Regulation of Thyroid Axis• TSH – – Thyrotrope cells of ant. Pituitary – 31 kDa hormone α and β subunits – α subunit similar to LH, FSH and hCG – Stimulated by TRH – TSH, TRH supressed by Thyroxine – Pulsatile secretion – Long half life (50 minutes)
• Iodine primarily derived from diet• RDA of iodine• Adults – 150 µg• Children – 90 – 120 µg• Pregnancy – 200 µg• Urinary iodine is >10 g/dL in iodine-sufficient populations• Plasma iodide partly replenished from thyroid loss, peripheral deiodination
CLASSIFICATION• Primary hypothyroidism with Goitre – Acquired Iodine deficiency(MCC) • Hashimoto’s (autoimmune type 2A) • Drugs synthesis or release of T4 (lithium,ethionamide,sulfonamides,iodide) • Food goitrogens or as endemic substances or pollutants • Thyroid infiltration (Reidels struma,cystinosis,scleroderma) • sarcoidosis,amyloidosis,hemochromatosis.
– Congenital • Iodide transport or utilization defect • Iodotyrosine dehalogenase deficiency • Organification disorders • Defects in thyroglobulin synthesis or processing
• Atrophic hypothyroidism – Acquired • Hashimoto’s disease (autoimmune thyroiditis type 2B) • Post ablative-follows surgery,I131 radiation• Congenital • Thyroid agenesis or dysplasia (80-85% of neonatal hypothyroidism) • TSH receptor defects • Thyroidal Gs protein abnormalities • Idiopathic TSH unresponsiveness
• Transient (post thyroiditis) hypothyroidism – Following subacute.painless, or post partum thyroiditis• Consumptive hypothyroidism – D3 over expression in hemangiomas
• Central hypothyroidism – Acquired • Pituitary origin (secondary) • Hypothalamic disorders (tertiary) • Bexarotene (RXR receptor agonist) • Dopamine and or severe illness
Thyroid Hormone Resistance• autosomal dominant disorder• characterized by elevated thyroid hormone levels and inappropriately normal or elevated TSH• . do not, in general, exhibit signs and symptoms that are typical of hypothyroidism because hormone resistance is partial and is compensated by increased levels of thyroid hormone
• . The clinical features of RTH can include goiter, attention deficit disorder, mild reduction in IQ, delayed skeletal maturation, tachycardia, and impaired metabolic responses to thyroid hormone.• mutations in the TR receptor gene.• . The diagnosis is suspected when unbound thyroid hormone levels are increased without suppression of TSH.• RTH must be distinguished from other causes of euthyroid hyperthyroxinemia (e.g., FDH) and inappropriate secretion of TSH by TSH-secreting pituitary adenomas (Chap. 333)..
RTH• In most patients, no treatment is indicated; the importance of making the diagnosis is to avoid inappropriate treatment of mistaken hyperthyroidism and to provide genetic counseling
euthyroid hyperthyroxinemia• These disorders result in increased total T4 and/or T3, but unbound hormone levels are normal.• Usually caused by mutations that affects TBG,Tranthyretin, or albumin
CLINICAL FEATURESMechanism Symptoms Signs Fatigue and weakness Slow movement andSlowing of slow speech Cold intolerancemetabolic Delayed relaxation of Dyspnea on exertionprocesses tendon reflexes Weight gain Bradycardia Cognitive dysfunction Carotenemia Mental retardation (infant) Constipation Growth failure
Accumulation Dry skin Coarse skin Hoarseness Puffy facies andof matrix loss of eyebrows Edemasubstances Periorbital edema Enlargement of the tongue
Other Decreased hearing Diastolic Myalgia and hypertension paresthesia Pleural and Depression pericardial effusions Menorrhagia Ascites Arthralgia Galactorrhea Pubertal delay
CLINICAL FEATURESSKIN AND APPENDAGES• Dry coarse skin• Pale cool extremities• Carotenemia• Poor wound healing• Easy bruisability• Dry brittle hair&nail
• Accumulation of hyaluronic acid, hygroscopic• Mucinious edema, boggy, non pitting• Eyes, dorsa of hand and feet, supraclavicular fossae• Tongue enlargement, thickening pf pharyngeal and laryngeal membranes• Decreased secretion of sweat and sebaceous glands
• Skin wounds heal slowly• Increase capillary fragility – easy bruisability• Hair lost from temporal aspect of eyebrow – Queen Annes sign
• Combination of large heart, hemodynamic and electrocardiographic changes and serum enzyme changes – myxedema heart• Thyroid replacement reverts to normal• Increased Total and LDL cholesterol – Reduced on thyroxine initiation – No change in HDL levels
