Hypothyroidism

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Hypothyroidism

Definition

Hypothyroidism is a hypometabolic state resulting from insufficient circulating thyroid hormone to meet the needs of peripheral tissues. It is classified as:

Primary - intrinsic thyroid gland failure (up to 99% of all cases)
Secondary/Central - lack of TSH stimulation from pituitary failure (rare)
Tertiary - hypothalamic failure (very rare)

It is the most common functional disorder of the thyroid gland, and thyroid disorders are the second most common endocrine condition after diabetes mellitus.

Epidemiology

Affects 1-2% of women in the United States
Subclinical hypothyroidism affects 4-10% of the general population
Incidence of subclinical hypothyroidism in pregnancy: 5-8%
Higher incidence in women (due to higher prevalence of autoimmune disease)
Risk increases with age; no specific racial/ethnic predilection

Etiology

Primary Hypothyroidism (most common)

Cause	Details
Hashimoto's thyroiditis (Chronic Autoimmune Thyroiditis)	Most common cause in the US and developed world. Antithyroid antibodies (anti-TPO, anti-Tg) attack thyroidal stroma causing progressive fibrosis. Female:male ratio 10-14:1, typically diagnosed in the 5th decade
Iodine deficiency	Most common cause worldwide; rare in the US due to iodized salt
Post-thyroidectomy	Surgical removal
Radioiodine (¹³¹I) therapy	For hyperthyroidism or thyroid cancer
Radiation to head/neck	External beam radiation therapy
Medications	Amiodarone, lithium, iodides (decrease T4/T3 release); phenytoin, rifampin (enhance elimination); iron, calcium, cholestyramine (interfere with absorption)
Infiltrative disorders	Sarcoidosis, amyloidosis, hemochromatosis
Thyroiditis	Postpartum, sporadic, subacute - can cause transient hypothyroidism
Congenital	Thyroid dysgenesis or dyshormonogenesis

Secondary/Central Hypothyroidism

Pituitary failure leading to inadequate TSH secretion. Diagnosis suggested by low-to-absent TSH with low circulating free T4, without signs of hyperthyroidism.

Clinical Features

The signs and symptoms range from asymptomatic (subclinical) to overt organ failure (myxedema coma).

General

Fatigue, weight gain, cold intolerance
Decreased sweating

Skin & Hair

Dry, coarse, pale, cool skin
Non-pitting edema (myxedema) - skin infiltration with glycosaminoglycans
Dry, brittle hair; hair loss
Lateral thinning of eyebrows (Queen Anne's sign)
Yellow tinge (carotenemia)
Thin, brittle nails

Neurologic

Slow mentation and speech
Impaired concentration and attention
Lethargy, decreased short-term memory
Agitation, psychosis ("myxedema madness")
Seizures
Ataxia, dysmetria
Carpal tunnel syndrome
Sensorineural hearing loss
Peripheral neuropathy, paresthesias

Musculoskeletal

Proximal myopathy, pseudohypertrophy
Delayed relaxation of deep tendon reflexes ("hung-up reflexes" / pseudomyotonic)
Polyarthralgias, joint effusions
Acute gout or pseudogout

Cardiovascular

Sinus bradycardia
Long QT interval with increased ventricular arrhythmia risk
Diastolic heart failure (delayed ventricular relaxation)
Pericardial effusion (usually asymptomatic)
Peripheral edema
Decreased exercise capacity, dyspnea on exertion

Respiratory

Dyspnea on exertion
Obstructive sleep apnea
Primary pulmonary hypertension (rare)

Gastrointestinal

Constipation, ileus
Gastric atrophy

Reproductive

Oligomenorrhea and amenorrhea, OR menorrhagia
Decreased fertility, early abortions
Decreased libido, erectile dysfunction

Head/Neck

Hoarseness, deep husky voice
Macroglossia
Periorbital swelling
Goiter (in Hashimoto's)

Diagnosis

Laboratory Tests

Test	Finding	Interpretation
TSH (most sensitive)	Elevated (>4.5 mIU/L)	Primary hypothyroidism screening test of choice
TSH markedly elevated (>10 mIU/L)	With low fT4	Overt primary hypothyroidism
TSH elevated, fT4 normal	-	Subclinical hypothyroidism
TSH low/normal, fT4 low	-	Central (secondary/tertiary) hypothyroidism
Anti-TPO antibodies	Elevated	Hashimoto's thyroiditis (primary cause); present in ~95%
Anti-thyroglobulin (Tg) antibodies	Elevated	Also seen in Hashimoto's
T3	Often low	Less sensitive than TSH

In secondary hypothyroidism: follow free T4, not TSH
Subclinical hypothyroidism: TSH >4.5 but <10 mIU/L with normal fT4; patient may be asymptomatic

Additional Lab Abnormalities (overt hypothyroidism)

Elevated cholesterol and triglycerides (decreased lipid clearance)
Elevated creatine kinase (CK) - from myopathy
Hyponatremia (SIADH-like state)
Normocytic or macrocytic anemia
Hyperprolactinemia (TRH stimulates prolactin)

Treatment

Levothyroxine (L-T4) - Drug of Choice

Levothyroxine (synthetic T4) is the hormone of choice for thyroid hormone replacement due to consistent potency and prolonged duration of action (plasma t½ ~7 days). It relies on peripheral deiodinases (Dio1, Dio2) to convert T4 → T3.

