2.8 DISORDERS OF THE THYROID GLAND Michael D. Rosario MD, FPSEM August 16, 2013 Legend: Italicized: Recordings Lecture outline: -Thyroid anatomy and physiology -Thyroid work up -Hypothyroidism -Hyperthyroidism -Thyroiditis -Special situations -Goiter -Thyroid cancer CONGENITAL HYPOTHYROIDISM ANATOMY AND PHYSIOLOGY OF THE THYROID GLAND Figure 2. Congenital hypothyroidism • • Occurs in 1/4000 newborns Part of neonatal screening o Transplacental passage of MATERNAL thyroid hormone occurs before the fetal thyroid glands to function (11th week) and provides partial hormone support to a fetus with congenital hypothyroidism o Clinical significance: early detection through neonatal screening allows early replacement in newborns preventing potentially severe developmental abnormalities Figure 1. Anatomy of the thyroid *** Thyroid gland of fetus will be fully developed at 11 weeks AOG before this, supply depends on the transplacental passage of maternal hormone REGULATION OF THE THYROID AXIS ANATOMY • 2 lobes + isthmus • Between cricoid cartilage and suprasternal notch • 12-20 grams, highly vascular and soft • 4 parathyroid glands posterior (behind the thyroid gland) o Removal: Hypocalcemia • Lateral nerves: Recurrent laryngeal nerves o Damage: Vocal cord paralysis ***Thyroidectomy may cause removal of parathyroid gland and damage to recurrent laryngeal nerves • Medullary C cells o Neural crest derivatives o Produce Calcitonin Calcium lowering hormone Minimal role in calcium homeostasis Clinical significance: Tumor marker for medullary thyroid cancer DEVELOPMENT • Orchestrated by coordinated expression of several developmental factors: TTF1, TTF2 and paired homeobox 8 (PAX-8) o Expressed selectively but not exclusively in the thyroid gland o Dictate thyroid cell development o Induction of thyroid specific genes for the following proteins Thyroglobulin (Tg) Thyroid peroxidase (TPO) Sodium iodide symporter (NIS) Thyroid stimulating hormone receptor (TSH-R) o Clinical significance: Mutations in these transcription factors or their target genes leads to congenital hypothyroidism Sarah M. | Hezer | Mariz | April | Tsen | Victor Figure 3. HPT Axis Hypothalamus • TRH (Thyrotropin releasing hormone) • Major positive regulator of TSH synthesis and secretion Pituitary • TSH (Thyroid stimulating hormone) • Stimulates thyroid hormone synthesis secretion • 31kDa hormone with alpha and beta sub-units • Most useful physiologic marker of thyroid hormone production Thyroid stimulating hormone receptor (TSH – R) • G protein coupled receptor (GPCR) • α subunit of stimulatory G protein o Activates adenylyl cyclase leading to increased production of cyclic AMP • Recessive loss of function mutation=hypoplasia or hypothyroidism UERM 2015B Page 1 of 16 a protein → Iodide oxidation (through hydrogen peroxide and TPO/thyroid peroxidase enzyme → After iodination.98% T4) But there is less unbound or Free T3 in the circulation because it is produced in lesser amounts and is cleared more rapidly ABNORMALITIES OF THE THYROID HORMONE BINDING PROTEINS Disease condition X linked TBG deficiency – Absent TBG leads to rapid hormone clearance Total T3 &T4 Free T3 and T4 TSH Clinical Expressed at the basolateral membrane of the thyroid follicular cells Also present in salivary glands (parotid. DIT) to recycle iodide THYROID PROTEINS HORMONE TRANSPORT BINDING CRETINISM • • Mental and growth retardation Affects children who: o Live in iodine deficient region o Not treated with iodine or thyroid hormone immediately during early life o Born to mothers with iodine deficiency which worsens the condition o Concomitant selenium deficiency Iodine supplementation has markedly reduced the prevalence of cretinism • IODINE DEFICIENCY Common sources of dietary iodine: Breads Cheese. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 2 of 16 . STORAGE AND RELEASE • Iodide is transported to the apical membrane where to be oxidized in an organification reaction that involves TPO and hydrogen peroxide The reactive iodine atom is added to selected tyrosyl residues within Tg The iodotyrosines in Tg are then coupled via an ether linkage in a reaction that is also catalyzed by TPO forming either T4 or T3 After coupling. nori) Soy sauce Shellfish Soy milk. increased thyroid blood flow Low Normal Normal Euthyroid Sarah M. submandibular). Dehalogenase enzymes deiodinate uncoupled mono and diiodotyrosines (MIT. COUPLING. Tg is taken back into the thyroid cell. Yogurt FIDEL – Fortification for Iodine Deficiency Elimination **Why salt? Does not spoil easily and consumed by a lot of people so effective vehicle. Thyroglobulin is reabsorbed in follicular cells (where T3 and T4 are cleaved) → released of T3 and T4 in circulation. Excess MIT and DIT.7% T3 vs 99. iodine is removed by dehalogenase → iodine goes back to pool.NIS Recommended intake 90-120 ug/day 150-250 ug/day 250 ug/day Purpose of binding proteins: Increase pool of circulating hormone Delay hormone clearance Modulate hormone delivery Thyroxine binding globulin (TBG) Low concentration but high affinity for thyroid hormones = 80% Albumin High concentration but low affinity = 10% T4 & 30% T3 Transthyretin (TTR aka TBPA) 10% T4 & little T3 Unbound hormones Biologically available for tissues T3 less tightly bound than T4 (99. Iodide absorption (via