Hyperthyroidism Beyond the TSH

Hyperthyroidism Beyond the TSH… SISK - 4/5/2008 Mark Lepsch 1 Department of Family Medicine The “Triage” Approach to Thyroid Disease Hypothyroidism: Symptoms: Fatigue, weight gain, constipation, dry skin Labs: High TSH + = Increase Synthroid Dose Hyperthyroidism: Symptoms: Anxious, weight loss, diarrhea, diaphoresis + Labs: Low TSH = Endocrine referral for ablation, resection, or funny drugs I haven’t seen since medical school, followed by return to me in 1 year with… 2 Department of Family Medicine “Triage” vs. Understanding of Thyroid Disease History, PE T3, Free T4 TSH reflex Hot/cold nodules TBG, SHBG Low vs. high uptake Thyroglobulin Thyroid Scan PTU, Tapazole T3RU Antibody titres RAIU I-123 RAIA I-131 Refer for surgery/ablation Adjust Synthroid dose 3 Department of Family Medicine Presentation Overview (1) Present cases (2) Review thyroid gland and diagnostic workup from family physician/endocrinologist standpoint. (3) Re-assess cases with our new-found knowledge (4) Discuss etiologies and treatments 4 Department of Family Medicine Case #1 C.S. is a 23 yo female pharmacist who presents to the clinic following 6 months of feeling “anxious” and “hyper”. She complains of loose stools, insomnia, and difficulty with concentration. She has a TSH which is low at 0.05. One week later she returns to the lab and has a TSH reflex which is low at 0.17, with a T4 that is normal at 1.1. She also tests positive for antibodies to Thyroglobulin (TG) and Thyroid peroxidase (TPO). One month later her TSH is back within the normal range. What is her diagnosis? What other labs would you like? 5 Department of Family Medicine Case #2 B.S. is a 23 year old athletic young track star who presents with a several month history of progressive “hyperthyroid” symptoms – diarrhea, heat intolerance, anxious, fidgeting, trouble concentrating, etc. Her TSH is low at 0.05, with a free T4 that is high at 3.0. Her TSI antibody test is positive. What is her diagnosis? What other labs would you like? 6 Department of Family Medicine Case #3 P. Ham is a 33 yo G3P2002 who presents to your clinic at 13 weeks complaining of feeling “big changes”. She is feeling much more energetic, even jittery at times. She is having bid stools (as opposed to q3d during the first trimester), feeling anxious, and occasionally feeling hot and flushed. She is very concerned about her thyroid as she knows that IgG antibodies can cross the placenta and potentially damage a fetal thyroid gland. Her T3RU is low but her TSH and T4 are normal. What is her diagnosis? What other labs would you like? 7 Department of Family Medicine Presentation Overview (1) Present cases (2a) Review thyroid gland (2b) Review diagnostic workup for hyperthyroidism from family physician/endocrinologist standpoint. (3) Re-assess cases with our new-found knowledge (4) Discuss etiologies and treatments 8 Department of Family Medicine Thyroid Gland Overview 9 Department of Family Medicine Quiz Question Question: The thyroid gland is located in the: A – neck B – abdomen C – ischiorectal fossa D – the supercharger of Shar’s subaru Answer: A - neck 10 Department of Family Medicine Quiz Question Question: The thyroid gland has 2 types of cells – 1. Follicular cells, which pump in Iodine and synthesize _______ and _____ to be released into circulation to regulate basal metabolic rate. 2. Parafollicular "C" cells - (C for clear) - synthesize and secrete ______ which acts to reduce osteoclastic activity. Answer: 1. Tri-iodothyronine (T3) and thyroxine (T4) 2. Calcitonin 11 Department of Family Medicine Thyroid Gland - Overview The functional units of the thyroid gland are thyroid follicles - irregular spheroidal structures composed of a single layer of cuboidal epithelial cells bounded by a basement membrane. The follicles are filled with a glycoprotein complex called thyroglobulin which stores thyroid hormone prior to secretion. Thyroid gland has 2 types of cells: 1. Follicular cells - pump in Iodine (I-), synthesize thyroid hormone (T3, T4). 2. Parafollicular "C" cells - (C for clear) - sythesize and secrete calcitonin reduces serum Ca2+ levels. 12 Department of Family Medicine Quiz Question Question: The first major enzyme in the production of thyroid hormone is called thyroid peroxidase. This enzyme is inhibited by which two medicines? Answer: PTU (Propylthiouracil) and Methimazole (Tapazole) 13 Department of Family Medicine Thyroid Gland - Overview 1. 