Thyroid Disease: The Most Commonly Missed Diagnosis

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Thyroid disease affects approximately 1 in 20 adults, rises steeply with age, and is significantly more prevalent in women. Despite this, it remains one of the most commonly missed diagnoses in clinical practice — its symptoms are non-specific, insidious in onset, and frequently attributed to depression, ageing, or stress before the thyroid is ever tested.

The Thyroid Gland and How It Works

The thyroid gland sits in the anterior neck and produces two principal hormones: thyroxine (T4) and triiodothyronine (T3). T4 is the predominant secretory product but is largely inactive; it is converted in peripheral tissues (primarily liver, kidney, and muscle) to the biologically active T3 by enzymes called deiodinases. This conversion can be impaired in chronic illness, caloric restriction, and by certain medications.

Thyroid function is controlled through the hypothalamic-pituitary-thyroid axis:

• The hypothalamus secretes TRH (thyrotropin-releasing hormone)
• TRH stimulates the pituitary to release TSH (thyroid-stimulating hormone)
• TSH drives thyroid T4 and T3 production
• Rising T4/T3 feeds back to suppress TSH (negative feedback)

This means TSH is the most sensitive single indicator of thyroid function. A high TSH signals that the pituitary is compensating for insufficient thyroid output — hypothyroidism. A suppressed TSH signals the thyroid is overproducing, switching off pituitary stimulation — hyperthyroidism. Free T4 (fT4) and free T3 (fT3) contextualise TSH and are essential for characterising the degree and type of dysfunction.

Hypothyroidism — The Underactive Thyroid

Prevalence: Overt hypothyroidism affects 2–5% of women and 0.1–2% of men. Subclinical hypothyroidism (elevated TSH with normal fT4) may affect up to 10–15% of postmenopausal women. Incidence increases substantially with age — it is not a condition that should be dismissed as "normal for their age."

Causes

• Autoimmune thyroiditis (Hashimoto's disease) — most common cause in iodine-sufficient countries including Ireland and the UK; associated with thyroid peroxidase antibodies (TPOAb)
• Previous radioiodine treatment (RAI) for hyperthyroidism or thyroid cancer
• Previous thyroidectomy (partial or total)
• Medications: amiodarone (interferes with T4→T3 conversion and can cause both hypo- and hyperthyroidism), lithium, immune checkpoint inhibitors (pembrolizumab, nivolumab — increasingly important as immunotherapy use expands), interferon-alpha, sunitinib
• Iodine deficiency — rare in Ireland and the UK but the most common cause globally
• Central hypothyroidism — pituitary or hypothalamic cause (TSH may be low or inappropriately normal despite low T4)

Symptoms — Often Attributed to Other Causes

• Fatigue and low energy — the most common presenting complaint; frequently attributed to depression, poor sleep, or busy lifestyle
• Weight gain — typically modest (1–5 kg), despite no change in diet; occasionally more significant
• Cold intolerance — feeling cold when others are comfortable; warm hands and feet are reassuringly NOT a feature
• Constipation — slow gut transit
• Dry skin and hair, brittle nails, diffuse hair thinning (not patchy — patchy suggests alopecia areata)
• Bradycardia — resting heart rate below 60 bpm without athletic explanation
• Depression, cognitive slowing, poor concentration — "brain fog" is a real and recognised symptom
• Menstrual irregularity — heavy periods (menorrhagia), oligomenorrhoea, or secondary amenorrhoea
• Myxoedema — periorbital puffiness, non-pitting oedema, hoarse voice in more severe or prolonged hypothyroidism
• Carpal tunnel syndrome, myalgia, raised creatine kinase (CK)
• Secondary effects in severe/prolonged disease: hypercholesterolaemia, hyponatraemia, pericardial effusion, heart failure, hypoventilation

Interpreting Thyroid Function Tests — A Practical Guide

• TSH >10 mIU/L + low fT4: Overt hypothyroidism — treat with levothyroxine
• TSH 4–10 mIU/L + normal fT4 + positive TPOAb: Subclinical hypothyroidism with autoimmune aetiology — treat; approximately 50% will progress to overt hypothyroidism within 5 years
• TSH 4–10 mIU/L + normal fT4 + symptoms + negative TPOAb: Consider a trial of levothyroxine and assess symptomatic response at 3 months
• TSH 4–10 mIU/L + normal fT4 + asymptomatic + TPOAb negative: Watch and wait; recheck TFTs at 6–12 months
• TSH 4–10 mIU/L in pregnancy or planning pregnancy: Treat — TSH target in pregnancy is <2.5 mIU/L in first trimester
• TSH slightly elevated (4–5 mIU/L) in isolation: Confirm with a repeat 6–8 weeks later before initiating treatment, unless symptomatic or pregnant

Treatment — Levothyroxine

Levothyroxine (L-T4) is the standard, evidence-based treatment for hypothyroidism. Starting dose:

• Young, healthy adults: 50–75 mcg daily initially; increase by 25 mcg every 6–8 weeks until TSH normalises
• Older patients or those with ischaemic heart disease: start 25 mcg and increase very slowly to avoid precipitating angina or arrhythmia
• Target TSH: 1.0–2.5 mIU/L in most patients. Simply achieving "within the normal range" (0.4–4.0 mIU/L) is insufficient — the upper half of the normal range may be associated with persistent symptoms in some individuals.

