Thyroid Disorders

1. Introduction

Thyroid disorders represent a prevalent category of endocrine dysfunction with profound systemic implications. The thyroid gland, through the synthesis and secretion of the iodothyronine hormones thyroxine (T₄) and triiodothyronine (T₃), regulates fundamental metabolic processes in virtually every tissue. Disorders of thyroid function, which primarily manifest as hormone deficiency (hypothyroidism) or excess (hyperthyroidism), are among the most common endocrine conditions encountered in clinical practice. Their management is a cornerstone of both endocrinology and clinical pharmacology, requiring a precise understanding of hormone physiology, diagnostic interpretation, and therapeutic intervention.

The historical recognition of thyroid disease dates back centuries, with descriptions of goiter found in ancient art and medical texts. The modern era of thyroidology began in the 19th century with the characterization of cretinism and myxedema, followed by the landmark discovery of the curative effect of sheep thyroid extract for myxedema in 1891. The isolation of thyroxine in 1914 and the subsequent elucidation of the hypothalamic-pituitary-thyroid (HPT) axis provided the foundation for contemporary diagnosis and treatment. The development of synthetic levothyroxine and thioamide antithyroid drugs in the mid-20th century revolutionized therapy, establishing pharmacotherapy as the mainstay of management for most patients.

The importance of thyroid disorders in medicine and pharmacology is multifaceted. From a public health perspective, their high prevalence, particularly subclinical disease, necessitates efficient screening and treatment strategies. Pharmacologically, thyroid hormone replacement represents one of the most frequently prescribed long-term therapies worldwide, while antithyroid drugs and other modalities for hyperthyroidism require careful dosing and monitoring due to narrow therapeutic indices and potential adverse effects. The systemic nature of thyroid hormone action means that dysfunction can mimic or exacerbate a wide range of other conditions, making accurate diagnosis essential.

Learning Objectives

• Describe the physiology of the hypothalamic-pituitary-thyroid axis and the synthesis, secretion, and peripheral metabolism of thyroid hormones.
• Differentiate the etiology, pathophysiology, clinical presentation, and diagnostic criteria for primary, secondary, and subclinical hypothyroidism and hyperthyroidism.
• Explain the pharmacology, therapeutic uses, dosing strategies, and monitoring parameters for levothyroxine, liothyronine, and antithyroid drugs (thioamides).
• Analyze the role of other therapeutic modalities in thyroid disorders, including radioactive iodine, surgery, and adjunctive agents like beta-blockers and iodine.
• Develop a systematic approach to the interpretation of thyroid function tests and the management of common clinical scenarios and special populations.

2. Fundamental Principles

Core Concepts and Definitions

The thyroid gland is a butterfly-shaped organ located anterior to the trachea. Its functional unit is the follicle, a spherical structure lined by thyrocytes and filled with colloid, which is primarily composed of thyroglobulin (Tg). Thyroid hormone synthesis is a complex process dependent on adequate dietary iodine intake. The key steps include active iodide transport via the sodium-iodide symporter (NIS), oxidation and organification of iodide onto tyrosine residues within Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT), and coupling of these iodotyrosines to form T₄ (two DIT molecules) and T₃ (one MIT and one DIT molecule). Secretion involves endocytosis and proteolytic cleavage of Tg, releasing T₄ and T₃ into the circulation.

Thyroid hormone transport and metabolism are critical to function. Over 99% of circulating T₄ and T₃ is bound to plasma proteins, primarily thyroxine-binding globulin (TBG), transthyretin, and albumin. Only the free, unbound fraction is biologically active. The majority of circulating T₃, the more metabolically active hormone, is derived from peripheral deiodination of T₄ by deiodinase enzymes (types 1, 2, and 3). Thyroid hormone action is mediated by nuclear thyroid hormone receptors (TRα and TRβ) that function as ligand-activated transcription factors, modulating the expression of a vast array of genes involved in metabolism, thermogenesis, growth, and development.

