Endocrinology & Family Medicine & Internal Medicine & Obstetrics
Hypothyroidism
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Hypothyroidism is a state of insufficient production of thyroid hormones - thyroxine (T4) and triiodothyronine (T3) - by the thyroid gland, leading to a generalized slowdown in metabolism. It is one of the most common endocrine diseases: its prevalence in the general population is 4-10 %, including subclinical forms, with a marked female predominance (F/H ratio 5-10:1). In Canada, the prevalence of patent hypothyroidism is estimated at 1.5-2 %, and that of fruste hypothyroidism at 5-10 %. The most common cause in developed countries is Hashimoto's autoimmune thyroiditis - an autoimmune disease in which anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-TG) antibodies progressively destroy the thyroid parenchyma. In developing countries, iodine deficiency remains the world's leading cause. Diagnosis is based on TSH (pituitary thyroid stimulating hormone) levels - the most sensitive marker of thyroid dysfunction - which, if elevated above 4.0-5.0 mIU/L (depending on the laboratory), indicate hypothyroidism, confirmed by low free T4. Levothyroxine (L-T4) replacement therapy is the reference treatment, simple, effective and well-tolerated for life in the vast majority of cases. Frustrated hypothyroidism (elevated TSH + normal free T4) is a controversial subject: treatment is recommended if TSH is ≥10 mIU/L, and discussed on an individual basis between 4.5 and 10 mIU/L. Hypothyroidism during pregnancy requires particular attention, as it is associated with significant fetal risks (delayed neurological development, spontaneous abortions, prematurity) and requires rapid adjustment of treatment.
Etiology, pathophysiology and clinical manifestations
- Hypothalamic-pituitary-thyroid axis and pathophysiology of hypothyroidism: normal regulation of the thyroid axis: TRH (thyreoliberin - hypothalamus) → TSH (thyroid stimulating hormone - anterior pituitary) → T4 (thyroxine) + T3 (triiodothyronine) (thyroid) → negative feedback from T4 and T3 on TSH and TRH + T4 = prohormone → converted to active (more potent) T3 by deiodinases (DIO1 + DIO2 + DIO3) → in peripheral tissues (liver + kidney + brain + heart) + DIO2 ensures local conversion of T4 to T3 in target tissuestarget tissues + DIO3 inactivates T4 into rT3 (reverse T3 - biologically inactive) → T3 binds to nuclear thyroid hormone receptors (TR-α + TR-β) → regulation of transcription of numerous genes → control of basic metabolism + thermogenesis + neurodevelopment + growth + cardiac + bone + hematopoiesis ; pathophysiology of hypothyroidism manifestations: reduced thyroid hormones → slowing of basal metabolism by 25-40 % → reduced thermogenesis → cold intolerance + reduced cardiac output (reduced contractility + HR → bradycardia) → increased peripheral vascular resistance → diastolic hypertension + accumulation of glycosaminoglycans in the dermis (mucin) → myxedema (swelling not taking up the bucket - especially the face) → myxedema (swelling not taking up the bucket - especially the face).taking up the bucket - especially face + hands + feet) → intestinal slowing → constipation + Reduced lipid clearance → hypercholesterolemia (increased LDL and total cholesterol) + reduced protein synthesis → myopathy + reduced myelination + cognitive impairment → reduced ADH clearance → fluid retention + hyponatremia → reduced erythropoietin metabolism → anemia + reduced prothrombin production → mild bleeding tendency ; classification of hypothyroidism: primary (most common - 95 % of cases): primitive thyroid gland deficit → high TSH + low free T4 → secondary: deficit of TSH secretion by the pituitary → low or normal TSH + low free T4 → causes: pituitary adenoma + pituitary surgery + irradiation + pituitary apoplexy + lymphocytic hypophysitis (autoimmune) → tertiary: deficiency of TRH secretion by the hypothalamus → low TSH + low free T4 (very rare) + peripheral hypothyroidism (resistance to thyroid hormones): TR receptor mutations → very rare
