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Thyroid Physiology & Non-Thyroidal Illness Syndrome Kristin Clemens PGY 4 Endocrine Rounds February 22nd, 2012 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 Hypothalamic-pituitarythyroid axis Thyroid Hormone Production Thyroid hormone production • Step 1 • TSH binds to receptor cAMP • Iodine trapping • Iodine from diet • Na/I symporter on basolateral membrane 1 • Step 2 • Iodine oxidized into inactive iodotyrosines MIT and DIT 2 Thyroid hormone • Step 3 • Inactive MIT and DIT added to tyrosyl residues on thyroglobulin (TG) • Mediated by hydrogen peroxide and thyroid peroxidase (TPO) 3 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 T4 and T3 • Feedback mechanisms in place 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 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 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 End result of binding • Fetal development • Metabolism of lipids and carbohydrates • Metabolic rate • GI motility • Bone formation and resorption • Myocardial contractility • SNS • Hematopoiesis etc. 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 • Non-thyroidal illness syndrome • Sick euthyroid syndrome 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 Sick Euthyroid Syndrome • Too simplistic • Constellation of disease – variable thyroid function tests • Truly euthyroid at tissue level? • Arem R et al, Metabolism, 1993 • Mean T3 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 Why does it happen? • Controversial • Adaptation to chronic illness • Minimize energy expenditure and catabolic effects • True hypothyroidism Common • Medical wards • Prevalence of a low serum T3 concentration is ∼50% • Low serum T4 concentration is ∼15% to 20% • Abnormal (low or high) serum TSH concentration ∼10% Thyroid function tests • Variable • Normal TSH, T4 • Low T3 and free T3 • “Low T3 syndrome” • Normal TSH • Low T4 • Low T3 and free T3 • Low TSH (>0.01 mU/L) • Low T4 • Low T3 and free T3 • Recovery • High TSH • Normal T3 and T4 Low T3? 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 • 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) Why? • Increased cytokines • Competition for limiting amounts of nuclear receptor co activators between the D1, D2 promoter and the promoters of cytokine-induced genes 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 Low T3: Drug therapy • Drugs may inhibit monoiodination • Amiodarone Low T4/T3? 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 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 Warner et al, Journal of Endocrinology, 2010 Pituitary • Cytokines may impair TSH secretion • IL6, TNF alpha, interferon • Correlated negatively with fT3 and positively with rT3 in hospitalized patients Inhibition Dopamine, steroids, somatostatin Furthermore.. • Loss of pulsatility • Decreased TSH bioactivity due to abnormal glycosylation (?from TRH deficiency) • Decreased T3 and T4 Warner et al, Journal of Endocrinology, 2010 Warner et al, Journal of Endocrinology 2010 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 • Iervasi et al, Circulation, 2002 • 573 consecutive patients with heart disease • Low fT3 (<3.1 pmol/L) or normal (>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 • 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 • 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 Replacement? • Controversial • Adaptive changes minimizing protein catabolism • Thyroid hormone deficiency may lead to decreased CO, increased SVR etc. that may benefit from replacement therapy • 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 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 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 Systematic review and metaanalysis • 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 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 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 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 • 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 Guidelines? • No current recommendations for T3/T4 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 • 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 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 • Impaired deiodinases, hypothalamic dysfunction • With treatment some physiologic parameters change • No proven benefit • Avoid checking TSH unless high clinical suspicion of dysfunction 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 Thanks!