Theoretical Foundations: The Hypothalamic-Pituitary-Thyroid (HPT) Axis

The HPT axis is a classic endocrine feedback loop. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates thyrotrophs in the anterior pituitary to synthesize and secrete thyroid-stimulating hormone (TSH). TSH binds to its receptor on thyroid follicular cells, stimulating every step of thyroid hormone synthesis and secretion. Circulating T₄ and T₃ exert negative feedback primarily at the pituitary level, suppressing TSH synthesis and secretion, and to a lesser extent at the hypothalamus, inhibiting TRH. This exquisitely sensitive system maintains thyroid hormone levels within a narrow physiological range. The set-point for feedback is such that small changes in free T₄ produce logarithmically inverse changes in TSH, making TSH the most sensitive indicator of thyroid status in primary thyroid disorders.

Key Terminology

• Primary Thyroid Dysfunction: Disorder originating at the level of the thyroid gland (e.g., Hashimoto’s thyroiditis, Graves’ disease).
• Central (Secondary/Tertiary) Thyroid Dysfunction: Disorder due to pituitary (secondary) or hypothalamic (tertiary) disease, leading to inadequate TSH secretion.
• Euthyroid: Normal thyroid function.
• Goiter: Enlargement of the thyroid gland, which may be diffuse or nodular, and toxic or non-toxic.
• Thyrotoxicosis: The clinical state resulting from excessive circulating thyroid hormones, regardless of source.
• Hyperthyroidism: A subset of thyrotoxicosis caused by excessive synthesis and secretion of hormone by the thyroid gland itself.
• Subclinical Disease: Biochemical evidence of thyroid dysfunction (abnormal TSH) with free T₄ and T₃ levels within the reference range.

3. Detailed Explanation

Hypothyroidism: Etiology and Pathophysiology

Hypothyroidism is characterized by insufficient thyroid hormone action on target tissues. Primary hypothyroidism, accounting for over 95% of cases, results from intrinsic thyroid gland failure. The most common cause worldwide is iodine deficiency, while in iodine-sufficient regions, autoimmune thyroiditis (Hashimoto’s disease) is predominant. In Hashimoto’s, cell-mediated and humoral immune responses lead to lymphocytic infiltration, follicular destruction, and eventual fibrosis. Other causes include iatrogenic factors (thyroidectomy, radioiodine therapy), drugs (lithium, amiodarone, tyrosine kinase inhibitors), congenital defects, and infiltrative diseases. Central hypothyroidism, due to pituitary or hypothalamic pathology, is less common and often occurs in the context of other pituitary hormone deficiencies.

The pathophysiological consequences stem from a generalized slowing of metabolic processes. Reduced basal metabolic rate leads to symptoms like fatigue, cold intolerance, and weight gain. Accumulation of glycosaminoglycans in interstitial spaces, particularly in the skin, causes non-pitting edema (myxedema). Cardiovascular effects include bradycardia, decreased cardiac output, and diastolic hypertension. Neurological manifestations range from slowed cognition and depression to peripheral neuropathy. Hypercholesterolemia is common due to reduced LDL receptor expression and clearance.

Hyperthyroidism: Etiology and Pathophysiology

Hyperthyroidism involves excessive thyroid hormone synthesis and secretion. Graves’ disease, an autoimmune disorder, is the most common cause. It is characterized by the production of thyroid-stimulating immunoglobulins (TSI) that bind to and chronically activate the TSH receptor, leading to unregulated hormone production and gland hyperplasia. Other etiologies include toxic multinodular goiter (where autonomous nodules develop), toxic adenoma (a single autonomous nodule), and thyroiditis (inflammation causing leakage of stored hormone, as in subacute or postpartum thyroiditis).