- Etiologies of primary hypothyroidism and clinical manifestations : causes of primary hypothyroidism: Hashimoto's thyroiditis (autoimmune thyroiditis - AIT): most common cause in developed countries → autoreactive CD4+ T lymphocytes → lymphocytic infiltration of the thyroid → progressive destruction of parenchyma → fibrosis → reduction of functional thyroid mass → anti-TPO antibodies (positive in 90-95 % of Hashimoto's) + anti-TG (positive in 50-60 %) → slow evolution over decades → sometimes transient hypertyroid phase (hashitoxicosis) during initial lysis → frequent association with other autoimmune diseases: T1DM + RA + SLE + rheumatoid arthritis + Biermer's disease + Addison's disease + celiac disease + diffuse goiter possible → postpartum thyroiditis: autoimmune thyroiditis triggered within 12 months postpartum → anti-TPO positive in 50-70 % → hypertyroid phase then hypothyroidism → resolution in 80-90 % of cases + iodine deficiency: world's leading cause of hypothyroidism + endemic goiter + prevention by salt iodization (Canada: iodized salt mandatory since 1949) + iatrogenic thyroiditis: after total or subtotal thyroidectomy → definitive hypothyroidism + after radioactive iodine (131I) → almost constant progressive hypothyroidism → cervical irradiation (cervical cancer + Hodgkin) → drugs : amiodarone (37 % iodine - Wolff-Chaikoff effect) + lithium (inhibition of HT synthesis) + interferon-alpha + sunitinib + sorafenib + carbamazepine (induction of T4 metabolism) → destructive thyroiditis (De Quervain's subacute + silent) → transient + congenital hypothyroidism : athyreosis + thyroid dysgenesis + enzymopathies → mandatory neonatal screening (TSH on blotting paper within 24-72h); clinical manifestations of hypothyroidism - protean picture: general symptoms: fatigue + somnolence + weight gain + cold intolerance + pallor + bradycardia + deep voice + macroglossia → cutaneous: dry + cold + yellowish skin (carotenoderma) + hair loss + depilation of the outer third of the eyebrow (Hertoghe's sign) + myxedema (swelling not taking up the bucket - especially face + orbits + hands) → musculoskeletal: myalgia + cramps + proximal muscle weakness + hyporeflexia (slowness of reflexes - religoidism) + morning stiffness + neuropsychiatric disorders: depression + concentration disorders + memory disorders + dementia (severe forms) + carpal tunnel syndrome (mucin deposition) + sleep apnea syndrome + epilepsy (myxedema coma) → cardiovascular: bradycardia + pericardial effusion + diastolic hypertension + increased LDL cholesterol → digestive: constipation + paralytic ileus (severe myxedema) + megacolon (severe forms) → gynecological: menorrhagia + amenorrhea + galactorrhea (hyperprolactinemia due to TRH excess) + infertility → biological: hyponatremia (inappropriate ADH) + normocytic normochromic anemia (or macrocytic if associated with Biermer anemia) + hypercholesterolemia + increased CPK (myopathy) + hyperprolactinemia + elevated LDH
Diagnosis, treatment and special situations
| Domain | Data, criteria and procedures | Key studies and recommendations |
|---|---|---|
| Biological diagnosis and imaging TSH - free T4 - free T3 - anti-TPO - anti-TG - ultrasound - screening - reference values - fruste hypothyroidism |
Biological workup of 1st intention: serum TSH (thyroid stimulating hormone) - most sensitive marker: method: high-sensitivity immunometry (3rd generation TSH) → detection limit: 0.01-0.02 mIU/L → normal: 0.4-4.0 mIU/L depending on most laboratories (some use 0.4-4.5 or 0.3-5.0) → fruste hypothyroidism (subclinical): TSH 4.0-10 mUI/L + normal free T4 → patent hypothyroidism: TSH >10 mUI/L + low free T4 → TSH assay alone is sufficient for initial screening of primary hypothyroidism + Free T4 (FT4): 2nd-line assay → to confirm hypothyroidism if TSH elevated + for diagnosis of central hypothyroidism (low or normal TSH + low free T4) + normal value: 10-23 pmol/L (depending on laboratory) → low = patent hypothyroidism + Free T3 (FT3): rarely useful in diagnosing hypothyroidism → T3 is the last to fall → its measurement is not