-dose corticosteroids until adrenal insufficiency is excluded, and supportive care in an intensive care setting
Role of T3 and combination therapy
- Routine use of combination T4/T3 therapy is not recommended by most guidelines due to limited evidence of benefit, but may be considered in select patients with persistent symptoms despite normalized TSH on T4 alone
Complications and prognosis
With appropriate levothyroxine replacement, prognosis is excellent and most patients achieve normal quality of life; however, treatment is typically lifelong in permanent hypothyroidism.
Complications of untreated or undertreated disease
- Dyslipidemia and increased cardiovascular risk
- Infertility and adverse pregnancy outcomes, including miscarriage and impaired fetal neurodevelopment
- Myxedema coma (rare but life-threatening)
- Pericardial and pleural effusions in severe, longstanding disease
Complications of over-replacement
- Iatrogenic hyperthyroidism with risk of atrial fibrillation and accelerated bone loss, particularly in older adults
Regular monitoring and dose adjustment minimize both under- and over-treatment risks.
"COLD": Cold intolerance, Obesity (weight gain), Lethargy/depression, Dry skin and delayed reflexes — core features of hypothyroidism.
Practice questions
1. A 42-year-old woman presents with fatigue, 10-pound weight gain, cold intolerance, and constipation over the past 6 months. Physical exam shows dry skin and delayed relaxation of the ankle reflex. Serum TSH is 18 mIU/L (reference 0.4-4.0) and free T4 is low. Which of the following is the most likely underlying etiology?
2. A 68-year-old man with known hypothyroidism on levothyroxine is brought to the emergency department by family after being found unresponsive at home in a cold apartment. On exam he is hypothermic, bradycardic, and hypotensive with depressed mental status. Which of the following is the most appropriate immediate step in management?
3. A 35-year-old woman with Hashimoto's thyroiditis on a stable dose of levothyroxine learns she is 8 weeks pregnant. Which of the following is the most appropriate next step regarding her thyroid management?
Frequently asked questions
What causes hypothyroidism?
Hypothyroidism is most often caused by Hashimoto's autoimmune thyroiditis in iodine-sufficient countries, or by iodine deficiency worldwide. Other causes include prior thyroid surgery, radioactive iodine treatment, certain medications like amiodarone and lithium, and pituitary disease causing secondary hypothyroidism. Autoimmune cases involve antibodies that gradually destroy thyroid tissue, reducing hormone output.
What are the first symptoms of hypothyroidism?
Early symptoms are often subtle and nonspecific, including fatigue, mild weight gain, cold intolerance, constipation, and dry skin. Many patients also notice hair thinning, low mood, or difficulty concentrating. Because these symptoms overlap with many common conditions, hypothyroidism is frequently diagnosed only after blood testing prompted by persistent or worsening symptoms.
How is hypothyroidism diagnosed?
Hypothyroidism is diagnosed primarily with a serum TSH test, which is elevated in primary hypothyroidism. A low free T4 confirms overt disease, while a normal free T4 with high TSH indicates subclinical disease. Anti-TPO antibody testing helps confirm an autoimmune cause such as Hashimoto's thyroiditis.
Is hypothyroidism curable?
Most forms of hypothyroidism are not curable but are highly manageable with lifelong levothyroxine replacement therapy. Some causes, such as subacute or postpartum thyroiditis, are transient and may resolve on their own. For permanent autoimmune or post-surgical hypothyroidism, daily hormone replacement restores normal function and quality of life indefinitely.
Hypothyroidism vs hyperthyroidism — what is the difference?
Hypothyroidism results from insufficient thyroid hormone and causes fatigue, weight gain, cold intolerance, and bradycardia, while hyperthyroidism results from excess thyroid hormone and causes weight loss, heat intolerance, tremor, and tachycardia. Laboratory testing distinguishes them clearly: hypothyroidism shows high TSH with low free T4, whereas hyperthyroidism shows low TSH with high free T4.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: E03.9
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.