Thyroid Disorders: Hypothyroidism, Hyperthyroidism & More

Thyroid Function & Disease

• RCSI Royal College of Surgeons in Ireland, Coláiste Ríoga na Máinleá in Éirinn; Department of Medicine.

Learning Outcomes

• Define hypothyroidism and hyperthyroidism
• Explain the pathophysiology of hyperthyroidism and hypothyroidism
• List the cardinal symptoms and signs of hyperthyroidism and hypothyroidism
• Explain how each symptom and sign is caused in hyperthyroidism and hypothyroidism
• Develop a differential diagnosis for hyperthyroidism and hypothyroidism
• Outline the overarching principles of investigation and management in thyroid disorders

Thyroid Hormone

• Thyroid hormone affects nearly every organ in the body in response to stress.
• Increases basal metabolic rate and thermogenesis.
• Cardiovascular system (CVS): increases beta-receptor expression for increased cardiac output and contractility.
• Respiratory: stimulates respiratory centres and increases lung perfusion for increased oxygenation.
• Skeletal muscle: increases fast-twitch muscle fibre expression.
• Metabolism: increases basal metabolic rate, carbohydrate metabolism, and protein anabolism.
• Growth: synergistically stimulates bone growth during childhood with growth hormone.
• Central Nervous System (CNS): affects mood, memory and sleep in adults; crucial for brain maturation during the prenatal period.
• Fertility, ovulation, menstruation.

Hypothyroidism

• Definition: a pathological disorder in which insufficient thyroid hormones are synthesised and secreted by the thyroid gland.
• Primary hypothyroidism (high TSH, low free T4): thyroid gland failure. Despite appropriate pituitary stimulation (TSH), the thyroid gland is unable to respond and produce T4.
• Central or secondary hypothyroidism: from deficient TSH secretion (generally due to pituitary lesions such as a pituitary tumor), low T4, and normal or low TSH. Despite the low T4 levels, there is no compensatory increase in TSH production.

Primary Hypothyroidism Differentials

• Congenital: agenesis of the thyroid gland (part of the heel-prick screening test at birth).
• Thyroid tissue destruction:
  • Autoimmune: Hashimoto's thyroiditis (thyroid peroxidase antibodies (TPO), most common cause in iodine sufficient countries); Reidel's thyroiditis (T cell/IgG4 mediated inflammation leading to fibrosis, extending beyond the thyroid capsule into surrounding tissues); Radiation (radioactive iodine treatment for thyrotoxicosis); Post-thyroidectomy; Infiltrative diseases of the thyroid (e.g., haemochromatosis).
• Anti-thyroid drugs: lithium, iodine-containing drugs, radioactive contrast material, amiodarone, checkpoint inhibitor immunotherapy

Hyperthyroidism

• Definition: a pathological disorder in which excess thyroid hormone is synthesised and secreted by the thyroid gland.
• Thyrotoxicosis: the clinical state associated with excess thyroid hormone activity.
• Primary hyperthyroidism: elevated free T4, suppressed/undetectable TSH (<0.1).
• Secondary hyperthyroidism: elevated T4 and elevated TSH.

Pathophysiology

• TSH binds to TSH receptors on thyroid cells, causing:
  • Production of T4 and T3
  • Hyperplasia/growth of the gland
• T3 and T4 affect most organs, increasing metabolism, growth, and development, and catecholamine effects.

Hypothyroidism Causes

• Primary gland insufficiency/failure: most common cause of hypothyroidism.
• Pituitary and hypothalamus (secondary and tertiary) are less commonly implicated.
• Decline in T4 and T3 production.
• Increase release of TSH from pituitary.
• Iodine deficiency: most common cause worldwide.
• Autoimmune (Hashimoto's) thyroiditis: most common cause in developed/iodine-sufficient countries.

Hypothyroidism Symptoms

• Symptoms related to decreased metabolic rate: bradycardia, weight gain, cold intolerance, poor appetite, hair loss, cold dry skin, fatigue, constipation, myopathy.
• Children: cretinism (old term) - short stature, intellectual disability.

