• 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
  • NHANES III - random sample of 17,353 people ≥ 12 years old in the U.S. The sample was devised to give an accurate representation of the geographic and ethnic makeup of the U.S. population. [6]
Prevalence of hypothyroidism in U.S. population ≥ 12 years old
(NHANES III study)
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)
(autoimmune thyroiditis)
  • 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 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 [8]
Symptoms of hypothyroidism
Hoarse voice
Deep voice
Constipation
Dry skin
Cold intolerance
(feeling cold)
Fatigue
Puffy eyes
Muscle cramps and weakness
Decreased cognitive function
(poor memory, slow thinking)

  • Reference [1,9]
Symptoms of severe hypothyroidism
Hyponatremia (low sodium)
caused by impaired free water excretion and SIADH
Myxedema
nonpitting edema with mucin deposits of the skin
Hypothermia
Respiratory failure
Ileus
Severe cognitive decline
delirium, dementia, seizure, coma
Adrenal insufficiency
Pituitary hyperplasia
Coagulopathy
von Willebrand syndrome, decreased Factor V, VII, VIII, IX, X
Cretinism
syndrome of mental retardation, deafness, short stature, and facial deformities seen in congenital hypothyroidism
Sleep apnea
Carpal tunnel syndrome




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








  • Ranges are from a subpopulation of 13,344 patients without thyroid disease or detectable thyroid antibodies
  • The NHANES III study published in 2002 randomly sampled 17,353 people ≥ 12 years old. The sample was devised to give an accurate representation of the geographic and ethnic makeup of the U.S. population.
  • Reference [15]
NHANES III - 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


  • Reference [1,16,20]
Factors that increase TBG
  • Inherited
  • Pregnancy
  • Neonatal state
  • Estrogens
  • Hepatitis
  • Porphyria
  • Clofibrate
  • Heroin
  • Methadone
  • Mitotane
  • 5-Fluorouracil
  • SERMs (tamoxifen, raloxifene)
  • Perphenazine
Factors that decrease TBG
  • Inherited
  • Androgens
  • Anabolic steroids
  • Glucocorticoids
  • Severe illness
  • Liver failure
  • Kidney disease
  • Niacin
  • L-Asparaginase
  • Acromegaly
Factors that alter T4 and T3 binding to TBG
  • Salicylates (e.g. aspirin)
  • Furosemide (Lasix®)
    at doses > 80 mg
  • Free fatty acids
  • Phenytoin
  • Carbamazepine
  • NSAIDs
  • Heparin


  • 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
  • The NHANES III study published in 2002 randomly sampled 17,353 people ≥ 12 years old. The sample was devised to give an accurate representation of the geographic and ethnic makeup of the U.S. population.
  • Reference [15]
NHANES III
% 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


  • 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
  • The NHANES III study published in 2002 randomly sampled 17,353 people ≥ 12 years old. The sample was devised to give an accurate representation of the geographic and ethnic makeup of the U.S. population.
  • Reference [15]
NHANES III
% 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
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)
  • 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

  • NOTE: 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
  • Check TSH at time of pregnancy confirmation and every 4 weeks during first half of pregnancy





  • *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. [PubMed abstract]
  • Reference [23]
European Thyroid Association treatment recommendations for subclinical hypothyroidism
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