HypothyroidismHypothyroidismBy: Elias S.By: Elias S.

HypothyroidismHypothyroidism• A common disorder associated with thyroid

hormone deficiency resulting from a defect anywhere in the hypothalamic-pituitary-thyroid axis– Majority primary thyroid D.– Less common TSH , TRH

• Prevalence– U.S. NHANES III on 17353 persons hypothyroidism… 4.6% (subclinical 4.3%, overt 0.3%)

• international 2-5% ( to 15% by the age of 75)• Autoimmune Hypothyroidism annual incidence: 4/1000 women, 1/1000 men

Prevalence cont…….Prevalence cont…….• Age: … with age

– More prevalent in elderly– Autoimmune hypoth.- Mean age at Dx- 60.

• sex: women >(5-8x) Men Framingham study in adults>60yrs

5.9%-women 2.4%- men Race: more common-Japanese

NHASESIII, U.S whites(5.1%)>Hispanic A.(4.1%)>African

A(1.7%)

causescauses• Worldwide:

– iodine deficiency most common cause• In areas of iodine sufficiency

– Autoimmune thyroiditis (Hashimoto’s)– Iatrogenic causes

• Hypothyroidism - Primary H.

- Central (secondary/tertiary)

• Primary hypothyroidism – 2 forms Subclinical Overt( clinical)(TSH, N FT4,N FT3) (TSH, FT4,FT3)

Autoimmune hypothyroidismAutoimmune hypothyroidism

• Ch. Autoimmune thyroiditis (Hashimoto’s thyroiditis)

– Caused by cell-and Ab mediatd destruction of thyroid tissue

– Both humoral and cellular factors contribute– Cytotxic T cells– Auto Abs.. TPO 95%, Tg 60%, TSH-R bloking Ab 20%, TBII 10-20%Two forms Hashimoto’s(goitrous)thyroiditis Atrophic thyroiditis

• Hashimotos(goitruos)thyroiditis• Marked

lymph.infiltration• Atrophy of thyroid follicles with absence of

colloid• Mild to moderate

fibrosis • Present with goiter• Minimal or no Sx

• Atrophic thyroiditis

fibrosis• Less lymph. infiltration• Thyroid follicles

completely absent • Late stage of

Hashimotos thyroiditis• Minimal residual

thyroid tissue

• Overt symptoms

Risk factorsRisk factors• Genetic suseptibility

– Polymorphism in: HLA DR3,-DR4,-DR5– CTLA-4(a T-cell regulating gene) in down’s S., Turners S.

• Env. Factors– High iodine intake– infection: congenital rubella s. - autoimmune H.– Cigarette smoking

Iatrogenic causesIatrogenic causes• Thyroidectomy

– 1-4wks after total thyroidectomy– In the 1st yr in the majority of subtotal t. If euthyroid at one year, 0.5-1% chance of

hypothyroidism each year

• Radioiodine(I-131)therapy• Months to yrs later• Dose dependant

• External neck/Total body irradiations• Anti-thyroid drugs (over Rx of Hyperth.)

Other causesOther causes• Iodine deficiency• Iodine excess (the wolf-chaikoff effect)• Drugs – Ethanolamine, Lithium, Amiodarone, INF-alpha, IL2

– In Hypothyroid P’ts taking T4: Chlestyramine,Iron salts - T4 absorption Rifampin, Phenytoin,Carbamazepin-

clearance Amiodarone, glucocotricoids - conversion of T4T3

Other causes cont…Other causes cont…• Infiltrative diseases – rare

– Fibrous thyroiditis(reidel’s th.),hemochromatosis,scleroderma,

leukemia,amyloidosis– Infections: Tbc., P.carini

• Subacut thyroiditis (De-quervain’s,granulomatous) • Silent(painless)thyroiditis –postpartum th.

ESR-ve TPOAB

Normal ESR, +TPOAb

Secondary/tertiary Secondary/tertiary Hypothyroidism(Central)Hypothyroidism(Central)

• <1% TSH or TRH

– Dx – inappropriatly low(low or N. TSH) low T4 and T3

• Causes• Hypopituitarism(tumor,surgery

irradiation,sheehan’s s.,hypophysitis)• Mutations in TSH/TSH-R gene• Hypothalamic Damage

(tumor,trauma,radiation,inf. D.)• Mutations in TRH-R gene• Drugs – Dopamine, lithium

• Dx - MRI

Congenital hypothyroidismCongenital hypothyroidism• 1:4000 newborns

• Thyroid g. agenesis 80-85%• Inborn errors of thyroid H. synthesis 10-15%• TSH-R Ab mediated(Moinfant) 5%• Anti-thyroid (Moinfant)

• Majority – appear normal at birth• <10% - prolonged jaundice,feeding

problem,hypotonia,enlarged tongue,delayed bone maturation, unblical H., cong.Malf.

