Dianne S Cheung, MD FACE Assistant Clinical Professor UCLA Health David Geffen School of Medicine CA-AACE Chapter Secretary

Dianne S Cheung, MD FACE Assistant Clinical Professor UCLA Health David Geffen School of Medicine CA-AACE Chapter Secretary

No Financial Disclosures

Objectives Which thyroid labs to order and interpret? Hot topic - Interference of biotin in our thyroid lab assays Thyroid ultrasound real time versus reports RAIU scans are they important? Thyroid cases Pregnancy Subclinical Hypothyroidism Subacute thyroiditis Hyperthyroidism Incidental Thyroid Nodule

Thyroid Action 1. TRH TSH 2. T3 and T4 3. T4 T3 tissues (liver/muscle) deiodinase 4. Some T4 and T3 conjugated liver, excreted in bile, partially hydrolyzed in intestine www.thyroid.org ATA

Total Thyroid hormones Relies on binding proteins Total T4 = Bound to TBG, albumin, or TBPA (99.97% serum T4) cannot uptake into cells (storage pool) Total T3 = Bound more tightly to albumin (less tightly to TBG or TBPA) (99.7%)

Total Thyroid hormones Raises serum TBG Estrogens Tamoxifen Raloxifen Methadone 5-flurouracil Clofibrate Heroin Mitotane Lowers serum TBG Androgens Danaxol Glucocorticoids Slow-release niacin I-asparaginase

Free thyroid hormones Free Hormone Hypothesis Only free hormone metabolically active and determines thyroid status (not total which is largely bound to binding proteins) 4 ways to measure T4 (free T4 estimates) Gold standard: Equilibrium Dialysis for T4 (expensive) Measures distribution of Free T4 at equilibrium across a dialysis membrane Direct free T4 (most common it s automated) Takes some binding abnormalities into account Free T4 index (thyroid hormone binding ratio via T3 resin uptake) takes into account some binding protein abnormalities but not all Total T4/TBG 2 ways to measure T3 Direct T3 (automated) not as reliable levels can vary Free T3 index

Typical thyroid labs normal ranges vary with lab Thyroid lab description interpretation or use Pitfalls examples TSH (3 rd gen) Free T4 auto Free T3 auto Initial lab for function Estimate of free T4 Estimate of free T3 TSH low = hyperthyroid TSH high = hypothyroid Can use for thyrotoxic patient If TSH high can use to look at degree of hyothyroidism Useful if hypoth from pituitary/hypothalamic dz Can use for thyrotoxic patient High in patients on T3 Low TSH in pituitary injury/disease High in TSHoma TSH lags recent hyper/graves treated Resistance to thyroid hormone Sick euthyroid Unreliable pregnancy can be falsely low (use TT4 or FT4 index) but can use if there is trimester specific ranges available NOT useful to dose LT4 Not reliable alone Total T4 Total bound and free T4 available Can use in pregnancy, Total T4 (and TT3) rise approximately 50% first half pregnancy and plateaus at 20 weeks NOT for hypothyroid assessment Drugs/illness alter binding protein levels In pregnancy TBG increase 2-fold higher than nonpregnant state Drugs can raise or lower TBG Total T3 Total bound and free T3 available Useful for thyrotoxic assessment NOT for hypothyroid assessment Drugs/illness alter binding protein levels In pregnancy TBG increase 2-fold higher than nonpregnant state Drugs can raise or lower TBG

Nonthyroidal illness and Reverse T3 D3 deiodinase induced in critical illness especially hypoxemia/ischemia clearance of rt3 to diiodothyronine (T2) is reduced in nonthyroidal illness because of inhibition of the 5'-monodeiodinase activity (D1) RT3 high in nonthyroidal illness Can use to differientiate central hypothyrodism from nonthryoidal illness Not useful to diagnose hypothyroidism or dosing thyroid medication as can be normal, high or low (variable) People with hypothyroid may have low RT3 but also still have enough T4 to convert to RT3 and be normal Burmeister. Thyroid 1995

So what lab to order? 1. Screening (assuming normal hypoth-pit axis) TSH first, if normal you re done TSH high order free T4 to determine degree of hypothyroidism TSH low order free T3 to determine degree of hyperthyrodism 2. If already on levothyroxine (LT4) order TSH to adjust dose If secondary to pituitary or hypothalmic disease, when TSH secretion impaired, use free T4 to titrate dose 3. If early hyperthyroid treatment TSH lags behind for weeks or months sometimes, check free T4 and free T3

Cure for Hair loss?