NIS) transported out in the apex (via pedrin. shellfish) is associated with increased incidence of autoimmune thyroid disease High levels – decreased NIS expression and iodine uptake Clinical significance o Radioactive iodine treatment for differentiated thyroid cancer o Mutation leads to a congenital hypothyroidism o *** Iodine uptake in thyroid cells is secondary to sodium iodide symporter. Table 1. there will also be uptake in parotid which is NORMAL) Affected by dietary iodine intake o Low levels – increased NIS expression and iodine uptake. mediated by NIS Clinical significance: o Iodine deficiency leads to goiter and possibly hypothyroidism and cretinism o Iodine oversupply through supplements or iodine enriched foods (kelp. Cow’s milk Eggs Frozen yogurt Ice cream Iodine-containing multivitamins Iodized table salt Saltwater fish Seaweed (dulce. goiter. autonomous function Somatic mutations=clonal expansion of affected thyroid cell=autonomously functioning thyroid nodules Thyroid • Thyroid hormones • Low levels o Increase basal TSH production o Enhance TRH mediated stimulation of TSH • High levels o Rapidly and directly suppress TSH gene expression and secretion o Inhibit TRH stimulation of TSH IODINE TRANSPORT TO THYROID • • • • Ingested iodine is bound to serum proteins (albumin) o Unbound iodine is excreted in urine Thyroid glands extracts iodine in the circulation in a highly efficient manner Iodine uptake the critical first step. Recommended Daily Intake Children Non pregnant adults Pregnant and lactating women IODINE UPTAKE . attached to tyrosine residue found in thyroglobulin converted to 3’ mono or 3’5’ di-iodo tyrosine → coupled to form T3 or T4 catalyze by thyroid peroxidase. where it is processed in lysosomes to release T4 and T3. lactating breast and placenta but a lower levels (so if radioiodine is given. ORGANIFICATION.• • Dominant gain of function mutation = thyroid cell hyperplasia. Deiodinases *** If hormone is in target cell. and receptors’ greater affinity for T3. Clinical significance: infant with very big hemangioma (high level of T3)→ inactivation of T3 and T4 resulting to congenital hypothyroidism • Primarily metabolism o Carbohydrate. Skeletal Muscle Type 1 Thyroid. Type 2 produces intracellular T3 in specific tissues. Type 3 produces reverse T3 and inactivating enzyme. greater T3 bioavailability in the plasma. will be acted upon by deiodinases (removal of one iodine from T4). gonads. Thyroid hormone receptors • • Figure 4. o The TR β2 isoform i s selectively expressed in the hypothalamus and pituitary. Active hormone: T3 Table 2. protein and vitamin metabolism o Regulation of oxygen consumption Other actions on mood. The aporeceptors bind to corepressor proteins that inhibit gene transcription. lipid. Types of deiodinases Type 2 Pituitary. Location ACTION OF THYROID HORMONES (TH) Child • Adult • Brain development Growth and development childhood T4 affinity Response to increased T4 Susceptibility to PTU Low Increased High Source of plasma T3 in thyrotoxic patients in latter stages of Provide Inactivate T3 intracellular and T4 Physiologic T3 in specific Most important role tissues. source of source of Reverse T3 plasma T3 ***↑ in T4 results to ↑ type 1 (produces active hormone and source of plasma T3 in thyrotoxic patient.Pregnancy or OCP use – Increased estrogen levels -elevated TBG Euthyroid Hyperthyroxine mia Increased binding affinity for T4 or T3 NUCLEAR THYROID HORMONE RECEPTORS High Normal Normal or Low Euthyroid High Normal Normal Euthyroid DEIODINASES Figure 5. muscle. where it plays a role in feedback control of the thyroid axis. Hemangiomas. Kidneys Enter cells by passive diffusion and via the monocarboxylate 8 (MCT8) transporter High affinity to nuclear thyroid hormone receptors (TRs) α & β which are expressed in most tissues. cognition. but their relative expression levels vary among organs o TR α is particularly abundant in brain. but susceptible to PTU). Brown Fat. heart. Adult and Fetal Liver. bone and muscle NON. reflecting T4 to T3 conversion by peripheral tissues. Receptors are occupied mainly by T3. Brain. it has some non genomic action o Vasculature – reduced systemic vascular resistance which rapidly occurs o Acts on glucose transporters in certain tissues allowing increased uptake of glucose • THYROID HORMONES RESISTANCE • Autosomal dominant o Similar hormonal abnormalities found other family members Mutation leading to loss of thyroid hormone receptor function • Sarah M. CNS. Liver. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 3 of 16 . kidney. Thyroid Placenta High Decreased Absent Increased Absent Type 3 Placenta. Thyroid hormone binding dissociates these corepressors and allows the recruitment of coactivators that enhance transcription.GENOMIC ACTION OF TH • Major effects of T3 are mediated by nuclear Thyroid Hormone Receptor regulation of target gene transcription However. and heart o TR β expression is relatively high in the pituitary and liver. Low TSH. C. Iodine uptake measures thyroid function High in Graves’ Disease Low in thyroiditis (hyperthyroid phase) Thyroid Function Thyroid Condition 1. Central Hypothyroidism Low FT3 B. Sick Euthyroid Syndrome 4. Normal TSH. Table 4. 131I) and 99mTc pertechnetate. attention deficit. the best is TPO (best indicator of autoimmune thyroid illness). Subclinical Hyperthyroidism 3. mild IQ reduction. 