STRANGE THYROID FUNCTION TESTS: REAL PATHOLOGY OR BIOLOGICAL PITFALL? Agnès Burniat, MD, PhD

Concordant thyroid tests: respecting the hypothalamus-pituitarythyroid axis regulation Discordant thyroid tests: not respecting the hypothalamuspituitary-thyroid axis regulation Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

EVOLUTION FROM SUBCLINICAL HYPOTHYROIDISM TO OVERT HYPOTHYROIDISM Concordant thyroid tests Euthyroidism: TSH, FT4, FT3: N Subclinical hypothyroidsm TSH ; FT4, FT3: N Overt hypothyroidism TSH ; FT4, FT3 N Months/ years Severe hypothyroidism TSH ; FT4, FT3

EVOLUTION FROM SUBCLINICAL HYPERTHYROIDISM TO OVERT HYPERTHYROIDISM Concordant thyroid tests Euthyroidism: TSH, FT4, FT3: N Subclinical hyperthyroidsm TSH ; FT4, FT3: N Overt hyperthyroidism TSH ; FT4 and/or FT3 Months/ Years

Discordant thyroid tests Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

CLINICAL CASE 1 What does the biologist see: ambulatory 47 years old male patient Reference values TSH ( mui /L) 2,74 0,4-4 ft4 (ng/dl) 0,45 0,8-1,7 FSH (UI/l) 2 2-8 LH (UI/l) 2,5 2-10 PRL (µui/ml) 631 35-350 Testostérone (ng/dl) 73,4 249-836 cortisol (ng/ml) 16 62-194 ACTH (pg/ml) 10,6 4,7-48,8 DHEAS (µg/dl) 23 100-450 IGF1 (ng/ml) 64 71-224

Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

?? Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

CLINICAL CASE 1: CLINICAL CONTEXT A 47 years old male patient with: No treatment Tiredness and muscle weakness since several months Weight gain (10 kilos the last 2 years) Decrease libido Snoring with recent diagnosis of sleep apnea (CPAP) Physical examination: TA 150/100 mmhg; BMI 29 kg/m 2 ; HR 62 Puffy face

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CLINICAL CASE 1: CLINICAL CONTEXT A 47 years old male patient with: What do you suspect from anamnesis and biology? What other questions could you ask him?? Headache -? Visual defect How to confirm the diagnosis?

CLINICAL CASE 1 Pituitary hormone tests: Reference values TSH ( mui /L) 2,74 0,4-4 ft4 (ng/dl) 0,45 0,8-1,7 FSH (UI/l) 2 2-8 LH (UI/l) 2,5 2-10 Hypogonadotropic hypogonadism PRL (µui/ml) 631 35-350 Testostérone (ng/dl) 73,4 249-836 cortisol (ng/ml) 16 62-194 Central adrenocortical deficiency ACTH (pg/ml) 10,6 4,7-48,8 DHEAS (µg/dl) 23 100-450 IGF1 (ng/ml) 64 71-224 Growth hormone deficiency

CLINICAL CASE 1: VISUAL FIELDS Left hemianopsia (loss of vision of half of the visual field) and right quadrantanopsia (one quarter) < optic chiasma compression

CLINICAL CASE 1: MRI Non-secreting macroadenoma with panhypopituitarism and compression of the optic chiasma

TAKE HOME MESSAGE 1 If thyroid tests suggest central hypothyroidism: Check (if existing) or suggest to check the other pituitary hormones, especially in case of suggestive clinical signs/symptoms (clinician)

CLINICAL CASE 2 What does the biologist see : ambulatory 26 years old man Reference values TSH ( mui /L) 0,4 0,4-4 ft4 (ng/dl) 0,24 0,93-1,7 ft3 (pg/ml) 3,1 2-4,4 No measurement of other pituitary hormones

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CLINICAL CASE 2: CLINICAL CONTEXT 26 years old man with Graves disease treated with methimazole 20 mg per day Initial biology (before treatment) TSH <0,03 mui/l ft4 8,3 ng/dl (0,8-2) ft3 > 20 pg/ml (2,1-4) TSI (13/10) 22,8 U/L (N < 1,5)

CLINICAL CASE 2: CLINICAL CONTEXT During treatment: Very low T4 with normal T3 and normal or slightly elevated TSH > high ft3/ft4 ratio

Specific context of known and treated Grave s disease Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

T3-predominant Graves disease: Mitsuru Ito et al. Eur J Endocrinol 2011;164:95-100