• Permanent neurologeic D. – if Rx is delayed

Mechanisms Symptoms Signs

Slowing ofMetabolic process

Fatigue, weaknessCold intoleranceDyspnea on exertionW’t gainSleepinessCognitive dysfunctionMental retardationConstipationGrowth failure

Slow mov’t, slow speechDelayed relaxation of tendon reflexesBradycardiaCarotenemia

Accumulation of Matrix

Dry skinHoarsness of voiceEdema

Rough thick skinPuffy face with loss of eye browPeriorbital edemaEnlargement of the tongue

others Decreased hearingMyalgia/ paresthesiaProximal M. weaknessDepressionMenst. IrregularityInfertility, LibidoArthralgiaPubertal delay

HTNPericardial/pleural effusionAscitisGalactorrhea

Neurologic manifestationsNeurologic manifestations Mental state, poor concentration• Poor memory , emotional lability• Carpal tunnel S. (25-30%)• Cerebellar ataxia (10-30%)• Peripheral neuropathy• Proximal muscle weakness• Hashimoto’s encephalopathy• Myxedema coma

Metabolic AbnormalitiesMetabolic Abnormalities• Hyponatremia• Hyperlipidemia (LDL, cholesterol)• Hyperuricemia (Gout) serum creatinin• carotenemia drug clearance drug toxicity

TSH

Elevated Normall

FT4

Normal Low

Pituitary D.Supected?

no yes

Mildhypothyroidism

Primaryhypothyroidism

No further test

FT4

TPOAb+ or SX

TPOAb-,noSx TPOAb+ TPOAb- low Normal

T4 RxAnnual

followup

AutoimmuneHypo.

T4 Rx

Rule outOther causes

Rule out drug effects,Sick euthyroid s.,

Then evaluate ant.pituit.f.

No further test

disorders that affect TSHdisorders that affect TSH• High TSH

• 1° hypothyroidism• Non-thyroidal

illness(5%)• Drugs: Dopamin antagonists, Amiodarone,

cholecystographic dyes• TSH-producing pit.

Adenoma• Adrenal insufficiency• Thyroid homone resistance S.

• Low TSH• 1° Hyperthyroidism• Incomplete recovery from Hyperthyroidism• Non-thyroidal illness (10%)• High HCG (early

pregnancy, molar P., choriocarcinoma)• Central hypothyroidism• Drugs: Dopamin, Glucocorticoids Somatostatin analogues Phenytoin

Other investigationsOther investigations• CBC, ESR• OFT, Electrolytes• Lipid profile• Uric acid• FNACentral hypothyroidism

– Imaging studies(sellar/supracellar)– Other hormonal profiles (pituitary)

TreatmentTreatment• Most P’ts …. Require lifelong Rx• The Goals Restoration of euthyroid State Reversion of Sx &Sns Reduction of gotre• Rx thyroid hormone replacement

Synthetic thyroxin(T4)– A pro-hormone, 80% absorbed– Active hormone production controlled by the patient’s own physiologic Mech.– Long half-life(7days)– Once daily when steady state is reached– Should be taken in an empty stomach

Replacement doseReplacement dose• Adults <60 with out evidence of Heart D.

1.6 mcg/kg/day (50-150)

• Older p’ts , p’ts with CHD1/2-1/4 of the dose(25-50mcg)

• P’t evaluation every 3-6wks• Measure T4(early phase), TSH• Dose adjustment by 12.5-25 ( or )

• Once steady state is reached• Maintenance dose, yearly evaluation with TSH

AdditionalAdditional adjustmentadjustment dose: Pregnancy

Estrogen Rx Nephrotic syndrom coadministration of drugs that clearance orabsorbtion dose: elderly

marked w’t loss androgen therapy

?T3 ?T3+T4?T3 ?T3+T4

• Not recommended– Wide fluctuations of serum T3 conc.– Multiple daily doses– Serum T4 remains low

• T3+T4 therapy– For some hypothyroid p’ts who remain

symptomatic despite Rx + normal TSH– Meta-analysis of 11 trials No benefit

Central HypothyroidismCentral Hypothyroidism• Think of other hormonal deficiencies

– T4 Rx to p’ts with untreard 2° adrenal

insuficiency acut adrenal crisis!• Glucocorticoid with T4 Rx if adr. Insuff.• Need less T4 than 1°hypothyroidism• Rx monitoring by- FT4 (TSH – no value)