Hypothyroidism¶
Chapter 395 | Part 12: Endocrinology and Metabolism
KEY CLINICAL POINTS¶
- Neonatal screening for congenital hypothyroidism is critical to prevent irreversible neurodevelopmental damage.
- Autoimmune hypothyroidism (Hashimoto’s thyroiditis) is the most common cause in iodine-sufficient regions.
- Thyroid ultrasound is essential for evaluating nodules, assessing size, and guiding fine-needle aspiration (FNA).
- Levothyroxine (LT4) replacement is the mainstay of treatment, with dosing adjusted based on TSH levels.
- Subclinical hypothyroidism requires monitoring, especially in pregnant women or those planning pregnancy.
1. DEFINITION & OVERVIEW¶
Hypothyroidism is a condition characterized by insufficient thyroid hormone production, leading to metabolic and physiological dysfunction. It can be primary (thyroid gland failure), secondary (hypothalamic/pituitary dysfunction), or tertiary (hypothalamic dysfunction).
Table 395-1: Causes of Hypothyroidism¶
| Category | Causes | Notes |
|---|---|---|
| Primary | Autoimmune (Hashimoto’s), Iatrogenic (131I, surgery), Drugs (lithium, amiodarone), Iodine deficiency | |
| Secondary | Hypopituitarism, TSH deficiency, Hypothalamic disease | |
| Transient | Silent thyroiditis, Postpartum thyroiditis, Subacute thyroiditis | |
| Congenital | Thyroid dysgenesis, Dyshormonogenesis, TSH-R mutations |
1.1 Clinical Spectrum¶
Hypothyroidism ranges from subclinical (elevated TSH with normal free T4) to overt (symptoms and signs of hypothyroidism). Congenital hypothyroidism is a medical emergency requiring immediate treatment.
1.2 Diagnostic Imaging¶
Thyroid ultrasound is the primary tool for evaluating nodules, assessing size, and guiding FNA. It helps differentiate benign vs. malignant nodules based on sonographic features (e.g., hypoechoic, irregular borders, microcalcifications).
2. EPIDEMIOLOGY¶
Iodine deficiency remains a global cause of hypothyroidism. In iodine-sufficient regions, autoimmune disease (Hashimoto’s) and iatrogenic causes are most common. Congenital hypothyroidism occurs in 1 in 2000–4000 newborns, with 65% due to thyroid dysgenesis.
2.1 Demographics¶
Autoimmune hypothyroidism is more common in women (female preponderance), especially postmenopausal. It peaks in 60-year-olds. Subclinical hypothyroidism affects 6–8% of women >60 years.
2.2 Risk Factors¶
Genetic predisposition (HLA-DR3/DR4), female sex, autoimmune comorbidities (T1DM, Addison’s, vitiligo), iodine excess, selenium deficiency, and smoking cessation.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Autoimmune destruction of thyroid follicles (Hashimoto’s), iodine deficiency, iatrogenic causes (surgery, radioiodine), and genetic mutations (e.g., TTF-1, NKX2-1) are key mechanisms. Thyroid lymphocytic infiltration and cytokine-mediated apoptosis drive pathogenesis.
Table 395-2: Genetic Causes of Congenital Hypothyroidism¶
| Defective Gene | Protein | Type of Hypothyroidism | Inheritance | Consequences |
|---|---|---|---|---|
| PROP-1 | Pituitary transcription factor | Central | Homozygous recessive | Combined pituitary hormone deficiencies |
| TTF-1 (TITF-1) | Transcription factor | Primary (thyroid dysgenesis) | Heterozygous loss of function | Thyroid hypoplasia, pulmonary issues |
| NKX2-1 | Homeobox transcription factor | Primary | Heterozygous loss of function | Thyroid dysgenesis, brain/lung abnormalities |
| DUOX2 | Thyroid peroxidase | Primary (dyshormon ogenesis) | Heterozygous loss of function | Organification defect |
3.1 Autoimmune Mechanisms¶
TPO and thyroglobulin antibodies mediate thyroid destruction. TSH-R-blocking antibodies cause hypothyroidism and thyroid atrophy. Complement activation and T-cell infiltration are central to pathogenesis.
3.2 Genetic Causes¶
Mutations in PROP-1, TTF-1, NKX2-1, and other genes cause congenital hypothyroidism. These defects lead to thyroid dysgenesis, dyshormonogenesis, or central hypothyroidism.