125I. Nephrotic syndrome) Free T3 and Free T4 (unbound) o Represents the biologically available hormonal pool o Isolated Free T3 elevation occurs in 2-5% of patients (T3 toxicosis) o Normal FT3 may occur in 25% of patients with Hypothyroidism *** TSH and unbound hormones (total hormones are highly protein bound so affected by various factors) Table 3. compensatory action of pituitary 2: A (Central hypothyroidism) 3: B (Subclinical hyperthyroidism) .asymptomatic 4: E (Hyperthyroidism) 5: D (Sick euthyroid syndrome) (See Thyroid Patterns in Appendix) THYROID PROTEINS AND ANTIBODIES Thyroglobulin (Tg) o Follow up of thyroid cancer o To rule out thyrotoxicosis factitia o Elevated in thyroiditis Antibodies to thyroid proteins o Anti thyroglobulin (Anti Tg) Follow up of thyroid cancer patients Autoimmune thyroid illness (not routinely included) o Anti Thyroid Peroxidase (Anti TPO) Autoimmune thyroid illness o Anti TSH receptor (TRAB) TSH stimulating – Hyperthyroidism TSH blocking – Hypothyroidism Sarah M. High TSH. | Hezer| Mariz| April| Tsen |Victor Figure 6. Low FT4. E. Notice pick-up in salivary gland (normal) UERM 2015B Page 4 of 16 . Hyperthyroidism High FT3 5. Among Ab. either faking it or taking thyroid medication). allowing thyroid imaging and quantitation of radioactive tracer fractional uptake. Radionuclide Imaging: Whole Body Scan ***Whole body scan done after thyroid cancer treatment to check for metastasis. delayed skeletal maturation o ***↑ Tg = sign of thyroid cancer recurrence and to rule out Thyrotoxicosis factitia (Thyrotoxicosis factitia: Tg is normal but px has symptoms of thyrotoxicosis. Low FT3 ***Answer: 1: C (Autoimmune hypothyroidism) – low production. Low TSH. Normal FT4. Low FT3 2. Thyroid Antibodies in subset of population (%) Patient Group THYROID WORK UP THYROID FUNCTION TESTS TSH Total T3 and Total T4 o Highly protein bound which can be affected by numerous factors (refer to abnormalities of thyroid hormone binding proteins) o Elevated when TBG is high (increased estrogen conditions) o Decreased when TBG is low (Androgens. High FT4. Low FT4. Thyroid Scan Imaging Figure 7.• • • They also function as antagonists of the remaining normal thyroid hormone receptors Elevated unbound thyroid hormone levels Inappropriately normal or elevated TSH The resistance is partial hence signs and symptoms of hypothyroidism are not full blown o Goiter. Normal TSH and FT4. Match the following TSH receptor Antibody 0% 80-95% 10-20% Thyroglobulin (TG) Antibody 5-20% 50-70% 80-90% Thyroid Peroxidase (TPO) antibody 8-27% 50-80% 90-100% • • General Population Grave’s Disease Autoimmune thyroiditis RADIONUCLIDE IMAGING The thyroid gland selectively transports radioisotopes of iodine (123I. Autoimmune Normal Hypothyroidism FT3 D. A. no calcification. in autoimmune hypothyroidism it is the blocking type).ULTRASOUND OF THE THYROID Figure 8.2nd most common. Classifications of Hypothyroidism *** Most common worldwide: iodine deficiency. IFN. subclinical.Complement fixation . merely amplifies ongoing autoimmune response o TPO ab: -Useful marker for autoimmunity . Pathogenesis of Hashimoto’s thyroiditis and Grave’s disease Figure 9. In iodine sufficient areas: autoimmune or iatrogenic (See appendix for algorithm– evaluation of hypothyroidism) ***Request for the complete panel (TSH. IL-1 o Impair thyroid cell function directly o Induce thyroid cells to express pro-inflammatory molecules o Renders thyroid cells more susceptible to apoptosis B cells o Secondary role. Can be passed on the fetus resulting to neonatal hypothyroidism Sarah M. Only does Biopsy if there are suspicious features Micro calcification Increased vascularity especially in the center Irregular/ill-defined border Genetic Factors o HLA-DR and CTLA-4 polymorphisms account for approximately half of the genetic susceptibility to autoimmune hypothyroidism. FT3. regular/defined border.Transplacental passage does not damage fetal thyroid o TSH receptor Ab: -Seen in 20% of patients with autoimmune hypothyroidism -Blocking antibodies which block TSH binding -Hypothyroidism and atrophy -Transplacental passage=neonatal hypothyroidism ***Autoimmune hypothyroidism: blocking antibodies leading to hypothyroidism and atrophy (remember there are 2 types of TSHreceptor antibodies. overt/clinical Histology CD8 + cytotoxic T cells o Primary mediator o Perforin-induced cell necrosis o Granzyme B induced apoptosis Local production of Cytokines o TNF. pernicious anemia. FT4) if suspecting thyroid disease (to avoid delay and multiple blood extraction) AUTOIMMUNE HYPOTHYROIDISM Hashimoto’s or Atrophic Goitrous Thyroiditis Thyroiditis Marked lymphocytic Lymphocytic infiltration with Less pronounced infiltration germinal cell formation Atrophy of thyroid Almost completely Thyroid follicles follicles with absent absent colloid Fibrosis Mild to moderate Extensive ***Autoimmune hypothyroidism. o Both of these genetic associations are shared by other autoimmune diseases(type 1 diabetes mellitus. Addison’s disease. HYPOTHYROIDISM PATHOGENESIS Figure 10. and vitiligo) Sex o Female preponderance: sex steroid effect on immune response vs X chromosome-related genetic factor Diet o A high iodine intake may increase the risk of autoimmune hypothyroidism by immunologic effects or direct thyroid toxicity Infection o Congenital Rubella syndrome associated with high frequency of autoimmune hypothyroidism o Viral thyroiditis does not induce subsequent autoimmune thyroid disease. Ultrasound of the Thyroid ***Nodule: hypoechoic compared to thyroid tissues. can present as atrophy or a goiter. