HYPOTHYROIDISM













  • Subclinical hypothyroidism defined as TSH > 4.5 mU/L and T4 ≥ 57.9 nmol/L
  • Clinical hypothyroidism defined as TSH > 4.5 mU/L and T4 < 57.9 nmol/L
  • Data from NHANES III Study
Prevalence of hypothyroidism in U.S. population ≥ 12 years old
Total White Black Mexican-American Remaining races
Subclinical hypothyroidism
(% of population)
4.3% 4.8% 1.6% 3.9% 4.0%
Clinical hypothyroidism
(% of population)
0.3% 0.4% 0.1% 0.2% 0.2%




  • Reference [1,6,23]
RISK FACTORS FOR PRIMARY HYPOTHYROIDISM
Risk factor Notes
Iodine deficiency
  • Most common cause worldwide
  • Rare in developed countries
Female sex
  • Females are affected more than males
Advancing age
  • Prevalence increases with age
Ethnicity
  • Whites are affected more than blacks and Mexican-Americans
Family history of autoimmune thyroid disease
Thyroid peroxidase antibodies (TPOAb)
  • In patients with subclinical hypothyroidism and elevated TPOAb titers, 4.3%/year will develop hypothyroidism
  • See autoimmune thyroiditis
Pregnancy
  • Postpartum thyroiditis - may see period of hyperthyroidism (1 - 6 months postpartum) followed by a period of hypothyroidism for 4 - 6 months
History of thyroid disease/treatment
  • Radioactive iodine
  • Thyroid surgery
  • External beam radiation treatment
Medications
Presence of other autoimmune disease
  • Type 1 diabetes (10% of patients with Type 1 diabetes have hypothyroidism)
  • Addison's disease
  • Pernicious anemia
  • Myasthenia gravis
  • Celiac disease
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Vitiligo
Genetic disorders
  • Down's syndrome
  • Turner's syndrome


  • Reference [1]
RISK FACTORS FOR SECONDARY HYPOTHYROIDISM
Cause Notes
Pituitary or hypothalamic tumors
  • Craniopharyngioma
Infiltrative inflammatory diseases
  • Granulomatous (ex. Sarcoidosis)
  • Lymphocytic (ex. lymphocytic hypophysitis)
Medications
Iatrogenic
  • Brain surgery
  • External beam radiation
Hemorrhagic necrosis
  • Sheehan's syndrome







  • Reference [1,10]
Screening recommendations for asymptomatic patients
Organizations Screening recommendation
  • USPSTF
  • American Academy of Family Practice
  • Insufficient evidence to make recommendation for screening nonpregnant, asymptomatic adults
  • American Thyroid Association
  • American Assoc of Clinical Endocrinologist
  • Consider screening patients ≥ 60 years old
  • Association for Clinical Biochemistry
  • British Thyroid Association
  • British Thyroid Foundation
  • Do not screen







  • Data from NHANES III Study. Ranges are from a subpopulation of 13,344 patients without thyroid disease or detectable thyroid antibodies.
  • Reference [15]
TSH Values in Thyroid Disease-free Population
2.5th - 97.5th percentile TSH (mIU/L) values
Age range 20 - 29
(Median)
30 - 39
(Median)
40 - 49
(Median)
50 - 59
(Median)
60 - 69
(Median)
70 - 79
(Median)
≥ 80
(Median)
Black 0.36 - 3.30
(1.10)
0.33 - 3.24
(1.10)
0.42 - 3.74
(1.30)
0.44 - 3.99
(1.40)
0.35 - 4.20
(1.58)
0.39 - 5.20
(1.50)
0.42 - 4.60
(1.50)
Mexican-American 0.47 - 3.62
(1.33)
0.40 - 3.75
(1.30)
0.40 - 3.99
(1.49)
0.55 - 4.85
(1.50)
0.51 - 5.54
(1.80)
0.59 - 7.12
(2.13)
0.55 - 7.84
(1.91)
White 0.46 - 3.60
(1.30)
0.46 - 3.76
(1.37)
0.57 - 3.95
(1.49)
0.52 - 3.97
(1.58)
0.56 - 4.31
(1.66)
0.46 - 5.60
(1.80)
0.41 - 6.56
(1.99)