2. 3. 4. 5. Iodide (I-) is pumped into thyroid follicular cells. 2I- are oxidized to I2, via thyroid peroxidase, which is inhibited by propylthiouracil and Methimazole. I2 + tyrosine forms Monoiodotyrosine (MIT) and Diiodotyrosine (DIT). MIT + DIT form T3 (Triiodothyronine) and T4 (Thyroxine). Note, T3 and T4 are formed on thyroglobulin, which is stored in follicular lumen. Upon TSH stimulation, iodinated thyroglobulin (T3-thyroglobulin, T4thyroglobulin) is taken back into follicular cells. Lysosomal enzymes degrade thyroglobulin, releasing T3 and T4 into circulation. IT3-TGB T4-TGB T3, T4 14 Department of Family Medicine Thyroid Gland – Overview (2) 6. Leftover MIT and DIT are degraded by thyroid deiodinase, releasing I2. Deficiency of thyroid deiodinase can mimic I2 deficiency. In circulation, T3 and T4 are bound to TBG (Thyroxine-Binding-Globulin). In hepatic failure, TBG is deficient and total T3, T4 decrease. In pregnancy, TBG is increased, and total T3, T4 are increased. More T4 is synthesized than T3, although T3 is 3-4x more active than T4. In peripheral tissues, T4 is converted to T3 or reverse T3 (rT3), which is inactive. 99% of T4 is bound, and 98% of T3 is bound to protein – only the free forms (unbound) are active. 3 proteins which bind thyroid hormone: - TBG – Thyroid Binding Globulin - Thyroxine Binding Prealbumin - Albumin 7. 8. 9. 15 Department of Family Medicine Questions? 16 Department of Family Medicine Hyperthyroidism - Overview “Thyrotoxicosis” – general term for increased levels of triiodothyronine (T3) and/or thyroxine (T4). Hyperthyroidism refers to causes of thyrotoxicosis in which thyroid produces too much thyroid hormone. Thyroid autonomy – refers to spontaneous synthesis and release of T3/T4 independent of TSH levels. We can have 2 types of hyperthyroidism – high-uptake and low-uptake. 17 Department of Family Medicine Presentation Overview (1) Present cases (2a) Review thyroid gland (2b) Review diagnostic workup for hyperthyroidism from family physician/endocrinologist standpoint. (3) Re-assess cases with our new-found knowledge (4) Discuss etiologies and treatments 18 Department of Family Medicine Thyroid Disease Diagnosis Quotation A very famous, very intelligent physician once said: “You can spend a lot of money doing them endocrine workups” Quiz Question: Name the time, date, person, location, and level of evidence… Quiz Answer: 13:49pm, 10/29/04, Dr. Steve Heim, precepting room. LOE “H” (Harper/Ham/Heim) 19 Department of Family Medicine Hyperthyroidism - Workup (1) Hx/PE (2) Labs (3) Imaging (4) Antibody tests 20 Department of Family Medicine Hyperthyroidism – Hx/PE - Nervousness, Palpitations, shakiness, Fine tremor – Irritability, emotional lability – Fatigue, muscle weakness – Diarrhea, Weight loss w/good appetite – Heat intolerance – Trouble concentrating – Brittle, fine hair – Tachycardia, flow murmurs – Warm, moist skin – Hyperreflexia with rapid relaxation phases – Goiter (with a bruit in Graves’ dx) *Note, weight gain is possible if compensatory polyphagia is large enough. 21 Department of Family Medicine Hyperthyroidism – Screening Labs 1. Decreased TSH 2. Increased Free T4, Free T3 3. Increased T3RU 4. Other lab abnormalities: - Mild leukopenia – Normocytic anemia – Elevations in hepatic transaminases and bone alkaline phosphatase – Mild hypercalcemia – Low albumin – Low cholesterol 22 Department of Family Medicine Hyperthyroidism – T3 Resin Uptake T3RU = T3 Resin Uptake 1. Normally, T4 is bound to TBG in serum, but some binding sites are open. 2. We administer radiolabelled T3, of which some binds to the open binding sites on TBG. 3. We then measure the radiolabelled T3 that did not bind: - If low, we had increased T4 binding capacity (Excess TBG) – If high, we had reduced T4 binding capacity (low TBG) Bound to T4 Open 23 Department of Family Medicine Hyperthyroidism – TSH, T4/T3, FT4/FT3, T3RU TSH Hyperthyroid Excess TBG Low Normal Total T4/T3 High High Low Low Free T4/T3 High Normal Low Normal T3RU (TBG) High Low Low High Hypothyroidism High Low TBG Normal 24 Department of Family Medicine Quiz Question Question: The first step in sorting out the etiology of hyperthyroidism is to decide if the cause is a “high-uptake” or “low-uptake” cause. Which