Hypothyroidism

Hypothyroidism

1. Introduction and Overview

Definition:

Hypothyroidism is a clinical syndrome resulting from insufficient production of thyroid hormones (T3 and T4), leading to a generalized reduction in basal metabolic rate and multisystem dysfunction.

Epidemiology:

• Prevalence:

  • Affects 4-10% of the global population, with higher rates in iodine-deficient regions.

  • Subclinical hypothyroidism prevalence: ~5-10%.

• Age: More common in older adults but can occur at any age.

• Sex: Affects women more than men (5-8 times higher prevalence).

• Ethnic Predisposition: More prevalent in Caucasians and Asians.

Relevance:

Untreated hypothyroidism can lead to severe complications such as myxedema coma, cardiovascular disease, infertility, and neurodevelopmental delays in congenital cases.

2. Etiology

Primary Causes:

1. Autoimmune Thyroiditis:

   • Hashimoto’s Thyroiditis (most common): Chronic lymphocytic thyroiditis causing gradual thyroid destruction.

   • Postpartum thyroiditis.

2. Iodine Deficiency: Most common cause globally.

3. Iatrogenic Causes:

   • Thyroidectomy, radioactive iodine therapy, external beam radiation.

4. Congenital Hypothyroidism:

   • Dysgenesis, agenesis, or dyshormonogenesis of the thyroid gland.

Secondary Causes:

1. Pituitary Dysfunction:

   • Inadequate TSH production due to pituitary adenomas or injury.

2. Hypothalamic Dysfunction:

   • Impaired TRH secretion (e.g., hypothalamic tumors, infiltrative diseases).

Risk Factors:

• Family history of autoimmune diseases.

• Female sex.

• Use of medications such as lithium, amiodarone.

• Prior neck irradiation or surgery.

3. Pathophysiology

Normal Physiology:

• The hypothalamic-pituitary-thyroid axis regulates thyroid hormone synthesis via TRH, TSH, and feedback inhibition.

• Thyroid hormones (T3 and T4) are critical for metabolism, thermogenesis, growth, and development.

Mechanisms of Disease:

1. Primary Hypothyroidism:

   • Destruction or dysfunction of thyroid tissue leads to reduced T3/T4 production and elevated TSH.

2. Secondary Hypothyroidism:

   • TSH deficiency causes inadequate stimulation of the thyroid gland.

3. Tertiary Hypothyroidism:

   • TRH deficiency impairs TSH secretion and thyroid function.

Key Pathways:

• Decreased thyroid hormones result in reduced mitochondrial oxidative phosphorylation, decreased heat production, and accumulation of glycosaminoglycans causing myxedema.

4. Clinical Features

Symptoms:

1. General: Fatigue, lethargy, cold intolerance, weight gain.

2. Neurological: Depression, memory impairment, slowed thinking.

3. Dermatological: Dry skin, hair thinning, brittle nails.

4. Cardiovascular: Bradycardia, decreased cardiac output.

5. Gastrointestinal: Constipation.

6. Reproductive: Menorrhagia, infertility, decreased libido.

Signs:

1. Physical Exam:

   • Puffy face, periorbital edema, macroglossia.

2. Dermatological:

   • Myxedema (non-pitting edema), dry, scaly skin.

3. Neurological:

   • Delayed deep tendon reflexes (hung-up reflex).

4. Cardiovascular:

   • Diminished heart sounds, pericardial effusion.

Stages and Progression:

• Subclinical Hypothyroidism: Mild elevation of TSH with normal T3/T4.

• Overt Hypothyroidism: Elevated TSH with low T3/T4.

• Myxedema Coma: Life-threatening severe hypothyroidism with hypothermia, bradycardia, and altered mental status.

Differentiating Features:

• Distinguished from other causes of fatigue or weight gain by specific symptoms (e.g., cold intolerance, bradycardia).

5. Diagnostic Approach

Clinical Diagnosis:

• Detailed history and physical examination focusing on symptoms of hypothyroidism.

