Presentation on theme: "Hypothyroidism Dra Roopa Mehta"— Presentation transcript:
1 Hypothyroidism Dra Roopa Mehta Departamento de Endocrinología y MetabolismoInstituto Nacional de Ciencias Médicas y NutriciónSalvador Zubirán
2 Introduction This is the most common pathological hormone deficiency The deficiency of thyroid hormones results in a slowing down of metabolic processesPrevalence 2-3% in the general populationMean age at diagnosis is mid-50sMale: Female 1:10
3 Introduction Classification: Time of onset: Congenital or acquired Severity: Clinical or subclinicalSite of dysfunction: Primary or secondary/tertiaryPathogenesis:The most characteristic finding is the accumulation of glycosaminoglycans (mostly hyaluronic acid) in interstitial tissue. This results in interstitial edema (e.g. in skin, heart muscle etc.). The accumulation is due to decreased destruction of glycosaminoglycans.
4 Congenital hypothyroidism Incidence : 1 in 4000Male: Female 1:2The most common cause worldwide is endemic iodine deficiency (<100mcg/day)In areas with sufficient iodine intake: 85% sporadic / 15% hereditaryThyroid dysgenesis (aplasia, hypoplasia and ectopic gland). (Associated with mutations in the genes for PAX8 and TTF-2 (transcription factors involved in morphogenesis and differentiation of thyroid gland)
5 Congenital hypothyroidism Dyshormonogenesis. Defects in thyroid hormone synthesis, secretion or utilization (autosomal recessive). Include mutations in genes for thyroid TSH receptor, thyroid peroxidase gene, iodine transporter and thyroglobulin.Also mutations in genes for transcription factors needed for pituitary thyrotrope differentiation (pit-1, prop-1, HES-X)3. Failure of thyroid descent- “ectopic” poorly functioning thyroid4. Maternal radioactive iodine treatment/ antithyroid drugs (propylthiouracil)5. Transplacental transfer of TSH receptor (blocking) antibody from mother with Hashimotos thyroiditis
6 Congenital hypothyroidism Symptoms:Jaundice, lethargy, feedingproblems, respiratory problems,constipation, hypothermiaSigns:Puffy face, goiterProtruding tongue (macroglossia)Hoarse cryDistended abdomenUmbilical herniaMuscle weakness (cannot sit up without help)Slow reflexes
7 Congenital hypothyroidism Diagnosis:Neonatal screening. Heel prick test hrs after birth. A low T4 (<6ug/dl) and elevated TSH (>30uU/ml)Marked retardation of bone maturation. Absence of proximal tibial and distal femoral epiphysis suggests hypothyroidismTreatment: Replacement therapyChildren: growth failure and mental retardationAdolescents: growth failure and precocious puberty may occur (pituitary hypertrophy)
8 Primary hypothyroidism Disease of thyroid characterised by low serum T4 and high serum TSH (above reference values)In adults >65 years incidence is approx. 10%Overall incidence in population is 1-2%Two forms of primary hypothyroidism:Overt hypothyroidism (low free T4, high TSH)Subclinical hypothyroidism (normal free T4 and T3, high TSH)
9 Causes of primary hypothyroidism Most frequent causes of overt/subclinical hypothyroidism- 1-4 :Chronic autoimmune (Hashimoto´s) thyroiditisThyroid surgery (2-4 weeks following after total thyroidectomy)Radiation treatment I131 (for treatment of Graves commonly)Drugs: iodine deficiency or excess, methimazole, propylthiouracil, lithium, amiodarone, interferon alphaExcessive iodine intake (radiocontrast dye, kelp)Infiltrative diseases- rare (e.g. hemochromatosis,TB, leukemia, amyloid etc.)Thyroiditis
10 Chronic autoimmune thyroiditis (Hashimoto´s) Most common cause in iodine sufficient areasMale: Female 1:7Goitrous and atrophic forms- differ in extent of lymphocytic infiltration, fibrosis, and thyroid follicular cell hyperplasiaHypothyroid or euthyroidAssociated autoimmune diseases: polyglandular syndromes 1 and 2, vitiligo, pernicious anemia etc.