routinely indicated in hypothyroidism → useful if T3 hyperthyroidism suspected + anti-TPO (anti-thyroperoxidase) antibodies: positive in 90-95 % of Hashimoto's thyroiditis → confirms autoimmune origin + prognostic value (patients with anti-TPO + fruste TSH have an increased risk of progression to patent hypothyroidism) + anti-thyroglobulin (anti-TG): positive in 50-60 % of Hashimoto's + useful if anti-TPO negative + echo-thyroid : indications: palpable goiter + palpable nodule + thyroid volume monitoring → Hashimoto's thyroiditis: hypoechoic + heterogeneous + micro-nodular + atrophic or goitrous appearance + increased vascularization (Doppler) → not routinely indicated for diagnosis of hypothyroidism alone + thyroid scintigraphy: indicated if nodule + hyperthyroidism + search for thyroid ectopy in newborns + not routinely indicated in hypothyroidism; TSH reference values - thresholds discussed: the upper threshold of normal TSH is subject to debate → Wartofsky 2005 - Journal of Clinical Endocrinology and Metabolism: proposal to lower the upper threshold to 2.5 mIU/L → not universally adopted → Hamilton 2008 - Journal of Clinical Endocrinology and Metabolism: upper TSH threshold increases with age (4.5-5.0 mIU/L in 60-80 year olds → 7.5-10 mIU/L in >80 year olds) → Garber 2012 - Endocrine Practice (ATA Guidelines): TSH 0.45-4.12 mUI/L = reference + treatment threshold for fruste hypothyroidism: TSH ≥10 mUI/L → treatment recommended → TSH 4.5-10 mUI/L → treatment discussed → benefits if: suggestive symptoms + pregnancy (or planned pregnancy) + anti-TPO positive (risk of progression) + age 80 years with TSH 5-10 mUI/L → no demonstrated benefit of treatment (Razvi 2012 - Archives of Internal Medicine: fruste thyroid + elderly subjects → treatment without cardiovascular or quality-of-life benefit); screening for hypothyroidism: targeted screening (not universal in general population in Canada): women ≥35 years every 5 years (according to SOGC) + patients with family history of thyroid disease + patients with autoimmune diseases (T1D + RA + IBD) + women before conception or in the 1st trimester of pregnancy + patients on amiodarone + lithium + after thyroidectomy or radioactive iodine + after cervical irradiation + patients with Down's syndrome + Turner + treatment with certain drugs (sunitinib + nivolumab + pembrolizumab → checkpoint-induced immune thyroiditis) + universal neonatal screening: TSH on blotting paper within 24-72h → congenital hypothyroidism → immediate treatment with LT4 → prevention of cretinism | Garber 2012 - Endocrine Practice (ATA Clinical Practice Guidelines): normal TSH 0.45-4.12 mIU/L + treatment recommendations according to TSH + Hamilton 2008 - JCEM: TSH increases physiologically with age → avoid overtreatment of elderly subjects + Razvi 2012 - Archives of Internal Medicine (meta-analysis): treatment of fruste hypothyroidism in elderly subjects → no demonstrated cardiovascular benefit → no improvement in quality of life + Wartofsky 2005 - JCEM: proposal to lower upper threshold → not universally adopted + SOGC 2019 (Clinical Practice Guideline): thyroid screening during pregnancy → TSH in 1st trimester → target TSH <2.5 mIU/L in 1st trimester + ATA 2017 (Alexander - Thyroid): recommendations for thyroid management during pregnancy + fruste hypothyroidism → North American reference + Bibbins-Domingo 2015 - JAMA (USPSTF): no systematic screening in asymptomatic general population → targeted screening |
| Levothyroxine (LT4) treatment - initiation, dosage and follow-up Levothyroxine - starting dose - titration - target TSH - interactions - intake - follow-up - coronary artery disease - elderly - combined forms LT4+LT3 |