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 5 of 16 . weakness o Dry skin o Feeling cold o Hair loss. Graves’ Disease Figure 11. | Hezer| Mariz| April| Tsen |Victor THYROTOXICOSIS Thyrotoxicosis o State of thyroid hormone excess o Ex. Excessive intake of levothyroxine Hyperthyroidism o Thyrotoxicosis due to excessive thyroid function o Ex. If TSH is within target (lower half of normal range) no need to adjust (if high or low. o Advocated because T4-T3 conversion is impaired in myxedema coma.5 to 25 ucg) Non-levothyroxine Replacement o Dessicated animal thyroid prepations (thyroid extract USP) are not recommended as the ratio of T3-T4 is nonphysiologic.SIGNS AND SYMPTOMS Symptoms: o Tiredness. Classification of thyrotoxicosis UERM 2015B Page 6 of 16 . Start levothyroxine replacement 1. o Excess liothyronine has the potential to provoke arrhythmias. ONLY request for TSH every 6-8 weeks (FT3 and FT4=unnecessary). myocardial infarction or cerebrovascular accidents. TREATMENT Levothyroxine Replacement 1. T3) has not been confirmed in several prospective studies. seizures. o advocated due to T4 to T3 impaired conversion in cases of Myxedema coma. Combined levothyroxine (200ucg) and liothyronine (25ucg) o Loading: levothyroxine(200ucg) and liothyronine(25ucg) o Maintenance: levothyroxine(50-100ucg/d) and liothyronine (10ucg every 8 hour) ***Use of liothyronine is advocated since in Myxedema coma. thinning of outer third of eyebrows (Queen Anne’s sign) o Difficulty concentrating and poor memory o Constipation o Weight gain with poor appetite o Dyspnea o Hoarse voice o Menorrhagia o Paresthesia o Impaired hearing Signs o Dry coarse skin o Cool peripheral extremities o Puffy face. may be given in combination. or the patient may be previously undiagnosed. because the short half-life necessitates three or four daily doses and is associated with fluctuating T3 levels. Sarah M. leading to hypoxia and hypercapnia. hands and feet(myxedema) o Diffuse alopecia o Bradycardia o Peripheral edema o Delayed tendon reflex relaxation o Carpal tunnel syndrome o Serous cavity effusions ***Decreased in metabolism (patient slows down literally) Almost always occurs in the elderly Hypothermia also a risk factor Hypoventilation. antidepressants). if allergic to levothyroxine (based on Dr. hypothermia History of treated hypothyroidism with poor compliance. ***Most severe form of hypothyroidism/ an endocrine emergency TREATMENT Levothyroxine o Loading dose: 500 ucg o Maintenance dose: 50-100 ucg g/d o Route: Intravenous(preferred) or nasogastric tube (though aborption may be impaired in myxedema) Liothyronine(T3) o Dose: 10 to 25 ucg every 8-12 hour intravenously or via nasogastric tube. pneumonia.5-25 ug/day *** Taken 30 minutes before breakfast (if taken incorrectly can results to poor absorption and patient may need higher dose). Adjust dose by 12.5 to 25 ucg until TSH goal of Lower half of Normal range is achieved HYPERTHYROIDISM Special situations: o Pregnancy: higher requirements. Rosario’s practice) MYXEDEMA COMA Clinical manifestations: Reduced level of consciousness. adjust in this range: 12. there is impairment in the conversion of T4 to T3. o Benefit of using levothyroxine combined with liothyronine (triiodothyronine. need to increase dose by 50 % and reduce after delivery o Elderly. coronary artery disease patients: starting dose 12.8ucg/kg BW(100150ucg/day) 2. o Factors that impair respiration may precipitate myxedema coma: drug(sedative. Liothyronine is usually indicated for 1). congestive heart failure. o There is no place for liothyronine alone as long-term replacement. levothyroxine is preferred over liothyronine (since levothyroxine only required less dosage and can be taken once a day unlike liothyronine which required multiple dosages). Check TSH every 6-8 weeks 3. anesthetics. preparing the patient for radioactive iodine uptake and 2). ***For replacement. plays a major role in pathogenesis.6-1. after used of antiretroviral drugs/therapy (HIV). PTPN22. THYROID DERMOPATHY <5% of patients Usually in association with moderate-severe TAO Pretibial myxedema o Anterio and lateral aspect of the lower leg o Non inflamed indurated plaque with deep pink or purple color and orange skin appearance Appears 1-2 years after development of hyperthyroidism May improve spontaneously so no active treatment necessary Thyroid acropachy o 1% of patients. atrial fibrillation in the elderly o Tremors o Goiter o Warm. tachycardia. may progress to corneal damage if severe 5-10 % severe EOM swelling leading diplopia Most serious manifestation: Optic nerve compressionpapilledema-loss of vision. loss of libido THYROID ASSOCIATED OPHTHALMOPATHY (TAO) Pathogenesis of TAO o TSH-R may be a shared autoantigen expressed in the orbit o Infiltration of the EOMs by activated T cells with release of cytokines: Orbital fibroblasts become activated with increased synthesis of glycosaminoglycans that trap water leading to ocular muscle swelling. Patients