Hypothyroidism

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Definition and Overview

CAUSES OF HYPOTHYROIDISM (Table 395-1)

Primary Hypothyroidism

• Autoimmune: Hashimoto's thyroiditis, atrophic thyroiditis
• Iatrogenic: Radioiodine (¹³¹I) treatment, subtotal/total thyroidectomy, external neck irradiation (lymphoma, cancer)
• Drugs: Iodine excess (including iodine-containing contrast media), amiodarone, lithium, antithyroid drugs, p-aminosalicylic acid, interferon-α and other cytokines, aminoglutethimide, tyrosine kinase inhibitors (e.g., sunitinib), immune checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembrolizumab)
• Congenital: Absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation
• Iodine deficiency
• Infiltrative disorders: Amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedel's thyroiditis
• Consumptive hypothyroidism: Overexpression of type 3 deiodinase in infantile hemangioma and other tumors

Transient Hypothyroidism

• Silent thyroiditis (including postpartum thyroiditis)
• Subacute thyroiditis
• Withdrawal of supraphysiologic thyroxine in individuals with intact thyroid
• After ¹³¹I treatment or subtotal thyroidectomy for Graves' disease

Secondary (Central) Hypothyroidism

• Hypopituitarism: Tumors, pituitary surgery or irradiation, infiltrative disorders, Sheehan's syndrome, trauma, genetic combined pituitary hormone deficiencies
• Isolated TSH deficiency or inactivity
• Drugs: Bexarotene, mitotane
• Hypothalamic disease: Tumors, trauma, infiltrative disorders, Prader-Willi syndrome

CONGENITAL HYPOTHYROIDISM

• Thyroid gland dysgenesis: 65%
• Inborn errors of thyroid hormone synthesis: 30%
• TSH-R antibody-mediated: 5%

1. Central hypothyroidism from abnormal hypothalamic-pituitary development (e.g., PROP-1, PIT-1, IGSF1, TSHβ mutations)
2. Abnormal thyroid gland development/dysgenesis (e.g., TTF-1, TTF-2/FOXE-1, PAX-8, NKX2-1, NKX2-5, GLIS3, JAG-1 mutations)
3. Abnormal thyroid hormone synthesis - dyshormonogenesis

AUTOIMMUNE HYPOTHYROIDISM (Hashimoto's Thyroiditis)

Classification

• Goitrous thyroiditis (Hashimoto's): associated with goiter
• Atrophic thyroiditis: minimal residual thyroid tissue (usually the end stage of Hashimoto's)

Prevalence

• Mean annual incidence: up to 4 per 1000 women and 1 per 1000 men
• More common in Japanese populations (genetic factors + chronic high-iodine diet)
• Typically occurs between 30-50 years of age; mean age at diagnosis is 60 years
• Subclinical hypothyroidism: 6-8% of women (10% over age 60), 3% of men
• Annual risk of developing clinical hypothyroidism: ~4% when subclinical hypothyroidism is associated with positive TPO antibodies

Pathology

• Marked lymphocytic infiltration with germinal center formation
• Atrophy of thyroid follicles with oxyphil (Hürthle cell) metaplasia
• Absence of colloid
• Mild to moderate fibrosis
• In atrophic thyroiditis: extensive fibrosis, less lymphocytic infiltration, follicles almost absent; a distinct form exists with IgG4-positive plasma cell infiltration

Pathogenesis

• HLA-DR polymorphisms are the best documented genetic risk factors: especially HLA-DR3, DR4, and DR5 in Caucasians
• Associations with PTPN22 and CTLA-4 polymorphisms (immunoregulatory functions)
• These associations are shared with other autoimmune diseases (type 1 DM, Addison's disease, pernicious anemia, vitiligo)
• A gene on chromosome 21 explains the association with Down's syndrome
• Female preponderance likely due to sex steroid effects on immune response; X chromosome-related factor may account for high frequency in Turner's syndrome

• High iodine or low selenium intake increases risk
• Decreased exposure to microorganisms in childhood increases risk
• Smoking cessation transiently increases incidence; alcohol intake appears protective