CLINICAL CASE 2 25 ft3/ft4 20 20 15 17,1 10 5 4,75 10,8 12,9 9 8,6 10,4 6,3 7,5 6 10,3 10,2 8,9 7,4 9 0 1,8 2,1 2,2

TAKE HOME MESSAGE 2 If thyroid tests are discordant: Ask if patient is taking some drugs affecting TSH/T4-3 production or measurement (strumazol, L-Thyroxine - medrol, amiodarone, heparin, etc)

CLINICAL CASE 3 What does the biologist see : hospitalized 58 years old man Reference values TSH ( mui /L) 0,34 0,4-4 ft4 (ng/dl) 0,6 0,8-1,7 ft3 (pg/ml) 1,3 1,8-4,6 Low T4, T3 and TSH

Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

?? Hospitalized 58 years old man? Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

CLINICAL CASE 3 What does the biologist also see : Patient hospitalized in the Intensive Care Unit Non-thyroidal illness?

Non-thyroidal illness - Euthyroid-sick syndrome (no intrinsic abnormality of HPT function) Meuwese, C. L. et al. (2013) Nonthyroidal illness and the cardiorenal syndrome. Nat. Rev. Nephrol.

Critical illness: acute phase Greet Van den Berghe, Thyroid, 2014

Critical illness: chronic phase functional central hypothyroidism Greet Van den Berghe, Thyroid, 2014 Fliers E et al. JCEM; 1997

Non-thyroidal illness: Prognosis factor? Meuwese, C. L. et al. (2013) Nonthyroidal illness and the cardiorenal syndrome. Nat. Rev. Nephrol.

Non-thyroidal illness: Prognosis factor? 100 patients in intensive care unit without known thyroid problem 64 36 Kumar KV et al, Indian J Endocrinol Metab, 2013

CLINICAL CASE 3: CLINICAL CONTEXT Child C cirrhosis; ethylism. Suspicion of cholangiocarcinoma Transferred to ICU for hemorrhagic shock from rupture of esophageal varicose veins + hepatic encephalopathy NTIS «chronic phase» severe disease

CLINICAL CASE 3:? GLOBAL PITUITARY FUNCTION Reference values TSH ( mui /L) 0,76 0,4-4 ft4 (ng/dl) <0,5 0,8-1,7 FSH (UI/l) 1 2-8 LH (UI/l) <1 2-10 Patient died 2 days later PRL (µui/ml) 417 <325 Testostérone (nmol/l) 1,7 8,6-29 cortisol (ng/ml) 146 62-194 DHEAS (ng/ml) 298 2000-3500 IGF1 (ng/ml) <15 71-224 Functional global pituitary insufficiency Very bad prognosis Central hypothyroidism Hypogonadotropic hypogonadism Relative central adrenocortical deficiency Growth hormone deficiency

TAKE HOME MESSAGE 3 Avoid testing thyroid function in patients hospitalized in the intensive care unit or more generally in severely sick patients except in case of known thyroid or pituitary disease or if high suspicion of

CLINICAL CASE 4 What does the biologist see : ambulatory 10 years old girl Reference values TSH ( µui /ml) 1,88 0,3-4 ft4 (ng/dl) 3,9 0,8-2 ft3 (pg/ml) 9,2 2,5-4,7 Anti-Tg (IU/ml) 90,3 <60 Anti-TPO (IU/ml) 46 <60

Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

?? Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

CLINICAL CASE 4: CLINICAL CONTEXT Normal birth and neonatal period Normal schooling except for long-standing concentration disorder No treatment No weight loss or gain, increased appetite, logorrheic, sweating, nervous. Accelerated growth but in the context of precocious puberty Physical examination: goiter (confirmed by US) and tachycardia (heartbeat 120/min)

?? Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

ft4???? TSH L-T4 therapy (very common) Assay interference (common) Resistance to thyroid hormone (very rare) Assay interference (very rare) TSH-secreting pituitary adenoma (very rare) 1 case per 50.000 live births 1 case per 10 6 population

2 THR genes (THRB and A) Coding for several THR isoforms (β and α) Nuclear receptor superfamily Bind T3 Transcription regulation Tânia M. Ortiga-Carvalho,Aniket R. Sidhaye & Fredric E. Wondisford. Nature Reviews Endocrinology 10, 582 591 (2014)