test is used for this? Be specific. Answer: RAIU (Radioactive Iodine Uptake) test. Note this is NOT a thyroid scan. 25 Department of Family Medicine Hyperthyroidism - Workup Radioactive Iodine Uptake Test – administer radiolabelled iodine (I-123)and measure the level 24 hours later. Usually, thyroid follicles take up about 1030% of administered dose. If the thyroid takes up >30%, this indicates hyperfunction. *Note - this is a FUNCTION test, not an IMAGING test. HIGH-UPTAKE HYPERTHYROIDISM - DDX - Graves’ dx. – Toxic multinodular goiter. – Solitary toxic adenoma. LOW-UPTAKE HYPERTHYROIDISM - DDX - Factitious hyperthyroidism – Iodine-induced hyperthyroidism – Thyroiditis – Disruptive, subacute, painless, post-partum 26 Department of Family Medicine Hyperthyroidism - Workup Thyroid Scan 1. Administer a radioactive isotope that localizes in thyroid gland. 2. Image the thyroid. DIFFUSE vs. SOLITARY IMAGE These patterns are seen in high uptake hyperthyroidism. 1. Diffuse tracer uptake – indicates Graves’ dx. 2. Mutiple discrete nodules – toxic multinodular goiter 3. Single area of intense uptake – Solitary toxic adenoma. NODULE EVALUATION Cold nodule – nonfunctional. Scary, because 20% risk of carcinoma. Hot nodule – functional. not malignant, but must be folllowed because can cause thyrotoxicosis. 27 Department of Family Medicine I-123 Thyroid Scan 28 Department of Family Medicine Hyperthyroidism - Antibodies Anti-Thyroglobulin Antibodies (TG) Anti-Thyroid Peroxidase Antibodies (TPO), aka Anti-Microsomal Antibodies Thyroid Stimulating Immunoglobulins (TSI), aka Anti-TSH Receptor Antibodies (TSHR-Ab) • Formerly called LATS (Long Acting Thyroid Stimulator) in 1950s, later discovered to be an IgG 29 Department of Family Medicine Hyperthyroidism – Antibodies * Chart displays % of people w/ antibodies TSHR-AB 80-95 10-20 0 0 0 0 TG 50-70 80-90 5-20 30-50 30-40 14 TPO 50-80 90-100 8-27 30-50 30-40 14 Graves Hashimotos General Population Relatives of Hashimoto’s patients Type 1 DM Pregnant Women 30 Department of Family Medicine Questions? 31 Department of Family Medicine Presentation Overview (1) Present cases (2a) Review thyroid gland (2b) Review diagnostic workup for hyperthyroidism from family physician/endocrinologist standpoint. (3) Re-assess cases with our new-found knowledge (4) Discuss etiologies and treatments 32 Department of Family Medicine Case #1 C.S. is a 23 yo female pharmacist who presents to the clinic following 6 months of feeling “anxious” and “hyper”. She complains of loose stools, insomnia, and difficulty with concentration. She has a TSH which is low at 0.05. One week later she returns to the lab and has a TSH reflex which is low at 0.17, with a T4 that is normal at 1.1. She also tests positive for antibodies to Thyroglobulin (TG) and Thyroid peroxidase (TPO). One month later her TSH is back within the normal range. Thyroiditis – stay tuned for details. 33 Department of Family Medicine Case #2 B.S. is a 23 year old athletic young track star who presents with a several month history of progressive “hyperthyroid” symptoms – diarrhea, heat intolerance, anxious, fidgeting, trouble concentrating, etc. Her TSH is low at 0.05, with a free T4 that is high at 3.0. Her TSHR antibody test is positive. Graves disease 34 Department of Family Medicine Case #3 P. Ham is a 33 yo G3P2002 who presents to your clinic at 13 weeks complaining of feeling “big changes”. She is feeling much more energetic, even jittery at times. She is having bid stools (as opposed to q3d during the first trimester), feeling anxious, and occasionally feeling hot and flushed. She is very concerned about her thyroid as she knows that IgG antibodies can cross the placenta and potentially damage a fetal thyroid gland. Her T3RU is low but her TSH and T4 are normal. Normal thyroid changes associated with pregnancy 35 Department of Family Medicine Presentation Overview (1) Present cases (2a) Review thyroid gland (2b) Review diagnostic workup for hyperthyroidism from family physician/endocrinologist standpoint. (3) Re-assess cases with our new-found knowledge (4) Discuss etiologies and treatments 36 Department of Family Medicine Hyperthyroidism – Etiologies Thyroid uptake high low 4. Factitous 5. Iodine induced 6. Thyroiditis Thyroid scan: 1. Diffuse tracer uptake – Graves’ dx. 2. Mutiple discrete nodules – toxic multinodular goiter 