Subclinical Hypothyroidism

ID: 83 yo female with refractory hypertension (on multiple antihypertensives with SBP ~170)

  • Has subclinical hypothyroidism which is being treated with levothyroxine (?link to refractory hypertension)


  • Primary hypothyroidism is characterized by a high serum thyroid-stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration
  • Subclinical hypothyroidism is defined biochemically as a normal free T4 concentration in the presence of an elevated TSH concentration. Secondary (central) hypothyroidism is characterized by a low serum T4 concentration and a serum TSH concentration that is not appropriately elevated

Primary hypothyroidism: 95%

  • TSH high, serum free T4 is low; subclinical (TSH high, serum free T4 normal)
  • Chronic autoimmune/lymphocytic (Hashimoto’s) thyroiditis: most common cause of hypothyroidism. Mainly older women. Anti-TPO (thyroid peroxidase) antibodies present in 75% of cases.
  • Iatrogenic: radioiodine, external Neck radiation, thyroidectomy
  • Iodine: deficiency (urine iodone <45 mcg/d) or excess
  • Drugs: rifampin, carbamazepine, phenobarbital, phenytoin, valproate, estrogen, cholestyramine, sucralfate, FeSO4, AlOH, CaCO3, lithium, interferon alpha, sunitinib, PPI? coffee?. Numerous mechanisms.
  • Infiltrative diseases: hemochromatosis, scleroderma, leukemia, tuberculosis, PCP

Hashimoto’s thyroiditis:

  • Presence of high serum concentrations of abs to thyroid peroxidase (TPO) and thyroglobulin
  • Do not routinely measure TPO abs in patients with primary overt hypothyroidism because almost all have chronic autoimmune thyroiditis – can be measured in subclinical hypothyroidism to predict likelihood of progression to permanent overt hypothyroidism

Secondary hypothyroidism: <1 %

  • TSH deficiency
  • Pituitary necrosis (eg. Sheehan’s syndrome), trauma, pituitary tumors
  • Treat with Thyrotropin (TSH, Thyrogen). Usually also need to replace other pituitary hormones.

Tertiary (central) hypothyroidism: <1%

  • TRH deficiency
  • Hypothalamic damage from tumors, trauma, radiation therapy, or infiltrative diseases.
  • Treat with Protirelin (TRH, Relefact TRH). Usually also need to replace other pituitary hormones.

In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as T4 secretion falls. As a result, the symptoms and the serum free T4 value must be used to make the diagnosis. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is suspected (eg, a young woman with amenorrhea and fatigue)

Hypothalamus — TRH –> Anterior Pituitary — TSH –> Thyroid Gland

Signs and symptoms:

CNS Fatigue, weakness, paresthesia, depression, cognitive dysfunction, decreased hearing, slow speech
HEENT Periorbital edema, tongue enlargement
RESP Dyspnea on exertion, pleural effusion, sleep apnea
CVS Bradycardia, diastolic hypertension, pericardial effusion, nonpitting edema (severe hypo), ↑ risk of CVD (HF, CHD, stroke, lipids)
GI Constipation, decreased taste
GU/Renal Menorrhagia, pubertal delay, galactorrhea, hyperprolactinemia
LIVER Ascites
ENDO Weight gain, ↑ LDL, ↑ total cholesterol
Lytes/HEME Hyponatremia (rare, only in severe), normochromic, normocytic hypoproliferative anemia
MSK/Bone Growth delay, myalgia, cramps, weakness, bradykinesia, carpal tunnel syndrome
DERM Dry, coarse skin, eczema thinning of hair, loss of eyebrows, cold sensitivity, brittle nails

The clearance of many drugs, including antiepileptic, anticoagulant, hypnotic and opioid drugs, is decreased in hypothyroidism. Thus, drug toxicity may occur if drug dose is not reduced. In addition, drugs that are administered at effective doses in patients who are hypothyroid may become less effective during T4 replacement.

Goal: Normalize TSH, T4, T3 + eliminate S&Sx.