• Thyroid lymphocytic infiltrate: activated CD8+ cytotoxic T cells (primary destructors) and B cells
• Local cytokines - TNF, IL-1, IFN-γ - promote thyroid cell apoptosis
• TPO antibodies are present in >90% of patients; thyroglobulin (Tg) antibodies in ~60%
• TSH-R blocking antibodies can contribute to hypothyroidism, particularly in atrophic thyroiditis
• These antibodies serve as markers of autoimmune disease but their pathogenic role is secondary

OTHER CAUSES OF HYPOTHYROIDISM

CLINICAL FEATURES (Table 395-3)

Symptoms

• Tiredness, fatigue, cold intolerance
• Weight gain (modest, mainly due to myxedematous fluid retention)
• Constipation
• Depression, poor concentration, mental sluggishness
• Muscle cramps, myalgia, weakness
• Bradycardia
• Irregular menses, menorrhagia
• Dry skin, hair loss, brittle nails
• Hoarse voice, macroglossia
• Carpal tunnel syndrome
• Hearing impairment
• Infertility

Signs

• Dry, coarse, pale/yellowish (carotenemia) skin
• Puffy face, periorbital edema, myxedema
• Loss of outer third of eyebrows (sign of severe/longstanding hypothyroidism)
• Bradycardia
• Goiter (in Hashimoto's) or small/absent gland (atrophic)
• Non-pitting edema (myxedema) - accumulation of glycosaminoglycans in soft tissues
• Delayed relaxation of deep tendon reflexes ("hung-up" reflexes) - classic sign
• Pleural/pericardial effusions
• Cardiomegaly, pericardial effusion
• Hypertension (diastolic)

Cardiovascular

• Elevated LDL cholesterol and triglycerides
• Increased risk of atherosclerosis and coronary artery disease
• Pericardial effusion (can be large but tamponade is rare)

Neurological/Psychiatric

• Cerebellar ataxia
• Peripheral neuropathy (including carpal tunnel syndrome)
• Depression, dementia (reversible with treatment)
• Psychosis ("myxedema madness")

Reproductive

• Anovulation, infertility
• Hyperprolactinemia (TSH stimulates prolactin release; TRH elevations cause galactorrhea)

LABORATORY DIAGNOSIS

• Elevated TSH is the most sensitive early indicator of primary hypothyroidism
• Low free T4 (and low T3 in severe cases) confirms overt hypothyroidism
• TPO antibodies positive in >90% of autoimmune hypothyroidism (marker of Hashimoto's)
• Tg antibodies positive in ~60%
• Normochromic or macrocytic anemia (macrocytic from B12 deficiency in associated pernicious anemia, or from hypothyroid effect on erythropoiesis)
• Elevated serum creatine kinase, LDH
• Hypercholesterolemia, hypertriglyceridemia
• Hyponatremia (SIADH-like effect from impaired free water excretion)
• ECG: bradycardia, low-voltage complexes, T-wave changes, prolonged QT

TREATMENT

Clinical (Overt) Hypothyroidism

• Full replacement dose: ~1.6 μg/kg body weight/day (typically 100-150 μg/day), taken at least 30 minutes before breakfast
• In Graves' disease post-treatment, lower doses typically suffice (75-125 μg/day) due to some residual autonomous function

• Adults <60 years, no cardiac disease: start at 50-100 μg/day
• Elderly or cardiac disease: start at 12.5-25 μg/day, with increments every 2-3 months

• TSH should be measured 6-8 weeks after initiating treatment or any dose change
• Goal: TSH in the normal range, ideally in the lower half
• Dose adjustments in 12.5- or 25-μg increments (or decrements)
• Once stable: annual TSH measurement

• Suppressed TSH (any cause including over-treatment) → increased risk of atrial fibrillation and reduced bone density
• ~10-15% of patients have persistent symptoms despite normal TSH - reason unclear
• Desiccated thyroid extract (USP) is NOT recommended (nonphysiologic T3:T4 ratio)
• LT4 + liothyronine (T3) combination - benefit not confirmed in prospective studies
• Liothyronine alone is NOT appropriate for long-term replacement (short half-life, fluctuating T3 levels)

• Poor adherence (most common)
• Malabsorption: celiac disease, small-bowel surgery, atrophic or H. pylori-related gastritis
• Oral estrogens or SERMs
• Drugs interfering with T4 absorption/metabolism: bile acid sequestrants, ferrous sulfate, calcium carbonate, PPIs