3. Single area of intense uptake – Solitary toxic adenoma. TPO, TG TSHR-Ab Antibody tests 7. Pregnancy 37 Department of Family Medicine Thyroid Diseases - Etiologies Graves Disease Thyroiditis Pregnancy 38 Department of Family Medicine Thyroid Diseases - Graves Etiology: Patient produces IgG antibodies which are agonists to the TSH receptor. Classic Triad (15-20%): Diffuse Thyroid enlargement, Hyperthyroidism, and Ophthalmopathy Short term: - Beta blockers - to reduce peripheral T4T3 conversion. Long term: - Thionamides - PTU or Methimazole - remission at 1 year in 33%, but 5-10% have serious side fx. - RIA (Radioactive Iodine Ablation), w/ I131. Hypothyroid in 50%. - Surgery, but risks are greater than RIA. 39 Department of Family Medicine Thyroid Diseases – Graves Rx Torring, et al. J Clinical Endo. and Metabolism, 1996: 81: 2986. Prospective, Randomized Trial, 179 patients. Thionamides RAIA (I-131) Surgical Resection (1) All equally effective at normalizing serum T4 at 6 weeks. (2) >95% of patients in all groups satisfied w/ therapy (3) Would you recommend this treatment to a friend (% saying yes): 68% 84% 74% (4) Relapse rate over 4 years: 40% 20% 5% (5) In USA, thionamides used to obtain euthyroid state, then 70% of thyroid specialists choose RAIA. (6) In Europe, thionamides used to obtain euthyroid state, then 20% patients move to RAIA. 40 Department of Family Medicine Thyroid Diseases - Etiologies Graves Disease Thyroiditis Pregnancy 41 Department of Family Medicine Quiz Question Question: What is the most common cause of hypothyroidism in iodine-sufficient populations? Answer: Hashimoto’s thyroiditis 42 Department of Family Medicine Thyroid Diseases – Thyroiditis Literally, thyroiditis means inflammation of the thyroid gland. Etiologies: - Acute thyroiditis (Suppurative) – Staph, Strep, MTB, T.P. – Autoimmune thyroiditis – Hashimotos, Atrophic, Juvenile - Drug induced thyroiditis - Amiodarone – Painless Thyroiditis – Postpartum thyroiditis – Type I DM – Subacute thyroiditis (Granulomatous) - Viral - Reidel’s stroma – Fibrosis of gland Rx: 1. In thyrotoxic stage, beta-blockers relieve adrenergic symptoms. Steroids? 2. **No ablative therapy (drugs, radioiodine ablation, surgery) 3. Watch for recovery hypothyroidism – consider synthroid. 43 Department of Family Medicine Thyroid Diseases – Subacute Thyroiditis Hx/PE: Low-grade fever, Pain in gland, Sx of hyper or hypothyroidism. Stages: (1) Inflammatory destruction causes release of T4, T3 into blood, thyrotoxicosis may ensue. (2) Transitory period (1-2) weeks of euthyroidism occurs after extra T4 is cleared from body. (3) Patients become hypothyroid as gland repairs itself (6-12mo) (4) Euthyroid state returns, with subtle abnormalities (See prognosis). Prognosis: Clinically patients recover fully, but serum thyroglobulin levels remain elevated and intrathyroidal iodine content is low for many months. 44 Department of Family Medicine Thyroid Diseases – Hashimoto’s Thyroiditis Hx: Age 40-50s, more common in women. Familial predisposition, associated with certain HLA haplotypes. Pathology: Autoimmune destruction of gland, leading to hypothyroidism. 45 Department of Family Medicine Thyroid Diseases - Etiologies Graves Disease Thyroiditis Pregnancy 46 Department of Family Medicine Thyroid Diseases – Pregnancy Normal: TRH and TBG both increase. TBG is increased as much as twofold, thus leading to elevated total T4 and T3. This leads to slightly increased binding of T4 and T3, thus potentially leading to slightly low Free levels of T4 and T3. However, the increased TRH usually increases T4 and T3 production enough to keep the free levels within normal range or even slightly high. This can cause transient decrease in TSH (10-20% of women). Graves disease: Most common hyperthyroid etiology in pregnancy (occurs in 0.2%) Diagnosis made by TSH < 0.01 and elevated free T3 or T4 levels. Iodine studies: Contraindicated during pregnancy. 47 Department of Family Medicine Thyroid - EBM • Avoid Calcium carbonate co-administration with levothyroxine. (LOE 1b) • Overtreating w/ Synthroid (suppression of TSH) inc. osteoporosis (LOE 4) • ACP screening – All women over age 50 w/ TSH (LOE 1a) • USPSTF screening – None (LOE 1a) • Levothyroxine (T4) = Levothyroxine + Liothyronine (T3) 48 Department of Family Medicine More Pictures… 49 Department of Family Medicine