Hypothyroidism¶

Chapter 395 | Part 12: Endocrinology · Part 12 – Endocrinology & Metabolism · Chapter 395

Key Clinical Points¶

A normal TSH level excludes primary (but not secondary) hypothyroidism.
Subclinical hypothyroidism is defined as biochemical evidence of thyroid hormone deficiency with few or no clinical features.
In patients taking ≥200 μg of LT4 daily, an elevated TSH often indicates poor treatment adherence.
Serum TSH decreases in the late first trimester of pregnancy; use 7–12 weeks' gestation range if specific ranges are unavailable.
Approximately 10–15% of patients may have persistent symptoms despite restoration of euthyroidism with LT4.
Suppressed TSH (any cause) increases risk of atrial fibrillation and reduced bone density.
Autoimmune hypothyroidism is more common in populations with high-iodine diets (e.g., Japanese).
Up to 20% of autoimmune cases have TSH-R blocking antibodies, which can cause thyroid atrophy.
For secondary hypothyroidism, the goal is maintaining free T4 in the upper half of the reference interval as TSH cannot monitor therapy.
Early treatment with T4 ensures normal IQ levels; delayed/suboptimal treatment may lead to neurodevelopmental abnormalities.
TPO and Tg antibodies are present in >95% of patients with autoimmune hypothyroidism.
Thyroid peroxidase (TPO) antibodies fix complement, but transplacental passage has no effect on the fetal thyroid.

DEFINITION & CLASSIFICATION¶

• Subclinical Hypothyroidism: ◦ > Definition (Harrison's 22e): biochemical evidence of thyroid hormone deficiency in patients who have few or no apparent clinical features of hypothyroidism. • Overt Hypothyroidism: ◦ Defined as clinical hypothyroidism or overt hypothyroidism. • Autoimmune Hypothyroidism: ◦ Also known as Hashimoto’s thyroiditis; may present as goitrous thyroiditis (with a goiter) or atrophic thyroiditis. • Secondary/Central Hypothyroidism: ◦ Resulting from defects in the pituitary or hypothalamus. • Transient Hypurdothyroidism: ◦ Temporary dysfunction of the thyroid gland. • Congenital Hypothyroidism: ◦ Present at birth.

Classification Systems¶

• Primary: Defect in the thyroid gland. • Secondary: Defect in the pituitary or hypothalamus. • Transient: Temporary dysfunction. • Congenital: Present at birth. • Autoimmune: Hashimoto’s thyroiditis, atrophic thyroiditis.

EPIDEMIOLOGY¶

• Incidence: ◦ Autoimmune hypothyroidism: up to 4 per 1000 women and 1 per 1000 men. • Demographics: ◦ Typically occurs between 30 and 50 years of age. ◦ Prevalence of overt hypothyroidism increases with age. ◦ Subclinical hypothyroidism: 6–8% of women (10% over age 60) and 3% of men. ◦ Mean age at diagnosis: 60 years. • Congenital: ◦ Occurs in about 1 in 2000–4000 newborns; neonatal screening is standard in most industrialized countries. • Gender Predominance: ◦ Higher in females likely due to sex steroid effects on immune response or X chromosome-related factors (e.g., Turner’s syndrome).

ETIOLOGY & PATHOPHYSIOLOGY¶

• Autoimmune Mechanism: ◦ Mediated by CD8+ cytotoxic T cells. ◦ Cytokines (TNF, IL-1, IFN-γ) induce apoptosis via death receptors (Fas) and oxidative stress. ◦ TPO and Tg antibodies are markers of autoimmunity; TPO antibodies fix complement. • TSH-R Antibodies: ◦ Up to 20% of autoimmune cases have TSH-R blocking antibodies. ◦ These do not stimulate the receptor but prevent TSH binding → cause hypothyroidism and thyroid atrophy (especially in Asian patients). ◦ Transplacental passage of these antibodies may cause transient neonatal hypothyroidism.

Primary Hypothyroidism Causes¶

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

Secondary Hypothyroidism Causes¶

• Hypopituitarism: Tumors, surgery/radiation, infiltrative disorders, Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone deficiencies. • Isolated TSH issues: Isolated TSH deficiency or inactivity. • Drugs: bexarotene, mitotane. • Hypothalamic disease: Tumors, trauma, infiltrative disorders, Prader-Willi syndrome.