4. CLINICAL FEATURES¶
Symptoms include fatigue, weight gain, cold intolerance, dry skin, constipation, and depression. Signs include myxedema, bradycardia, delayed reflexes, and goiter. Congenital cases present with jaundice, feeding difficulties, and umbilical hernia.
Table 395-3: Signs and Symptoms of Hypothyroidism¶
| Symptoms | Signs |
|---|---|
| Fatigue, weakness | Dry skin, cool extremities |
| Cold intolerance | Puffy face, nonpitting edema |
| Weight gain | Bradycardia, delayed reflexes |
| Constipation | Carpal tunnel syndrome |
| Depression | Paresthesia, impaired hearing |
4.1 Adult Manifestations¶
Fatigue, weight gain, cold intolerance, dry skin, constipation, depression, and peripheral edema. Severe cases may present with myxedema coma.
4.2 Pediatric Features¶
Slow growth, delayed maturation, intellectual impairment (if untreated before age 3), and delayed puberty. Thyroid enlargement may be present.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate from multinodular goiter, thyroid cancer, and other causes (e.g., pituitary disease, drug-induced hypothyroidism). Asymmetric goiter in Hashimoto’s may mimic thyroid cancer or lymphoma.
5.1 Imaging Findings¶
Ultrasound distinguishes Hashimoto’s (heterogeneous echogenicity) from thyroid cancer (solid nodules with irregular borders). Pseudonodules (lymphocytic infiltrates) may mimic true nodules.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis relies on elevated TSH and low free T4. TPO antibodies confirm autoimmune etiology. Neonatal screening uses TSH testing. Algorithm in Figure 395-2 guides evaluation.
Table 395-2: Secondary Causes of Hypothyroidism¶
| Cause | Description |
|---|---|
| Hypopituitarism | Tumors, surgery, irradiation, Sheehan’s syndrome |
| Isolated TSH deficiency | Drug-induced (bexarotene, mitotane) |
| Hypothalamic disease | Tumors, trauma, Prader-Willi syndrome |
6.1 Laboratory Tests¶
TSH, free T4, TPO antibodies, and thyroglobulin antibodies. Serum T3 and reverse T3 may be used in complex cases.
6.2 Diagnostic Algorithm¶
- Measure TSH. 2. If elevated, measure free T4. 3. If TSH is low, check for pituitary disease. 4. TPO antibodies confirm autoimmune etiology. 5. FNA for suspicious nodules.
7. MANAGEMENT & TREATMENT¶
Levothyroxine (LT4) is the standard therapy. Dosing is adjusted based on TSH levels. Special considerations include pregnancy, elderly patients, and drug interactions.
7.1 LT4 Replacement¶
Dose: 1.6 µ g/kg/day (100–150 µ g/day). Start with 25–50 µ g/day, titrate based on TSH. Monitor TSH every 6–8 weeks. Avoid concurrent iodine-containing agents.
7.2 Special Populations¶
Pregnancy: Target TSH <2.5 mIU/L preconception. Elderly: Start with lower doses to avoid cardiac decompensation. Drug interactions: Avoid calcium, iron, and antacids with LT4.
8. PROGNOSIS & COMPLICATIONS¶
Untreated hypothyroidism leads to myxedema coma, heart failure, and cognitive decline. Subclinical hypothyroidism may progress to overt disease. Congenital cases require lifelong treatment.
8.1 Complications¶
Cardiac dysfunction, infertility, peripheral neuropathy, and increased risk of atrial fibrillation with LT4 overreplacement.
9. SPECIAL CONSIDERATIONS¶
Neonatal screening is critical. Congenital hypothyroidism requires immediate LT4 therapy. Monitor for drug interactions and adjust dosing in pregnancy or renal failure.
9.1 Pregnancy¶
Maintain TSH <2.5 mIU/L preconception. Monitor closely due to increased thyroid hormone requirements. Avoid iodine-containing contrast media.
9.2 Pediatric Cases¶
Early treatment prevents intellectual disability. Growth hormone may be needed in severe cases. Monitor for delayed puberty.
10. KEY POINTS & CLINICAL PEARLS¶
- Neonatal screening prevents congenital hypothyroidism. 2. TPO antibodies confirm autoimmune etiology. 3. LT4 dosing is individualized based on age, weight, and TSH. 4. Avoid iodine-containing agents during treatment. 5. Monitor for drug interactions and adjust dosing in special populations.