Resistance to thyroid hormones (RTH) First described as a clinical entity in 1967 (Refetoff et al. JCEM 1967; 27:279-294) TH receptors first isolated and described in 1986 Thyroid hormone resistance is an inherited condition in 85% of cases (autosomal dominant) (15% de novo mutations) RTH: Mutation is found in the TRB gene in 85% of cases Mutations result in the production of a mutant receptor that inhibits the function of wild-type THR = dominant-negative mutation > need for higher levels of thyroid hormones to achieve the same intracellular effect

THRβ RTH THR β Hyperthyroidism signs through the alpha signalling: Tachycardia, sweating, nervousness, etc THRα T4 T3 THR β Eu - vs hypothyroidism signs through the mutated beta signalling: Growth delay, mental deficiency (homozygous) THRα THR β

THRβ RTH Clinical phenotypes RTH β are highly variable even for a same/given mutation in a same family - Depending on the mutation and the degree of individual tissue responsiveness Most patients with RTH β are heterozygous 4 patients with homozygous mutations with more severe phenotype Goiter (75%; < TSH+) No symptoms > growth (18%) and bone delay (29%) maturation, tachycardia (effort), heart malformation, impaired earing (21%), visual and intellectual disabilities (38%), attention deficit/hyperactivity disorder

Clinical case 4 Family history of thyroid disease? Thyroid function in the parents? Reference values TSH ( µui /ml) 1,88 0,3-4 ft4 (ng/dl) 2,9 0,8-2 ft3 (pg/ml) 6,8 2,5-4,7 Same profile in the mother Pituitary MRI: N THRB mutation Treatment: β-blockers

TAKE HOME MESSAGE 4 If thyroid tests are discordant and possibly consistent with a genetic inherited disease: Ask for family medical history and control thyroid tests in first-degree relatives.

CLINICAL CASE 5 What does the biologist see : ambulatory 40 years old woman Reference values TSH ( µui /ml) 3,46 0,4-4 ft4 (ng/dl) 2,29 0,9-2 ft3 (pg/ml) 5,9 1,8-4,6

ft4???? TSH L-T4 therapy (very common) Assay interference (common) Resistance to thyroid hormone (very rare) Assay interference (very rare) TSH-secreting pituitary adenoma (very rare)

CLINICAL CASE 5: CLINICAL CONTEXT Send by her general practitioner in 2005 for strange thyroid tests She underwent left lobectomy for cold nodule in 1983 Under 75 µg of l-t4 since surgery No family history of thyroid disease (both parents died of cancers) - no children - not pregnant Treatment: Seroxat and alprazolam (depression), L T4 Stable weight normal menstrual cycles sweating, nervousness Physical examination: BMI 21kg/m2; HR 82 ; BP 130/70

What do you suggest? sweating, nervousness Best Pract Res Clin Endocrinol Metab. 2013 Dec; 27(6): 745 762.

CLINICAL CASE 5 Repeat thyroid testing (also in other labs) in the morning before taking L-T4: 04/2004 TSH 3.17 T4L 2.46 (0.9-2) 10/2004 TSH 3.05 T4L 2.43 T3L 6.9 04/2005 TSH 4.65 T4L 2.2 T3 L 6.5 04/2005 TSH 3.46 T4L 2.29 T3L 5.9 4 weeks after the stop of L-T4 TSH 4.0 µui/ml, ft3 5,7 pg/ml (1,8-4,6), ft4 2 ng/dl (0,8-1,7)

CLINICAL CASE 5: MEDICAL HISTORY PREVIOUS BIOLOGY Left hemi-thyroidectomy for 2 cm papillary thyroid cancer Thyroid test in october 1983 under «suppressive» L-Thyroxine treatment: TSH 0.9; ft4 ft3 N What is the most likely diagnosis?

CLINICAL CASE 5: MRI

TSH (mu/l) CLINICAL CASE 5: TRH-TEST TRH-test 10 8 6 4 2 0 0 60

CLINICAL CASE 5

TAKE HOME MESSAGE 5 If thyroid tests are discordant: Ask for previous thyroid test to distinguish between acquired and inherited affections.

TAKE HOME MESSAGES: Thyroid function test interpretation can be challenging for the biologist and the clinician Discussion between the clinician and the biologist is essential to achieve the right diagnosis Clinical context is basic (age, treatment, signs, symptoms, general health status) Think first to the most frequent etiologies (L-thyroxine treatment)

TAKE HOME MESSAGES: Control the other pituitary hormones if suspicion of central hypothyroidism (after discussion with the clinician) To distinguish between acquired and genetic disorders: Importance of the family history If possible, check thyroid function in the first-degree relatives Try to find previous thyroid tests

Thank you for your attention