Hypothyroidism and Hyperthyroidism

1. Introduction

Thyroid disorders represent a prevalent category of endocrine disease, with hypothyroidism and hyperthyroidism constituting the primary manifestations of thyroid dysfunction. These conditions arise from an imbalance in the production of thyroid hormones—thyroxine (T₄) and triiodothyronine (T₃)—which are critical regulators of basal metabolic rate, thermogenesis, growth, and development. The clinical management of these disorders is a cornerstone of endocrinology and requires a thorough understanding of thyroid physiology, pathophysiology, and pharmacology.

The historical understanding 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 seminal discovery of the curative effects of thyroid extract for hypothyroidism. 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.

From a pharmacological perspective, thyroid disorders are particularly instructive. They exemplify the principles of hormone replacement therapy, the management of autoimmune disease, and the use of drugs to modulate endocrine function. The therapeutic agents involved, ranging from synthetic hormones to thionamide derivatives and radioactive isotopes, demonstrate specific mechanisms of action, pharmacokinetic considerations, and narrow therapeutic indices, making their study essential for safe and effective clinical practice.

Learning Objectives

• Describe the normal physiology of the hypothalamic-pituitary-thyroid axis and the synthesis of thyroid hormones.
• Differentiate the etiologies, pathophysiological mechanisms, and clinical presentations of hypothyroidism and hyperthyroidism.
• Explain the mechanisms of action, pharmacokinetics, therapeutic uses, and adverse effects of drugs used to treat thyroid disorders.
• Interpret standard thyroid function tests and apply them to diagnose and monitor therapy for thyroid dysfunction.
• Develop a rational therapeutic plan for common thyroid disorders, including special populations such as pregnant patients.

2. Fundamental Principles

The fundamental principles underlying thyroid function and dysfunction are rooted in endocrine feedback loops and hormone synthesis. A grasp of these core concepts is prerequisite to understanding disease states and their management.

Core Concepts and Definitions

The thyroid gland is a butterfly-shaped organ located anterior to the trachea. Its primary function is the synthesis, storage, and secretion of the iodine-containing hormones T₄ and T₃. Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). TSH, in turn, binds to receptors on thyroid follicular cells, stimulating every step of thyroid hormone production and release. Circulating T₄ and T₃ exert negative feedback on both the pituitary and hypothalamus, primarily by suppressing TSH secretion.

Hypothyroidism is defined as a clinical state resulting from insufficient production or action of thyroid hormones. Hyperthyroidism (thyrotoxicosis) refers to the clinical, physiological, and biochemical findings that result when tissues are exposed to excessive levels of thyroid hormones. It is crucial to distinguish primary disorders (originating in the thyroid gland itself) from central or secondary disorders (originating from pituitary or hypothalamic dysfunction).

Theoretical Foundations: The Hypothalamic-Pituitary-Thyroid Axis

The HPT axis is a classic example of an endocrine feedback loop. The system is designed to maintain circulating thyroid hormone levels within a narrow physiological range. The set-point for this loop is determined by the sensitivity of the thyrotroph cells in the pituitary to negative feedback. Disruption at any level—hypothalamus (TRH), pituitary (TSH), or thyroid (T₄/T₃)—can lead to clinical dysfunction. The axis is also influenced by non-thyroidal factors, including illness, stress, and certain medications, which can complicate interpretation of thyroid function tests.

Key Terminology

• Thyroglobulin (Tg): A large glycoprotein synthesized by thyroid follicular cells that serves as the scaffold for thyroid hormone synthesis.
• Thyroid Peroxidase (TPO): The key enzyme catalyzing the oxidation, organification, and coupling reactions in thyroid hormone synthesis.
• Thyroid-Stimulating Immunoglobulins (TSI): Autoantibodies that mimic TSH by binding to and activating the TSH receptor, causing unregulated hormone production in Graves’ disease.
• Wolff-Chaikoff Effect: The adaptive decrease in thyroid hormone synthesis that occurs in response to a large iodine load, a mechanism that protects against iodine-induced hyperthyroidism.
• Euthyroid: A state of normal thyroid function.
• Myxedema: A term often used for severe hypothyroidism, characterized by non-pitting edema due to accumulation of glycosaminoglycans in the dermis.
• Thyroid Storm: A life-threatening exacerbation of hyperthyroidism characterized by hyperthermia, tachycardia, and altered mental status.

