Hyper/ Hypothyroidism Lee Anderson III MD MPH Hypothalamicpituitaryadrenal axis Thyroid Function Average thyroid produces 80-100 g/day T4 and 4-8 g/day T3. Both are reversibly bound by thyroxinebinding globulin(TBG), thyroxine binding prealbumin (TBPA), and albumin. T4 converted to T3 and rT3 periperally.

Converted by iodothyronine deiodinase Diagnostic testing TSH plasma TSH is the initial test of choice for thyroid disorder. Plasma free T4 (immunoassay vs equilibrium dialysis) Plasma free T3 (very rarely useful) T3 thyroiditis (only order when suspect Hyperthyroid - suppressed TSH, nl T4) Plasma total T4 Thyroglobulin: used in suspected thyroiditis and

monitoring thyroid cancer Thyroid Ab: thyroid peroxidase, TSI(cross placenta) Plasma calcitonin: medullary carcinoma(men2a, 2b) Effect drugs on thyroid function

Decrease t4 iodine, phenytoin Inhibit tsh: high dose steroids, dopamine Decrease TBG: androgens Inhibit t4 binding to TBG: furosemide, salicylates Displacement t4 from tbg: heparin, LMWH Increase TBG: estogens. Inhibit periperhal conversion: amiodarone, steroids, propranolol. Imaging

Thyroid scans: technetium and radioactive iodine (useful in suspected thyroiditis) RAIU: occasionally helpful in diff dx hyperthyroidism. Normal range 10-30%. Can also be used to calculate dose of RAI. Radioisotope thyroid scan: only indication is palpable thyroid nodule in patient w/ hyperthyroidism.

Ultrasound is not used to assess function. Prevalence of nodules 20-60%. Does not have a role in evaluation of hyper/ hypothyroidism(except in pregnancy/breastfeeding or recent iodine exposure can use color doppler in these cases) MKSAP #52 24 y/o F w/ 1 wk h/o neck discomfort radiates to jaw, palpitations, fast heart rate, anxiety, fever. Sore throat 4 weeks ago which resolved after a few days. No other sx, no h/o thyroid or endocrine disorder. Only med is OCP. Physical examination shows an anxious-appearing woman. Temperature is 37.5 C (99.5 F), blood pressure is 140/60 mm Hg, pulse rate is 110/min, and respiration rate is 16/min; BMI is 23. Cardiopulmonary examination reveals tachycardia, but other findings are normal. The thyroid gland is slightly enlarged and tender with no nodules. No thyroid bruit is heard, and no cervical

lymphadenopathy is palpated. No eye findings or pretibial myxedema is noted. The patient has a fine bilateral hand tremor. Laboratory studies: Erythrocyte sedimentation rate: 45 mm/h Thyroid-stimulating hormone: <0.01 U/mL (0.01 mU/L) Thyroxine (T ), free: 4.1 ng/dL (53 pmol/L) 4 Triiodothyronine (T ): 300 ng/dL (4.6 nmol/L) 3 A Doppler thyroid ultrasound shows an enlarged thyroid gland with heterogeneous echotexture without cervical lymphadenopathy; no significant vascular flow is evident. Which of the following is the most appropriate next step in management? Bilateral fine-needle aspiration biopsy

Methimazole Serum thyroglobulin measurement 24-Hour radioactive iodine uptake test Answer This patient should have a 24-hour radioactive iodine uptake (RAIU) test. She most likely has subacute thyroiditis, a form of destructive thyroiditis, given her neck discomfort, history of a transient possible viral infection 4 weeks ago, fever, elevated erythrocyte sedimentation rate (ESR), and biochemical findings (elevated serum free thyroxine [T4] and triiodothyronine [T3] levels and low serum thyroid-stimulating hormone level). The RAIU test measures thyroid gland iodine uptake over a timed period, usually 24 hours. In

patients with destructive thyroiditis (or exposure to exogenous thyroid hormones), results of the RAIU test will be less than normal (<5% at 24 hours). In contrast to destructive thyroiditis, Graves disease will show an elevated (or sometimes normal) RAIU, which indicates endogenous excess synthesis and production of thyroid hormones. Hypothyroidism. Symptoms Cold Intolerance Lethargy/fatigue Weight gain (modest) Dry skin/hair loss

