1. Thyroid Physiology & Non-Thyroidal Illness Syndrome Kristin Clemens PGY 4 Endocrine Rounds February 22 nd, 2012

2. Objectives Brief overview of thyroid physiology Define non-thyroidal illness syndrome Learn about the causes of non-thyroidal illness syndrome Biochemical manifestations Understand mechanisms behind thyroid function tests Learn about the prognostic implications of non-thyroidal illness Examine literature for utility of replacement therapy

3. Hypothalamic-pituitary- thyroid axis

5. Thyroid Hormone Production

6. Thyroid hormone production Step 1 TSH binds to receptor - cAMP Iodine trapping Iodine from diet Na/I symporter on basolateral membrane 1

7. Step 2 Iodine oxidized into inactive iodotyrosines MIT and DIT 2

8. Thyroid hormone Step 3 Inactive MIT and DIT added to tyrosyl residues on thyroglobulin (TG) Mediated by hydrogen peroxide and thyroid peroxidase (TPO) 3

9. Thyroid hormone Step 4 Thyroglobulin transferred back into cells Phagolysosomes Release of T4, T3, MIT, DIT MIT, DIT, iodine are recycled Free hormones move across the basolateral membrane into the circulation – 17:1 4

10. T4 and T3 Feedback mechanisms in place

11. Protein binding Bound to thyroid binding globulin, transthyretin, albumin in peripheral circulation Increase circulatory pool of hormone and delay clearance 99.98% T4 and 99.7% of T3 protein bound 2x10 -11 M T4 free and 6x10 -12 T3 free and bioavailable

12. Peripheral conversion Deiodinase enzymes on plasma membrane and ER Thyroid, liver, kidney, pituitary gland, brain, fat 80% T3 from peripheral conversion D1 and D2 convert T4 to T3 T3 most metabolically active D3 inactivates T4 and T3 rT3 hormonally inactive with possible inhibitory role on T3 at cellular level

14. Thyroid hormone at the tissue level Transporter proteins including TCT8, MCT10 Into the nucleus Receptors are variably spliced into unique isoforms – alpha and beta subunits Different receptors in different tissues

15. End result of binding Fetal development Metabolism of lipids and carbohydrates Metabolic rate GI motility Bone formation and resorption Myocardial contractility SNS Hematopoiesis etc.

17. Case 60 year old lady Admitted to medicine with urosepsis No known history of thyroid disease TSH 0.5 mIU/L, free T4 11 pmol/L, free T3 2.0 pmol/L

18. Non-thyroidal illness syndrome Sick euthyroid syndrome

19. Non-Thyroidal Illness Changes in thyroid hormone concentrations that arise following any acute or chronic illness Not caused by an intrinsic abnormality in thyroid function Trauma, surgery, sepsis, heart disease, brain injury, starvation, psychiatric admissions

20. Sick Euthyroid Syndrome Too simplistic Constellation of disease – variable thyroid function tests Truly euthyroid at tissue level? Arem R et al, Metabolism, 1993 Mean T 3 concentrations in the cerebral cortex, liver, kidney, and lung were lower by 46% to 76% in patients who died of non thyroidal illness, as compared with those who died suddenly Values in heart and skeletal muscle were similar

21. Why does it happen? Controversial Adaptation to chronic illness Minimize energy expenditure and catabolic effects True hypothyroidism

22. Common Medical wards Prevalence of a low serum T 3 concentration is ∼ 50% Low serum T 4 concentration is ∼ 15% to 20% Abnormal (low or high) serum TSH concentration ∼ 10%

23. Thyroid function tests Variable Normal TSH, T4 Low T3 and free T3 “Low T3 syndrome”

24. Normal TSH Low T4 Low T3 and free T3

25. Low TSH (>0.01 mU/L) Low T4 Low T3 and free T3

26. Recovery High TSH Normal T3 and T4

28. Low T3?

29. Low T3: Dysfunction of deiodinases In starvation models and critical illness, diminution of both hepatic and renal D1 and D2 activity and an increase in D3 T3 production lessens in favour of reverse T3 production

