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Created: 2025-10-10, curriculum
1. Basic Science
The most critical insight from pathophysiology is understanding the hypothalamic-pituitary-thyroid (HPT) axis and its negative feedback loop. Subclinical hypothyroidism (SCH) is defined biochemically by an elevated serum Thyroid-Stimulating Hormone () level with a normal free thyroxine () concentration.
This state represents compensated or mild thyroid failure. The pituitary gland, sensing a slight decline in thyroid hormone production, increases its output of to stimulate the thyroid gland more vigorously. This increased stimulation is just enough to maintain a normal circulating level, but the elevated serves as a sensitive marker of the underlying thyroid insufficiency.
This knowledge directly informs management by clarifying that SCH is not a benign laboratory finding but a sign of genuine thyroid stress. The treatment strategy—supplementing with exogenous levothyroxine—is logical because it reduces the physiological 'burden' on the thyroid gland. By providing the hormone the body is struggling to produce, it satisfies the negative feedback loop, causing the pituitary to reduce its output back to the normal range. This alleviates the strain on the thyroid and, in theory, prevents progression to overt hypothyroidism and mitigates potential long-term consequences of a persistently elevated .
2. Epidemiology
The most critical epidemiological finding is the clear demographic pattern of SCH: its prevalence increases significantly with age and is substantially higher in women than in men. It affects approximately 4–10% of the adult population, rising to as high as 20% in women over the age of 60.
The key risk factors that should inform public health and preventative strategies include:
Age and Sex: Being an older female is the strongest predictor.
Autoimmune Disease: A personal or family history of autoimmune conditions (e.g., type 1 diabetes, pernicious anaemia, coeliac disease) increases risk, as autoimmune thyroiditis (Hashimoto's disease) is the most common cause in iodine-sufficient regions.
Previous Thyroid Insult: A history of neck radiation, thyroid surgery, or treatment with certain medications (e.g., lithium, amiodarone) are major risk factors.
Iodine Status: While less common in the UK, iodine deficiency remains a global cause.
These findings mandate a targeted screening approach rather than universal screening. Clinicians should have a low threshold for testing in older women, individuals with autoimmune diseases, and those with a relevant medical history, particularly if they present with non-specific but suggestive symptoms like fatigue, weight gain, or cognitive slowing.
These are the most important, evidence-based insights that provide the greatest benefit in the diagnosis and management of subclinical hypothyroidism.
Confirm the Diagnosis Before Acting: A single elevated reading is insufficient for diagnosis. levels can fluctuate due to non-thyroidal illness, time of day, or transient thyroiditis. The most critical first step after an initial elevated result is to repeat the thyroid function test in 2–3 months to confirm persistence. This single action prevents premature diagnosis and unnecessary lifelong treatment.
Treat When TSH is Persistently > 10 mIU/L: There is strong consensus and evidence supporting treatment with levothyroxine for patients with a persistently elevated greater than 10 mIU/L. At this level, there is a higher risk of progression to overt hypothyroidism and an increased risk of adverse cardiovascular events and mortality, particularly in younger patients (<65-70 years). Treatment has been shown to improve lipid profiles and may mitigate these risks.
Approach Mild TSH Elevation (4.5–10 mIU/L) with Caution, Especially in the Elderly: For the majority of patients who fall into this 'grey zone', large-scale randomised controlled trials (e.g., the TRUST trial) have shown no significant benefit from levothyroxine treatment on symptoms or quality of life, particularly in individuals over 65. Initiating treatment in this group often leads to medicalisation without clear benefit and carries risks of iatrogenic hyperthyroidism. A strategy of active monitoring ('watch and wait') is often the most appropriate initial approach for asymptomatic older adults in this category.
These practices are essential for delivering comprehensive and high-quality care beyond the highest-impact items.
Use Thyroid Peroxidase (TPO) Antibodies to Stratify Risk: Checking for TPO antibodies in patients with SCH is crucial. Their presence indicates an autoimmune aetiology (Hashimoto's thyroiditis) and is associated with a much higher annual rate of progression to overt hypothyroidism (approximately 4–5% per year) compared to those who are TPO antibody-negative (<2% per year). A positive TPO antibody test can lower the threshold for initiating treatment in patients with a in the 4.5–10 mIU/L range, especially if they are symptomatic or younger.