3. Detailed Explanation

An in-depth exploration of thyroid hormone synthesis, regulation, and the pathophysiological deviations leading to disease is required to appreciate the clinical manifestations and therapeutic strategies.

Thyroid Hormone Synthesis and Metabolism

The synthesis of thyroid hormones is a complex, multi-step process dependent on adequate dietary iodine intake (recommended ~150 µg/day). The process involves:

1. Iodide Uptake: Follicular cells actively transport iodide from the blood against a concentration gradient via the sodium-iodide symporter (NIS).
2. Oxidation and Organification: Iodide is transported into the follicular lumen and oxidized to iodine by thyroid peroxidase (TPO). Iodine is then incorporated into tyrosine residues on thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine (DIT).
3. Coupling: TPO further catalyzes the coupling of two DIT molecules to form T₄, or one MIT and one DIT to form T₃. These hormones remain stored within thyroglobulin in the colloid.
4. Release: In response to TSH, thyroglobulin is endocytosed back into the follicular cell and proteolyzed, releasing T₄ and T₃ into the circulation.

Approximately 80% of circulating T₃, the biologically active hormone, is produced by peripheral deiodination of T₄ by 5′-deiodinase enzymes in tissues such as the liver and kidney. Thyroid hormones are highly protein-bound (>99%), primarily to thyroxine-binding globulin (TBG), which influences measured serum levels.

Pathophysiology of Hypothyroidism

Hypothyroidism results from inadequate thyroid hormone action at the tissue level. Primary hypothyroidism, accounting for over 95% of cases, is most commonly caused by autoimmune thyroiditis (Hashimoto’s disease), where cell-mediated immunity destroys thyroid tissue. Other causes include iatrogenic factors (thyroidectomy, radioiodine therapy), iodine deficiency (rare in iodine-sufficient regions), and drug-induced causes (e.g., lithium, amiodarone). Central hypothyroidism, due to pituitary or hypothalamic disease, is less common.

The physiological consequences are a generalized slowing of metabolic processes. Reduced basal metabolic rate leads to decreased thermogenesis, cold intolerance, and weight gain. Accumulation of glycosaminoglycans in interstitial spaces causes non-pitting edema (myxedema), pericardial effusion, and hoarseness. Reduced sympathetic nervous system activity contributes to bradycardia, constipation, and lethargy. In severe, long-standing cases, myxedema coma, a medical emergency characterized by hypothermia and obtundation, may develop.

Pathophysiology of Hyperthyroidism

Hyperthyroidism is characterized by excessive thyroid hormone production and action. The most common cause is Graves’ disease, an autoimmune disorder driven by TSH receptor-stimulating antibodies (TRAb or TSI). Other etiologies include toxic multinodular goiter, solitary toxic adenoma, and thyroiditis (e.g., subacute, postpartum). Exogenous causes, such as factitious thyrotoxicosis from hormone ingestion or amiodarone use, must also be considered.

The excess thyroid hormones create a hypermetabolic state. Increased basal metabolic rate causes weight loss despite increased appetite, heat intolerance, and sweating. Heightened sensitivity to catecholamines results in 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). Thyroid storm represents an extreme, decompensated state often precipitated by infection or surgery.

Factors Affecting Thyroid Function and Drug Response

Several factors can influence thyroid physiology and the pharmacokinetics of thyroid medications.

4. Clinical Significance

The clinical significance of thyroid disorders extends across all medical specialties due to the systemic nature of thyroid hormone action. Accurate diagnosis and appropriate management are critical for patient outcomes.

Relevance to Drug Therapy

Pharmacotherapy for thyroid disorders is a lifelong commitment for many patients, necessitating a deep understanding of drug characteristics. Levothyroxine sodium, a synthetic T₄, is one of the most prescribed medications worldwide. Its narrow therapeutic index requires precise dosing and monitoring. The goal of therapy is to normalize TSH levels in primary hypothyroidism, which typically correlates with euthyroidism at the tissue level. For hyperthyroidism, the thionamide drugs methimazole and propylthiouracil inhibit TPO, reducing hormone synthesis. Radioactive iodine (¹³¹I) ablates thyroid tissue, and beta-adrenergic antagonists provide symptomatic relief by blunting catecholamine-mediated effects.

