Drug Therapy of Hypothyroidism

Drug Therapy of Hypothyroidism

1. Definition, scope & rationale for replacement therapy

• Hypothyroidism is the clinical state of thyroid hormone deficiency; when severe it is termed myxedema, after the characteristic non-pitting thickening of subcutaneous tissue (Ord, 1878, attributed it to excess "mucus") (G&G 13e Ch.47, pp.947, 943).
• It is the most common disorder of thyroid function (G&G 13e Ch.47, p.947).
• Therapeutic principle: hypothyroidism is treated by thyroid hormone replacement — restoring circulating hormone to physiological levels. Unlike hyperthyroidism (which needs synthesis-blocking/ablative drugs), hypothyroidism needs supply of the deficient hormone (G&G 13e Ch.47, p.941; KDT 8e Ch.18, p.272).
• The thyroid normally secretes predominantly the prohormone T₄ (thyroxine), which is converted in liver and peripheral tissues to the active hormone T₃ (3,5,3′-triiodothyronine); replacement therapy exploits this by giving T₄ and letting the body generate T₃ (G&G 13e Ch.47, pp.941, 949).
• Most important use of thyroid hormone is replacement therapy in deficiency states, and synthetic l-thyroxine (levothyroxine) is the preparation of choice (KDT 8e Ch.18, p.272).

1.1 Aetiological classification of hypothyroidism (drives the monitoring target)

• Primary hypothyroidism — failure of the thyroid gland itself; serum TSH is elevated with low/low-normal free T₄. This is the basis for using TSH as the monitoring target (G&G 13e Ch.47, p.947).
• Worldwide, iodine deficiency is the commonest cause; in iodine-sufficient (non-endemic) areas, chronic autoimmune (Hashimoto) thyroiditis — antibodies against thyroid peroxidase (TPO) and sometimes thyroglobulin — accounts for most cases (G&G 13e Ch.47, p.947; KDT 8e Ch.18, p.272).
• Central hypothyroidism — diminished TSH stimulation: secondary (pituitary failure) or tertiary (hypothalamic failure); here only free T₄ is decreased and TSH is NOT reliable, so free T₄ is the monitoring target (G&G 13e Ch.47, p.947).
• Congenital hypothyroidism (congenital iodine deficiency syndrome / "cretinism") — endemic (severe environmental iodine deficiency) or sporadic (abnormal thyroid development or a hormone-synthesis defect); a major preventable cause of intellectual disability (G&G 13e Ch.47, pp.947, 949; KDT 8e Ch.18, p.272).
• Drug-induced hypothyroidism — important culprits: radioactive iodine (¹³¹I), iodides, lithium, and amiodarone (KDT 8e Ch.18, p.272).

1.2 Clinical features (target organs to track on therapy)

• Symptoms: fatigue, lethargy, cold intolerance, mental slowness/depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches/stiffness, irregular menses, infertility (G&G 13e Ch.47, p.947).
• Signs: goiter (primary only), bradycardia, delayed relaxation phase of deep-tendon reflexes, cool/dry skin, hypertension, non-pitting edema, facial puffiness (G&G 13e Ch.47, p.947).
• Cardiovascular signature: bradycardia, decreased cardiac index, pericardial effusion, increased peripheral vascular resistance, decreased pulse pressure, elevated mean arterial pressure — relevant to over-replacement risk and to cautious dosing in cardiac patients (G&G 13e Ch.47, p.947).
• Hypercholesterolemia is characteristic — T₃ normally up-regulates hepatic LDL receptors (via TRβ1); deficiency raises LDL (G&G 13e Ch.47, p.947).
• T₄ corrects the anaemia of hypothyroidism, suggesting T₄ is facilitatory to erythropoiesis (KDT 8e Ch.18, p.271).