Hypothyroidism (additional signs and symptoms)

• Psychological: poor memory, concentration, and poor hearing.
• Pharynx: hoarseness
• Heart: slow pulse rate, pericardial effusion
• Muscular: delayed reflex relaxation
• Extremities: coldness, carpal tunnel syndrome
• Lungs: shortness of breath, pleural effusion
• Skin: paresthesia, myxedema
• Intestines: constipation, ascites
• Reproductive system: menorrhagia

Hashimoto's Thyroiditis

• Autoimmune inflammation of thyroid tissue
• Most common cause of hypothyroidism.
• Females > males.
• Gradual thyroid failure due to autoimmune-mediated destruction of the thyroid gland.
• With or without goiter formation (due to lymphocytic infiltration and scar tissue formation).
• Diagnosis: evidence of hypothyroidism, high serum concentrations of antibodies against thyroid antigen (TPO antibodies).
• Intense and diffuse lymphocytic infiltration of the thyroid, with follicular destruction as the characteristic pathological hallmark.

Subclinical Hypothyroidism

• Persistently high TSH with a normal T4.
• Very common (up to 8%).
• Can progress to overt hypothyroidism (2-5% per year).
• Treat if: TSH >10, Pre or during pregnancy, Infertility, Symptomatic patients, Questionable benefit if TSH 4-10 especially in older age.

Hyperthyroidism Differentials

• Graves' disease
• Toxic multinodular goitre (MNG)
• Toxic adenoma
• Drug-induced: Amiodarone
• Excess exogenous use ("factitious")
• Subacute viral thyroiditis
• Thyrotoxicosis/thyroid storm

Hyperthyroidism Causes

• Graves' disease (autoimmune), toxic multinodular goitre (multiple, slow-growing nodules developing autonomous thyroid hormone production; almost always benign, but rare potential for malignancy), toxic adenoma (solitary autonomous nodule), viral thyroiditis (de Quervain's/subacute granulomatous thyroiditis, characterised by tender diffuse goitre; predictable course: hyperthyroidism first, then hypothyroidism, then euthyroid (occasionally hypothyroidism may be permanent)), Less common: pituitary adenoma, drug-induced (e.g., amiodarone, checkpoint inhibitor immunotherapy), factitious (excessive exogenous use).

Hyperthyroidism Symptoms

• Hypermetabolism: heat intolerance, weight loss, increased appetite, sweating.
• Palpitations: tachycardia (sinus, atrial fibrillation).
• Hypertension, heart failure, tremor, myopathy, restlessness, anxiety, depression.
• Additional symptoms: nervousness/tremor, mental disturbances/irritability, difficulty sleeping, bulging eyes/unblinking stare/vision changes, enlarged thyroid (goiter), menstrual irregularities/light period, frequent bowel movements, warm, moist palms, first-trimester miscarriage/excessive vomiting in pregnancy, hoarseness, deepening of voice, persistent dry or sore throat, difficulty swallowing, palpitations/tachycardia, impaired fertility, weight loss or gain, heat intolerance, increased sweating, sudden paralysis.

Graves' Disease

• Antibodies against TSHR (TSH receptor) expressed on thyroid cells (predominantly, but also in adipocytes, fibroblasts, bone cells).
• Leads to inappropriate activation of thyroid cells (TSH agonist), causing increased T4 and T3 production.
• Increased TSH receptor activation also causes hyperplasia/growth of the gland.
• Factors that predispose to Graves' disease: genetic susceptibility, immune tolerance failure, molecular mimicry, Females > males, smoking, iodine-containing drugs (e.g. amiodarone). Computed tomography (CT) scan contrast media may precipitate Graves' disease.
• Overall incidence approximately 4.6 per 1000 during 10 years of observation.
• Antibodies: TRAbs (TSH receptor antibodies). Sensitivity and specificity over 90%.
• Manifestations: hyperthyroidism (most common), goitre (usually diffusely enlarged), thyroid eye disease, dermopathy (pretibial myxedema), acropathy.