Constipation Myalgia/arthalgias Menorrhagia, reduced fertility Hoarse voice Signs Delayed DTR relaxation Facial and periorbital puffiness Bradycardia Poor memory/dementia Myxedema Pleural/pericardial effusions

CTS Deafness Hypoventillation Hypothermia Diastolic HTN Labs abnl: hyponatremia, elevated cholesterol, TG, CK, hyperprolactinoma EKG: low voltage, diffuse t wave abnormality EKG in hypothyroidism ( http://lifeinthefastlane.com/)

Should we screen? Differential ddx Primary (95%) Autoimmune (Hashimoto, atrophic) Iatrogenic Drugs: amiodarone, lithium, anti-thyroid meds, interferon, IL-2, iodine containing contrast media Infiltrative disorder

(amyloidosis, sarcoidosis, hemochromatosis, scleroderma, Riedels thyroiditis) *Celiac dz: can cause decreased LT4 absorption Transient Silent thyroiditis(postpartum thyroiditis) Subacute thyroiditis Withdrawal of thyroxine in individual w/ intact thyroid

Subtotal thyrodectomy or after I131 tx. Secondary: (look for other signs of hypopituitarism, MRI) -hypopituitarism: tumor, sx, radiation, infiltrative d/o, Sheehan syndrome Isolated TSH deficiency Hypothalamic disease Treatment If no residual thyroid function: start 1.6 mcg/kg (requirements down to 1 mcg/kg in

elderly) If otherwise healthy elderly patient, starting dose 50 mcg. Pts w/ cardiac disease start 25-50 mcg/day. If some residual function can start lower dosing 75-125 mcg/day. Guidelines do not recommend use of desiccated thyroid. Treatment Question. A 65 y/o F comes to establish in clinic. On armour

thyroid for past 15 years at 1 grain (60mg)/day. Feels great on armour thyroid and does not want to take other thyroid medication. Exam normal. Labs: TSH 1.2(0.2-4.2) FT4 0.5 (0.9-1.7) T3: 2.1(0.8-2) What would you recommend. - Increase armour thyroid dose. - No changes - Measure FT3

Special considerations Pregnancy - increased dosage (approximately 30%50%) Mild/subclinical hypothyroid Tx if sx hypothyroid, goiter, hypercholesterolemia requiring treatment, pregnancy, TSH>10. Severe illness (TSH cut off 20). Marked TSH elevation c/w hypothyroid. Myxedema coma mortality 20+%

IF hypoventillation, hypotension can consider IV levothyroxine (50-100 mcg IV, can be given Q6-Q8h for 24 hrs, then 75-100 mcg Q24h. Rapid thyroid replacement can precipitate adrenal crisis, thus give hydrocortisone 50 mg IV Q8h. MKSAP #4 A 28-year-old woman is evaluated for a 1-year history of a nonpainful swelling in her neck. Her health has been otherwise excellent, with no weight loss, nervousness, or excessive tiredness. She is interested in becoming pregnant. Her mother and maternal grandmother have thyroid disease treated with levothyroxine. On physical examination, blood pressure is 130/80 mm Hg, pulse rate is 94/min and regular, and respiration rate is 16/min; BMI is 27. Her thyroid gland is minimally enlarged

bilaterally and feels firm. No specific nodules or cervical lymphadenopathy is palpated. Results of cardiac, pulmonary, abdominal, and extremity examinations are normal. Laboratory studies: Thyroid-stimulating hormone (TSH) 6.5 U/mL (6.5 mU/L) Thyroxine (T4), free: 1.2 ng/dL (15 pmol/L) Triiodothyronine (T3), free 4.0 ng/L (6.1 pmol/L) Thyroid peroxidase antibodies 640 units/L (normal, <20 units/L) Most appropriate next step: FNA Levothyroxine Repeat TSH measurement in 6 weeks

