Hypothyroidism basics to Clinical
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I now have excellent comprehensive content from Harrison's 22E (2025), Washington Manual, Rosen's Emergency Medicine, and Family Medicine. Let me now compile the full, detailed clinical response.
Hypothyroidism: Basics to Clinical
1. Definition & Overview
Hypothyroidism is a hypometabolic state resulting from insufficient circulating thyroid hormone to meet the body's requirements. It is the most common functional disorder of the thyroid gland and the second most common endocrine condition after diabetes mellitus.
- Prevalence: 1-2% of women in the US have overt hypothyroidism
- Subclinical hypothyroidism: affects 4-10% of the general population
- Female-to-male ratio in Hashimoto's thyroiditis: 10-14:1
- Higher risk in older age groups
(Rosen's Emergency Medicine, 8th Ed.; Textbook of Family Medicine 9e)
2. Etiology & Classification
Primary Hypothyroidism (99% of cases - intrinsic gland failure)
| Category | Specific Causes |
|---|---|
| Autoimmune | Hashimoto's thyroiditis (most common in iodine-sufficient regions), atrophic thyroiditis |
| Iatrogenic | Thyroidectomy (subtotal/total), radioiodine (¹³¹I) therapy, external neck irradiation |
| Drugs | Amiodarone, lithium, iodine excess, antithyroid drugs, interferon-α/β, interleukin-2, tyrosine kinase inhibitors (sunitinib), immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab), thalidomide, bexarotene |
| Congenital | Thyroid dysgenesis (65%), dyshormonogenesis (30%), TSH-R antibody mediated (5%) |
| Infiltrative | Amyloidosis, sarcoidosis, hemochromatosis, scleroderma, Riedel's thyroiditis |
| Iodine deficiency | Most common cause worldwide (rare in US due to iodized salt) |
Transient Hypothyroidism
- Silent thyroiditis (including postpartum thyroiditis)
- Subacute thyroiditis (3-6 months of hypothyroidism)
- After ¹³¹I treatment or subtotal thyroidectomy for Graves' disease
Secondary (Central) Hypothyroidism (<1%)
- Hypopituitarism: pituitary tumors, surgery, irradiation, infiltrative disorders
- Hypothalamic disease (TRH deficiency)
- Rare; always look for other pituitary hormone deficits
(Harrison's Principles of Internal Medicine 22E, 2025)
3. Hashimoto's Thyroiditis (Autoimmune Hypothyroidism)
The most common cause in the US and developed world.
Pathogenesis: Anti-TPO (thyroid peroxidase) antibodies and anti-thyroglobulin (Tg) antibodies attack the thyroidal stroma - TPO antibodies are considered the primary mediators - leading to progressive fibrosis and loss of functioning gland.
Key features:
- Most often diagnosed in the fifth decade
- Progressive - more gland becomes fibrotic over time
- Diagnosis: elevated TSH + low/low-normal FT4 + positive TPO antibodies
- TPO antibodies are common; their presence does not change management and need not routinely be measured once diagnosis is established
Progression to overt hypothyroidism in subclinical disease: ~2.5% per year
(Textbook of Family Medicine 9e; Washington Manual of Medical Therapeutics)
4. Pathophysiology
The HPT Axis:
- Hypothalamus secretes TRH (thyrotropin-releasing hormone)
- TRH stimulates the anterior pituitary to release TSH (thyroid-stimulating hormone)
- TSH stimulates the thyroid to produce T4 (thyroxine) and T3 (triiodothyronine)
- T3 is the active hormone; ~80% of circulating T3 comes from peripheral conversion of T4
In primary hypothyroidism:
- Gland fails → ↓ T4/T3 → negative feedback is removed → TSH rises markedly
In secondary hypothyroidism:
- Pituitary or hypothalamic failure → ↓ TSH → ↓ T4 (TSH may be low, normal, or mildly elevated - unreliable alone)
Subclinical hypothyroidism: Impaired thyroid function, increased TSH secretion maintains normal free T4 - the patient is biochemically compensated.
5. Clinical Features
Hypothyroidism is a great masquerader - symptoms are nonspecific and develop gradually.