11 Chronic autoimmune thyroiditis (Hashimoto´s) Pathogenesis:Cell and antibody mediated destruction of thyroid glandDiffuse lymphocytic infiltrate + circulating autoantibodiesLymphocytes become sensitized to thyroid antigens resulting in formation of autoantibodies: thyroperoxidase (TPO in 95%), thyroglobulin (Tg in 60%) and TSH receptor blocking antibody (TSH-R )Genetic predisposition: HLA-DR5, HLA-B8 histocompatibility antigens
12 Yellow arrows = lymphoid aggregates with germinalcentersRed arrows = diffuselymphocytic infiltrateBlue arrows = small atrophicfollicles lined by hurtle cells
13 Drugs causing hypothyroidism Methimazole/ Thiamazole: Block biosynthesis of thyroid hormones by inhibiting production of thyroid peroxidasePropylthiouracl: In addition blocks peripheral conversion of T4-T3Iodine: Deficiency and excess (inhibition of iodide organification and T4 and T3 synthesis esp. with underlying autoimmune disease)Lithium: interferes with release of thyroid hormones, causing transient elevation of TSH in a third and persistent hypothyroidism in 10% (esp. with underlying autoimmune disease)Amiodarone (iodine containing): inhibits thyroid hormone production and peripheral conversion (esp. with underlying autoimmune disease)22% with overt or mild hypothyroidism in one study. Long half life (40-100d)
14 Drugs causing hypothyroidism Inhibition of thyroid hormone synthesis and/or releaseThionamides, lithium, aminoglutethimidine, iodine and iodine containing drugs (amidarone, kelp, contrast)Decreased absorption of T4Cholestyramine, calcium carbonate, omeprazole, iron sulphate, raloxifene,Immunedysregulation (ABs)Interferon alpha, interleukin-2Destructive thyroiditisSunitinib
15 Transient primary hypothyroidism Subacute thyroiditis (granulomatous/Quervains)viral in origin (coxackie, mumps, adenovirus)fever/malaise and tender thyroidunilateral hard massLymphocytic thyroiditis (painless/silent/postpartum)Usually in postpartum women (2-12 weeks) (8% of postpartum women)painless thyroid enlargement80% with elevated TPO antibodies
16 Transient primary hypothyroidism Both conditions have low RAIUBoth present with transient hyperthyroidism (4-8 weeks) followed by a euthyroid phase. Patients may remain euthyroid or progress to a hypothyroid phase that lasts 2-3 months followed by recovery (85% SAT, 75% LT)Patients often need temporary replacement therapyIn LT, persistent thyroid abnormalities such as goiter and/or frank hypothyroidism occur in one third of patients. Recurrence probable in subsequent pregnancy
18 Subclinical hypothyroidism Asymptomatic state (subclinical symptoms) with normal serum and free T4 but elevated TSHPrevalence 4-8.5%; up to 15% in women >60 yearsCauses same as for overt hypothyroidism- commonly chronic autoimmune thyroiditis, post radiation, inadequate replacement therapyContinuum between euthyroidism and hypothyroidismThe distinction between a normal TSH and elevated TSH is arbitraryIs treatment recommended???
19 Subclinical hypothyroidism CONSEQUENCES AND RISKSSymptoms of hypothyroidism; weight gainNeuropsychiatric symptoms: depression, loss of memoryNeuromuscular symptoms: >CPK, weakness, peripheral neuropathyCoronary artery disease (atherosclerosis) and cardiac dysfunction (reduced myocardial contractility); >CRPElevated total and LDL cholesterolProgression to overt hypothyroidism
20 Subclinical hypothyroidism Arguments for treatmentReduction of risk for CV disease (improve myocardial function and lower LDL), prevention of goiter growth and improvement in subclinical symptomsArguments against treatmentCost, lifelong commitment to medication in asymptomatic patients, risk of angina and arrhythmias in susceptible patients
21 Subclinical hypothyroidism In patients with TSH levels >10mU/L-Treat with T4 to reduce CAD risk and prevent progression to overt hypothyroidism (especially in patients with high serum TPO antibody titers and >65years)TSH between mU/L: some studies have shown risk for CAD and presence of hypothyroid symptoms
22 Subclinical hypothyroidism When evaluating such patients take into account:Clinical manifestations (symptoms and/or goiter)Presence of TPO antibodiesAgeWomen of reproductive age with infertility or pregnantProgression of TSH levels with time (can normalise)TSH between 3-4.5mU/L: only significant risk appears to be progression to overt hypothyroidism over time