Levothyroxine sodium (L-T4 - Synthroid - Euthyrox - Eltroxin) - reference treatment: mechanism: replacement of endogenous T4 → peripheral conversion to active T3 by deiodinases → complete substitution of the thyroid axis → starting dose: young healthy adult: 1.6-1.8 µg/kg/d ideal weight → example: 65 kg woman → 100-120 µg/d → adult >65 years or coronary artery disease: start at low dose (12.5-25 µg/d) + increase gradually (25 µg every 4-8 weeks) → risk of precipitating angina or MI if induction too rapid → severe hypothyroidism (myxedema): also start cautiously → take levothyroxine: on an empty stomach in the morning 30-60 min before breakfast → or at bedtime (4h after last meal) → Bolk 2010 - Archives of Internal Medicine: taken at bedtime → better absorption + lower TSH → can replace morning intake for patients who forget + coffee + and water do not consume within 30 min of intake (reduced absorption) → drug interactions reducing absorption: calcium (calcium salts + antacids) + ferrous iron + sucralfate + cholestyramine + sevelamer + PPIs → take 4 h apart → interactions increasing metabolism (enzyme inducers): rifampicin + phenytoin + carbamazepine + phenobarbital → increase LT4 dose → estrogens (pill + HRT) → increase TBG → increase LT4 requirements → adjust for pregnancy and contraception; titration and follow-up: check TSH at 4-6 weeks after any dose change → T4 status regimen in 4-6 weeks → do not measure TSH too early + target TSH: primary hypothyroidism: 0.5-2.5 mIU/L (below mid-normal range) → pregnancy: TSH <2.5 mUI/L in 1st trimester + TSH 70 years): target TSH slightly higher 1.0-4.0 mUI/L (risk of atrial fibrillation + osteoporosis if TSH too low) → regular follow-up: TSH annually once stable + adjust dose if significant weight gain + pregnancy + menopause + new medication + change of brand (variable bioavailability between generics) → follow-up for resolution of symptoms (4-8 weeks delay for most) + TSH dosage if symptoms persist despite normal TSH → Stott 2017 - NEJM (TRUST RCT n=737): treatment of fruste hypothyroidism in elderly subjects ≥65 years → LT4 vs placebo → no difference on quality of life + fatigue + symptoms → major result → supports lack of systematic treatment in elderly subjects with mild fruste TSH; combined treatment LT4 + LT3 - controversial: about 10-15 % of patients treated with LT4 alone persist with symptoms (fatigue + cognitive impairment + mood) despite normalized TSH → hypothesis: some patients have insufficient T4 → T3 conversion (deiodinase polymorphisms - DIO2) → combined LT4 + LT3 (liothyronine) treatment: data: Bunevicius 1999 - NEJM: T4 + T3 vs T4 alone → improved cognition and mood → but: results not confirmed in later meta-analyses + Joffe 2007 - Journal of Clinical Endocrinology and Metabolism: meta-analysis → LT4 alone = LT4 + LT3 → no overall benefit → Wiersinga 2019 - Lancet Diabetes and Endocrinology: review → subgroup of patients with DIO2 polymorphisms → could benefit from LT3 → not routinely recommended → LT4 alone = standard of care → LT3 (Cytomel): if added → reduced dose (5-20 µg/d) + fractionated × 2/d (T3 = short 8h half-life) + increased monitoring (atrial fibrillation + osteoporosis) | Bolk 2010 - Archives of Internal Medicine (RCT): LT4 taken at bedtime vs morning → lower TSH + better absorption → valid alternative + Stott 2017 - NEJM (TRUST RCT n=737 patients ≥65 years): treatment fruste hypothyroidism in elderly subjects → no benefit on quality of life or symptoms → major result in favor of non-intervention in elderly subjects with slightly elevated TSH + Bunevicius 1999 - NEJM: T4 + T3 vs T4 alone → improved cognition → result not confirmed in meta-analyses + Joffe 2007 - JCEM (meta-analysis 11 trials): LT4 alone = LT4 + LT3 → no overall benefit → LT4 alone = standard + Wiersinga 2019 - Lancet Diabetes and Endocrinology: review → DIO2 polymorphisms → possible benefit of LT3 in a subgroup + ATA 2014 Garber Guidelines: LT4 = standard → LT3 not routinely recommended → Razvi 2008 - JCEM: fruste hypothyroidism + cardiovascular risk → beneficial treatment in <65 years → no benefit in ≥65 years + Andersen 2015 - BMJ: LT4 overdose in elderly subjects → risk of atrial fibrillation + fractures → avoid overcorrection |
| Hypothyroidism in pregnancy TSH target <2.5 mIU/L - increased LT4 requirements - anti-TPO - fetal risks - postpartum thyroiditis - neonatal |