Symptoms (History)
- Cold intolerance (classic)
- Fatigue, somnolence, poor memory ("brain fog")
- Constipation
- Menorrhagia (in women)
- Myalgias
- Hoarseness
- Weight gain (mild; hypothyroidism does NOT cause marked obesity)
- Depression
Signs (Physical Examination)
| System | Finding |
|---|---|
| Skin | Dry, coarse skin; hair thinning/loss |
| Face | Facial and periorbital non-pitting edema (myxedema) |
| Cardiovascular | Bradycardia, pericardial effusion |
| Neurological | Slow (hung-up) tendon reflex relaxation - classic sign |
| Respiratory | Hypoventilation, pleural effusion (rare) |
| Other | Carpal tunnel syndrome, deafness (rare), macroglossia, goiter (in Hashimoto's) |
Myxedema refers to the non-pitting, doughy edema caused by glycosaminoglycan deposition in soft tissues. It is the hallmark of severe hypothyroidism.
(Washington Manual of Medical Therapeutics; Rosen's Emergency Medicine)
6. Laboratory & Diagnostic Testing
Primary Hypothyroidism
| Test | Finding | Interpretation |
|---|---|---|
| TSH (first-line, best test) | >4.5 mIU/L | Elevated - most sensitive test |
| TSH >10 mIU/L | Markedly elevated | Confirms overt primary hypothyroidism |
| TSH 4.5-10 mIU/L + normal FT4 | Mildly elevated | Subclinical hypothyroidism |
| Free T4 | Low | Confirms overt disease when TSH is elevated |
| TPO antibodies | Positive | Indicates autoimmune etiology |
Other lab findings:
- Hyponatremia (SIADH mechanism)
- Elevated cholesterol and LDL
- Elevated triglycerides
- Elevated creatine kinase (CK) - can mimic myopathy
- Anemia (normocytic or macrocytic)
Secondary Hypothyroidism
- TSH: low, normal, or mildly elevated (NOT reliable alone)
- Free T4: low - use this to diagnose
- Always evaluate for other pituitary hormone deficits and pituitary/hypothalamic mass lesion
Subclinical Hypothyroidism
- TSH mildly elevated (<20 mIU/L), free T4 normal
- May have nonspecific symptoms and mildly elevated cholesterol/LDL
- Progress to overt hypothyroidism at 2.5%/year
Note on sick euthyroid syndrome: In severe nonthyroidal illness, free T4 may be low on routine assay and TSH may be moderately elevated (<20 mIU/L) in euthyroid patients recovering from illness - this does NOT diagnose hypothyroidism. Markedly elevated TSH (>20 mIU/L) still establishes primary hypothyroidism.
(Washington Manual; Tintinalli's Emergency Medicine; Harrison's 22E)
7. Treatment
Levothyroxine (LT4) - Drug of Choice
Mechanism: Synthetic L-isomer of thyroxine; 70-80% GI absorption (predominantly small intestine); T4 peaks ~4 hours after ingestion; T3 rises slowly as T4 converts peripherally.
Dosing:
| Patient | Starting Dose |
|---|---|
| Adults <60 yrs, no cardiac disease | 50-100 μg/day |
| Elderly or cardiac disease | Start low: 12.5-25 μg/day (titrate slowly) |
| Full replacement (no residual function) | 1.6 μg/kg/day (typically 100-150 μg) |
| Pregnancy | Increase dose immediately; check TSH monthly through second trimester |
Administration tips:
- Take 30-60 minutes before breakfast or at bedtime (improves absorption)
- Half-life of T4 is ~7 days - missed doses can double up
Monitoring:
- Check TSH 6-8 weeks after starting or changing dose
- Goal: TSH in normal range (ideally lower half of reference)
- Once stable: check TSH annually
- Adjust in 12.5-25 μg increments
Causes of increased LT4 requirements:
- Malabsorption (celiac disease, small bowel surgery, H. pylori gastritis)
- Oral estrogens or SERMs
- Drugs interfering with T4 absorption: bile acid sequestrants, ferrous sulfate, calcium, sevelamer, sucralfate, PPIs, aluminum hydroxide
- Drugs accelerating T4 metabolism: rifampicin, carbamazepine, phenytoin, amiodarone, tyrosine kinase inhibitors
Suppressed TSH (overtreatment): Increases risk of atrial fibrillation and reduced bone density - avoid over-replacement.