RESPIRATORY SYSTEM• Hoarse voice• Pleural effusion – Radiological – Rarely cause dyspnoea• Myxedematous involvement of resp muscles and depression of respiratory drives – Decreased alveolar ventilation – Carbon dioxide retention• Obstructive Sleep Apnoea common
ALIMENTARY TRACT• Decreased apetite• Modest weight gain(fluid retention) 10% of body weight• Constipation(myxedema megacolon)• Myxedema ileus• Ascites(raised protein glycosaminoglycans)• Pernicious anemia(autoimmune)• Raised CEA, raised aminotranferases due to decreased clearance
MUSCULO SKELETAL SYSTEM• Weakness,cramps worsened by cold• Arthralgia• Increased muscle mass-firm• Role in bone maturation• Short limb dwarfism(Bone age<chr age)• Epiphyseal dysgenesis(x ray)• Myoclonus
RENAL• Decreased RBF &GFR• Increased uric acid• Decreased urine flow• Reversal of (n)diurnal pattern of urine excretion• Mild proteinuria
PITUITORY & ADRENOCORTICAL FN.• Enlarged pituitary, hyperplasia of thyrotropes, rarely mass effect• Raised prolactin(galactorrhea)• Urinary cortisol decreases,plasma level normal• Long standing primary hypothyroidism, adrenocortical insufficiency may be precipitated by thyroxine/stress
REPRODUCTIVE SYSTEM• Sexual immaturity• Delay in puberty, Anovulaton• Menorrhagia, amenorrhea• Impotence, oligospermia• Precocious sexual development -rarely in primary hypothyroidism
ENERGY & METABOLISM• Low BMR• Positive nitrogen balance• Decreased secretion of GH• Serum proteins increase• Decreased glucose uptake by adipose tissue and skeletal muscles• Insulin response to glucose delayed• Increased sensitivity to exogenous insulin
• True obesity is rare in hypothyroidism• Raised LDL & TG,low HDL• Hyperhomocystinemia-lead to atherosclerosis• Hyponatremia• Hypoglycemia
DIAGNOSIS• Decreased freeT4,raised TSH : primary hypothyroidism• Decreased TSH, Decreased Free T4, in secondary(central)• Degree of TSH elevation correlates with severity.• Free T4 is done in pregnancy• Anti thyroglobulin and anti TPO Ab: Hashimoto’s• Absence of TPO Ab: post undiagnosed subacute/viral thyroiditis/ post hyperthroid hpothyroidism• TSH may take several months to reach normal
INDIVIDUAL CAUSES• Hashimotos thyroiditis – Most common cause of hypothyroidism in areas with sufficient dietary intake – There is mononuclear cell infiltrate and destruction of follicles – Chronic thyroiditis defined as evidence of intrathyroidal lymphocytic infiltration.mainly Tcell mediated destruction – Occurs more commonly in women,prevalence increases with age
– Auto immune thyroiditis leads on to thyroid cell apoptosis leading to follicular destruction– Almost 90% destruction before symptoms manifest– HLA DR-3 ,HLA-DR5,seen with Downs syndrome and gonadal dysgenesis,polymorphisms in CTLA4– Pregnancy ,drugs,low doses of irradiation,certain viral infections may increase risk
– Goiter hallmark finding,moderate size firm,freely mobile,lymph node enlargement unusual– Increased prevalence of thyroid carcinoma– Diagnosis confirmed by autoantibodies,TPO AB more common than TyAb
• Iodine deficiency – Thyroid iodine clearance rates and RAIU are increased – Decreased urinary excretion of stable iodine – Results in cretinism
• Drugs – Lithium inhibits thyroid hormone release and in high conc. can inhibit organic binding reactions – Underlying autoimmune disease increase susceptibility
• Atrophic hypothyroiodism – (primary myxedema) – More common in women between ages of 40 and 60 – May represent end stage of an autoimmune thyroiditis in which goiter did not devolop or went unnoticed – May be associated with TSH receptor blocking antibodies
• Post ablative hypothyroidism • Following total/subtotal thyroiodectomy • Subtotal resection of the diff.goiter of gravesor multinodular goiter • Radioiodine treatment – Manifests during the first yr after surgery – FT4I is low in patients with postablative hypothyroidism,serum TSHlevels may be anomalously low for several months
• Transient hypothyroidism defined as period of reduced fT4I with supressed, normal or elevated,TSH levels that are eventually followed by a euthyroid state • Seen with post viral,postpartum thyroiditis,painless lymphocytic thyroiditis – Mild to moderate symptoms of hypothyroidism – May have a transient period of hyperthyroidism
• Consumptive – Seen with hemangiomas – Due to increased expression of D3deiodinase enzyme – Serum reverse T3 elevated – Thyroglobulin >1000 ng/ml