The systemic effects of thyroid hormone excess are essentially the opposite of deficiency, representing a hypermetabolic state. Increased thermogenesis and metabolic rate cause weight loss despite increased appetite, heat intolerance, and sweating. Sympathetic nervous system activation, though catecholamine levels are normal, leads to tachycardia, palpitations, tremor, and anxiety. Increased bone turnover can lead to osteoporosis. In Graves’ disease, unique extrathyroidal manifestations include ophthalmopathy (proptosis, periorbital edema) and dermopathy (pretibial myxedema), mediated by autoimmune reactions against shared antigens in orbital fibroblasts and skin.

Factors Affecting Thyroid Function and Drug Response

Multiple factors can influence thyroid physiology and the pharmacokinetics and pharmacodynamics of thyroid drugs.

*NTIS: Non-thyroidal illness syndrome (euthyroid sick syndrome)

4. Clinical Significance

Relevance to Drug Therapy

The management of thyroid disorders is predominantly pharmacological. For hypothyroidism, the goal is physiological hormone replacement. For hyperthyroidism, the goal is to reduce hormone synthesis, release, or action. The choice of agent, dose, and monitoring strategy is dictated by the specific disorder, its etiology, severity, and patient-specific factors such as age, comorbidities, and reproductive status. Pharmacotherapy must also account for the hormone’s long half-life (≈7 days for levothyroxine) and the delayed onset of full therapeutic effect, as well as the potential for serious adverse effects with antithyroid drugs, such as agranulocytosis and hepatotoxicity.

Practical Applications and Clinical Examples

The interpretation of thyroid function tests (TFTs) is the critical first step. A standard initial test is TSH. If TSH is elevated, free T₄ is measured to confirm primary hypothyroidism. If TSH is suppressed, free T₄ and free T₃ are measured to confirm and characterize thyrotoxicosis. The pattern of TFTs guides the etiological workup (e.g., TSI, thyroid ultrasound, radioactive iodine uptake scan). In central disorders, TSH is not reliable, and diagnosis relies on a low free T₄ in the context of pituitary disease.

Treatment decisions are based on this diagnostic framework. For overt primary hypothyroidism, levothyroxine is initiated at a full (1.6 µg/kg/day) or partial dose, with the goal of normalizing TSH. For subclinical hypothyroidism, treatment may be considered if TSH is >10 mIU/L or if symptomatic with TSH > upper reference limit. For Graves’ hyperthyroidism, first-line therapy in many regions is a thioamide (methimazole or propylthiouracil) to achieve euthyroidism, often followed by definitive therapy with radioactive iodine or surgery. Beta-adrenergic blockers are used adjunctively for symptomatic control of adrenergic symptoms.

5. Clinical Applications and Examples

Case Scenario 1: Primary Hypothyroidism

A 45-year-old female presents with a 6-month history of progressive fatigue, weight gain of 5 kg, dry skin, and cold intolerance. Physical examination reveals a BMI of 28, cool dry skin, mild periorbital puffiness, and a delayed relaxation phase of deep tendon reflexes. Thyroid function tests show TSH 18.2 mIU/L (reference 0.4-4.0) and free T₄ 0.6 ng/dL (reference 0.8-1.8). Thyroid peroxidase (TPO) antibodies are positive. A diagnosis of autoimmune (Hashimoto’s) hypothyroidism is made.

Pharmacotherapy Approach: Levothyroxine sodium is initiated. Given the patient’s weight (≈75 kg), a full replacement dose would be approximately 75 × 1.6 = 120 µg daily. In a young, otherwise healthy patient, starting at the full dose is acceptable. However, a conservative approach might start at 75-100 µg daily. The medication must be taken on an empty stomach, at least 30-60 minutes before breakfast or other medications (especially calcium, iron, PPIs). The TSH level is rechecked after 6-8 weeks, and the dose is titrated by 12.5-25 µg increments to achieve a TSH within the lower half of the reference range (e.g., 1.0-2.5 mIU/L). Once stable, monitoring annually is typically sufficient.