T4 + T3 Combination Therapy
- Investigated but not routinely recommended (ATA guidelines 2025)
- No confirmed benefit in prospective studies for most patients
- ~10-15% of patients have persistent symptoms despite normal TSH - reason unclear
When to Treat Subclinical Hypothyroidism
- TSH >10 mIU/L: treat with levothyroxine
- TSH 5.1-10 mIU/L + symptomatic: treat
- Untreated patients: monitor annually; start T4 if symptoms develop or TSH rises >10 mIU/L
(Harrison's 22E; Washington Manual; Rosen's Emergency Medicine)
8. Special Populations
Pregnancy
- Hypothyroidism in pregnancy: high TSH + low free T4 (or TSH >2.5 mIU/L first trimester by some guidelines)
- Untreated hypothyroidism risks: miscarriage, preeclampsia, preterm birth, fetal neurocognitive impairment
- Check TSH as soon as pregnancy is confirmed; recheck monthly through second trimester
- Increase LT4 dose by 25-30% as soon as pregnancy confirmed (thyroid demand rises from week 4-6)
- Subclinical hypothyroidism in pregnancy: 5-8% incidence
Elderly
- Start at very low doses (12.5-25 μg) due to cardiac risk
- Symptoms may be more subtle (fatigue, cognitive decline)
Congenital Hypothyroidism
- 1 in 2000-4000 newborns; neonatal screening mandatory in industrialized countries
- If untreated: cretinism (irreversible intellectual disability, growth retardation)
- Causes: thyroid dysgenesis (65%), dyshormonogenesis (30%), TSH-R antibody mediated (5%)
- Treatment must begin within the first weeks of life
9. Myxedema Coma - The Life-Threatening Extreme
Definition: Severe, decompensated hypothyroidism - the most extreme manifestation. Usually occurs in untreated or undertreated hypothyroidism, often precipitated by an acute illness.
Triggers (Precipitants)
- Infection (most common - especially respiratory)
- Cold exposure
- Sedative drugs / opioids / anesthesia
- Surgery, trauma
- Myocardial infarction, stroke
Clinical Features
- Altered mental status (stupor to coma)
- Hypothermia (hallmark - temp can be <30°C)
- Hypoventilation + hypercapnia → CO₂ narcosis
- Bradycardia, hypotension
- Hyponatremia
- Hypoglycemia
- Non-pitting edema (myxedema facies)
- Absent or sluggish reflexes
Treatment (Box 117.8 - Rosen's Emergency Medicine)
Priority order:
- Airway/ventilation - intubate if needed; monitor for alkalosis
- Fluid resuscitation - 0.9% NS (or D5/0.9% NS if hypoglycemic); avoid hypotonic fluids
- Thyroid hormone replacement:
- IV LT4 loading dose: 200-400 μg IV (use lower end in elderly, small patients, CAD, arrhythmia history)
- Subsequent daily: 1.6 μg/kg body weight PO; reduce to 75% if IV route
- In very ill patients: consider adding IV liothyronine (T3)
- Glucocorticoids: Hydrocortisone 100 mg IV every 8 hours - empiric adrenal support (concurrent adrenal insufficiency common; treat before or with T4 to avoid adrenal crisis)
- Hyponatremia: Fluid restriction; only 0.9% NS; if Na⁺ <120 mEq/L → 3% saline 50-100 mL boluses
- Rewarming: Passive only (regular blankets) - active rewarming causes vasodilation and cardiovascular collapse; if heating blankets used, pretreat with IV fluids
- Treat precipitating cause - especially infection (broad-spectrum antibiotics empirically)
- Avoid mechanical stimulation (vagal response risk)
Mortality of myxedema coma remains 20-40% even with treatment. Diagnosis is often clinical - do not wait for labs before treating.
(Rosen's Emergency Medicine 10th Ed.)
10. Key Clinical Pearls
| Pearl | Detail |
|---|---|
| TSH is the single best screening test | Normal TSH excludes primary hypothyroidism |
| TSH >20 μU/mL = overt primary hypothyroidism | Even in nonthyroidal illness |
| Slow tendon reflex relaxation | Most specific physical sign |
| In pregnancy | Increase LT4 dose by ~25-30% from day 1 |
| Adherence issue pattern | Normal/high FT4 + elevated TSH despite high LT4 dose (took pills before the test) |
| Suppressed TSH = overtreatment risk | AF and osteoporosis |
| Myxedema coma | Give hydrocortisone BEFORE or WITH LT4 to prevent adrenal crisis |
| Secondary hypothyroidism | TSH unreliable - use free T4; always look for other pituitary deficits |
Sources:
- Harrison's Principles of Internal Medicine 22E (2025) - Weetman, Mandel, Jameson
- Washington Manual of Medical Therapeutics
- Rosen's Emergency Medicine: Concepts and Clinical Practice, 10th Ed.
- Textbook of Family Medicine 9e
- Tintinalli's Emergency Medicine
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