• Central hypothyroidism – Due to TSH deficiency caused by acquired or congenital pituitary(secondary hypothyroidism) and hypothalamic origins (tertiary hypothyroidism) – Decreased secretions of other hormones – Hypothyroidism due to central cause milder than primary
• Subclinical hypothyroidism• Asymptomatic pt with – low normalT4 – slightly elevated TSH(5.5-15MIU/L)• Seen in hashimoto/graves after treatment with Sx/Radioiodine• Asso.with Type I DM,PBC,pernicious anemia.• Presence of TPO Ab will require therapy• If no therapy ,patients to be monitored 6 -12 monthly both clinically and biochemically• Treat with T4(low dose)
Sick Euthyroid Syndrome• Any acute, severe illness cause abnormalities of circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease• A decrease in total and unbound T3 levels (low T3 syndrome) with normal levels of T4 and TSH(MC)• The magnitude of the fall in T3 correlates with the severity of the illness.• increased reverse T3 (rT3)• (low T4 syndrome) has a poor prognosis
TREATMENT OF HYPOTHYROIDISM• T4 is the choice• Replacement dose-1.6 – 1.8 µg/kg bwt(lean body mass)• Start with replacement dose initially except in elderly and CAD• R/o adrenal insufficiency before Rx• Hypothyroidism after graves-lower doses(as there is underlying autonomous function)• Dose adjusted on basis of TSH levels and clinical assessment• the goal of treatment being a normal TSH, ideally in the lower half of the reference range ( 0.4- 2.5 )
• TSH measured after 2 months• Clinical effects may lag behind(3-6 mon)• Increments in 12.5-25microgram dose• Over Rx-AF, osteoporosis,pseudotumour cerebri in children• Once TSH stable-yearly checkup with TSH• T3 not used because of short t1/2
Advice to patients• Levothyroxine has a t1/2 of 7 days &it will take a week or more to start feeling better. If one tablet is missed out there will be no noticeable effect• If muscle stiffness, weakness, or cognitive defects are present these may take upto 6 months to fully resolve• Levothyroxine should be taken in empty stomach to maximise absorption• Treatment is generally lifelong
• Early clinical response in moderate to severe hypothyroidism is a diuresis of 2-4Kg• Serum sodium level rises• Thereafter pulse rate ,pulse pressure increases, appetite improves and constipation disappears.• Psychomotor activity increases, delay in reflexes disappears• Hoarseness abates slowly and skin changes clears late.
• For rapid control T4 intravenous 500 microgram single dose• Or orally T3 25 microgram orally every 12 hrs
Hypothyroidism and pregnancy• Increased requirements(also during estrogen Rx)• Increase dose by 30%• TSH meaured once every trimester• Try to achieve euthyroidism prior to conception
Special considerations• ELDERLY-Start with lower dosage• CAD-Start at 25-50 and gradually increase every 2-3 months• EMERGENCY Sx-safe(routine sx-defer until euthyroid)
Potential causes of TSH elevation in thyroxine-treated patients with primary hypothyroidism• Suboptimal dosing• Inadequate prescribed dosage• Noncompliance• Dispensing error (incorrect dose or formulation change)
Co morbid conditions• Disorders causing malabsorption - eg, coeliac disease• Previous small bowel surgery
Drug interactions• Phenytoin• Carbamazepine• Phenobarbital• Rifampin
Coexisting conditions• Pregnancy• Nephrotic syndrome• Other systemic illnesses
MYXEDEMA COMA• Ultimate stage of severe long standing hypothyroidism• Mostly in older patients• Hypothermia is charecterestic• All manifestations of hypothyroidism are florid seizures can occur• Delayed relaxation may be lackinf if areflexic• Alveolar hypoventilation ,narcosis and SIADH
MYXEDEMA COMA• PPTED BY CLINICAL FEATURES• Infection • Hypotension• CHF • Hypothermia• MI • Hypoglycemia• GI bleed • Hyponatremia• CVA • Hypoventilation&• Drugs- hypercapnia sedatives,anaesthetic • Seizures s,antidepressants
MYXEDEMA COMA• Levothyroxine 500-800microgram iv bolus(nasogastric route also) followed by 50-100 microgram daily OR• T3 10-25 microgram BD (Side effect :arrhythmia)• Hydocortisone 5-10 mg/hr 50 mg Q6H• Combined T4 200 +T3 25 iv bolus followed by 25 T3 and 100 T4 after 24 hrs and 50 T4 daily• Supportive treatment and mechanical ventilation
Thyrotoxicosis refers to the clinical syndrome inwhich free triiodothyronine (T3), free thyroxine(T4), or both are elevated and the peripheraltissues are hypermetabolic, irrespective of thesource of the excess hormones.