Or Thyroid lab confusion?

What is Biotin (Vitamin B7)? Water soluble vitamin Naturally found in meat, fish, eggs, dairy Action: catalyst for carboxylase enzymes important in macronutrient metabolism Recommended Daily Allowance (RDA): 30 µg/day 10-15 mg/day or 333-fold of RDA found in biotin supplements that are popular for presumptive health benefits Popular for (Li et al, JAMA 2017;318) Hair and nails Multiple sclerosis Diabetic neuropathy Lipid disorders Images from www.inlifehealthcare.com

Biotin (Vitamin B7): FDA Safety Communication 11/28/17 Biotin in blood or other samples taken from patients who are ingesting high levels of biotin in dietary supplements can cause clinically significant incorrect lab test results. The FDA has seen an increase in the number of reported adverse events, including one death, related to biotin interference with lab tests. Death was a patient who was ingesting high levels of biotin supplement showing low troponin who suffered MI had falsely low troponin levels attributed to biotin interference (www.fda.gov)

Biotin (Vitamin B7): FDA Safety Communication 11/28/17 Biotin in patient samples can cause falsely high or falsely low results, depending on the test. Incorrect test results may lead to inappropriate patient management or misdiagnosis. For example, a falsely low result for troponin, a clinically important biomarker to aid in the diagnosis of heart attacks, may lead to a missed diagnosis and potentially serious clinical implications. The FDA has received a report that one patient taking high levels of biotin died following falsely low troponin test results when a troponin test known to have biotin interference was used. (www.fda.gov)

Biotin (Vitamin B7): FDA Safety Communication 11/28/17 Most of the published research on biotin interference covers hormone tests, such as Intact parathyroid hormone (PTH) thyroid stimulating hormone (TSH) T4 and T3 tests (total and free) Troponin However, because biotin is used in so many immunoassays, scientists say it could interfere with many others (HCG, FSH, LH, prolactin, vitamin D25OH, etc)

Biotin (Vitamin B7): Interference Biotin technology in many automated assays Biotinylated antibodies and analogues strongly bind to streptavidin Depends on Assay If sandwich assay where analyte is sandwiched between two antibodies result may be falsely lowered due to inference If competitive assay where analyte competes with labeled analyte for binding, may be falsely elevated due to intereference Image from Thermofisher labs

Thyroid Assays using biotin Thyroid lab Type Assay Result TSH Sandwich or immunometric Falsely low FT4, Total T4 Competitive Falsely high FT3, Total T3 Competitive Falsely high TBII Competitive Falsely high

Is it Graves? Kids on High dose Biotin Kummer S et al NEJM 375;7 August 18, 2016

Recommendations Hold all biotin containing vitamins for 48-72 hours prior to lab draw Vitamins can include MVI Prenatal vitamins Hair and Nail vitamins B complex

Case 1 32 yo female who is G1P0 approximately 11 weeks pregnant was referred to endocrinology by her OB following initial screening test showing TSH 0.09 ng/dl for 2 nd opinion. Patient has lost approximately 8-lbs in the last 4-weeks She is tachycardic with HR 100 bpm She reports pale, tremor, anxiety and heat intolerance On exam she has nontender slightly enlarged thyroid gland, no palpable nodules, no proptosis or lid lag She was seen by another MD and told to start PTU immediately for the treatment of Graves disease in pregnancy Ultrasound was ordered to evaluate for nodules

Case 1 US report highly vascular heterogenous enlarged thyorid gland

Case 1 PTU yes or no? What else do you want to know?