are very difficult to interview because of severe anxiousness. PTU blocks peripheral conversion of T4 to T3 Page 7 of 16 UERM 2015B . increased iodine intake. CD25. ***risk factor associated with opthalmopathy: Genetics. moist skin o Muscle weakness. Euthyroid ophthalmopathy . Treatment options Thionamides Inhibits oxidative process required for iodination of tyrosine groups Inhibits coupling of iodotyrosinases to form T3 and T4 Thionamides clinical effect is seen on 1 month. irritability.PATHOGENESIS Thyroid Stimulating Immunoglobulins (TSI) o Synthesized in the thyroid gland. if severe: use High dose of Steroids (oral/IV) if not decompress by surgery – removing bone wall or radiotherapy. agitation. smoking. eye discomfort. after delivery. | Hezer| Mariz| April| Tsen |Victor ***Management is mostly supportive . hyperdefecation.years) before or after dx of thyrotoxicosis in 75% Unilateral only in 10 % of patients Earliest symptoms: gritiness. bone marrow and lymph node o Aka TRAB RISK FACTORS Polymorphism in HLA-DR. TSHR Stress via the Neuroendocrine system Smoking o Minor risk: Graves’ disease o Major risk: TAO Postpartum Increased iodine uptake After use of HAART tx or alemtuzumab tx o Achieve euthyroid status o Smoking cessation o Reassurance Mild-moderate o Artificial tears. Course dose not follow thyroid disease o Worsens first 3-6mos. palpitation. o Plateaus next 12-18mos. dysphoria o Heat intolerance and sweating o Palpitations o Fatigue and weakness o Weight loss despite increased appetite o Diarrhea o Polyuria o Oligomenorrhea. strongly associated with dermopathy FEATURES OF GRAVES’ DISEASE Positive anti TPO Ophthalmopathy Dermopathy (See Appendix for Evaluation of Thyrotoxicosis) HYPERTHYROIDISM: TREATMENT OPTIONS Figure 12. proximal myopathy o Lid retraction or lab o Gynecomastia Symptoms o Hyperactivity. CTLA-4. eye ointment and use of dark glasses o Periorbital edema-upright sleeping position or diuretic o Eye patches when sleeping to avoid corneal exposure ***Elderly may have Apathetic Thyrotoxicosis: weight loss (some don’t – rather increases appetite). heat intolerance. excessive tearing 1/3 have proptosis. muscle weakness (proximal mostly affected) Severe ophthalmopathy o First line: high dose oral steroids or pulse steroids followed by oral steroids o Orbital decompression: removal of bone from any wall of the orbit o External beam radiotherapy SIGNS AND SYMPTOMS Signs o Tachycardia. o Spontaneous improvement in soft tissue changes Fulminant in 5% of patients Intervention in the acute phase if there is optic nerve compression or corneal ulceration General measures Sarah M. Stress.may occur in the absence of Grave’s disease(10%) Usually occurs 1 year (+/. diarrhea. ipodate. surgery (especially on the thyroid).. and intravenous fluids. FT3 . thyroid peroxidase action: starting 40-60mg – once or twice a day ***Doc Rosario: Starts the meds and followed up patient after 2 weeks – check for possible Side effects (because in 2 weeks –may have already a clinical improvement. then stop gradually. Mortality rate due to cardiac failure. Large doses of propylthiouracil (600 mg loading dose and 200–300 mg every 6 h)per orem. dexamethasone. even with treatment. and the doses can be easily adjusted. Precipitants: acute illness (e. stroke. antibiotics if infection is present. or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism. trauma.g. 2mg every 6 h).g.. accompanied by fever. RAI. and jaundice. identification and treatment of the precipitating cause. Additional therapeutic measures include glucocorticoids (e. Radioactive Iodine. oxygen. may have poor compliance. dosage 450-600mg/day. diabetic ketoacidosis). o A saturated solution of potassium iodide (5 drops SSKI every 6 h). especially in the early stages before anti-thyroid drugs take effect Useful in patients with hypokalemic paralysis ***PTU – in selected cases – usually given in the first 3 months of pregnancy (organogenesis) Methimazole – “recommended” Latest guidelines in most cases Doc Rosario: Give the meds up to 1 year assuring that the TSH is normal. seizures. | Hezer| Mariz| April| Tsen |Victor . infection.Chaikoff effect Thyroid storm (give 1 hour after thionamides) Decrease vascularity pre-op Steroids Thyroid storm Beta Blockers Adjunct to treatment To control adrenergic symptoms.Hepatic Dysfunction CVS o Tachycardia o CHF o Atrial Fibrillation Greater than 45 points is highly suggestive of Thyroid Storm 25 to 44 points is Impending Less than 25 is Unlikely (See appendix for corresponding points and scoring) TREATMENT Management requires intensive monitoring and supportive care. but if does: proceed to definitive treatment – Surgery. cooling.why not TSH? = TSH may resume abnormal for 6months: o Note: as long as the FT4 and FT3 going down and has clinically signs of improving – there’s no need to increase the dose. NGT or per rectum o Has inhibitory action on T4 to T3 conversion Stable Iodide given one hour after the first dose of propylthiouracil o Wolff-Chaikoff effect o The one hour delay allows the antithyroid drug to prevent the excess iodine from being incorporated into new hormones.5 mg every 12 h). or ipodate or iopanoic acid (0. or hyperthermia is as high as 30%. and measures that reduce thyroid hormone synthesis. BURCH WARTOFSKY SCORE The scoring includes the following variables: Temperature CNS GIT. tachycardia) specially with propanolol and inderal. Dec palpitation.Thyroid Gland Size o Decrease 1/3-1/2 o Unchanged or enlarged remaining half TSH may remain subnormal for 6 months Maximum remission rates (30-50%) are achieved by 18-24 months o Relapse likely if severe hyperthyroidism or with large goiters ***PTU – has additional blocking in the T4-T3 peripheral conversion – Deiodenized enzyme TYPE 1. delirium.