• Primary hyperthyroidism • Secondary hyperthyroidism – Graves disease (60-80%) – TSH-secreting pituitary adenoma – Toxic multinodular goiter – Thyroid hormone resistance syndrome: – Toxic adenoma occasional patients may have features of – Functioning thyroid carcinoma metastases thyrotoxicosis – Activating mutation of the TSH receptor – Chorionic gonadotropin-secreting tumours – Activating mutation of Gs (McCune-Albright – Gestational thyrotoxicosis syndrome) – – Struma ovarii – Drugs: iodine excess (Jod-Basedow phenomenon)• Thyrotoxicosis without hyperthyroidism – Subacute thyroiditis – Silent thyroiditis – Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma – Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue
Heat intolerance, palpitations,anxiety, fatigue, weight loss, and irregular menses. Tremor, tachycardia, wide pulse pressure, lid lag, and warm, moist skin Gynecomastia, and spider angiomas.
Normochromic normocytic anemiaSerum ferritin may be highGrave’s disese – ITP , spleenomegaly, lymphadenopathy – Pernicious anemia – Anti-neutrophilic antibody Urinary frequency and nocturia
Graves’ disease – Diffuse, nontender, symmetric goiter Ophthalmopathy, consisting of protrusion of the orbits, periorbital soft tissue swelling, inflammation, and extraocular muscle dysfunction Graves’ dermopathy with characteristic thickened skin plaques, usually over the lower extremities, accompanied by nonpitting edemaThyroid Acropachy
InvestigationTFT : TSH by ICLA and T3 & T4 by RIAAnti TPO antibody , TSIUSG thyroid & FNACRAIURadioiodine scan
With Graves’ disease and toxic nodular goiter, there tends to be a higher proportion of T3, with a T3/ T4 ratio of greater than 20.With thyrotoxicosis caused by thyroiditis, iodine exposure, or exogenous levothyroxine intake, there is generally a greater proportion of T4, with a T3/ T4 ratio of less than 15
TSHR antibodies are detectable only inautoimmune thyroid disease.Persistence after treatment is predictive oftreatment failure.Indication : Euthyroid exophthalmos Pregnancy During therapy
Doppler USGTypically, a thyroid gland secreting excessivehormones would be enlarged and have enhancedDoppler flow.In subacute, postpartum, or silent thyroiditis, orexogenous causes of hyperthyroidism, thethyroid gland would be expected to be small,with decreased Doppler flow.
ThionamidesInhibiting the iodination of tyrosines and coupling of theiodotyrosines to form T3 and T4 in the thyroid.Decreases concentrations of thyroid stimulating antibodiesin Graves’ diseaseDecreases peripheral conversion of T4 to the activehormone T3
Titration regimenStarting doseMMI 20 mg to 30 mg dailyPTU 100 mg three times dailyDose titrated based on unbound T4
Thyroid function tests are repeated every 4 to6 weeks for the first 4 to 6 months .On average, 30% to 40% of patients treatedwith antithyroid drugs go into remissionlasting 10 years or more
Treatment with PTU or MMI for 12 to 18 monthsor longer results in long-term remission in 40% to60% of patients with Graves’ disease, but theremission rate is lower in patients treated for ashorter period of timeFranklyn JA. The management of hyperthyroidism. N Engl J Med1994;330(24):1731–8.
Larger goiter size, younger age, and higherpretreatment serum T3 levels predict a longerduration to euthyroidism with MMI treatment,and poorer long-term remission ratesAllahabadia A, Daykin J, Holder RL, treatment for Graveshyperthyroidism. J Clin Endocrinol Metab 2000;85(3):1038–42.
Block-replace regimen*The initial dose of antithyroid drug is heldconstant and the dose of L thyroxine is adjustedto maintain normal unbound T4 levels.Here starting dose is highMaxi remission rate are achieved by 6 mon *BMJ 332 1369 - 2006
The doses of these drugs do not need to bealtered in children, the elderly, or personswith renal failure
Adverse effectsFever, rash, urticaria, and arthralgias occur in1% to 5%, more common at higher doses.Change the patient to another thionamide.