Case 1 On further questioning Patient reports nauseated and severe vomiting in the last 4-weeks She is not able to eat more than just a few bites of food and has not been hydrating Labs were ordered showing TT3, TT4, and free T4 index normal TSRAbs: TSI negative and TBII negative antitpo negative Tg Ab negative

HCG and TSH Homology Human chorionic gonadotropin (hcg) is one of a family of glycoprotein hormones, including TSH, with a common alpha subunit and a unique beta subunit. There is considerable homology between the beta subunits of hcg and TSH. As a result, hcg has weak thyroid-stimulating activity Thyroid-stimulating activity in sera of normal pregnant women correlates with serum hcg levels Thyroid gland of normal pregnant women may be stimulated by hcg to secrete slightly excessive quantities of T4 Maternal thyroid glands may secrete more thyroid hormone during early pregnancy in response to the thyrotropic activity of hcg that overrides the normal operation of the hypothalamic-pituitary-thyroid feedback system. Biochemical hyperthyroidism associated with hyperemesis gravidarum has been attributed to hcg. Yoshimura et al. Thyroid. 1995 Oct;5(5):425-34.

Case 1 things to know Alexander EK et al. 2017 ATA guidelines for the diagnosis and management of thyroid disease in during pregnancy and postpartum TSH may be decreased in 1 st trimester of normal pregnancy due to HCG stimulating effect on TSH receptor Peak HCG level occurs at 7-11 weeks gestation Serum TSH <0.1 mu/l may be present in approximately 5% of women by week 11 of pregnancy Any subnormal TSH level should be evaluated with serum TT4 (0r FT4) and T3 values Biochemical overt hyperthyroidism is confirmed in presence of suppressed or undectable TSH and inappropriately elevated serum TT4, FT4, or T3

Case 1 - What to ask? Alexander EK et al. 2017 ATA guidelines for the diagnosis and management of thyroid disease in during pregnancy and postpartum Take a good history Physical exam Measure maternal serum FT4 or TT4 Measure maternal serum TRAbs and TT3

Case 1 Gestational Transient Thyrotoxicosis Alexander EK et al. 2017 ATA guidelines for the diagnosis and management of thyroid disease in during pregnancy and postpartum Depends on severity symptoms If hyperemesis gravidum control vomiting and treat dehydration Antithyroidal drugs (ATDs) not indicated because serum T4 returns to normal at 14-18 weeks gestation and early ATD use increase risk of birth defects Small beta blocker dose can be used over limited time In some isolated cases ATDs have been used for symptomatic relief without improvement in OB outcomes compared to supportive care but no studies comparing the two have been reported.

Case 2 62 yo male with who presented to his primary care MD for annual physical, was found on screening to have TSH 6.7 (normal lab 0.4-4.5 miu/l) He denies fatigue, weight gain, or cold intolerance He reports that thyroid problem with my mom but I don t know what Patient is reporting hard time losing weight with BMI 42 On physical exam his thyroid gland was small and unremarkable Patient is here to ask if he should take thyroid medication to lose weight due to the TSH elevation

Case 2 On redraw TSH again was slightly elevated at 7.0 antitpo was negative Thyroid ultrasound showed normal appearing homogenous gland without nodules or increase in vascularity Do we treat?

Subclinical Hypothyroidism (SHypo) Defined as usually normal T4 levels TSH outside of upper limit normal reference range for lab but <10 miu/l Most patients are asymptomatic Strong expert support for treatment of patients with serum TSH concentrations >10 miu/l However the routine treatment of asymptomatic patients with TSH values between 4.5 and 10 miu/l remains controversial

Subclinical Hypothyroidism Biondi B, Cooper DS SO Endocr Rev. 2008;29(1):76. Epub 2007 Nov 8.

Severity of primary hypothyroidism symptoms

What is the cut off for normal TSH?