Importance of euthyroidism during pregnancy: maternal T4 is the only source of thyroid hormones for the fetus until 10-12 weeks' gestation (the fetus does not yet produce its own HT before then) → maternal T4 deficiency during organogenesis → delayed fetal cerebral neurodevelopment → reduced IQ → learning disabilities → spontaneous abortions + preeclampsia + intrauterine growth retardation + prematurity → Haddow 1999 - NEJM: untreated maternal hypothyroidism → Q.I. of children significantly reduced (-7 points on average) → risk of mental retardation → seminal publication → Casey 2005 - Obstetrics and Gynecology: maternal fructal hypothyroidism → increased risk of spontaneous abortions + obstetric complications + increased LT4 requirements during pregnancy: +25-50 % from the first weeks → mechanism: increase in TBG (estrogens) → increase in total T4 required + increase in feto-placental tissue mass + increase in renal iodine clearance + increase in placental T4 degradation (DIO3) → practical adjustment: if LT4 taken before pregnancy → increase dose by 20-30 % as soon as pregnancy is confirmed → without waiting for biological control → check TSH at 4-6 weeks + each trimester → TSH targets during pregnancy: 1st trimester: TSH <2.5 mIU/L → 2nd and 3rd trimesters: TSH 10 mUI/L → LT4 → with gradual weaning at 12-18 months if euthyroidism persists (resolution possible) | Haddow 1999 - NEJM: untreated maternal hypothyroidism → reduced fetal IQ -7 points → mental retardation → demonstration of neurological impact → major publication that transformed screening recommendations + Casey 2005 - Obstetrics and Gynecology: maternal fructal hypothyroidism → obstetrical risks (miscarriages + complications) + Stagnaro-Green 2011 - Thyroid: ATA guidelines hypothyroidism and pregnancy → TSH targets + screening + treatment + Alexander 2017 - Thyroid (ATA Management Guidelines for Thyroid Diseases in Pregnancy): 2017 update → North American reference + SOGC 2019: universal 1st trimester screening recommended in Canada → 1st trimester TSH + Korevaar 2016 - Lancet Diabetes and Endocrinology: low maternal T4 → impaired fetal neurocognitive development even with normal TSH → implication on treatment thresholds + ESPGHAN 2019: nutritional recommendations on iodine during pregnancy + Thyroid Canada 2019: Canadian recommendations adapted for practice. |
| Myxedematous coma, central hypothyroidism and special situations Myxedema coma - emergency - hydrocortisone - LT4 IV - adrenal insufficiency - amiodarone - lithium - after thyroidectomy - elderly subjects |
Myxedematous coma (myxedema coma) - life-threatening endocrinological emergency: extreme and rare form of untreated severe hypothyroidism → mortality: 20-40 % even with optimal treatment → precipitating factors: infection + sedative drugs + cold exposure + trauma + surgery + MI + stroke + discontinuation of replacement therapy → clinical picture: altered consciousness (from torpor to coma) + deep hypothermia (sometimes 4-5 mUI/L + central (secondary) hypothyroidism: TSH low + normal or slightly elevated + free T4 low → pituitary MRI mandatory → cause: pituitary adenoma + apoplexy + irradiation + Sheehan + treatment: LT4 → followed by free T4 (not TSH - because hypothalamic-pituitary axis is impaired) → target free T4 in upper third of normal; hypothyroidism in Down syndrome and Turner syndrome: prevalence 15-30 % + annual screening recommended → TSH annually; hypothyroid myopathy: very high CPK (often 1,000-10,000 IU/L) → rhabdomyolysis possible → normalization under LT4 → do not assign to statins without checking thyroid → hypothyroidism and sleep apnea syndrome: frequently associated → hypothyroidism worsens OSAHS → LT4 treatment → partial improvement of OSAHS + elderly subject (>70-75 years): target TSH slightly higher (1.0-4.0 mIU/L) → avoid overcorrection → risk of atrial fibrillation (Andersen 2015 - BMJ: TSH <0.5 mUI/L under LT4 in elderly subjects → risk of AF × 3 + fractures × 2) + risk of angina + osteoporosis → start at low doses (25 µg/d) + very slow titration | Idrose 2019 - BMJ: myxedematous coma → LT4 + LT3 IV associated → mortality 20-40 % → recent reference on management + Wartofsky 2006 - Journal of Intensive Care Medicine: treatment of myxedematous coma → systematic hydrocortisone + LT4 IV → Andersen 2015 - BMJ (cohort n=14,337 elderly subjects): LT4 + elderly subjects under- or over-treated → TSH <0.5 mUI/L → AF × 3 + fractures × 2 → caution in treatment management in elderly subjects + Stott 2017 - NEJM (TRUST RCT): fruste hypothyroidism + elderly subjects → no benefit of treatment + Razvi 2008 - JCEM: fruste hypothyroidism + cardiovascular risk → benefit of treatment in <65 years → not in ≥65 years + Alexander 2017 - Thyroid (ATA Guidelines): hypothyroidism and pregnancy + hypothyroidism after thyroidectomy + amiodarone → recommendations + ATA 2014 (Garber - Endocrine Practice): clinical guidelines adult hypothyroidism → recommendations for LT4 treatment + Thyroid Canada 2019 + Canadian Thyroid Association: Canadian resources + SOGC 2019: hypothyroidism in pregnancy + screening + treatment + Haddow 1999 NEJM + Casey 2005 OG: foundations of screening and treatment policy in pregnancy. |
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TSH is the most sensitive test for detecting primary hypothyroidism - a normal TSH practically excludes primary hypothyroidism: in pregnant women or those planning pregnancy, TSH should be kept below 2.5 mUI/L in the 1st trimester - levothyroxine requirements increase by 25 to 50 % in the first few weeks, and adjustment should be immediate upon confirmation of pregnancy, without waiting for a biological check-up. Levothyroxine should always be taken on an empty stomach, 30 to 60 minutes before breakfast, away from calcium and iron supplements and PPIs, which reduce absorption.
Situations requiring urgent or emergency consultation
Progressive alteration of consciousness + hypothermia + bradycardia + hypoventilation + facial myxedema + severe hyponatremia in a patient untreated or who has stopped levothyroxine → myxedematous coma → call 911 → medical resuscitation → LT4 IV 200-400 µg + hydrocortisone 100 mg IV × 3 (before LT4) → mechanical ventilation if necessary → gradual rewarming → treat triggering cause → mortality 20-40 % even treated.
Pregnant woman with TSH >4.0 mIU/L in first trimester or known elevated TSH untreated at time of conception → hypothyroidism in pregnancy → urgent endocrinological consultation → initiate or increase LT4 immediately → target TSH <2.5 mUI/L → biological control at 4 weeks → risk of fetal neurological retardation if hypothyroidism not corrected in the first few weeks.
Patient on amiodarone or lithium with marked fatigability, weight gain, bradycardia and TSH >10 mUI/L → iatrogenic hypothyroidism → urgent medical consultation → initiate LT4 + monitor TSH every 3 months + discuss with cardiologist or psychiatrist whether to maintain the drug or replace it.
Massive elevation of CPK (10,000-50,000 IU/L) + proximal muscle weakness + very high TSH discovered on workup → severe hypothyroid myopathy with rhabdomyolysis → medical emergencies → LT4 + IV hydration + renal monitoring (myoglobinuria → AKI) → do not assign to statins without systematic thyroid screening.
Consult at Clinique Omicron
Les médecins de Clinique Omicron diagnostiquent et traitent l'hypothyroïdie dans ses différentes formes, prescrivent et interprètent le bilan thyroïdien complet (TSH + T4 libre + anti-TPO + anti-TG), initient et ajustent le traitement par lévothyroxine selon les cibles recommandées, assurent le suivi annuel de la TSH, et orientent vers l'endocrinologue pour les formes complexes (hypothyroïdie centrale + coma myxœdémateux + hypothyroïdie réfractaire). Des consultations sont disponibles dans plusieurs points de service au Québec et en télémédecine. Pour prendre rendez-vous, Choose your online service.
The content of this page is provided for information purposes only and does not replace the advice of a physician or endocrinologist. Any adjustment of levothyroxine therapy, particularly in pregnancy, should be made under medical supervision.
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