Subclinical Hypothyroidism

• TSH >10 mIU/L
• Woman who wishes to conceive or is currently pregnant

Pregnancy

• Goal TSH: <2.5 mIU/L (lower half of trimester-specific range) before and throughout pregnancy
• Increase LT4 from once-daily to nine doses per week immediately upon confirmed pregnancy
• Athyroic women require ~45% more LT4; those with Hashimoto's require less (some residual function)
• TSH monitoring: every 4 weeks during first half of pregnancy; every 6-8 weeks after 20 weeks
• Return to pre-pregnancy doses after delivery
• Separate prenatal vitamins and iron supplements from LT4 ingestion
• Although thyroid autoantibodies in euthyroid women are associated with miscarriage/preterm delivery, RCTs of LT4 prior to conception in this population have NOT shown benefit

Elderly Patients

• May require ~20% less thyroxine than younger patients
• Starting dose: 12.5-25 μg/day with careful increments every 2-3 months
• In known coronary artery disease, full replacement may not be achievable despite optimal antianginal therapy
• Emergency surgery is generally safe in untreated hypothyroidism; routine surgery should be deferred until euthyroid

MYXEDEMA COMA

• Reduced level of consciousness (with possible seizures)
• Hypothermia (can reach 23°C/74°F)
• All features of severe hypothyroidism (Table 395-3)

• Drugs: sedatives, anesthetics, antidepressants
• Pneumonia, CHF, MI, GI bleeding, stroke
• Sepsis
• Cold exposure
• Hypoventilation → hypoxia and hypercapnia (major pathogenic role)
• Hypoglycemia and dilutional hyponatremia

1. LT4: IV bolus of 200-400 μg as loading dose, then daily oral 1.6 μg/kg/day (reduce by 25% if IV); or same dose via nasogastric tube if IV not available
2. Liothyronine (T3): Loading dose 5-20 μg IV or NG, then 2.5-10 μg every 8 h (lower doses for smaller/older patients and those with cardiovascular risk)
3. Hydrocortisone: 50 mg IV every 6 h (impaired adrenal reserve in profound hypothyroidism)
4. External warming only if temperature <30°C (risk of cardiovascular collapse if warmed too quickly); use space blankets to prevent further heat loss
5. Ventilatory support with regular blood gas analysis (usually needed in first 48 h)
6. Broad-spectrum antibiotics pending exclusion of infection
7. Avoid hypotonic IV fluids (worsens water retention due to reduced renal perfusion and inappropriate vasopressin secretion)
8. Hypertonic saline or IV glucose for severe hyponatremia/hypoglycemia
9. Avoid/minimize sedatives; monitor medication levels (drug metabolism is impaired)

SPECIAL CONSIDERATIONS

• Pseudotumor cerebri (rare): may occur in children on LT4 replacement, idiosyncratic, presents months after starting treatment
• TSH screening: recommended in women planning pregnancy; high-risk individuals (family history, autoimmune disease, prior neck irradiation)

Hypothyroidism - Harrison's 22nd Edition

1. DEFINITION

• Insufficient production of thyroid hormone
• Worldwide: Iodine deficiency = most common cause
• Iodine-sufficient areas: Autoimmune (Hashimoto's) + iatrogenic = most common

2. CAUSES

🔵 Primary

🟡 Transient

• Silent thyroiditis (including postpartum)
• Subacute thyroiditis
• Withdrawal of supraphysiologic thyroxine
• After ¹³¹I or subtotal thyroidectomy for Graves'

🔴 Secondary (Central)

• Hypopituitarism (tumors, surgery, Sheehan's, irradiation)
• Isolated TSH deficiency (very rare)
• Drugs: bexarotene, mitotane
• Hypothalamic disease (tumors, trauma, Prader-Willi)

3. CONGENITAL HYPOTHYROIDISM

Prevalence

• 1 in 2000-4000 newborns
• Neonatal screening done in most industrialized countries
• 2x more common in girls

Causes

• Thyroid gland dysgenesis → 65%
• Inborn errors of synthesis (dyshormonogenesis) → 30%
• TSH-R antibody-mediated → 5%