-avoid pregnancy within Six months HOW TO START: Starts 1st 3months (check-up every month) Hypothyroidism – monitor TSH Hyperthyroidism – monitor FT4. Methimazole – more potent. THYROIDITIS Classification based on duration: 1. vomiting. Propranolol should also be given to reduce tachycardia and other adrenergic manifestations (40– 60 mg orally every 4 h. iopanoic acid Wolff. may be given orally. Acute Bacterial Fungal Radiation (Iodine 131 treatment) UERM 2015B Page 8 of 16 Sarah M. If no recurrence – good. Monitoring thionamide use (See Appendix for Comparison of Methimazole vs Propylthiouracil ) Lithium Alternative to thionamides Iodine Saturated solution of Potassium Iodide (SSKI). or 2 mg intravenously every 4 h) o High doses of propranolol decrease T4 to T3 conversion. coma.each tab is 50mg – 3-4x a day. THYROID STORM A rare endocrine emergency Life-threatening exacerbation of hyperthyroidism. arrhythmia. a Figure 14. Figure 15. Treatment o Anti inflammatory agents (steroids) not necessary o Thyrotoxic phase Propranolol to ameliorate symptoms Antithyroid drugs – no role o Hypothyroid phase Levothyroxine SUBACUTE VIRAL THYROIDITIS Aka granulomatous.. occurs in middle aged women o Dense extensive fibrosis with no thyroid dysfunction o Maybe associated with idiopathic fibrosis at other anatomic sites o Presents with painless goiter and compressive symptoms o Treatment: Surgical relief of compressive symptoms. jugular venous thrombosis o Fever o Thyrotoxic symptoms appear abruptly Lab Tests o Elevated ESR and WBC count o Thyroid Function depends on phase o May present with a low radioiodine uptake initially o Thyroid antibodies are low Treatment o First Line: Large doses of Aspirin & NSAIDS o Second Line/Alternative: Steroids o Monitor TSH and FT4 every 2 weeks Thyrotoxic phase o Propranolol to ameliorate symptoms o Antithyroid drugs – no role Hypothyroid phase o Levothyroxine For a prolonged phase Low doses to allow TSH mediated recovery SILENT THYROIDITIS Aka Painless Occurs in patients with underlying autoimmune thyroid disease. exquisitely tender SICK EUTHYROID SYNDROME Any acute. c. lymphadenopathy Lab Tests o Elevated ESR and WBC count o Normal Thyroid Function Treatment o Antibiotic treatment o Surgery for abscess Uncommon Complications o Tracheal obstruction. Clinical phases of Subacute viral thyroiditis a. Recovery Phase: Increased TSH eventually due to thyroid recovery. Post-partum thyroiditis o Occurs in 5% of women 3-6 months after pregnancy o May recur in subsequent pregnancies Lab tests o Low ESR and WBC count o Thyroid function depends on phase o May present with a low radioiodine uptake initially o THYROID ANTIBODIES ARE PRESENT. FT4. mediastinitis.2. fever and dysphagia o Small tender goiter. Increased FT4. retropharyngeal abscess. Unless a thyroid disorder is strongly suspected. Amiodarone Subacute Viral or Granulomatous thyroiditis Silent and Postpartum Throiditis Mycobacterial Infection Chronic Autoimmune o Hashimoto’s Thyroiditis o Atrophic Thyroiditis Riedel’s Thyroiditis Parasitic Thyroiditis Traumatic (after palpation) Thyroiditis ACUTE INFECTIOUS THYROIDITIS Rare suppurative infection with an abrupt presentation Predisposing factors o Piriform sinus seen in children and young adults o Long standing goiter or degeneration in a thyroid malignancy in older adults Signs and Symptoms o Thyroid pain referred to throat or ears. Hypothyroid phase: decreased FT3. severe illness can cause abnormalities of circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease. TPO antibodies are present Hashimoto’s thyroiditis Riedel’s thyroiditis o Rare. decreased TSH b. • Signs and symptoms o May initial present with URTI like symptoms o Painful thyroid referred to jaw and ear. | Hezer| Mariz| April| Tsen |Victor UERM 2015B . Thyrotoxic Phase: 6 weeks . 3. the routine testing of thyroid function should be avoided in acutely ill patients. de Quervain’s thyroiditis Many viruses implicated Common in Females ages 30-50 yrs than males There is patchy inflammatory infiltrate with disruption of thyroid follicles and presence of multinucleated giant cells May progress to granulomas with accompanying fibrosis CHRONIC THYROIDITIS Focal Thyroiditis o 20-40% of euthyroid autopsy cases o Associated with autoimmunity. septicemia. Page 9 of 16 • Sarah M. only resolution of the test results with clinical recovery can clearly establish this disorder. high iodine levels persist for 6 months after discontinuation of the drug Initial effect • Inhibit thyroid hormone release – Decreased T4 • Wolff Chaikoff • Follow up effect • Inhibits Deiodinase activity • Metabolites function as weak antagonists of thyroid hormone action • Increased T4. Increased thyroid hormone metabolism by the placenta 5. | Hezer| Mariz| April| Tsen |Victor UERM 2015B . Estrogen-induced rise in TBG during the first trimester. which