Persistent fatigue is among the most common presenting complaints in primary care — and among the most diagnostically challenging. While the differential is broad, thyroid dysfunction is among the most frequently overlooked explanations, partly because standard screening protocols have significant limitations and partly because subclinical hypothyroidism produces a symptom constellation — fatigue, cold intolerance, weight gain, cognitive fog, dry skin, constipation — that is easily attributed to other causes including depression, anemia, sleep disorders, or simply the demands of modern life.
How the Thyroid Regulates Everything
The thyroid gland produces two primary hormones: thyroxine (T4), the circulating storage form, and triiodothyronine (T3), the biologically active form that enters cells and binds nuclear receptors to regulate gene expression. Virtually every cell in the body has thyroid hormone receptors, which explains why hypothyroidism — insufficient thyroid hormone activity — produces such diverse and systemic symptoms. T3 regulates basal metabolic rate, body temperature, cardiac contractility, protein synthesis, lipid metabolism, gut motility, and neurotransmitter sensitivity.
The TSH Limitation
Standard thyroid screening measures TSH — thyroid-stimulating hormone — produced by the pituitary gland. When thyroid output is insufficient, the pituitary responds by producing more TSH; high TSH signals hypothyroidism, low TSH signals hyperthyroidism. This feedback loop is elegant, but it has meaningful diagnostic limitations in clinical practice.
The population reference range for TSH (approximately 0.4–4.0 mIU/L) encompasses significant biological variability. Some individuals are clinically hypothyroid at TSH values within the "normal" range due to individual set-point differences, pituitary sensitivity variations, or tissue-level conversion impairments. Patients with Hashimoto\'s thyroiditis — the most common cause of hypothyroidism in the developed world — may have fluctuating TSH values that appear normal on a single screening but represent meaningful average underperformance.
Hashimoto\'s: The Autoimmune Driver
The majority of hypothyroidism in iodine-sufficient countries results from Hashimoto\'s thyroiditis — an autoimmune condition in which immune cells progressively infiltrate and destroy thyroid tissue. Standard TSH screening does not identify Hashimoto\'s; thyroid peroxidase antibodies (TPO Ab) must be specifically ordered. A patient can have elevated TPO antibodies — evidence of active autoimmune attack on the thyroid — and a currently normal TSH, representing a pre-symptomatic window in which dietary and lifestyle interventions may be most impactful.
Emerging evidence supports a role for dietary factors in Hashimoto\'s management. Selenium, present in Brazil nuts, seafood, and organ meats, is a cofactor for thyroid hormone synthesis enzymes and for selenoproteins that protect thyroid tissue from oxidative damage. Multiple RCTs have demonstrated significant reductions in TPO antibody titers following selenium supplementation in Hashimoto\'s patients. Gluten elimination, while lacking strong RCT evidence in Hashimoto\'s without concurrent celiac disease, is reported to reduce antibody titers and symptoms in a subset of patients, likely reflecting the significant overlap between celiac disease autoimmunity and thyroid autoimmunity.
When to Ask for More Complete Testing
Patients experiencing persistent fatigue, weight gain, cold sensitivity, constipation, dry skin, hair thinning, or cognitive slowing despite a "normal" TSH result have grounds to request a more complete thyroid panel including free T4, free T3, and TPO antibodies. Optimal TSH for symptomatic resolution in patients already on thyroid hormone replacement is generally accepted to be 1.0–2.5 mIU/L — considerably below the upper end of most laboratory reference ranges — and T3 supplementation may be appropriate for patients who feel symptomatic on T4-only therapy due to impaired peripheral T4-to-T3 conversion.