Genetic Categories

1. Central - abnormal hypothalamic-pituitary development (PROP-1, PIT-1, IGSF1, TSHβ mutations)
2. Dysgenesis - abnormal thyroid development (TTF-1, TTF-2/FOXE-1, PAX-8, NKX2-1, NKX2-5, GLIS3 mutations)
3. Dyshormonogenesis - abnormal hormone synthesis/processing

Key Points

• Transient if mother has TSH-R blocking antibodies or took antithyroid drugs
• Untreated → cretinism (intellectual disability, short stature, neurological deficits)
• Maternal thyroid hormone crosses placenta and partially supports fetus before fetal thyroid functions

4. AUTOIMMUNE HYPOTHYROIDISM (Hashimoto's Thyroiditis)

Classification

• Goitrous type → Hashimoto's thyroiditis (goiter present)
• Atrophic type → Minimal residual thyroid tissue (usually end-stage Hashimoto's)
• A distinct form exists with IgG4-positive plasma cell infiltration

Progression

• Autoimmune destruction gradually reduces thyroid function
• Phase 1: TSH rises but T4 normal → Subclinical hypothyroidism
• Phase 2: T4 falls, TSH >10 mIU/L → Overt/Clinical hypothyroidism

Prevalence

• Incidence: 4/1000 women/year, 1/1000 men/year
• More common in Japanese (genetic + high-iodine diet)
• Typical age: 30-50 years; mean diagnosis age: 60 years
• Subclinical hypothyroidism: 6-8% women (10% if >60 yrs), 3% men
• Annual progression to clinical hypothyroidism: ~4% if TPO antibody positive

Pathology (Histology)

• Marked lymphocytic infiltration with germinal center formation
• Oxyphil (Hürthle cell) metaplasia of thyroid follicles
• Absence of colloid
• Mild to moderate fibrosis
• Atrophic type: extensive fibrosis, less lymphocytes, follicles almost absent

Pathogenesis - Genetic Factors

• HLA-DR3, DR4, DR5 (Caucasians) - best documented risk factors
• PTPN22 and CTLA-4 polymorphisms
• Same genetic associations shared with: Type 1 DM, Addison's, pernicious anemia, vitiligo
• Chromosome 21 gene → association with Down's syndrome
• Female preponderance → sex steroids + X-linked factors (also explains Turner's syndrome link)

Pathogenesis - Environmental Factors

• High iodine / low selenium intake → increased risk
• Decreased exposure to microorganisms in childhood → increased risk
• Smoking cessation → transiently increases incidence
• Alcohol intake → appears protective

Pathogenesis - Immune Mechanisms

• CD8+ cytotoxic T cells → primary mediators of thyroid cell destruction
• Local cytokines (TNF, IL-1, IFN-γ) → promote apoptosis of thyroid cells
• TPO antibodies → present in >90% of patients
• Thyroglobulin (Tg) antibodies → present in ~60%
• TSH-R blocking antibodies → especially in atrophic thyroiditis
• Antibodies = markers of disease; direct pathogenic role is secondary

5. CLINICAL FEATURES

Symptoms

• Tiredness, fatigue
• Cold intolerance
• Weight gain (modest - mainly myxedematous fluid)
• Constipation
• Depression, poor concentration
• Muscle cramps, myalgia, weakness
• Irregular menses, menorrhagia
• Dry skin, hair loss, brittle nails
• Hoarse voice, macroglossia
• Carpal tunnel syndrome
• Hearing impairment
• Infertility

Signs

• Dry, coarse, pale/yellowish skin (carotenemia)
• Puffy face, periorbital edema
• Loss of outer third of eyebrows (longstanding disease)
• Bradycardia
• Goiter OR small/absent thyroid
• Non-pitting edema (myxedema) - glycosaminoglycan deposition
• Delayed DTR relaxation ("hung-up" reflexes) - classic sign
• Diastolic hypertension
• Pleural/pericardial effusions
• Cardiomegaly

Cardiovascular Effects

• Elevated LDL cholesterol + triglycerides
• Increased atherosclerosis and CAD risk
• Pericardial effusion (can be large; tamponade rare)