is sustained during pregnancy 3. Increased urinary iodide excretion • Maternal hypothyroidism occurs in 2 –3% of women of child-bearing age and is associated with increased risk of developmental delay in the offspring.The major cause of these hormonal changes is the release of cytokines such as IL-6. • The diagnosis of SES is frequently presumptive. Clinical phases of sick euthyroid syndrome • AMIODARONE EFFECTS ON THYROID FUNCTION Type III antiarrhythmic agent Structural relation to thyroid hormone. bodies way of adapting illness. given the clinical context and pattern of laboratory values. • • Figure 16. slightly high FT4. which stimulates the TSH-R and decreases TSH 2.Pemberton’s sign Treatment: • Iodine replacement • Levothyroxine replacement • Young pxs: 100 mcg/day targeting low to normal TSH • Elderly: 50 mcg/day • Efficacy greater for younger pxs. Women with a precarious iodine intake are most at risk of developing a goiter during pregnancy. Alterations in the immune system. to lessen catabolic rate: Findings: Low TSH. or amelioration of an underlying autoimmune thyroid disease 4. exacerbation. Increased rT3 and transient TSH increase (20mIU/L) • TSH normalize in 1-3 months ***Hyperthyroidism (thyrotoxicosis) – provide antithyroid drugs and anti-inflammation Amiodarone Effects – HYPOTHYROIDISM • • • • • Correlated to iodine intake Higher incidence in iodine replete countries Pathogenesis: inability to escape from the Wolff Chaikoff effect in autoimmune thyroiditis More common in women and those with positive TPO antibodies Treatment: May continue amiodarone and just start levothyroxine replacement • • GOITER DIFFUSE NONTOXIC GOITER Simple goiter o Most commonly caused by iodine deficiency o Compensatory effort to trap iodide o Endemic goiter if it affects > 5% of the population o Women>Men o Greater prevalence of autoimmune thyroid disease o Increased iodine demands during pregnancy o TSH levels normal to slight increase only o But probably there is increased sensitivity to its effects o Patient will present OBSTRUCTIVE SYMPTOMS Goitrogens • Cassava root – thiocyanate • Cruciferous vegetables – brussels sprouts. • Treatment of SES with thyroid hormone (T4 and/or T3) is controversial ***In sick euthyroid – T4 is shunted to T3 (reversed) – Decreased FT3 – increased reversed T3. cauliflower • Milk from areas where goitrogens are present in grass • S/Sxs o Obstructive symptoms o Tracheal obstruction esp substernal goiter o dysphagia o External jugular vein . TSH screening for hypothyroidism is indicated in early pregnancy and should be considered in women who are planning pregnancy. Thyroid hormone requirements are increased by 25–50 ucg/d during pregnancy. steroids leading to THYROID AND PREGNANCY Five factors alter thyroid function in pregnancy 1. cabbage. particularly if they have a goiter or strong family history of autoimmune thyroid disease. Decreased T3. and iodine supplementation should be considered to prevent maternal and fetal hypothyroidism and neonatal goiter. soft goiters • Significant regression: within 3-6 months • Surgery: Near total thyroidectomy • Radioiodine: reduced goiter size by about 50% in the majority of pxs in 6-12 months NONTOXIC MULTINODULAR GOITER • • Most nodules are polyclonal in origin TSH usually not elevated Page 10 of 16 • Amiodarone Effects – THYROTOXICOSIS Type 1 AIT • With underlying thyroid problems (subclinical Hyperthyroidism/Nodular goiter) • Jod Basedow phenomenon leads to excessive thyroid hormone synthesis • Doppler shows increased vascularity • Tx: Anti-Thyroid drugs Type 2 AIT • No underlying thyroid problems Sarah M. low FT 3 • • • • Drug induced lysosomal activation destructive thyroiditis Doppler shows decreased vascularity Tx: oral contrast agents. Transient increase in hCG during the first trimester. leading to the onset. 39% iodine by weight • Stored in adipose tissues. • • • • Most are asymptomatic and euthyroid. atrial fibrillation or weight loss Aggravated by recent exposure to iodine Anti thyroid drugs o May stimulate growth of goiter o Spontaneous remission does not occur – lifelong tx Radioiodine o Treat areas of autonomy and decrease goiter size o Treated areas may be replaced by other new autonomous nodules Surgery • • Figure 17. • Difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels. keeps muttering “my precious” HR elevated BMI: 17 Neck mass with bruit Irregularly irregular bruit TSH low FT4 and FT3 are high Page 11 of 16 Figure 18. Gollum. | Hezer| Mariz| April| Tsen |Victor UERM 2015B . Obstructive symptoms Ultrasound: Look for characteristics suggestive of malignancy Levothyroxine replacement rarely effective to reduce goiter size Radioiodine treatment may decrease goiter size by 4050% WELL DIFFERENTIATED ***Classified according to histologic features Papillary • Most common 70-90% • Histology: Psammoma bodies. Findings on thyroid scan Sarah M. or adjacent structures • Hematogenous spread TOXIC MULTINODULAR GOITER • • • • • Presence of autonomously functioning nodules Subclinical or mild thyrotoxicosis Elderly patient: tremors.do Biopsy. POORLY DIFFERENTIATED Anaplastic • Poor prognosis • Poor response to radioiodine treatment • Chemotherapy ineffective Others: Medullary • Association with Multiple Endocrine Neoplasia 2 • Serum calcitonin is a marker of