Thyroid scan Levothyroxine: This patient should begin receiving levothyroxine therapy because she is at high risk for overt hypothyroidism, given her positive family history, positive thyroid peroxidase antibody assay, small goiter, and desire to become pregnant. Currently, she has subclinical hypothyroidism, which is defined by the presence of an elevated serum thyroid-stimulating hormone (TSH) level with concomitant thyroxine (T4) and triiodothyronine (T3) levels in the reference range. Patients typically have mild or no symptoms of hypothyroidism. The potential causes of subclinical hypothyroidism are the same as for overt hypothyroidism. Evidence suggests that patients with subclinical hypothyroidism also have mild elevations in total cholesterol, LDL cholesterol, and even C-reactive protein levels, and

some recent meta-analyses have shown an increased risk for atherosclerosis and cardiac events. However, no data support treatment with levothyroxine to reverse or improve outcomes for these risks. Consensus does exist for treatment of patients with serum TSH levels greater than 10 microunits/mL (10 milliunits/L). Additionally, many advocate a lower threshold for instituting levothyroxine therapy in patients (such as this patient) with antithyroid peroxidase antibodies, a strong family history of thyroid disease, a goiter, or pregnancy. MKSAP 56 An 88-year-old man is evaluated during a routine physical examination. He reports occasional tirednessbut has no other symptoms, such as nervousness, weight gain or loss, joint discomfort, constipation, palpitations, or dyspnea. The patient has a history

of hypertension. Medications are daily lisinopril and daily low-dose aspirin. Physical examination shows an alert and oriented older man. Blood pressure is 140/85 mm Hg; all other vital signs are normal. Cardiac examination shows a grade 1/6 crescendo-decrescendo systolic murmur, and pulmonary examination findings are normal. The thyroid gland is not palpable; no cervical lymphadenopathy is noted. Results of examination of the extremities, including pulses, are normal. Laboratory studies: Complete blood count Normal Comprehensive metabolic profile Normal Thyroid function tests (repeated and confirmed) Thyroid-stimulating hormone 6.8 U/mL (6.8 mU/L) Thyroxine (T ), free 1.1 ng/dL (14 pmol/L) 4

Thyroid peroxidase antibody titer Normal Most appropriate treatment? LT4 observation MKSAP 56 Observation This patient should be monitored for evidence of hypothyroidism and should receive no pharmacologic therapy at present. In older persons with abnormal results on thyroid function testing, such as are seen in this patient, the tests should be repeated several times over a period of months to ensure the stability and accuracy of the results. The normal thyroidstimulating hormone (TSH) range for most ambulatory outpatients is 0.5-5.0

microunits/mL (0.5-5.0 milliunits/L). However, the normal range is different during pregnancy and in patients older than 80 years. Several studies have shown that an elevated serum TSH level in older patients is not associated with detrimental medical outcomes (such as depressive symptoms and impaired cognitive function) but, in fact, is associated with a lower mortality rate. Although the precise numbers are somewhat controversial, the normal reference range most likely is approximately 1 to 7 microunits/mL (1-7 milliunits/L). It is now recognized that older patients generally should not be given levothyroxine solely for an elevated TSH level. A full consideration of the patient and the clinical context is necessary. Drugs impacting thyroid hormone

replacement requirements Hyperthyroidism, thyrotoxicosis Symptoms Heat intolerance Weight loss Anxiety/irritability Palpitations Oligomenorrhea Hyper-defecation. Dyspnea Fatigue/weakness Osteoporosis

Note apathetic thyrotoxicosis frequent in elderly. Incidence 2% women, 0.2% men. Signs Brisk reflexes Tremor

Lid lag Sinus tachycardia, A.Fib Warm/moist skin Palmar erythema Hair loss Muscle weakness /wasting HF exacerbation Periodic paralysis EKG changes: sinus tach/a.fib rvr, LVH by LV voltage w/o e/o LV strain Labs: mild hypercalcemia, elevated ALKP, low total cholesterol and low HDL.

EKG Ddx thyrotoxicosis Graves dz (60-80%), Hashitoxicosis Toxic multinodular goiter Toxic adenoma Drug induced (iodine containing meds) Thyroiditis (subacute, painless, postpartum, radiation) Factitous Ectopic (struma ovarii, metastatic follicular cancer) Chorionic gonadotropin induced (chorangiocarcinoma, hydatidiform mole, hyperemesis gravidarum)

TSH secreting pituitary adenoma. McCune-Albright syndrome Evaluation Graves

Autoimmune thyroid stimulating immunoglobulins(TSI) bind to TSH receptor Diffuse goiter soft and nontender. May have bruit or thrill over thyroid. Graves opthalmopathy: proptosis 5-10% Pretibial myexedema:

plaque like thickening over shins, due to dermal GAG deposition. Tx graves Antithyroid drugs: many have recurrence 6 months after therapy discontinued. Permanent remission 2030% Methimazole PTU(during 1st trimester pregnancy) Radioactive iodine (I-131) tx of choice (in the US).