30. Peeters et al, J Clin Endocrinol Metab, 2003 Studied serum thyroid hormone levels and expression of D1, 2, 3 in liver and skeletal muscles of 65 deceased ICU patients Liver D1 down regulated Liver and muscle D3 up regulated – not normally present mRNA levels corresponded with enzyme activity (p<0.001)

31. Why? Increased cytokines Competition for limiting amounts of nuclear receptor co activators between the D1, D2 promoter and the promoters of cytokine-induced genes

32. Low T3: Decreased transport of T4 Kaptein et al, J Clin Invest, 1982 Decrease in T4 transport into peripheral tissues including liver by 30-65% Major site for production of T3 and clearance of rT3 Hepatic ATP depletion

33. Low T3: Drug therapy Drugs may inhibit monoiodination Amiodarone

34. Low T4/T3?

35. Low T4: Altered protein binding Transthyretin and thyroxine binding globulin levels may fall markedly due to impaired synthesis, rapid breakdown during illness Inhibitors of T4 binding might also be present (?free fatty acids) Low total hormones Free hormones variable depending on lab measurement – low free T3

36. Low TSH, T3, T4? Central hypothyroidism Impaired function of hypothalamus Decreased TRH mRNA in critical illness models Mechanisms Decreased leptin in states of fasting Altered feedback at level of hypothalamus suppressing TRH production

37. Warner et al, Journal of Endocrinology, 2010

38. Pituitary Cytokines may impair TSH secretion IL6, TNF alpha, interferon Correlated negatively with fT3 and positively with rT3 in hospitalized patients

39. Inhibition Dopamine, steroids, somatostatin

40. Furthermore.. Loss of pulsatility Decreased TSH bioactivity due to abnormal glycosylation (?from TRH deficiency) Decreased T3 and T4

41. Warner et al, Journal of Endocrinology, 2010

43. Warner et al, Journal of Endocrinology 2010

44. Correlated with mortality Becker et al, Crit Care Med, 1982 Lower free hormones in those with greater burn size and in non survivors Reverse T3 higher

45. Iervasi et al, Circulation, 2002 573 consecutive patients with heart disease Low fT3 ( 3.1 pmol/L) 1 year follow up, 25 deaths in group 1 and 12 in group 2 (14.4 vs. 3%, p<0.001) Modelling noted that fT3 was most important predictor of death (HR 3.5, p<0.001) over age, lipids, EF

46. Chinga-alayo et al, Intensive Care Med, 2005 113 patients from 3 ICU’s CV, respiratory, sepsis, neuro, metabolic, trauma, GI and renal patients Followed prospectively until they died or were discharged Evaluated if the inclusion of hormones recorded in the first hour of ICU admission improved the APACHE II score predicting mortality in the ICU

47. Chinga-Alayo et al Non survivors had lower TSH and T3 concentrations When combined with the APACHE II score, improved prediction Best logistic regression model for ICU mortality included APACHE II, TSH and T3 hormones (AUC 0.88 vs. 0.75, p<0.001) For every 10 ng/dL decrease in T3, there was a 49% increase in risk of dying after adjusting for APACHE II and TSH

48. Replacement?

49. Controversial Adaptive changes minimizing protein catabolism Thyroid hormone deficiency may lead to decreased CO, increased SVR etc. that may benefit from replacement therapy

50. Novitzky et al, Cardiology, 1996 Reduced mortality in CABG after T3 supplementation Mullis-Jansson et al, J Thorac Cardiovasc Surg, 1999 Decrease in ischemia and hemodynamic variables, reduced inotrope requirements Klemperer et al, N Engl J Med 1995 Improved ventricular performance and lower SVR Outcomes however, variable

51. Systematic review Kaptein et al, JCEM, 2009 Effectiveness of T3 in improving morbidity and mortality in adults with nonthyroidal illness 1950-2008 Included if at least 24 hours of treatment, no hypothyroidism, control group 7 RCT’s, good quality T3 dose 120-200 ug per 70 kg per day, T4 dose 100-300 ug per kg per day Treated for 7-90 days TSH, TSH response to TRH, T4 levels after T3, HR, CO, SVR, morbidity and mortality