Consider Treatment in Specific 'Grey Zone' Populations: While routine treatment for a between 4.5–10 mIU/L is not recommended for all, it should be strongly considered in certain subgroups:
Symptomatic Younger Patients: In patients under 65–70 with persistent and attributable symptoms (e.g., fatigue, cognitive difficulties), a therapeutic trial of levothyroxine is a reasonable option after a shared discussion.
Pregnancy and Infertility: Women who are pregnant, planning pregnancy, or undergoing investigation for infertility should be treated to a lower target (e.g., <2.5 mIU/L), as untreated SCH is associated with adverse obstetric and neonatal outcomes.
Patients with Goitre: The presence of a goitre suggests a more significant underlying thyroid pathology and may warrant treatment.
Follow a 'Start Low, Go Slow' Dosing Strategy: When initiating levothyroxine, the typical starting dose for a healthy adult is 25–50 micrograms daily. The dose should be titrated based on a repeat test after 6–8 weeks, aiming for a in the lower half of the reference range (e.g., 0.4–2.5 mIU/L). In elderly patients or those with ischaemic heart disease, the starting dose should be even lower (e.g., 12.5–25 micrograms daily) to avoid precipitating cardiac symptoms.
Implement Regular Monitoring for All Patients:
Treated Patients: Once stable on a dose, annual monitoring is sufficient unless symptoms recur.
Untreated Patients: Those being managed with active monitoring should have their checked annually (or every 6 months if TPO antibody positive) to monitor for progression to overt hypothyroidism.
1. Clinical Pearls
Timing Matters: follows a diurnal rhythm, peaking overnight. A borderline-high result from an afternoon test might be definitively elevated if re-checked with a morning sample.
Check for Biotin: High-dose biotin supplements, often taken for hair and nail health, can interfere with many thyroid immunoassays, typically causing a falsely low and falsely high and free T3 (), mimicking hyperthyroidism. Always ask about supplement use.
Absorption is Key: Advise patients to take levothyroxine on an empty stomach, at least 30–60 minutes before food, coffee, or other medications (especially iron, calcium, and proton pump inhibitors), to ensure consistent absorption.
The Therapeutic Trial: When uncertain if symptoms are due to SCH, a 3–6 month trial of levothyroxine is reasonable. If there is no discernible improvement in symptoms once the has normalised, the medication is unlikely to be beneficial and can be stopped.
2. Common Pitfalls
The Symptom Attribution Trap: Attributing non-specific symptoms like fatigue, weight gain, or low mood solely to mild SCH is a common error. These symptoms are highly prevalent in the general euthyroid population. Avoid creating a false expectation that levothyroxine will be a panacea.
Ignoring Non-Thyroidal Illness (Sick Euthyroid Syndrome): In acutely unwell or hospitalised patients, can be transiently elevated during the recovery phase. Thyroid function testing should be avoided in this context unless there is strong suspicion of primary thyroid dysfunction.
Failing to Age-Adjust TSH: Healthy older adults (>75-80 years) often have a higher baseline than younger individuals. Using a standard reference range (e.g., up to 4.5 mIU/L) may lead to over-diagnosis and over-treatment in this population. Some labs are now providing age-specific reference ranges.
Chasing the Numbers: Rigidly treating to a specific target without considering the patient's clinical state is poor practice. An asymptomatic 85-year-old with a stable of 6.5 mIU/L likely requires no intervention.
3. Guiding Principles
Embrace Shared Decision-Making: For the 'grey zone' of 4.5–10 mIU/L, the decision to treat is a classic preference-sensitive choice. Present the evidence clearly: explain the lack of proven benefit for symptom improvement versus the certainty of committing to lifelong medication, regular blood tests, and potential side effects. Use phrases like, "The evidence suggests that for many people in your situation, treatment does not improve symptoms, but it does for some. We can either monitor this for now or try a course of treatment to see if it helps you. What are your thoughts?"
Manage Expectations: Be transparent about the uncertainty of benefit. If a decision is made to start treatment, explain that any improvement in symptoms may be subtle and take several months. This prevents disappointment and encourages adherence during the titration period.
Prioritise 'First, Do No Harm': The risk of iatrogenic hyperthyroidism from over-treatment is real and is associated with atrial fibrillation and osteoporosis, particularly in the elderly. In cases of diagnostic or therapeutic uncertainty, a conservative approach of watchful waiting is often the safest path.