  • Reference [19]
Hyperthyroidism Hypothyroidism High TBG Low TBG
Total T4 High Low High Low
T3 resin uptake High Low Low High



  • Data from NHANES III Study. Ranges are from a subpopulation of 16,533 who did not report thyroid disease, goiter, or taking thyroid medications.
  • Positive TPOAb defined as ≥ 0.5 U/ml
Percent of Thyroid Disease-free Patients with Positive TPOAb
Age range 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 - 79 ≥ 80
Female 10.4 12.6 15.8 17.1 23 26.2 26.5
Male 5.5 8.4 10.6 10.1 10.2 12 10.6


  • Data from NHANES III Study. Ranges are from a subpopulation of 16,533 who did not report thyroid disease, goiter, or taking thyroid medications.
  • Positive TgAb defined as ≥ 1.0 U/ml
Percent of Thyroid Disease-free Patients with Positive TgAb
Age range 20 - 29 30 - 39 40 - 49 50 - 59 60 - 69 70 - 79 ≥ 80
Female 8.5 13.6 16 16.4 19.6 20.6 25.2
Male 5 6.6 6.8 7.9 9.6 12.9 10.1





  • Reference [9,20]
Medication Interaction
Drugs that may affect the absorption of thyroid hormone
  • Calcium carbonate
  • Ferrous sulfate
  • Aluminum hydroxide
  • Sucralfate (Carafate®)
  • Proton pump inhibitors (e.g. omeprazole)
  • H2 antagonists (e.g. famotidine)
  • Bile acid sequestrants
  • Raloxifene (Evista®)
  • Orlistat (Xenical®)

Separating dosing by 4 hours may limit interaction
Amiodarone (Cordarone®)
  • Contains iodine
  • May inhibit thyroid hormone production
  • Up to 22% of patients on amiodarone develop hypothyroidism
Lithium
  • May interfere with thyroid hormone release
  • Up to 10% of patients on lithium develop persistent hypothyroidism
Estrogens and SERMs (tamoxifen, raloxifene)
  • Estrogens and SERMs may increase TBG levels
  • Hypothyroid patients may require larger doses of levothyroxine after starting estrogen/SERM therapy
  • Check TSH levels after starting estrogens/SERMs in hypothyroid patients
Androgens (testosterone)
  • Androgens may decrease TBG levels
  • Hypothyroid patients may require lower doses of levothyroxine after starting androgen therapy
  • Check TSH levels after starting androgens in hypothyroid patients
Enzyme inducers (e.g. phenobarbital, phenytoin, carbamazepine, rifampin)
  • Enzyme inducers may increase the metabolism of thyroid hormone
Opioids (e.g. methadone, morphine)
  • Opioids may increase TBG levels
  • Hypothyroid patients may require larger doses of levothyroxine after starting opioid therapy
Clofibrate
  • Clofibrate may increase TBG levels
  • Hypothyroid patients may require larger doses of levothyroxine after starting clofibrate therapy
Interferon alpha (pegylated interferon)
  • May initiate thyroid autoimmunity
  • May cause hypo- or hyperthyroidism
Iodine supplements (e.g. Kelp)
  • High intake of iodine supplements may suppress thyroid function
Sertraline (Zoloft®)
  • May increase thyroid hormone clearance
Tyrosine kinase inhibitors (e.g. imatinib, sunitinib)
  • May increase thyroid hormone clearance
Thalidomide
  • May cause hypothyroidism by an unknown mechanism
Stavudine
  • May cause hypothyroidism by an unknown mechanism








  • Reference [11,12,13]
Screening for thyroid disease in asymptomatic pregnant females
Organization Screening recommendation
American Endocrine Society No consensus agreement on whether or not to screen
American Thyroid Assoc **See table below
American College of Obstetricians and Gynecologists Does not recommend universal screening
European Thyroid Assoc Does not recommend routine, universal screening