Laboratory Investigations:

1. Thyroid Function Tests:

   • Elevated TSH with low free T4 confirms primary hypothyroidism.

   • Low/normal TSH with low T4 suggests secondary or tertiary hypothyroidism.

2. Autoimmune Markers:

   • Antithyroid peroxidase (anti-TPO) and antithyroglobulin antibodies (Hashimoto’s).

3. Other Tests:

   • Lipid profile (hypercholesterolemia common).

Imaging Studies:

1. Ultrasound:

   • Used for structural abnormalities (e.g., nodules, goiter).

2. MRI/CT:

   • Pituitary imaging in secondary hypothyroidism.

Functional Testing:

• TRH stimulation test to differentiate secondary from tertiary causes.

Diagnostic Criteria:

• Overt hypothyroidism: Elevated TSH and low free T4.

• Subclinical hypothyroidism: Elevated TSH with normal T4.

6. Management

Medical Management:

1. Hormone Replacement Therapy:

   • Levothyroxine (LT4):

     • First-line therapy.

     • Dosage: 1.6 mcg/kg/day, adjusted based on TSH levels.

     • Side effects: Overreplacement can lead to hyperthyroidism symptoms.

   • Start with lower doses in elderly or cardiac patients (e.g., 12.5–25 mcg/day).

2. Adjunctive Therapy:

   • Treat hyperlipidemia and associated anemia if present.

Surgical Management:

• Rarely indicated unless hypothyroidism is associated with large goiter causing obstructive symptoms.

Emergency Management:

• Myxedema Coma:

  • IV levothyroxine and hydrocortisone.

  • Supportive care: Warming, fluids, electrolyte correction.

7. Prognosis

Natural History:

• Without treatment, hypothyroidism progresses to complications like myxedema coma or cardiovascular disease.

Outcomes with Treatment:

• Excellent prognosis with timely and appropriate levothyroxine replacement.

Long-Term Impacts:

• Risk of osteoporosis or atrial fibrillation with overreplacement.

8. Complications

Primary Disease Complications:

1. Cardiovascular:

   • Atherosclerosis, coronary artery disease, heart failure.

2. Neurological:

   • Cognitive impairment, peripheral neuropathy.

3. Myxedema coma (severe untreated cases).

Therapeutic Complications:

• Overreplacement causing subclinical or overt hyperthyroidism.

9. Prevention

Primary Prevention:

• Iodine supplementation in iodine-deficient areas.

Secondary Prevention:

• Screening in high-risk populations (e.g., postpartum women, elderly).

Tertiary Prevention:

• Regular monitoring of TSH and T4 during treatment to prevent complications.

10. Patient Education

Disease Understanding:

• Explain hypothyroidism, its symptoms, and the role of hormone replacement therapy.

Self-Monitoring:

• Report any signs of under- or over-replacement (e.g., fatigue, palpitations).

Lifestyle Advice:

• Maintain a balanced diet and regular exercise. Avoid iodine-rich supplements without medical advice.

When to Seek Help:

• Symptoms of severe hypothyroidism or myxedema coma.

11. Recent Research and Advances

• New Diagnostic Tools: Emerging biomarkers for early detection of hypothyroidism.

• T3 Supplementation: Studies exploring combined T3/T4 therapy in select patients.

• Gene Therapy: Investigating genetic approaches to treat congenital hypothyroidism.

12. Case Studies

Example:

A 50-year-old woman presents with fatigue, weight gain, and dry skin. Lab tests reveal elevated TSH and low T4, confirming hypothyroidism. She is started on levothyroxine, and symptoms resolve within 3 months.

13. References

1. American Thyroid Association (ATA) Guidelines for Hypothyroidism (2022).

2. Harrison’s Principles of Internal Medicine, 21st Edition.

3. Brunicardi FC, Andersen DK, Billiar TR. Schwartz's Principles of Surgery, 11th Edition.