Arthralgias, classified as a “minor” reaction,should prompt drug discontinuation, since thissymptom may be a harbinger of a severetransient migratory polyarthritis known as“the antithyroid arthritis syndrome.”
Agranulocytosis occurs in 0.5% of patients treatedwith methimazole or PTU . The effect appears to bedose-mediated for methimazole, with an increasedrisk for agranulocytosis in patients taking more than40 mg dailyPTU-associated agranulocytosis is not dose-related . If agranulocytosis develops, thionamidemedications must be immediately discontinued
Most cases of agranulocytosis occur within thefirst 90 days of treatment, but thiscomplication can occur even a year or moreafter starting therapy
Drug discontinued if the granulocyte count isless than 1000/mm3Close monitoring of the granulocyte count if itis between 1000-1500 /mm3
Prospective monitoring of the WBC count onfollow-up visits is not recommended, since theonset of agranulocytosis is typically acute andnot detected by periodic surveillance.
PTU-induced hepatotoxicity manifests as acutehepatitis which resolves with removal of the PTU;may progress to fulminant hepatic failurePatients taking methimazole may develop areversible cholestasis
ANCA, primarily p-ANCA, is present in 20% of patients on PTUtherapyTaking PTU for a longer duration are more likely to developANCA positivity , and titers may decrease after discontinuationof PTU.ANCA-positive vasculitis is rare (arthralgias, skin lesions, renalmanifestations, fever, and alveolar hemorrhage)Sato H, Hattori M, et al. High prevalence of ANCA positivity in Graves’ disease treated with PTU. J Clin Endocrinol Metab 2000;85(11):4270
Methimazole has been associated with rareoccurences of cutis aplasia , oesophageal &choanal atresia.
Indications for thionamidesGraves disease for long term remissionToxic nodular goitre prior to surgery to control toxicityPrior to Radioiodine therapy to prevent crisisPregnant and lactating women
Inorganic iodide ( SSKI or Lugol’s solution)decreases thyroid hormone synthesis in theshort term (Wolff-Chaikoff effect)Iopanoic acid, an iodine-rich oralcholecystographic agent, is a potent inhibitor ofthe conversion of T4 to T3
Beta blockersGlucocorticoids (inhibit conversion of T4 –T3)Cholestyramine (more rapid decrease in circulating hormone levels.)Potassium perchlorate competitively inhibits transport of iodide into the thyroid.
80% to 90% of patients become euthyroidwithin 8 weeks of a single dose ; remaining10% to 20% require a second, or even a thirddose of radioactive iodine
ComplicationsUltimately causes permanent hypothyroidismin over 90% of treated patients .Depends on the dosage.10 % in first year; 5% per year thereafter.
Radiation thyroiditisWorsened thyrotoxicosisDevelopment or progression of Graves’ ophthalmopathy (prevented by cotreatment with glucocorticoids)
PrecautionsMost radioactive iodine is eliminated in the urine, saliva and feces in 4-8 weeks.Have double flushing of toilet and frequent hand washing for several weeksNo close contact with children and pregnant patients for 48-72 hours
Follow upThyroid function returns to normal in 2 to 6months.Hypothyroidism occurs within 4 to 12 months asa natural complication of the radioiodine; as aconsequence, lifelong therapy with L-thyroxine is routine
Indications for RaIGraves disease in elderly, even adolescentsHyperfunctioning nodule.
SurgicalSubtotal thyroidectomy results in a rapid cureof hyperthyroidism in over 90% of casesPatients are frequently treated with inorganiciodide for 10 to 14 days before thyroidectomy.
Transient hypocalcemia is seen in up to 25% ofpost-thyroidectomy patientsHypothyroidism may develop in upto 80% ofpatients in the year following surgery
Indication for Surgery Graves disease with large goitre, not responding to drugs, associated ophthalmopathy , pregnancy Toxic nodular goitre
Considerations in the treatment of hyperthyroidismCause & Severity of hyperthyroidismPatient preferencePatient ageGoiter sizePatient compliancePresence of ophthalmopathy (in Graves’disease)Pregnancy (current or planned) ; Lactation
Subacute thyroiditis• Aspirin or NSAIDS• Glucocorticoid therapy: prednisone 40 to 60 mg OD for a week, followed by gradual tapering over 4 weeks.• Thyrotoxicosis generally resolves spontaneously