Neurological/Psychiatric

• Cerebellar ataxia
• Peripheral neuropathy
• Depression → dementia (reversible with treatment)
• "Myxedema madness" (psychosis)

Reproductive

• Anovulation, infertility
• Hyperprolactinemia → galactorrhea (TRH elevations stimulate prolactin)

6. LABORATORY FINDINGS

7. TREATMENT

LT4 (Levothyroxine) - Standard of Care

• Full replacement: ~1.6 μg/kg/day (typically 100-150 μg/day)
• Taken ≥30 min before breakfast
• After Graves' disease treatment: lower doses (75-125 μg/day)

• Check TSH 6-8 weeks after starting or changing dose
• Goal: TSH in lower half of normal range
• Dose adjustments: 12.5-25 μg increments/decrements
• Once stable: annual TSH

• Suppressed TSH (over-treatment) → atrial fibrillation + reduced bone density
• ~10-15% of patients have persistent symptoms despite normal TSH

• ❌ Desiccated thyroid extract (USP) - nonphysiologic T3:T4 ratio
• ❌ LT4 + T3 combination - benefit not confirmed
• ❌ Liothyronine (T3) alone - short half-life, 3-4 doses/day needed, fluctuating levels

Causes of Increased LT4 Requirements

• Poor adherence (most common - patient with high TSH but normal T4 = took tabs just before test)
• Malabsorption: celiac disease, small bowel surgery, H. pylori gastritis
• Oral estrogens or SERMs
• Drugs: bile acid sequestrants, ferrous sulfate, calcium carbonate, PPIs

8. SUBCLINICAL HYPOTHYROIDISM

• ✅ TSH >10 mIU/L
• ✅ Woman wishing to conceive or pregnant

• Most other patients

• Young/middle-aged with symptoms OR cardiac risk

9. HYPOTHYROIDISM IN PREGNANCY

• Untreated maternal hypothyroidism → adverse fetal neural development + miscarriage/preterm delivery
• TSH goal: <2.5 mIU/L (lower half of trimester-specific range)
• Immediately on confirmed pregnancy: Increase LT4 from once-daily to 9 doses/week
• Athyroic women need ~45% more LT4 vs. those with Hashimoto's
• Monitoring: Every 4 weeks (first half) → every 6-8 weeks (after 20 weeks)
• Return to pre-pregnancy dose after delivery
• Separate prenatal vitamins and iron from LT4
• LT4 before conception in euthyroid TPO-antibody positive women → RCTs show NO benefit

10. HYPOTHYROIDISM IN THE ELDERLY

• Require ~20% less thyroxine than younger patients
• Start at 12.5-25 μg/day; increase every 2-3 months
• Full replacement may be impossible in severe CAD
• Emergency surgery: generally safe even if untreated
• Routine surgery: defer until euthyroid

11. SECONDARY (CENTRAL) HYPOTHYROIDISM

• Usually part of pan-hypopituitarism; isolated TSH deficiency = very rare
• TSH may be low, normal, or slightly elevated (bioinactive TSH forms secreted)
• Diagnosis: low free T4 (not TSH)
• Treatment goal: maintain free T4 in upper half of reference range (TSH cannot guide monitoring)

12. MYXEDEMA COMA (Most Severe Form)

Key Facts

• Mortality: 20-40% despite intensive treatment
• Outcomes independent of T4 and TSH levels
• Almost always in the elderly

Clinical Features

• Reduced consciousness (± seizures)
• Hypothermia (can reach 23°C / 74°F)
• All features of severe hypothyroidism

Precipitating Factors

• Drugs: sedatives, anesthetics, antidepressants
• Pneumonia, CHF, MI, GI bleeding, stroke
• Sepsis
• Cold exposure
• Hypoventilation → hypoxia + hypercapnia (major pathogenic role)
• Hypoglycemia, dilutional hyponatremia

Treatment Steps

QUICK MEMORY AID

HYPOTHYROIDISM = "SLOW DOWN"
S - Slow reflexes (hung-up DTRs)
L - Low temperature (cold intolerance)
O - Obesity/weight gain
W - Weakness, fatigue

D - Dry skin, hair loss
O - Outer eyebrow loss
W - Weight gain + constipation
N - No menstruation (menorrhagia/anovulation)