Population	Initial Dose	Notes
Healthy adults	1.6-1.7 µg/kg/day (average replacement)	Based on lean body mass
Elderly (>60 yrs) or cardiac disease	Start 12.5-50 µg/day (subreplacement)	Increase by 25 µg/day every 6 weeks
Subclinical hypothyroidism (TSH >10)	Treatment recommended	Start at low dose
Subclinical hypothyroidism (TSH 4.5-10)	Treat if symptomatic	Otherwise monitor
Central hypothyroidism	Target normal free T4 (not TSH)	-

Monitoring: Follow-up TSH approximately 6 weeks after any dose change (accounts for T4's 1-week half-life and TSH lag time)
Once dose is stable, check TSH annually
Take on empty stomach, 30-60 minutes before breakfast for best absorption

Combination T4 + T3 Therapy

Not routinely recommended - the vast majority of controlled trials do not show superiority over T4 alone
Desiccated thyroid (T4:T3 ratio ~4:1; 60 mg ≈ 65 µg levothyroxine) - occasionally preferred by patients; some report weight loss
Liothyronine (synthetic T3) alone is less desirable for chronic use: shorter half-life (~20 h), more frequent dosing, transient T3 spikes above normal range
A trial of combination T4+T3 may be reasonable if patient remains symptomatic with TSH in therapeutic range

Subclinical Hypothyroidism

TSH >10 µU/mL: experts agree treatment is indicated
TSH 4.5-10 µU/mL: treat if symptomatic or if pregnant

Pregnancy

All pregnant patients with elevated TSH should be treated with levothyroxine
Target TSH in the lower half of the normal range
Check TSH every 4-6 weeks; dose requirements typically increase in first trimester
Women planning pregnancy should optimize preconception TSH to reduce risk of first-trimester elevation

Myxedema Coma (Severe/Life-Threatening Hypothyroidism)

Myxedema coma is a medical emergency - the extreme end of untreated or undertreated hypothyroidism. Mortality approaches 30% even with optimal treatment; approaches 100% without treatment.

Recognition (Myxedema Coma Triad)

Hypothermia - temperature usually <36°C; <32°C is a poor prognostic sign; as low as 24°C reported; may be near-normal if infection is the precipitant
Altered mental status - lethargy and confusion to stupor/coma; agitation, psychosis, seizures ("myxedema madness")
Precipitating event - infection (pneumonia most common), MI, GI bleed, trauma, drugs (sedatives, narcotics), hyponatremia, hypoglycemia

Classic Profile

Older woman in winter
Known hypothyroidism or thyroidectomy scar
Myxedema facies: puffy eyelids and lips, large tongue, broad nose
Hypotension refractory to fluids and pressors unless thyroid hormone administered
Slow, shallow respirations with hypercapnia/hypoxia

Management of Myxedema Coma

IV levothyroxine - 200-500 µg loading dose IV, then 50-100 µg/day
IV liothyronine (T3) - some centers add T3 for faster action (T3 is the active hormone)
Hydrocortisone 100 mg IV - empirically given before thyroid hormone, as undetected adrenal insufficiency can be precipitated by thyroid hormone replacement
Supportive care: intubation/ventilation, rewarming (passive preferred), IV fluids, treat precipitating illness
Avoid aggressive rewarming (can cause cardiovascular collapse)
Treatment often initiated based solely on clinical findings without waiting for labs

Special Considerations

Drugs That Cause or Worsen Hypothyroidism

Amiodarone - contains ~37% iodine; can cause both hypo- and hyperthyroidism
Lithium - inhibits thyroid hormone synthesis and release
Interferon-alpha, checkpoint inhibitors (immune-related thyroid dysfunction)
Iron, calcium supplements, cholestyramine - impair levothyroxine absorption (separate by at least 4 hours)

Hashimoto's Thyroiditis (Chronic Autoimmune Thyroiditis)

Caused by TPO antibodies (primary) and anti-Tg antibodies attacking thyroidal stroma
Progressive fibrosis → declining T4 production
Average replacement dose in adults: 1.6 µg/kg/day L-thyroxine
TSH followed annually to ensure adequate control
Some patients have transient hyperthyroidism early ("Hashitoxicosis")

Key Takeaways

Feature	Detail
Most common cause (US)	Hashimoto's thyroiditis (autoimmune)
Most common cause (worldwide)	Iodine deficiency
Best screening test	Serum TSH
Treatment of choice	Levothyroxine (T4), 1.6-1.7 µg/kg/day
Monitoring interval	Every 6 weeks after dose change; annually once stable
Emergency form	Myxedema coma - treat with IV T4 ± T3 + steroids
Key DTR finding	Delayed relaxation ("hung-up" reflexes)
Key ECG finding	Sinus bradycardia, prolonged QT

Sources: ROSEN's Emergency Medicine, 9th Ed. - Textbook of Family Medicine, 9th Ed. - Goodman & Gilman's Pharmacological Basis of Therapeutics, 14th Ed.

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