54. Other outcomes Variable outcomes otherwise LVEF <30% had reduced stay with T3 dose of 125 mg/70 kg per day for 7 days before and variable duration afterward surgery but no impact on mortality

55. Systematic review and meta- analysis Kaptein et al, JCEM, 2010 Treatment of non thyroidal illness in immediate post op with T3 1950-March 2010 Excluded if no controls, hypothyroidism 14 RCT’s CABG or valve surgery (13), renal transplant (1) 0.0275-0.0333ug/kg/hr in low dose group, 0.175 to 0.333 ug/kg/hr in high dose Duration of therapy from 6-120 hours (2 with up to 5 days of pre-op treatment) Mortality, TSH and T4, CO, SVR, HR, A fib, inotrope requirements, PCWP, length of ICU stay

58. Dose-response effect? Noted 2 clusters of SVR in low and high T3 group (?correlation) No correlation between CI values expressed as a % basal and total T3 doses in 6 studies – higher T3 did not have greater effect on CI

60. Other outcomes Variable change in TSH and T4 (short duration of T3 therapy and monitoring) Variable IV T3 on MI and infarction not conclusive Insufficient data for analysis for duration of ICU and hospital stays

61. Conclusions In immediate post op group, high dose T3 in CABG group may increase CI and decrease SVR Unsure of adverse outcomes and no mortality benefit

62. Studies of critically ill limited by low sample sizes, variable hormone doses, likely heterogenous populations (variable baseline hormones, therapy initated at variable times during illness) Mild, short duration of illness may not benefit Those suffering a severe and prolonged NTIS may be tissue hypothyroid and represent a group that might benefit Larger sample RCT’s may be beneficial

63. Guidelines? No current recommendations for T3/T4

64. Additional research VandenBerghe et al, JCEM, 1999 In critical illness suppressed pulsatile release of GH and TSH 14 patients in intensive care for at least 2 weeks with anticipation of additional 2 weeks of stay Mean age 68, critically ill for 40 days Infusion of TRH and GH/placebo After infusion, TSH increased as did T4 Anabolic markers improved – leptin etc Protein degradation reduced No detectable difference in responsiveness of axis between survivors and non-survivors

65. Pappa T et al, Eur J Clin Invest 2011 TR beta agonists in critically ill Selective activation may allow increase in metabolic rate and restoration of T3 without cardiac acceleration mediated by TR alpha

66. Summary Thyroid physiology complex Can help understand TFT’s Non thyroidal illness common – up to 50% on medical ward Clinical diagnosis – primary hyperthyroidism, primary hypo or secondary hypothyroidism may mimic Patients with nonthyroidal illness may have variable thyroid function with several underlying mechanisms

67. Impaired deiodinases, hypothalamic dysfunction With treatment some physiologic parameters change No proven benefit Avoid checking TSH unless high clinical suspicion of dysfunction

68. References Chinga-Alayo E, et al. Thyroid hormone levels improved the prediction of mortality among patients admitted to the intensive care unit. Intensive Care Med 2005; 31: 1356-1361. Dulawa A, et al. Hormonal supplementation in endocrine dysfunction in critically ill patients. Pharm Reports 2007; 59: 139-149. Iervasi G et al. Low T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003; 107: 708-713. Kaptein EM, et al. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2008: 94: 3663-3675. Kaptein EM, et al. Thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab 2010; 95: 4526-4534. Pappa TA, et al. The nonthyroidal illness syndrome in the non-critically ill patient. European J of Clinical Investigation 2010; 41: 212-220. VandenBerghe G, et al. Reactivation of pituitary hormone release and metabolic improvement by infusion of GHRP and TRH in patients with protracted critical illness. JCEM 1999; 1311-1323. Warner MH, et al. Mechanisms behind the non-thyroidal illness syndrome: an update. J of Endocrinol 2010; 205: 1-13 Williams Textbook of Endocrinology Werner and Ingbar’s The Thyroid

69. Thanks!