Surgery recurrence possible, potential hypocalcemia, RLN injury. Beta blocker: should be considered in all patients w/ symptomatic thyrotoxicosis, and strong recommendation for elderly patients w/ thyrotoxicosis and others w/ resting HR >90 BPM or underlying cardiovascular dz. Radioactive Iodine First line for treatment of Graves dz in US. Single dose effective in 90%

Majority become hypothyroid w/in 2-3 months. If continued hyperthyroidism after 6 months, repeat RAI dose. Avoid in patients w/ severe graves opthalmopathy. (can worsen this) Cannot use during pregnancy or breastfeeding. Question

30 y/o F w/ graves dz s/p RAI 9 months ago. Currently asymptomatic. Labs: FT4 wnl TSH: 0.05 What do you recommend: MMI Repeat RAI No intervention. MKSAP #8 28 y/o F. Worsening eye sx. 6 mo h/o graves dz. MMI started w/ normalization of labs but discontinued

due to neutropenia. Eye sx progressing w/ to severe discomfort (burning and itching) in both eyes and diplopia when she looks upward and laterally. On physical examination, temperature is 37.2 C (99.0 F), blood pressure is 130/70 mm Hg, pulse rate is 90/min, and respiration rate is 16/min; BMI is 23. Examination of the thyroid gland shows an enlarged smooth gland without nodules. Examination of the eyes shows significant bilateral chemosis and erythema. Bilateral moderate proptosis and right lid and globe lag are noted. Visual acuity is normal. Laboratory studies: Thyroid-stimulating hormone <0.01 U/mL (0.01 mU/L) Thyroxine (T ), free 2.4 ng/dL (31 pmol/L) 4 Triiodothyronine (T ) 230 ng/dL (3.5 nmol/L) 3 Thyroid-stimulating immunoglobins 340% (normal, <110%)

An MRI of the orbits shows bilateral proptosis and increased size of the extraocular muscles, especially the right inferior rectus muscle. Increased retro-orbital fat is seen, and the optic nerves appear normal Which of the following is the most appropriate treatment for this patient's hyperthyroidism? Oral iodine solution Propylthiouracil Radioactive iodine therapy Thyroidectomy MKSAP #8

This patient should undergo thyroidectomy. Clinically significant ophthalmopathy occurs in approximately 5% to 10% of patients with Graves disease. Ophthalmopathy severity varies from mild to severe and may involve lid changes, proptosis or exophthalmos, and inflammatory eye changes, such as chemosis, conjunctival injection, periorbital edema, or iritis. Extraocular muscle involvement can result in double vision, whereas optic nerve compression can result in reduced visual acuity and even blindness. The precise pathophysiology of Graves ophthalmopathy is not well understood. A primary management focus in Graves ophthalmopathy is to establish a euthyroid state because persistent hypothyroidism or hyperthyroidism exacerbates disease activity. The medical treatment for

ophthalmopathy includes local measures followed by a trial of corticosteroids. In patients with Graves disease, thyroid surgery usually is reserved for those with a severe allergy or intolerance to iodine or antithyroid drugs, large or obstructive goiters, or ophthalmopathy. Tx other causes First line treatment TMNG and toxic adenoma is RAI (except in pregnancy) TMNG surgery if compressive symptoms(Pemberton's maneuver, etc) Toxic adenoma: RAI or surgery.

Treat transient forms symptomatically w/ BB. Iodine induced can tx w/ MMI + BB until euthyroid Subacute Thyroiditis Painful gland Elevated ESR Mild hyperthyroid phase followed by phase of transient hypothyroidism Resolved w/o treatment.

Thyroid Storm Mortality 15-20% Tx thyroid storm Triphasic changes in thyroid hormone levels associated with destructive thyroiditis. Drug induced thyrotoxicosis

Dx/Tx unusual causes thyrotoxicosis Resources: MKSAP, board basics Uptodate Guidelines for the Treatment of Hypothyroidis m (2014) ATA practice guideline Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American

Association of Clinical Endocrinologists Harrisons Lifeinthefastlane.com

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