Thyroid status also profoundly affects the pharmacokinetics and pharmacodynamics of non-thyroid drugs. Hypothyroidism can reduce hepatic metabolism and glomerular filtration rate, potentially increasing the plasma concentrations of drugs cleared by these pathways. Conversely, hyperthyroidism can accelerate drug metabolism, potentially reducing efficacy. This is particularly relevant for drugs with narrow therapeutic indices, such as warfarin, where hyperthyroidism increases sensitivity to its anticoagulant effect.

Practical Applications in Diagnosis

The diagnosis of thyroid dysfunction relies primarily on the interpretation of thyroid function tests (TFTs). The single most sensitive and cost-effective test for primary thyroid disorders is the TSH assay. An elevated TSH indicates primary hypothyroidism, while a suppressed TSH suggests hyperthyroidism. Subsequent measurement of free T₄ (FT₄) confirms the diagnosis and assesses severity. In central disorders, TSH is an unreliable guide, and diagnosis depends on measuring FT₄ in the context of clinical suspicion. Additional tests, such as thyroid peroxidase antibodies (anti-TPO) for Hashimoto’s, TSH receptor antibodies (TRAb) for Graves’ disease, and thyroid ultrasound, are used to determine etiology.

Clinical Examples of Therapeutic Decision-Making

Therapeutic strategies are tailored to the specific etiology, severity, and patient characteristics. For a young patient with newly diagnosed Graves’ disease, a course of methimazole for 12-18 months may be attempted to induce remission. For an older patient with a large toxic multinodular goiter causing compressive symptoms, definitive therapy with radioiodine or surgery is often preferred. In hypothyroidism, the standard of care is levothyroxine monotherapy, initiated at low doses (1.6 µg/kg/day, but lower in elderly or cardiac patients) and titrated based on TSH measurements 6-8 weeks after dose changes. The use of combination T₄/T₃ therapy remains controversial and is not routinely recommended.

5. Clinical Applications and Examples

Applying theoretical knowledge to clinical scenarios solidifies understanding and prepares students for patient care.

Case Scenario 1: Primary Hypothyroidism

A 45-year-old female presents with a 6-month history of fatigue, weight gain of 5 kg, cold intolerance, dry skin, and constipation. Physical examination reveals a body mass index of 28 kg/m², bradycardia (heart rate 54 bpm), delayed deep tendon reflexes, and mild periorbital edema. The thyroid gland is non-palpable.

Diagnostic Approach: Thyroid function tests are ordered. Results show TSH 18.2 mIU/L (reference 0.4-4.0) and FT₄ 0.6 ng/dL (reference 0.8-1.8). Anti-TPO antibodies are positive at 350 IU/mL. This confirms the diagnosis of autoimmune (Hashimoto’s) hypothyroidism.

Therapeutic Plan: Levothyroxine is initiated at a dose of 75 µg daily, taken on an empty stomach at least 30 minutes before breakfast. The patient is counseled to separate ingestion from calcium or iron supplements by at least 4 hours. A follow-up TSH is scheduled for 8 weeks to assess response, with a goal TSH in the lower half of the reference range (e.g., 1-2 mIU/L).

Case Scenario 2: Graves’ Disease with Hyperthyroidism

A 32-year-old female presents with palpitations, anxiety, heat intolerance, and a 7 kg weight loss over 2 months despite increased appetite. She notes a “bulging” of her eyes. Examination reveals a resting tachycardia of 110 bpm, a fine tremor, a diffusely enlarged and non-tender thyroid gland (goiter), and mild bilateral proptosis with lid retraction.

Diagnostic Approach: TFTs reveal TSH < 0.01 mIU/L and elevated FT₄ of 3.5 ng/dL. TRAb (TSI) testing is positive. A radioactive iodine uptake (RAIU) scan, if performed, would show diffusely increased uptake, confirming Graves’ disease.