Hyperthyroidism — The Overactive Thyroid

Causes

• Graves' disease — most common; autoimmune condition driven by TSH receptor-stimulating antibodies (TRAb) that mimic TSH action. Affects women 5–10× more than men; peak incidence 20–40 years.
• Toxic multinodular goitre — common in older patients; multiple autonomously functioning nodules
• Toxic adenoma — single autonomously functioning nodule
• Thyroiditis — post-partum, subacute (de Quervain's — painful, post-viral), silent thyroiditis. Transient hyperthyroidism followed by transient hypothyroidism.
• Amiodarone-induced thyrotoxicosis — two types with different pathophysiology and treatment requirements. Type 1: iodine excess driving increased synthesis. Type 2: destructive thyroiditis releasing stored hormone. Distinction requires specialist assessment.
• Excess exogenous thyroid hormone — over-replacement or factitious

Symptoms

• Weight loss despite maintained or increased appetite
• Heat intolerance, sweating, warm moist skin
• Palpitations, tachycardia — AF in 10–15% of patients, especially older individuals
• Tremor — fine resting tremor of the outstretched hands
• Anxiety, irritability, emotional lability, insomnia
• Diarrhoea or increased bowel frequency
• Proximal muscle weakness — difficulty rising from a chair, climbing stairs
• Oligomenorrhoea or amenorrhoea; reduced libido in both sexes
• Graves'-specific features: exophthalmos (proptosis), lid lag, lid retraction, pretibial myxoedema (non-pitting skin thickening over shins), thyroid acropachy. These features are pathognomonic of Graves' and do not occur with other causes of hyperthyroidism.

TSH Interpretation in Hyperthyroidism

• TSH <0.1 mIU/L + elevated fT4 and/or fT3: Overt hyperthyroidism — specialist referral required
• TSH <0.1 mIU/L + normal fT4 and fT3: Subclinical hyperthyroidism — consider treatment if TSH persistently suppressed, patient over 65, or has AF or osteoporosis risk factors
• TSH mildly suppressed (0.1–0.4 mIU/L): May reflect non-thyroidal illness, early subclinical hyperthyroidism, or levothyroxine over-replacement. Recheck in 6–8 weeks.

Treatment Options for Hyperthyroidism

• Antithyroid drugs (ATDs): Carbimazole first-line in UK and Ireland (propylthiouracil (PTU) preferred in first trimester of pregnancy and thyroid storm). Can be used in titration or block-and-replace regimen. 12–18 months of treatment offers 40–60% remission rate in Graves' disease. Rare but serious side effects: agranulocytosis (sore throat, fever → stop and check FBC), hepatotoxicity (PTU > carbimazole).
• Radioiodine (RAI): Definitive treatment for Graves' and toxic nodular disease. Contraindicated in pregnancy (absolutely), breastfeeding, and significant active thyroid eye disease. Most patients become hypothyroid post-RAI and require lifelong levothyroxine.
• Thyroidectomy: Total thyroidectomy for large goitre with compressive symptoms, patient preference (avoiding radiation or long-term medication), failed drug therapy, or coexisting thyroid malignancy.

Thyroid Antibodies — What They Mean

• TPO antibodies (anti-thyroid peroxidase): Positive in Hashimoto's thyroiditis (90%) and Graves' (60–75%). Confirm autoimmune aetiology. In subclinical hypothyroidism, TPOAb positivity is the most important predictor of future progression — a compelling indication to treat.
• TSH receptor antibodies (TRAb): Specific for Graves' disease. Confirm the diagnosis, predict response to antithyroid drug treatment (higher titre = lower remission rate), and are critical in pregnancy — maternal TRAb crosses the placenta and can cause neonatal thyrotoxicosis.
• Thyroglobulin antibodies (TgAb): Present in 40–60% of Hashimoto's; less specific. Clinically most important in thyroid cancer follow-up — TgAb interfere with the thyroglobulin assay used to detect recurrence.

Thyroid Nodules — When to Worry

Thyroid nodules are an extremely common finding — detectable by ultrasound in 50–68% of the general population. The vast majority (94–95%) are benign. However, a structured approach to risk stratification is essential.

Ultrasound Features Suggesting Malignancy

• Hypoechoic relative to surrounding thyroid tissue
• Irregular or microlobulated margins
• Microcalcifications
• Taller-than-wide orientation on transverse view
• Extra-thyroidal extension
• Pathological lymph nodes in the central or lateral neck compartment

Clinical Red Flags Requiring Urgent Referral

• Hoarse voice or dysphonia (recurrent laryngeal nerve involvement)
• Dysphagia — compression or invasion of oesophagus
• Rapid increase in nodule size over weeks to months
• Hard, fixed consistency on examination
• Palpable cervical lymphadenopathy
• Family history of medullary thyroid cancer, MEN2, or papillary thyroid cancer
• History of head and neck radiation in childhood

When Specialist Endocrinology Referral Is Needed

• All newly diagnosed hyperthyroidism — requires specialist workup, cause identification, and treatment selection
• Thyroid eye disease of any degree
• Thyroid nodule with suspicious ultrasound features or clinical red flags
• Goitre causing compressive symptoms (voice change, dysphagia, stridor)
• Subclinical hypothyroidism in pregnancy or preconception planning
• Persistent symptoms despite apparently adequate levothyroxine — dose review, absorption assessment, T4/T3 conversion evaluation
• Difficulty stabilising levothyroxine dose (absorption problems, compliance issues, malabsorption conditions)
• Thyroid disease as part of a polyglandular syndrome (type 1 diabetes + thyroid disease + Addison's → consider autoimmune polyglandular syndrome)
• Amiodarone-induced thyroid dysfunction — requires specialist management