  • Reference [26]
The ATA recommends screening the following patients
  • A history of hypothyroidism/hyperthyroidism or current symptoms/signs of thyroid dysfunction
  • Known thyroid antibody positivity or presence of a goiter
  • History of head or neck radiation or prior thyroid surgery
  • Age > 30 years
  • Type 1 diabetes or other autoimmune disorders
  • History of pregnancy loss, preterm delivery, or infertility
  • Multiple prior pregnancies (≥ 2)
  • Family history of autoimmune thyroid disease or thyroid dysfunction
  • Morbid obesity (BMI ≥ 40)
  • Use of amiodarone or lithium, or recent administration of iodinated radiologic contrast
  • Residing in an area of known moderate to severe iodine insufficiency



  • Reference [21, 26]
Women with diagnosis of hypothyroidism
Prior to pregnancy
  • Women with hypothyroidism who are planning pregnancy should have their levothyroxine doses adjusted to achieve a TSH value < 2.5 mIU/L
During pregnancy
  • Treat to achieve trimester-specific TSH values (see TSH in pregnancy above)
  • The majority of newly pregnant women will require increased doses of levothyroxine during pregnancy
    • Two acceptable methods for the initial increase in levothyroxine dose after pregnancy occurs are:
      • Increase daily levothyroxine dose by 20 - 30%
      • Increase current levothyroxine dose from once daily to 9 doses per week
  • Monitor TSH levels every 4 weeks during first half of pregnancy
  • Check TSH at least once between 28 and 32 weeks
  • After delivery, reduce levothyroxine dose to preconception levels and check TSH 6 weeks postpartum
  • T3 products (ex. Armour thyroid) are not recommended
Women with subclinical hypothyroidism (elevated TSH [2.5 - 10 mIU/L] and normal Free T4)
Whom to treat
  • Women with subclinical hypothyroidism who are TPOAb positive should be treated
  • Women with subclinical hypothyroidism who are TPOAb negative and have a TSH > 10 mU/L should be treated
  • Treatment guidelines are the same as women with overt hypothyroidism (see above)
  • Women with subclinical hypothyroidism who are not initially treated should be monitored with a serum TSH and Free T4 approximately every 4 weeks until 16 – 20 weeks gestation and at least once between 26 and 32 weeks gestation
Studies
  • A study published in 2017 found no benefit of treating subclinical hypothyroidism in pregnancy [PubMed abstract]
Women with normal thyroid function (normal TSH and free T4) who have positive thyroid antibodies
Monitoring
  • Check TSH at time of pregnancy confirmation and every 4 weeks during first half of pregnancy
Studies
  • A study published in 2019 found no effect of thyroid supplementation on live birth rates among women with normal thyroid function and positive thyroid peroxidase antibodies. [PubMed abstract]






  • A study published in the NEJM in 2017 found that treating subclinical hypothyroidism in elderly patients (N=737, average age 74 years) had no effect on hypothyroid symptoms or tiredness. [PMID 28402245]
  • Reference [28,23]
British Medical Journal recommendations for subclinical hypothyroidism (2019)
  • Do not treat patients with elevated TSH (up to 20 mIU/L) and a normal free T4 who are asymptomatic or report nonspecific symptoms (e.g. fatigue, constipation, poor memory)
  • Recommendation may not apply to young adults (≤ 30 years) and/or patients with severe symptoms
  • Recommendation does not apply to women who are trying to become pregnant and patients with TSH > 20 mIU/L
European Thyroid Association treatment recommendations for subclinical hypothyroidism (2013)
Age TSH value Recommendation
≤ 70 years < 10
  • If hypothyroid symptoms are present, treat for 3 months and assess response to therapy
  • If hypothyroid symptoms are absent, observe and repeat TSH and free T4 in 6 months
≤ 70 years ≥ 10
  • Treat with levothyroxine
> 70 years < 10
  • Observe and repeat TSH and free T4 in 6 months
> 70 years ≥ 10
  • Consider treatment if clear symptoms of hypothyroidism or high vascular risk