Case Scenario 2: Graves’ Disease Hyperthyroidism

A 32-year-old female presents with palpitations, anxiety, heat intolerance, and a 7 kg weight loss over 2 months. Examination reveals a resting tachycardia of 110 bpm, a fine tremor, a diffusely enlarged and mildly tender thyroid gland, and mild bilateral exophthalmos. TFTs show TSH <0.01 mIU/L, free T₄ 3.5 ng/dL, free T₃ 550 pg/dL (reference 230-420). TSI is positive. A diagnosis of Graves’ disease with mild ophthalmopathy is confirmed.

Pharmacotherapy Approach: First-line antithyroid therapy with methimazole is indicated. A typical starting dose for moderate disease is 20-30 mg daily. Propylthiouracil is reserved for specific situations like first-trimester pregnancy or thyroid storm due to its higher risk of hepatotoxicity. A beta-blocker, such as propranolol 20-40 mg three times daily or atenolol 25-50 mg daily, is initiated for rapid control of adrenergic symptoms. The patient must be educated on the warning signs of agranulocytosis (fever, sore throat) and advised to discontinue methimazole and seek immediate medical attention if these occur. TFTs are monitored every 4-6 weeks initially. Once euthyroid, the methimazole dose is tapered to a maintenance dose (5-10 mg daily) for a planned course of 12-18 months, after which it may be discontinued to see if remission has occurred. Definitive therapy with radioactive iodine ablation or thyroidectomy may be considered if the disease relapses or if the patient prefers a permanent solution.

Problem-Solving: Management of Amiodarone-Induced Thyroid Dysfunction

Amiodarone, a class III antiarrhythmic, is 37% iodine by weight and can cause both hypothyroidism (AIT Type 2) and hyperthyroidism (AIT Type 1 and 2). Management is complex. For amiodarone-induced hypothyroidism, levothyroxine replacement is initiated while continuing amiodarone if it is clinically necessary. For AIT, the first step is to differentiate Type 1 (iodine-induced excess synthesis in abnormal thyroid tissue) from Type 2 (destructive thyroiditis). Type 1 may be treated with high-dose thioamides, often with potassium perchlorate. Type 2 is often treated with glucocorticoids. In severe or mixed cases, thyroidectomy may be required. This scenario underscores the necessity of monitoring TFTs before and periodically during amiodarone therapy.

6. Summary and Key Points

Summary of Main Concepts

• Thyroid hormone homeostasis is maintained by the HPT axis negative feedback loop, with TSH being the most sensitive marker of primary thyroid function.
• Hypothyroidism is most commonly caused by autoimmune destruction (Hashimoto’s) and is treated with lifelong levothyroxine replacement, dosed to normalize the TSH.
• Hyperthyroidism is most commonly caused by autoimmune stimulation (Graves’ disease) and may be managed with thioamide drugs (methimazole), radioactive iodine ablation, or thyroidectomy.
• Thyroid function tests must be interpreted in the clinical context, considering the patterns indicative of primary vs. central disease, thyrotoxicosis, and non-thyroidal illness.
• Pharmacotherapy requires careful attention to dosing, administration guidelines (empty stomach for levothyroxine), drug interactions, and monitoring for both efficacy and adverse effects.

Clinical Pearls

• The goal of levothyroxine therapy in primary hypothyroidism is a TSH within the reference range, often tailored to the lower half for most adults.
• Methimazole is the preferred thioamide for Graves’ disease except in early pregnancy or thyroid storm, due to its once-daily dosing and superior safety profile.
• Subclinical thyroid disease requires individualized decision-making, with treatment generally recommended for subclinical hypothyroidism with TSH >10 mIU/L and considered for symptomatic patients with TSH above the reference range.
• In pregnancy, thyroid hormone requirements increase by 25-50%; TSH should be monitored every 4 weeks during the first half of pregnancy and at least once during the second half.
• Radioactive iodine (I-131) is contraindicated in pregnancy and breastfeeding and typically leads to permanent hypothyroidism requiring subsequent levothyroxine replacement.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.