23 Secondary and Tertiary hypothyroidism Account for <1% of patients with hypothyroidism (adulthood or childhood)Inappropriately low or normal TSH concentration (in presence of low T4 and T3)Secondary hypothyroidism caused by TSH deficiency(often pituitary tumors, Sheehan's syndrome, surgery/radiotherapy)Tertiary hypothyroidism caused by TRH deficiency (hypothalamic damage from tumors, trauma, radiation, infiltrative diseases)Secondary and tertiary hypothyroidism cannot be distinguished by biochemical tests- MRI should be requested (mass lesion), other hormone deficiencies
24 Clinical manifestations of hypothyroidism Depends on degree of hormone deficiency (overt, subclinical)Depends on speed of development of hormone deficiency (gradual, better tolerated)
25 Signs and symptoms SYMPTOMS Fatigue/ lethargy Non-pitting edema of face(periorbital edema) and handsParaesthesiasDeep hoarse voiceLoss of memory/<ConcentrationSomnolence/ Cold intoleranceDepressionConstipation (ileus)Arthralgia/ Myalgia with proximalweaknessDry skin and hair lossWeight gain /Carpal tunnel synd.Menstrual irregularitiesGrowth retardation in childrenDeficiency of other hormonesSIGNSYellowish tinge to skin (>carotenes)BradycardiaSystemic arterial hypertensionGoiter or small thyroidDry, cold skinSlow reflexes
26 Clinical Manifestations CARDIOVASCULAR SYSTEM:Impaired muscle contraction, bradycardia and reduced cardiac output. Hypertension- >Peripheral vascular resistanceCardiac enlargement due to interstitial edema but often due to pericardial effusionLow voltage complexes on ECGRESPIRATORY SYSTEM:Hypoventilation -Respiratory muscle weakness-Impaired ventilatory response to hypoxia and hypercapnia-Sleep apnea (retention of CO2)
27 Clinical Manifestations GASTROINTESTINAL SYSTEM:Slowing of peristalsis leads to constipationANEMIA:Usually normochromic, normocytic anemia-Impaired Hb synthesis due to thyroxine deficiencyIron def. due to menorrhagia and impaired intestinal absorptionFolate deficiency from impaired intestinal folate absorptionPernicious anemia with Vit-B12 def. megaloblastic anemia
28 Clinical Manifestations REPRODUCTIVE SYSTEM:Oligo / amenorrhea (16%) Menorrhagia (7%)Hyperprolactinemia occurs because of absence of inhibitory effect of thyroid hormone on prolactin secretion and causes galactorrhea and amenorrheaNEUROMUSCULAR SYSTEM:Carpal tunnel syndrome>CPK- muscle cramps, proximal weaknessSlow relaxing reflexes
29 Clinical Manifestations RENAL SYSTEM:Decreased glomerular filtration rate-Impaired ability to excrete a water load (hyponatremia)SKIN AND HAIR:Glycosaminoglycan, mainly hyaluronic acid, accumulate in skin and tissues causing retention of sodium and water- puffy skinReduced blood flow and calorigenesis- hypothermia and decreased sweatingCarotenemia.Loss of lateral eyebrows
30 Clinical Manifestations METABOLIC ABNORMALITIES:Hyponatremia (<free water clearance because of inappropriate ADH production)Hyperlipidemia: reduced number of lipoprotein lipase receptors, reduced degradation of lipoproteins and reduced lipoprotein lipase activity(4.2% of patients with hyperlipidemiaHypercholesterolemia 56%Hypertriglyceridemia 1.5%Mixed hyperlipidemia 34%)Hyperhomocystinemia
31 Diagnostic tests Clinical evaluation Measure T4 (total or free), T3 (total or free) and TSHThyroid antibodies: anti TPOanti TgCerebral MRI / CT when searching for mass lesion (Enlargement of pituitary also occurs in primary hypothyroidism due to hyperplasia of thyrotropes)TRH test for diagnosis of central hypothyroidism
32 Hypothyroidism T3 + T4 + TSH T3 + T4 + TSH nl / Suspicion of hypothyroidismThyroid function testsHypothyroidismNormal size or small thyroidGoiterIncreased TSHTSH normal or reducedPrimary hypothyroidismCentral hypothyroidismT T TSHT3 + T4 + TSH nl /
33 Hypothyroidism Hypothyroidism Primary hypothyroidism Central hypothyroidismAnti thyroid AB+Anti thyroid AB-Drugs:LithiumAmiodaroneEtc.Surgery or tx 131IAutoimmune thyroiditisPostpartumthyroiditisPituitary MRI or CTTRH test
34 TreatmentNormal metabolic state should be restored gradually as rapid increase in metabolic rate may precipitate cardiac arrhythmiasThyroxine (100mcg) or mixture of T3(20mcg) and T4(100mcg)Exclude adrenal insufficiency before initiating tx.Given 1x daily in morning (T4 t1/2=7days)- fastingIn elderly, with ischemic heart disease, initial dose 25ug; increased gradually at 4 week intervalsMonitor improvement in clinical symptoms and normalization of TSHSecondary hypothyroidism- free T4 used for monitoring response to tx.