Transient Hypothyroidism Causes¶

• Silent thyroiditis (including postpartum). • Subacute thyroiditis. • Withdrawal of suptherapeutic thyroxine in patients with intact thyroid. • Post-131I treatment or subtotal thyroidectomy for Graves’ disease.

Genetic Causes of Congenital Hypothyroidism¶

• PROP-1: Central; Homozygous recessive; Combined pituitary deficiencies (except ACTH). • PIT-1: Central; Homozygous/heterozygous loss of function; GH, PRL, and TSH deficiency. • IGSF1: Central; X-linked; Loss of TSH-R expression, testicular enlargement. • TSHβ: Central; Heterozygous loss of function; TSH deficiency. • TTF-1 (TITF-1): Primary; Heterozygous loss of function; Thyroid hypoplasia, choreoathetosis, pulmonary problems. • TTF-2 (FOXE-1): Primary; Homozygous recessive; Thyroid agenesis, choanal atresia, spiky hair. • PAX-8: Primary; Heterozygous loss of function; Thyroid dysgenesis, kidney abnormalities. • NKX2-5: Primary; Heterozygous loss of function; Thyroid dysgenesis, heart abnormalities. • JAG-1: Primary; Heterozygous loss of function; Alagille syndrome type 1, heart abnormalities. • TSH receptor: Primary; Homozygous recessive; Resistance to TSH. • Gαs (Albright hereditary osteodystrophy): Primary; Heterozygous/Homozygous; Resistance to TSH. • DUOX2 (THOX2): Primary; Heterozygous/Homozygous; Organification defect. • Thyroid peroxidase: Primary; Homozygous recessive; Defective organification of iodide. • Pendrin (SLC26A4): Primary; Homozygous recessive; Pendred syndrome (deafness, organification defect). • Dehalogenase 1 (IYD): Primary; Homozygous recessive; Loss of iodide reutilization.

CLINICAL FEATURES¶

• General Presentation: ◦ Onset is usually insidious; patients may only notice symptoms once euthyroid. • Physical Findings: ◦ Skin: Dry, decreased sweating, thinning of epidermis, hyperkeratosis. ◦ Myxedema: Increased dermal glycosaminoglycans → skin thickening without pitting (puffy face, edematous eyelids). ◦ Pigmentation: Pallor with yellow tinge due to carotene accumulation. ◦ Hair/Nails: Retarded nail growth; hair is dry, brittle, and falls out easily (diffuse alopecia). • Systemic Symptoms: ◦ Gastrointestinal: Constipation, weight gain despite poor appetite. ◦ Reproductive: Decreased libido, oligomenorrhea/amenorrhea, increased miscarriage risk. Prolactin may be modestly elevated. • Cardiovascular: ◦ Bradycardia, reduced contractility, increased peripheral resistance (potential hypertension). ◦ Pericardial effusions (up to 30%) and serous cavity effusions. • Neuromuscular/Other: ◦ Slow relaxation of tendon reflexes, pseudomyotonia, carpal tunnel syndrome. ◦ Hoarse voice/clumsy speech due to fluid in vocal cords. • Cognitive: Impaired memory and concentration; rare cases of ataxia or psychosis.

Symptoms and Signs¶

• Common Symptoms: Tiredness, weakness, feeling cold, hair loss, difficulty concentrating, constipation, weight gain, dyspnea, hoarse voice, paresthesia. • Clinical Signs: Dry coarse skin, cool extremities, puffy face/hands/feet (myxedema), diffuse alopecia, bradycardia, peripheral edema, delayed tendon reflex relaxation, carpal tunnel syndrome, serous cavity effusions.

Pediatric Manifestations¶

• Growth: Slow growth and delayed facial/dental maturation. • Pituitary: May be enlarged due to thyrotroph hyperplasia. • Musculoskeletal: Myopathy with muscle swelling (more common in children). • Puberty: Usually delayed; occasionally precocious puberty. • Neurodevelopment: Intellectual impairment if onset is before age 3 and deficiency is severe.

DIFFERENTIAL DIAGNOSIS¶

• Hashimoto’s vs. MNG/Carcinoma: ◦ Asymmetric goiter in Hashimoto's may mimic multinodular goiter (MNG) or carcinoma. ◦ Both MNG and carcinoma can have positive thyroid antibodies. • Lymphoma: ◦ Rare, but strongly associated with preexisting autoimmune thyroiditis. • Imaging Differentiation: ◦ Ultrasound: Shows presence of nodules vs. heterogeneous echogenicity/enlargement in Hashimoto's. ◦ Pseudonodules: Hypoechoic areas from lymphocytic infiltrates; no fine-needle aspirate (FNA) needed.