Therapeutic Plan: Three main options are considered: antithyroid drugs, radioiodine, or surgery. Given her age and moderate symptoms, methimazole 20 mg daily is started. Propranolol 20 mg three times daily is added for symptomatic control of tachycardia and tremor. The patient is warned about potential adverse effects of methimazole, including agranulocytosis (presenting as fever/sore throat). FT₄ is monitored monthly initially, with the methimazole dose adjusted to maintain euthyroidism. A 12-18 month course is planned to assess for potential remission.

Problem-Solving: Management of Subclinical Thyroid Dysfunction

Subclinical Hypothyroidism is defined as an elevated TSH with a normal FT₄. The decision to treat is not automatic. Treatment is generally recommended if TSH is >10 mIU/L, or if TSH is between 4.5-10 mIU/L and the patient is symptomatic, has positive thyroid antibodies (suggesting progression to overt disease), or is pregnant. A trial of low-dose levothyroxine may be considered in symptomatic patients.

Subclinical Hyperthyroidism involves a suppressed TSH with normal FT₄ and FT₃. Treatment is advised for patients with TSH persistently < 0.1 mIU/L, especially if they are over 65, have cardiac risk factors (atrial fibrillation, osteoporosis), or symptoms. The underlying cause (e.g., autonomous nodule) guides the choice of therapy.

Application to Specific Drug Classes: Amiodarone and Thyroid Dysfunction

Amiodarone, a potent class III antiarrhythmic, is 37% iodine by weight and has structural similarity to thyroid hormone. It can cause both hypothyroidism and hyperthyroidism (Amiodarone-Induced Thyroid Dysfunction, AITD). Type 1 AIT occurs in patients with underlying thyroid autonomy (e.g., nodular goiter); the iodine load leads to excessive hormone synthesis. Type 2 AIT is a destructive thyroiditis causing release of preformed hormone. Management differs: Type 1 may respond to thionamides, while Type 2 is best treated with corticosteroids. This scenario underscores the importance of monitoring TFTs before and during amiodarone therapy and understanding the pathophysiology to select correct treatment.

6. Summary and Key Points

The management of hypothyroidism and hyperthyroidism is a fundamental and frequently encountered task in clinical medicine and pharmacy. Mastery of the underlying principles is essential for safe and effective patient care.

Summary of Main Concepts

• Thyroid hormone synthesis is a TSH-regulated process dependent on iodine and involving oxidation, organification, and coupling reactions catalyzed by thyroid peroxidase.
• The hypothalamic-pituitary-thyroid axis maintains hormone homeostasis via a negative feedback loop, with TSH being the most sensitive indicator of primary thyroid dysfunction.
• Hypothyroidism is most commonly autoimmune (Hashimoto’s) and treated with lifelong levothyroxine replacement, dosed to normalize the TSH.
• Hyperthyroidism is most commonly autoimmune (Graves’ disease) and managed with thionamide drugs (methimazole/propylthiouracil), radioactive iodine ablation, or thyroidectomy.
• Thyroid function tests must be interpreted in clinical context, considering factors like pregnancy, non-thyroidal illness, and concomitant medications that affect absorption or metabolism.

Clinical Pearls

• Levothyroxine should be taken on an empty stomach, separated from calcium, iron, PPIs, and certain foods by at least 4 hours to ensure consistent absorption.
• In primary hypothyroidism, the therapeutic target is a TSH within the reference range, typically 0.5-2.5 mIU/L for most adults, with lower targets in pregnancy.
• Methimazole is the preferred thionamide for Graves’ disease except in the first trimester of pregnancy or during thyroid storm, where propylthiouracil may be used.
• Patients on antithyroid drugs must be instructed to discontinue the medication and seek immediate medical attention if they develop fever or sore throat, due to the risk of agranulocytosis.
• Thyroid storm is a medical emergency treated with aggressive supportive care, high-dose PTU or methimazole, inorganic iodide, beta-blockers, and corticosteroids.
• When monitoring therapy, allow 4-6 weeks for TSH to reach steady-state after a levothyroxine dose change, and 2-4 weeks for FT₄ to reflect a change in antithyroid drug dose.

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