  • Synthetic Levothyroxine (T4):
    • Young healthy adults: Start “full replacement dose”: 1.6 mcg/kg/d (50-200ug/d)
    • ELDERLY: Start 50 mcg/d; may be 1 μg/kg/d in elderly (50-100 μg/d).
    • CAD: Start 12.5-25 μg/d and monitor for angina.
    • 12.5-25 mcg/d dosage adjustments. Initiate with T4 monotherapy.
  • T4+T3 not superior to T4 alone on body weight, lipids, symptoms, cognition, QOL.
  • IV formulation available (500μg/vial = $125)

Do you treat in subclinical hypothyroidism?:

  • TSH > 10 mU/L: treat to prevent progression to overt hypothyroidism
    • data linking subclinical hypothyroidism with atherosclerosis and myocardial infarction and the increased risk of progression to overt hypothyroidism
    • supported by ATA, AACE, European thyroid association guidelines
  • TSH 7-9.9 mU/L: treat most under age 65-70 yo d/t association of increased CV mortality in younger patients. ?benefit in older patients and concerns of safety in older pts (↑ risk of exacerbation and induction of angina and CAD)
  • TSH ULN-6.9mU/L: treat <65 to 70 who have sxs suggestive of hypothyroidism. Consider if high titers of anti-TPO abs, and patients with goiter. For older patients, these levels of TSH may be age-appropriate.

  • Infertility or attempting pregnancy: suggest initiating T4 replacement (TSH values above 1st trimester-specific normal reference range with normal free T4)


  • Re-measure TSH 4-8 weeks after initiation or dose change.
  • Questionable role for fT4, no role for T3 in routine monitoring.
  • TSH annually once stable & when conditions change.
  • Avoid chronically low TSH even if asymptomatic due to osteoporosis risk (TSH <0.1 to 3.6 x ↑ in hip fracture risk & 4.5 x ↑ in vertebral fracture risk vs. normal TSH in women >65 y/o. [Ann Intern Med 2001;134:561-568, BMJ 2011;342:d2238].)
  • NOTES: Targeting lower half of TSH range no better than upper half w.r.t. Sx, QOL, cognition. [JCEM 2006:91: 2624 –2630].
  • Factors possibly requiring UPWARD dosage adjustment: worsened thyroid function, pregnancy, hi-fiber diet, concurrent rifampin, carbamazepine, phenobarbital, phenytoin, estrogen, cholestyramine, sucralfate, FeSO4, AlOH, CaCO3, lithium, nephrotic syndrome
    • ASSESS ADHERENCE (most common reason)
  • Factors possibly requiring DOWNWARD dosage adjustment: nephrotic syndrome, weight loss, androgen therapy.

Primary Hypothyroidism & Pregnancy:

  • Screening in normal healthy women: no consensus.
  • Recommendations range from screen all women before pregnancy (AACE) to screen only if high-risk (family history or goiter).
  • TREAT with T4 if TSH > ~4 mU/L.
  • If not on T4 therapy prior to pregnancy, no consensus about optimal initial dose. Some have suggested 1.2-1.4 mcg/kg/d initially. A retrospective study showed T4 50mcg/d (avg) was associated with reduced pregnancy loss and increased preterm delivery, preeclampsia, gestational diabetes.
  • Women with pre-existing primary hypothyroidism: Counsel women with primary hypothyroidism before pregnancy. If already on T4 before detecting pregnancy: Increase L-thyroxine intake by 20-30% immediately + contact caregivers urgently. [e.g. take an extra L- thyroxine dose twice weekly beginning immediately]
  • MONITORING: TSH ~q4 weeks until ~20 weeks, and at least once ~30 weeks. T4 requirements go up as early as 4-6 weeks of pregnancy, and increase through weeks 16-20, then plateau until delivery. 50 and 85% of LT4-treated hypothyroid women need a dose increase during pregnancy. Target TSH: 0.4-2.5 mU/L throughout pregnancy. Return to preconception T4 dose following delivery, TSH @ 6 weeks.

Considering patient’s refractory hypertension which is uncontrolled on multiple antihypertensives, trialing treatment of subclinical hypothyroidism to manage hypertension is appropriate (go low and slow).