Distinguishing Features¶

• Hashimoto’s: Asymmetric goiter, heterogeneous echogenicity, antibodies present. • Multinodular Goiter: Multiple nodules, antibodies may be present. • Thyroid Carcinoma: Nodules, antibodies may be present. • Primary Lymphoma: Rare; associated with autoimmune thyroiditis. • Pseudonodules: Hypoechoic areas (lymphocytic infiltrates); no FNA required.

DIAGNOSTIC APPROACH¶

Initial Screening: Measure TSH.
If TSH is Elevated:
Measure unbound T4 (FT4).
If FT4 is Normal → Determine if patient is TPOAb^+ or symptomatic.
Yes → Consider T4 treatment.
No → Annual follow-up.
If FT4 is Low → Confirm etiology.
If TPOAb^+ → Autoimmune hypothyroidism → T4 treatment.
If TPOAb^- → Rule out other causes of hypothyroidism → T4 treatment.
If TSH is Normal:
Assess for pituitary disease.
If Pituitary Disease Suspected?
No → No further tests (likely mild primary hypothyroidism).
Yes → Measure FT4.
If FT4 is Normal → No further tests.
If FT4 is Low → Rule out drug effects, sick euthyroid syndrome, then evaluate anterior pituitary function.

Laboratory Evaluation¶

• TSH: Primary screening test. • Unbound T4: Confirms clinical hypothyroidism if TSH is elevated; used to monitor secondary hypothyroidism (target: upper half of reference range). • TPO/Tg Antibodies: Present in >95% of autoimmune cases. • Other Labs: - Creatine phosphokinase: Increased. - Cholesterol/Triglycerides: Elevated. - Anemia: Normocytic or macrocytic.

MANAGEMENT & TREATMENT¶

Initial Dosing (No residual function):
Standard: 1.6 μg/kg body weight (typically 100–150 μg) daily.
Timing: Ideally taken at least 30 min before breakfast.
Special Cases:
Post-Graves' disease: Lower doses typically required (75–125 μg/d).
Adults <60 w/o heart disease: Start at 50–100 μg daily.
Monitoring & Adjustment:
TSH response is gradual; measure 6–8 weeks after dose change.
Adjustments: 12.5- or 25-μg increments.
Goal: Normal TSH (ideally in lower half of range).
Clinical Timing:
Clinical effects are slow; full relief may take months after TSH normalization.
Adherence & Safety:
Suppressed TSH → Risk of atrial fibrillation and reduced bone density.
High TSH with high FT4 (in patients on ≥200 μg) → Sign of poor adherence.
Missed dose: Take two doses at once (T4 half-life is 7 days).
Pregnancy:
Monitor to ensure euthyroidism; TSH drops in late first trimester.
Drug Interactions/Malabsorption:
Rule out: Celiac, small-bowel surgery, gastritis (H. pylori), etc.
Drugs interfering with T4: Calcium, iron, proton pump inhibitors, amiodarone, carbamazepine, phenytoin, tyrosine kinase inhibitors.

Treatment Strategy¶

• Trial of Treatment: Consider for young/middle-aged patients with symptoms or heart risk. • Confirmation: Ensure TSH elevation is sustained over 3 months before starting treatment. • Initial Dose (Symptomatic): Start at 25–50 μg/d to normalize TSH.

COMPLICATIONS & PROGNOSIS¶

• Persistent Symptoms: 10–15% of patients may have symptoms despite euthyroidism. • Over-treatment (Suppressed TSH): - Increased risk of atrial fibrillation. - Reduced bone density. • Neurodevelopmental: Delayed treatment or severe initial deficiency can lead to subtle abnormalities; early treatment ensures normal IQ.

SPECIAL POPULATIONS¶

• Pregnancy: - Maternal hypothyroidism affects fetal neural development and increases risk of miscarriage/preterm delivery. - Monitor TSH to maintain euthyroidism throughout pregnancy. • Pediatrics: - Focus on growth, puberty, and myopathy; early treatment is critical for IQ.