Thyroid Eye Disease

• AKA Graves' orbitopathy (occurs in approximately 25% of patients with Graves' ; most patients have mild disease).
• Autoimmune disease of the orbit and retro-ocular tissues (occurring in patients with Graves' disease, and rarely in patients with Hashimoto's Thyroiditis).
• Activation of orbital fibroblasts and preadipocytes TSHRs and IGF-1 receptors and initiating cellular expansion and inflammation, leading to mucopolysaccharide accumulation, muscle swelling, and increase in pressure within the orbit.
• The eyeball is pushed forward, leading to extraocular muscle dysfunction and impaired venous drainage causing periorbital swelling (exophthalmos).
• Symptoms: proptosis (bulging), conjunctival inflammation, periorbital oedema, lid retraction, lagophthalmos (inability to close eyelids fully) strabismus, optic neuropathy (compression).
• Worsening factors: smoking, radioactive iodine.
• Treatment depends on severity. Mild disease: selenium. Moderate-severe disease: steroids, immunosuppressants, teprotumumab (if available).

Myxoedema

• Severe hypothyroidism- life-threatening (rare presentation of hypothyroidism).
• Accumulation of mucopolysaccharides in subcutaneous tissues: thickening of skin.
• All low! (Hyponatraemia, hypoglycaemia, hypotension, hypothermia, heart failure, confusion, coma, high mortality).
• Myxoedema coma: treat with IV levothyroxine or IV T3 under specialist endocrine supervision.

Thyroid Storm/Thyrotoxic Crisis

• Life-threatening emergency (10-30% mortality even with early recognition and treatment). Rare condition.
• Acute severe thyrotoxicosis usually in patients with longstanding untreated hyperthyroidism, precipitated by stress (e.g., infection, surgery, trauma, childbirth).
• Symptoms: fever (heat intolerance extends into fever/pyrexia), agitation, confusion, seizures, coma, tachycardia, AFIB, heart failure (high output).
• Treatment: Beta-blocker (selective), high-dose thionamides, iodine solution, corticosteroids.

Goitre

• Enlarged thyroid gland causing swelling in the anterior neck, midline.
• Superior extension limited by the sternothyroid muscle; will grow downwards.
• Can ultimately cause tracheal/oesophageal compression.
• Common to both hypo and hyperthyroidism, depending on the underlying cause.
• Multiple causes of enlargement: iodine deficiency, excess TSH stimulus, inflammation, scarring, masses.
• Characteristics can be informative: diffuse (e.g., Graves’ disease), multiple nodules (toxic multinodular goitre), single palpable nodule (single mass e.g., adenoma), tender (acute thyroiditis).

Investigations- Thyroid Function Tests

• Bloods: Thyroid function tests (TSH, T4, T3), Antibodies (Anti-TPO, TSH receptor antibodies).
• Imaging: Thyroid ultrasound (selected cases only), FNA (fine needle aspiration), Radioiodine or technetium uptake, useful for hyperthyroid patients with physical examination suggesting nodular thyroid disease to determine etiology.

Treatment- Hypothyroidism

• Levothyroxine (T4) (e.g. Eltroxin), dose is approximately 1.6 mcg/kg body weight per day if complete thyroid failure. Dose titrated to achieve normal TSH in primary hypothyroidism.
• Should be taken on an empty stomach with water. Avoid taking with other medications that interfere with its absorption (e.g., calcium, ferrous sulfate, soy products).
• 'Start low and go slow' in the elderly and those with unstable heart disease.
• Exclude or treat adrenal insufficiency before commencing levothyroxine in patients with suspected central hypothyroidism to avoid adrenal crisis. Aim is to keep T4 in the middle of the normal range, ignore TSH.

Treatment- Hyperthyroidism

• Pharmacological: Thyroid hormone synthesis inhibitors (carbimazole, prophylthiouracil), Thyroid hormone secretion blockade (iodides), Beta-adrenergic blockers (propranolol, atenolol), NSAIDs for pain, corticosteriods (severe), Procedural: radioactive iodine ablation.
• Surgical: total thyroidectomy (refractory disease, compressive features, cosmetic). Complication: Hypothyroidism, hypoparathyroidism, RLN injury.

Test your knowledge on thyroid disorders. Questions cover hypothyroidism, hyperthyroidism, Hashimoto's thyroiditis, and thyroid hormone effects on cardiovascular and skeletal muscle system.