Age and TSH

Cardiac benefits of treating SHypo Subclinically hypothyroid patients had a more prolonged isovolumetric relaxation time and an impaired time-to-peak filling rate (which are parameters of altered left ventricular diastolic function) than controls Biondi B, Cooper DS SO Endocr Rev. 2008;29(1):76. Epub 2007 Nov 8.

Case 2 Garber et al. ATA/AACE Guidelines for Hypothyroidism in Adults Endocr Pract.2012;18(No. 6) The prevalence of SHypo has been reported to be between 4 and 10% of adult population samples thus common SHypo is more frequent in areas of iodine sufficiency 4.2% in iodine-deficient areas compared with 23.9% in areas of abundant iodine intake Depends on the cutoff used to define SHypo and differences in age, gender, and dietary iodine intake in the populations studied.

Case 2 Garber et al. ATA/AACE Guidelines for Hypothyroidism in Adults Endocr Pract.2012;18(No. 6)

Case 3 19 year old female college student developed severe strep throat with painful tender thyroid gland She presents with difficulty swallowing, weight loss of 5-lbs in 2-weeks, insomnia, tremor, and heat intolerance She was given antibiotics for presumed strep throat, but her thyroid gland continues to be enlarged and tender to the touch despite finishing course What does she have?

Subclinical thyroiditis Cause: viral or postviral, typically with h/o URI 2-8 weeks prior to thryoiditis Presents: pain 96% time, tender gland Mechanism: inflammation damages thyroid follicles activating protelysis of thyroglobulin in follicles leading to upregulated release of T4 and T3 Continues until depletes thyroglobulin stores Phases: HYPER NORMAL HYPO NORMAL Each phase lasts 2-8 weeks Recovery usually complete

Subclinical thyroiditis Self limiting Some due get severely hyperthyroid Labs: Suppressed TSH, high T3 and T4 High sed rate or CRP Can get RAIU scan Typically avoid FNA unless concern about lymphoma, abscess, cancer though waiting for thyroiditis to improve is best for quality of FNA result Ultrasound thyroid gland rule out thyroid nodules or masses Doppler color flow low flow = thyroiditis versus high flow = Graves

Subclinical thyroiditis RAIU scan usually shows low uptake in thyroiditis <1-3% Singh K. NucRadshare.com

Subacute thyroiditis treatment Pain relief (no observational studies, just clinical experience so no correct way) NSAIDs: naproxen 250-500mg twice daily, ibuprofen up to 800mg qid Prednisone: start 40mg daily and reduce 5-10mg every 5-7 days Pain should get better after 1-2 days, if severe pain returns after dose lowered, go back up to the higher dose and maintain for 1-2 weeks dose and taper again You can taper faster or slower based on symptoms but goal is to use the lowest dose of steroids to achieve symptom relief Sympotmatic thyroiditis Can use beta blockers but avoid thionamidies (PTU or methimazole) since hyperthyrodism is not due to thryoid hormone synthesis excess Radioactive iodine is not effective or indicated = remember RAIU scan uptake is very low, so it would not work

Case 4 30 yo female physician presents to me with 4-month history of anxiety, palpitaitons, and weight loss (10-lbs) She also noted right upper neck swelling for approximately 6-months but denies compressive symptoms She is a radiologist and had a her colleague at the hospital proceed to do ultrasound guided fine needle aspiration The pathology came back indeterminate despite multiple needle passes and bloody, the patient is now concerned she may have a thyroid malignancy which is causing her symptoms She was told that based on the indeterminant FNA (follicular lesion unknown significance) she had a 5-15% chance of malignancy

Case 4 She has no lab work, said she is fine and just wanted another FNA On physical exam HR 102 bpm, palpable right approximately 2cm soft and mobile nodule, nontender, overall gland is enlarged 2 times normal Patient has hand tremor and is diaphoretic I proceeded to ultrasound her first

Case 4 Seshadri KG 2017 IJEM

Case 4

Case 4 What do we do next? FNA? Labs? Radioactive iodine uptake scan? surgery since previous FNA was Indeterminant?