KEY PEARLS & HIGH-YIELD POINTS¶

• T4 vs. TSH: TSH is superior for screening; FT4 is required to confirm clinical hypothyroidism when TSH is elevated. • Adherence Trap: High TSH with high/normal FT4 in a patient on ≥200 μg LT4 indicates they only took the pill recently before the blood draw. • TPO Antibodies: Presence in >95% of autoimmune cases; not required for diagnosis but useful to confirm etiology. • Secondary Hypothyroidism: TSH cannot be used to monitor therapy; must maintain FT4 in the upper half of the reference range. • Drug Interactions: Many common drugs (e.g., PPIs, calcium, iron) interfere with LT4 absorption.

Reference Tables¶

TABLE 395-1 Causes of Hypothyroidism Primary Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis…¶

Harrison's 22e, p.3027

Primary
Autoimmune hypothyroidism: Hashimoto’s thyroiditis, atrophic thyroiditis
Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of
neck for lymphoma or 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 hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis,
TSH-R mutation
Iodine deficiency
Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma,
cystinosis, Riedel’s thyroiditis
Overexpression of type 3 deiodinase in infantile hemangioma and other tumors
Transient
Secondary
Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders,
Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone
deficiencies
Isolated TSH deficiency or inactivity
Drugs: bexarotene, mitotane
Hypothalamic disease: tumors, trauma, infiltrative disorders, Prader-Willi
syndrome

TABLE 395-2 Examples of Genetic Causes of Congenital Hypothyroidism¶

Harrison's 22e, p.3028

DEFECTIVE GENE PROTEIN	TYPE OF HYPOTHYROIDISM	INHERITANCE	CONSEQUENCES
PROP-1	Central, hypothyroidism	Homozygous recessive	Combined pituitary hormone deficiencies, including thyroid-stimulating hormone (TSH), with preservation of adrenocorticotropic hormone
	Central, hypothyroidism	Homozygous or heterozygous loss of function
IGSF1	Central, hypothyroidism	X-linked loss of function	Loss of TSH receptor (TSH-R) expression, testicular enlargement
	Central, hypothyroidism	Heterozygous loss of function
TTF-1 (TITF-1)	Primary, thyroid dysgenesis	Heterozygous loss of function	Variable thyroid hypoplasia, choreoathetosis, pulmonary problems
	Primary, thyroid dysgenesis	Homozygous recessive
PAX-8	Primary, thyroid dysgenesis	Heterozygous loss of function	Thyroid dysgenesis, kidney abnormalities
	Primary, thyroid dysgenesis	Heterozygous loss of function
NKX2-5	Primary, thyroid dysgenesis	Heterozygous loss of function	Thyroid dysgenesis, heart abnormalities
	Primary, thyroid dysgenesis	Homozygous recessive
JAG-1	Primary, thyroid dysgenesis	Heterozygous loss of function	Thyroid dysgenesis, Alagille syndrome type 1, heart abnormalities
	Primary, thyroid dysgenesis and dyshormonogenesis	Homozygous recessive
Gα (Albright hereditary S osteodystrophy)	Primary, thyroid dyshormonogenesis	Heterozygous loss of function, imprinting	Resistance to TSH
	Primary, thyroid dyshormonogenesis	Homozygous recessive
DUOX2 (THOX2)	Primary, thyroid dyshormonogenesis	Heterozygous loss of function	Organification defect
	Primary, thyroid dyshormonogenesis	Homozygous recessive
Thyroid peroxidase	Primary, thyroid dyshormonogenesis	Homozygous recessive	Defective organification of iodide
	Primary, thyroid dyshormonogenesis	Homozygous recessive
Pendrin (SLC26A4)	Primary, thyroid dyshormonogenesis	Homozygous recessive	Pendred syndrome: sensorineural deafness and partial organification defect in thyroid
	Primary, thyroid dyshormonogenesis	Homozygous recessive

TABLE 395-3 Signs and Symptoms of Hypothyroidism (Descending Order of Frequency) SYMPTOMS Tiredness, weakness Dry skin…¶

Harrison's 22e, p.3028

SYMPTOMS	SIGNS
Tiredness, weakness Dry skin Feeling cold Hair loss Difficulty concentrating and poor memory Constipation Weight gain with poor appetite Dyspnea Hoarse voice Menorrhagia (later oligomenorrhea or amenorrhea) Paresthesia Impaired hearing	Dry coarse skin; cool peripheral extremities Puffy face, hands, and feet (myxedema) Diffuse alopecia Bradycardia Peripheral edema Delayed tendon reflex relaxation Carpal tunnel syndrome Serous cavity effusions