residual or recurrent disease Lymphoma • Rapidly expanding thyroid mass • Highly sensitive to external radiation (rapidly expanding!) SAMPLE CASES Case 1: Mr. What is his problem (aside from losing the ring)? Appears anxious. but if DECREASED uptake. Findings on thyroid scan: heterogenous uptake with areas of increased and decreased uptake HYPERFUNCTIONING SOLITARY NODULE • • • • • • Solitary autonomously functioning thyroid nodule Mild thyrotoxicosis Medical treatment is not an optimal long term treatment Radioiodine ablation Surgery: Enuceation or lobectomy Ethanol injections or percutaneous radiofrequency thermal ablation Figure 20. nerves. Provided suppressive levothyroxine – Decreased TSH (note: TSH stimulates growth of thyroid cells) then monitor by blood test. Findings on thyroid scan: Focal uptake with diminished uptake in the remainder (normal tissue) as activity in those areas are suppressed ***Check TSH: if Decreased do thyroid scan – if INCREASED uptake – no need for BIOPSY. e.g. cleaved nuclei with an “orphan-Annie” appearance caused by large nucleoli. THYROID CANCER Most common malignancy of the endocrine system Figure 19. If purely cystic – no need for biopsy. on Lymph nodes. Treatment of Well Differentiated **Treatment: Surgery the RAI to destroy remaining tissues not removed by surgery. and the formation of papillary structures • Locally invasive Follicular • More common in iodine-deficient regions. 150-250 ug day d.Case 2: Patient A at ICU bed 3 presents with palpitations on his 3rd HD (hospital day). OCP use d. Which of the following times is the best time to perform the TSH? a. TSH was requested which showed a suppressed TSH. Euthyroid Hyperthyroxinemia Answer: A Case 6 : SE is a 64/F admitted at the ICU for Heart Failure for the past 14 days referred for further evaluation of palpitations. Which of the following medications being given to him could explain this findings? a. Sick Euthyroid Syndrome Answer: D Sarah M. Levothyroxine Anwer: both b&d – Dopamine. 12 noon c. Px F. glucocorticoids and somastatin suppress TSH when these agents are administered in pharmacological doses. X linked TBG Deficiency b. She asks you. Dobutamine b. 6 pm d. Pregnancy c. What is your explanation for the thyroid function pattern? a. slightly high FT4. what is the recommended daily intake of iodine for a pregnant like her? a. She has no prior history of thyroid illness. No other signs or symptoms of thyroid dysfunction. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 12 of 16 . Low T4 and T3 but normal Free T4 and TSH. Case 3: Patient A came in for screening for thyroid disease. Your impression is: A. TSH excursions are modest compared to other pituitary hormones because of TSH has a relatively long plasma half-life. Case 4: Patient I came in for her prenatal check-up. 250 ug/day Answer: D. Secondary hypothyroidism B. 8 am after overnight fast b. Thyroid function tests showed low TSH. However. 12 mn Answer: any of the following is correct. since TSH has relatively long half-life and no need to undergo fasting. Less than 90 ug/day b. Simvastatin d. a 34 yr old female came in with the following thyroid function results. 90-120 ug/day c. single measurements of TSH are adequate for assessing its circulating level. Subacute Thyroiditis D. refer to table of recommended daily intake Case: 5. Consequently. and low FT 3. TSH is released in a pulsatile manner and exhibits a diurnal rhythm – highest level at night. Hyperthyroidism C. Hydrocortisone c. APPENDIX Figure 21. Evaluation of Hypothyroidism Figure 22. Evaluation of Thyrotoxicosis Sarah M. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 13 of 16 . | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 14 of 16 . pituitary is compensating.Table 4. Thyroid Patterns THYROID DISORDER Hyperthyroidism Subclinical Hyperthyroidism Primary Hypothyroidism Secondary Hypothyroidism TSH Low Low High Low or Inappropriately Normal FRE T4 High Normal Low Low Normal TOTAL T4 High Normal Low Low Normal SIGNS AND SYMPTOMS Present Absent Present Absent/Present Absent Subclinical High Hypothyroidism Increased TBG Normal Decreased TBG Normal ***Primary hypothyroidism: ↑ TSH. Methimazole vs Propylthiouracil Table 5. but NORMAL. TSH and FT4. patient is asymptomatic Figure 23. in Normal Increased Absent Normal Decreased Absent secondary: problem is in pituitary or hypothalamus so ↓ TSH (inadequate elevation in TSH or remain inappropriately normal since normal response is high and normal response means abnormal) ***↑ or ↓ TBG and total T4. Comparison of drugs used to treat hyperthyroidism PTU Methimazole Thiocyanate Iodine (SSKI) IpodateIopanoate Lithium Dexamethasone Propanolol INHIBIT ORGANIFIC ATION Yes Yes IMPAIR CONVERSION OF T4 TO T3 BY D1 Yes (600mg) IODIDE TRANSPORT INHIBITORS (NIS) INHIBIT HORMONE RELEASE ADDITIONAL INFO Yes Yes Yes Yes (additive to PTU) Weakly Yes Yes 3 drops BID with 7-10 day preop to decrease vascularity Target Lithium: 1meq/L With addition of PTU and SSKI will produce rapid T3 decrease in 48 hours Sarah M. Burch Wartofsky Scoring Figure 27.Figure 25. Approach to patient with thyroid nodule (ATA 2009 Guidelines for Thyroid Nodules & DTC) Sarah M. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 15 of 16 . Sarah M. | Hezer| Mariz| April| Tsen |Victor UERM 2015B Page 16 of 16 .