Case 4 I advised the patient I would like to order thyroid labs as her nodule is quite vascular to rule out hyperthyroidism TSH 0.02 Free T3 (2x ULN) Free T4 (1.5x ULN) TRAbs (TSI, TBII negative) antitpo and TgAb negative

Case 4 radioactive iodine uptake scan

Case 4 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis Ross, Burch, et al., Thyroid. Oct 2016, 26(10): 1343-1421. Beta-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis Strong recommendation, moderate-quality evidence patients with overtly Toxic multinodular goiter or toxic adenoma be treated with RAI therapy or thyroidectomy. On occasion, long-term, low-dose treatment with MMI may be appropriate. Weak recommendation, moderate-quality evidence

Case 4 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis Ross, Burch, et al., Thyroid. Oct 2016, 26(10): 1343-1421. For patients with single toxic nodule the risk of treatment failure is < 1% after surgical resection (ipsilateral thyroid lobectomy or isthmusectomy). Typically, euthyroidism is achieved within days after surgery. The prevalence of hypothyroidism varies from 2% to 3% following lobectomy for TA For patients with TA who receive RAI therapy there is a 6% 18% risk of persistent hyperthyroidism and a 3% 5.5% risk of recurrent hyperthyroidism There is a 75% response rate by 3 months and 89% rate by 1 year following RAI therapy for TA

Case 4 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis Ross, Burch, et al., Thyroid. Oct 2016, 26(10): 1343-1421. Nonfunctioning nodules on radionuclide scintigraphy or nodules with suspicious ultrasound characteristics should be managed according to published guidelines regarding thyroid nodules in euthyroid individuals. Strong recommendation, moderate-quality evidence (ATA 2015 thyroid nodules guidelines) If surgery is chosen as treatment for TMNG or TA, patients with overt hyperthyroidism should be rendered euthyroid prior to the procedure with MMI pretreatment, with or without b-adrenergic blockade. Preoperative iodine should not be used in this setting. Strong recommendation, low-quality evidence.

Case 4 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis Ross, Burch, et al., Thyroid. Oct 2016, 26(10): 1343-1421. Patient wished to proceed with surgery Pre-surgery ultrasound did not show ipsilateral nodule(s) Patient was given methimazole 20mg daily and propranolol 10mg tid She was rendered euthyroid prior to surgery Proceeded with right thyroidectomy Pathology was benign thyroid nodule Patient did not require thyroid hormone replacement post surgery

Case 5 62 yo male presents with concerns that he has a tumor sticking out of my neck he has noticed only in the last few months Radiology report patient brought of recent thyroid ultrasound identified 4.5 cm right mid thyroid nodule which is partially cystic and smaller 1.5 cm right lower solid nodule but no parathyroid adenoma noted reading He presented to me for possible ultrasound guidedbiopsy of both nodules

When to FNA thyroid nodule? Is it based on size of nodule? Does appearance matter? Ultrasound guidance? Radioactive iodine uptake scan needed? Cold or hot nodule important?

Case 5 real time ultrasound

Case 5 Ultrasound report did not mention parathyroid adenoma Note polar artery and echogenic line

Case 5 -Additional studies and history TSH was 1.20 ipth 130, Ca 10.7-10.9, ionized Ca 1.40, VitD25 OH 32 Does report being told by other MDs to stop taking calcium or avoid dairy DEXA bone density done T -2.6 AP spine

Case 5 Right inferior parathyroid adenoma confirmed on 4D CT-parathyroid scan Ultrasound guided FNA done of right 4.5 cm nodule was benign adenoma with cystic degeneration Patient proceeded to right inferior parathyroidectomy and right lobectomy

Case 5 - Lessons Review the ultrasound report If you can, do one yourself or view the images If uncertain ask for real-time ultrasound to be done by radiologist or endocrinologist Determine based on ultrasound characteristics if thyroid nodules need to be biopsied Always take a good history