  • Reference [1,20]
Patient factor Recommendation
Little residual thyroid function or markedly elevated TSH
  • Start therapy at approximately 0.73 mcg/lb/day or 1.6 mcg/kg/day
  • Dosing should be based on ideal body weight (IBW)
    • IBW (male) = 110 lbs + 5 lbs for each inch over 5 feet (50 kg + 2.3 kg for each inch over 5 feet)
    • IBW (female) = 100 lbs + 5 lbs for each inch over 5 feet (45.5 kg + 2.3 kg for each inch over 5 feet)
  • Patients who have had thyroidectomy or radioiodine therapy may require higher doses
TSH ≤ 10 mIU/L or subclinical hypothyroidism
  • Lower doses are typically adequate
  • Starting dose of 25 - 50 mcg once daily may be appropriate in most patients
Elderly patients
  • Lower doses (20 - 25% less) are typically adequate because of decreased lean body mass
  • Goal TSH values may be higher (see TSH values)
Patients with coronary artery disease
  • Start with lower doses (12.5 - 25 mcg once daily)
  • Increase dose gradually
  • Monitor for symptoms of angina
Pregnancy
Other dosing recommendations
Food
  • Food decreases the absorption of levothyroxine
  • Levothyroxine should be taken on an empty stomach, preferably 60 minutes before breakfast or ≥ 3 hours after the evening meal
Dosing based on TSH level
  • One study found the following dosing regimen based on TSH level alone to be effective in most patients:
    • TSH 4 - 8 mUI/L: 25 mcg once daily
    • TSH 8 - 12 mUI/L: 50 mcg once daily
    • TSH > 12 mUI/L: 75 mcg once daily
Intravenous levothyroxine
  • Intravenous dose of levothyroxine should be 70% of oral dose
Monitoring therapy
  • Recheck TSH levels 4 - 8 weeks after initiating therapy, after dose adjustments, and after changing levothyroxine preparations
  • Adjust dose in increments of 12.5 - 25 mcg per day
  • For small dose adjustments, TSH levels may take 8 weeks or longer to stabilize
  • Symptoms of hypothyroidism (e.g. dry skin) may take 3 - 6 months to resolve after TSH levels have normalized
  • Once TSH levels have normalized, recheck TSH at 6 months and then yearly






  • Reference [4]
ETA guidelines for dosing combination therapy
Thyroid product
  • Separate T4 and T3 products should be used for combination therapy so that physiologic ratios of T4 and T3 can be achieved
  • Cytomel® is a common T3 product, and Synthroid® and Levoxyl® are common T4 products. See thyroid preparations for more
  • Combination products (e.g. Armour® thyroid) are not recommended because they contain lower ratios of T4:T3 than what is physiologic. For example, Armour thyroid contains 38 mcg of levothyroxine and 9 mcg of liothyronine per 60mg giving it a T4:T3 ratio of 4.2:1
Calculating dosage
  • The ETA lists 4 similar methods for calculating T4 and T3 doses. One method is detailed below.
  • The goal of therapy is to achieve a physiologic dose ratio between 13:1 and 20:1 while taking into account the pharmacodynamic equivalence ratio of 1:3 for T3 to T4
    • Step 1 - Take levothyroxine dose that has normalized TSH (designated "StartT4")
    • Step 2 - T3 (liothyronine) dose = StartT4 / 17
    • Step 3 - New T4 (levothyroxine) dose = StartT4 - 3(T3 dose)
    • Example:
    • Step 1 - Patient is on 100 mcg of levothyroxine and has normal TSH. StartT4 = 100 mcg
    • Step 2 - T3 (liothyronine) dose = 100 mcg / 17 = 5.88 mcg
    • Step 3 - New T4 (levothyroxine) dose = 100 mcg - 3(5.88 mcg) = 82.35 mcg
    • Step 4 - After rounding to available dosage forms, patient could be given liothyronine 6.25 mcg (1 and 1/4 of liothyronine 5 mcg) and levothyroxine 88 mcg
  • If possible, the liothyronine dose should be given in two divided doses (one before breakfast and the largest one before sleeping)
  • Levothyroxine should be given once daily in the morning
Monitoring therapy
  • Thyroid tests (TSH, free T4, free T3) should be checked 6 - 8 weeks after starting therapy and with dosage changes
  • Blood should be drawn before the morning dose
  • If dose adjustment is necessary, it is recommended that only one component be changed, preferably the T3