What is hypothyroidism, its pathophysiology, and management?

Hypothyroidism: From Anatomy to Management

Hypothyroidism is a common endocrine disorder characterized by insufficient thyroid hormone production, requiring lifelong hormone replacement therapy with levothyroxine as the standard treatment, with dosing based on patient characteristics and regular monitoring of thyroid function tests.

Anatomy and Physiology

• The thyroid gland is a butterfly-shaped organ located in the anterior neck
• Composed of two lobes connected by an isthmus
• Primary function is production of thyroid hormones:
  • Thyroxine (T4): main hormone secreted by the thyroid
  • Triiodothyronine (T3): more active form, mostly converted from T4 in peripheral tissues
• Thyroid hormone production is regulated by the hypothalamic-pituitary-thyroid axis:
  • Hypothalamus produces thyrotropin-releasing hormone (TRH)
  • TRH stimulates pituitary to release thyroid-stimulating hormone (TSH)
  • TSH stimulates thyroid gland to produce T4 and T3
  • Negative feedback loop: T3/T4 inhibit TRH and TSH production

Pathophysiology

Hypothyroidism is classified based on the level of dysfunction:

1. Primary hypothyroidism (most common, >95% of cases):

   • Dysfunction of the thyroid gland itself
   • Characterized by elevated TSH and low free T4
   • Main causes:
     • Chronic autoimmune thyroiditis (Hashimoto's disease) - most common in developed countries 1
     • Iodine deficiency - most common worldwide 2
     • Post-surgical or post-radiation thyroid gland destruction
     • Medications (amiodarone, lithium)

2. Secondary/Central hypothyroidism:

   • Dysfunction at pituitary or hypothalamic level
   • Characterized by low/normal TSH and low free T4
   • Requires evaluation of other pituitary hormones 1

3. Subclinical hypothyroidism:

   • Elevated TSH with normal free T4 and T3
   • May progress to overt hypothyroidism at rate of 2-5% annually 1

Clinical Presentation

Symptoms of hypothyroidism result from decreased metabolic rate and include:

• Fatigue and weakness
• Cold intolerance
• Weight gain despite normal or decreased appetite
• Constipation
• Dry skin and hair loss
• Hoarseness and voice changes
• Menstrual irregularities
• Memory impairment and depression
• Myalgias and arthralgias

Advanced hypothyroidism may lead to:

• Myxedema (non-pitting edema)
• Bradycardia and hypothermia
• Delayed relaxation of deep tendon reflexes
• Myxedema coma (life-threatening emergency)

Diagnosis

Diagnosis is primarily laboratory-based:

1. Primary screening test:

   • Serum TSH measurement 2
   • Most sensitive indicator of thyroid dysfunction

2. Confirmatory tests:

   • Free T4 (FT4) level
   • Free T3 (FT3) level in select cases

3. Additional testing (when indicated):

   • Anti-thyroid peroxidase (anti-TPO) antibodies to confirm autoimmune etiology
   • Anti-thyroglobulin antibodies
   • Lipid panel (often elevated in hypothyroidism)

Imaging has no role in the initial workup of hypothyroidism in adults 2.

Management

Indications for Treatment

Definite indications for treatment 3, 1:

• All patients with overt hypothyroidism
• Subclinical hypothyroidism with TSH >10 mIU/L
• Pregnant women or women planning pregnancy with any degree of hypothyroidism
• Patients with goiter or positive anti-TPO antibodies

Controversial indications (individualized approach) 3, 1:

• Subclinical hypothyroidism with TSH ≤10 mIU/L in non-pregnant adults
• Consider treatment if symptomatic or with infertility

Medication Selection

Levothyroxine (T4) monotherapy is the standard treatment 3, 1:

• Replaces the main hormone produced by thyroid gland
• Long half-life allows once-daily dosing
• Peripheral conversion to T3 maintains physiologic hormone levels

Dosing Guidelines

Starting dose depends on age, weight, and comorbidities 3:

Population	Starting Dose	Target TSH Range
Adults <70 years without cardiac disease	1.6 mcg/kg/day	0.5-2.0 mIU/L
Elderly patients or those with cardiac conditions	25-50 mcg/day	1.0-4.0 mIU/L
Pregnant women	Adjusted to restore TSH to trimester-specific reference range	0.5-2.0 mIU/L

Special considerations:

• In severe and prolonged hypothyroidism, adrenocortical insufficiency may be present and should be corrected before starting thyroid replacement 4
• In central hypothyroidism, treatment is monitored using free T4 levels, not TSH 3

Monitoring

1. Initial follow-up:

   • Check TSH and free T4 6-8 weeks after starting therapy or changing dose 3
   • Adjust dose as needed to achieve target TSH

2. Long-term monitoring:

   • Once stable, check TSH every 6-12 months 3
   • More frequent monitoring in pregnancy, changing medication regimens, or suspected non-compliance

Potential Complications of Treatment

• Overtreatment can lead to iatrogenic hyperthyroidism
• Risks include atrial fibrillation and osteoporosis, particularly in elderly patients 3, 1
• Rapid replacement in patients with coronary artery disease may precipitate angina or myocardial infarction 4

Special Populations

Elderly Patients

• Start with lower doses (12.5-25 mcg/day)
• Increase gradually every 6-8 weeks
• Target higher TSH (1.0-4.0 mIU/L) 3
• Consider avoiding treatment in patients >85 years with mild subclinical hypothyroidism 3

Pregnant Women

• Increase weekly levothyroxine dose by 30% upon confirmation of pregnancy 5
• Monitor TSH every 4-6 weeks during pregnancy
• Adjust dose to maintain trimester-specific TSH targets

Patients with Heart Disease

• Start with very low dose (12.5-25 mcg/day)
• Increase by small increments (12.5-25 mcg) every 6-8 weeks
• Monitor for cardiac symptoms

Conclusion

Hypothyroidism is a common endocrine disorder that requires lifelong management. With appropriate diagnosis and treatment, most patients can achieve normal thyroid function and resolution of symptoms. Regular monitoring and dose adjustments are essential for optimal management.