35 Factors that increase the requirement for T4 Pregnancy, Estrogen therapy, Weight gainDrugs which increase catabolism of T4:Rifampin, Carbamazepine, Phenytoin, PhenobarbitolMalabsorption or increased excretion of T4:Gastrointestinal disorders, Impaired acid secretionDrugs which interfere with T4 absorption:Ferrous sulfate, Cholestyramine or colestipol, SucralfateAluminum hydroxide gels, Calcium Carbonate, SertralineRaloxifene, OmeprazoleNephrotic syndromeProgressive thyroid dysfunction
37 Myxedema Coma End-stage of untreated hypothyroidism- medical emergency Clinical manifestations:Decreased mental status, hypothermia, bradycardia, hypotension, hypoventilation (>pCO2), hypoglycemia, typical myxedematous facies and skin, hyponatremia (impaired water excretion and disordered regulation of vasopressin secretion), slow relaxing reflexes, coma and deathPrecipitated by intercurrent illness such as infection, stroke or CNS depressantsIf untreated 100% mortality
38 Myxedema Coma Identify and treat intercurrent illness Antibiotic therapy after blood culturesPassive external rewarming for hypothermia. 0.5degrees celsius / hrWarm humidified O2, mechanical ventilation if necessaryand cardiac monitor for arrhythmiasCorrect hyponatremia (fluid restriction), hypotension and hypoglycemiaTake blood for TFTs and cortisol before starting tx. If hypocortisolemic start hydrocortisoneT ug iv followed by ug / dailyIf no response within 24-48hrs, T3 10ug iv 8 hourly
39 CASO CLINICOMujer de 27 años con antecedentes familiares de enfermedad tiroidea (una tía materna con enfermedad de Graves y una hermana con hipotiroidismo)Ciclos menstruales regulares hasta hace dos años, actualmente x 2-3Un año con piel seca, fatiga y estreñimientoEF: peso 68 kg (previo 63), TA 130/70 FC 58 x minEdema bipalpebral, piel seca, tiroides palpable pequeña, ROTS lentos
41 CASO CLINICOA 29 year old woman with a history of a diffuse goiter with normal TFTs. She gave birth to a healthy baby 4 months ago. A month ago she developed symptoms of tremor, irritability and mild heat intolerance.T ug/dl (4.5-12)TSH 0.03mIU/ml (0.32-5)Today she has fatigue, dry skin, somnolence and difficulty concentrating at workOn examination, 92kg, 130/70, no lid lag or exophthalmus. Thyroid diffusely enlarged. No bruit. Family history of Graves disease
42 CASO CLINICO Does this woman have Graves disease? New TFTs: free T4 0.6ng/dl ( )T3 78ng/dl (80-200)TSH 27.3mIU/ml (0.32-5)What is the diagnosis? How is it treated?
43 CASO CLINICOA 51 year old man presents with a 5 week history of right sided neck pain radiating to right ear. He has had a mild URTI 7 weeks ago. He is physically fit with a normal pulse of 50; but in last 2 weeks this has risen to 70. He feels nervous and irritable.On examination, slightly enlarged tender thyroid gland, with no lymphadenopathy.TFTs: free T4 1.9ng/ml ( )TSH 0.03mIU/ml ( )U/S diffusely enlarged thyroid glandRAU scan 2hr uptake 1.9% 24hr 2.3% (Norm=20%)
44 CASO CLINICO What disorder does this man have? Appropriate treatments include:SurgeryProphylthiouracil or methimazolePropranalolIbuprofenPredisoloneRadioactive iodine
45 CASO CLINICO72 year old woman brought to ER in respiratory arrrest (respiratory frq-6). Not responsive. Family says she has been disorientated last 2 weeks. PMH: depression, hypothyroidism, and peptic ulcer disease. (captopril, levothyroxine, ranitidine)On examination minimally responsive. Thin woman. Cool dry skin. Bilateral crepitations on pulmonary examinationTemperature 95 farenheitIntubated and mechanically ventilatedNa 119mmmol/l ( )K 3.7mmol/l ( )
46 CASO CLINICO Arterial pH 7.31 (7.35-7.45) Plasma osmolality 258mOsm/kg ( )Toxicology negativeWhat tests would you ask for?Why might hyponatremia be present?How should this patient be treated?