Review

Subclinical hypothyroidism: When to treat

Sidra Azim, MD and Christian Nasr, MD
Cleveland Clinic Journal of Medicine February 2019, 86 (2) 101-110; DOI: https://doi.org/10.3949/ccjm.86a.17053

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Tables

  • TABLE 1

    Causes of elevated thyroid-stimulating hormone

    Subclinical hypothyroidism
    Autoimmune (Hashimoto) thyroiditis
    Suboptimal treatment of overt hypothyroidism
    Partial thyroidectomy
    Radioactive iodine ablation
    External beam radiation of head and neck
    Infiltrative diseases of the thyroid (amyloidosis, sarcoidosis, hemochromatosis, Riedel thyroiditis, scleroderma)
    Drugs, eg, iodine contrast, amiodarone, lithium, tyrosine kinase inhibitors (sunitinib, sorafenib), interferon alpha, or immune response modulators (ipilimumab, alemtuzumab, pembrolizumab)
    Iodine deficiency
    Excess iodine
    Thyroid dysgenesis
    Physiologic increases
    Diurnal variation
    Recovery phase of euthyroid sick syndrome
    Recovery phase of subacute, painless, or postpartum thyroiditis
    Other causes
    Assay variability
    Substances that interfere with TSH assays (heterophile antibodies, rheumatoid factor, biotin, macro-TSH or abnormal TSH isoforms)
    Central hypothyroidism or hyperthyroidism
    Thyroid hormone resistance
    Impaired renal function
    Adrenal insufficiency
    Obesity
    Older age

    • Based on information in references 1, 2, and 16.

  • TABLE 2

    Adverse effects of subclinical hypothyroidism and the role for levothyroxine

    Adverse effectEvidence of adverse effectRole for treatment with levothyroxine
    Metabolic syndrome, obesity, diabetesAssociations observed, but cause and effect are unclear23,24No evidence to support
    DyslipidemiaRelationships observed between thyroid-stimulating hormone (TSH) elevation and altered lipid profiles13,43Associated with improved lipid profiles2,34,44–46
    Cardiovascular endothelial dysfunctionIncreased risk of myocardial infarction, atherosclerosis, aortic calcification,48 cardiovascular disease and mortality37; increased arterial stiffness and systemic vascular resistance45,53Lessens cardiovascular risk and mortality in patients < 65 years
    StrokeConflicting data: no association in patients ≥ 65 years, but some association in those < 65Lessens cardiovascular risk and mortality in patients < 65 years
    Psychiatric and cognitive dysfunctionAssociated with worsened preexisting depression and bipolar disease; may affect cognition65May improve mood, anxiety, cognition in older patients35
    Neuromuscular dysfunction, exercise intoleranceAssociated with skeletal muscle dysfunction, exercise intolerance71Limited data on treatment; role is unclear75
    Bone healthAssociated with increased risk of hip fracture attributed to suppression of bone turnover by elevated TSH18,76,77Too few clinical studies to define a role
    Thyroid cancerSome data suggest elevated TSH is associated with higher risk79–82More studies needed to understand association
    Infertility, recurrent miscarriageInconclusive evidence links subclinical hypothyroidism with infertility86; infertility rate is higher in women who also have positive thyroid peroxidase antibody than in women without autoimmunity87Some studies have shown lower rates of miscarriage with levothyroxine when TSH > 4.0 mlU/L86,91–92; insufficient data to support its use in patients with subclinical hypothyroidism and infertility; however, consider in euthyroid patients with positive peroxidase antibody and recurrent miscarriage90
    Pregnancy complicationsAssociated with several pregnancy-related complications including preeclampsia, hypertension, placental abruption, and postpartum hemorrhage in some studies,26,96 but not in others; if present, screen for autoimmunityNo recommendations; insufficient evidence to evaluate role of treatment
    Preterm delivery, pregnancy lossAssociated with high risk of miscarriage, preterm delivery, pregnancy loss at even mildly elevated TSH levels (2.5-5 mIU/L)99;104–107; risk is as high as 60% with TSH levels > 6 mIU/L and higher with positive thyroid peroxidase antibody108–110Improves maternal and fetal outcomes, including risk of low birth weight and low Apgar score, in women with subclinical hypothyroidism and TSH 2.5-10 mIU/L93,106; evidence less clear with TSH 2.5-4 mIU/L86; not recommended for the subgroup of pregnant patients with negative thyroid peroxidase antibody and TSH within pregnancy-specific range or < 4 mIU/L
  • TABLE 3

    Factors favoring levothyroxine therapy in subclinical hypothyroidism

    Thyroid-stimulating hormone (TSH) level > 2 times the upper limit of normal or > 8 mIU/L
    Progressive rise in TSH
    Goiter
    Positive antithyroid antibodies
    Pregnancy or planning pregnancy
    Infertility or ovulatory dysfunction
    Childhood or adolescence
    Dyslipidemia
    Established cardiovascular disease or risk factors for cardiovascular disease
    Depression or bipolar disease
    Therapeutic trial for clinical symptoms of hypothyroidism
    Patient preference
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