MOLECULAR BASIS OF THE NON-THYROIDAL ILLNESS SYNDROME IN CRITICAL ILLNESS

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1 MOLECULAR BASIS OF THE NON-THYROIDAL ILLNESS SYNDROME IN CRITICAL ILLNESS BTC AWARD LECTURE LIESE MEBIS 21th May 2011 Laboratory of Intensive Care Medicine Katholieke Universiteit Leuven, Belgium

2 Critical illness A condition whereby a patient, through trauma or disease, becomes dependent on pharmacological and/or mechanical support of his vital functions, without which he/she would die shortly

3 Thyroid (patho)physiology during critical illness? + neuroendocrine dysfunction TRH TRH Low- syndrome TSH TSH or non-thyroidal illness (NTI) D1, D2 D1, D3 D1, D2 D1, D3 or r r euthyroid sick syndrome D1, D3 D1, D2 D1, D3 D1, D2

4 Associations with mortality and morbidity /r ratio is associated with increased mortality in the ICU (Peeters et al., JCEM, 2005) Many symptoms in critically ill patients can be related to the low levels. Signs of hypothyroidism? CNS depression Need for inotropes Hypothermia Diaphragm dysfunction Polyneuropathy Weaning failure Kidney failure Tegumentum dystrophy. Are the low levels harmful???

5 Is the low syndrome an adaptive response? PRO CON Problem: lack of well powered RCT for TH treatment in the ICU First increase our understanding of the pathophysiology of the low syndrome or NTI

6 Suppressed D1 and upregulated D3 activity in critical illness Liver D1 / r Liver D3 8 6 p < 0.01 ** ** p < 0.01 * * p = I II III IV 0 I II III IV 0 I II III IV Human liver biopsies (N=76) D1 D3 r I II III cardiovascular collapse MOF with sepsis MOF with SIRS D3 IV severe brain damage Peeters R et al. JCEM 2003 D1

7 Study 1: The type II iodothyronine deiodinase (D2) D2 is expressed in skeletal muscle TRH D2 can contribute to circulating TH levels (Luiza Maia et al, JCI, 2005) TSH Is D2 reduced and hereby contributing to the low levels during critical illness? D2? D1 D3 r D3 D1 D2?

8 D2 is increased in skeletal muscle of critically ill patients T (nmol/l) T (nmol/l) r (nmol/l) TSH (miu/l) P < P < P < P < ,25 2,00 1,75 1,50 1,25 1,00 0,75 0,50 0,25 0,00 P = 0.02P < P = NS P < ,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 P = NS P < ,25 2,00 1,75 1,50 1,25 1,00 0,75 0,50 0,25 0,00 P = NS P < Relative D2 mrna D2 activity (fmol/min/mg) 2,50 2,25 2,00 1,75 1,50 1,25 NS P = ,012 0,010 0,008 0,006 NS P = Healthy control Acute surgical stressed Prolonged ill 1,00 0,75 0,004 0,50 0,25 0,002 0,00 0,000 Mebis L et al. JCEM, 2007

9 From patient to rabbit Weekers F et al. Endocrinology, 2002, 143: Debaveye Y et al. Endocrinology 2005, 246:

10 D2 is regulated by TH levels during critical illness AUC (nmol/l over 4 days) P < P < Relative D2 mrna P = P = ,2 1, ,8 0,6 NS AUC (nmol/l over 4 days) P < NS 0,4 0,2 0,0 Saline TRH + GHRP-2 +

11 Adaptive response of D2 during critical illness D1 r D1 D3 r D3 D2 r D2

12 Study 2: Thyroid hormone transporters nucleus D1, D2 D3 MCT8 TR D3 r D1, D2 cytoplasm MCT10 Changes in TH transporters cause low levels during prolonged critical illness?

13 MCT8 clinical relevance o Association between mutations in a thyroid hormone transporter (MCT8) and severe X-linked psychomotor retardation (Friesema et al., Lancet, 2004) = Allan-Herndon-Dudley syndrome (AHDS) congenital hypotonia spasticity severe psychomotor delays muscle hypoplasia generalized muscle weakness limited speech o Changes in serum TH levels: elevated free low to below normal free normal TSH

14 Healthy control Expression of MCT8 and MCT10 in critically ill patients Acute surgical stressed Prolonged ill Liver Muscle 2.00 * 12 * 2,25 2,00 1,75 1,50 1,25 1,00 0,75 0,50 0,25 0, T (nmol/l) * T (nmol/l) * 2,25 2,00 1,75 1,50 1,25 1,00 0,75 0,50 0,25 0,00 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 TSH (miu/l) * r (nmol/l) * MCT10 MCT * P < vs. acute ill group, P = 0.05 vs. acute ill group Mebis L et al, EJE 2009

15 Healthy Relative TH transporter mrna expression in rabbit tissues Critically ill (nmol/l) * * * (nmol/l) * * MCT10 MCT8 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 Liver * * * * MCT10 MCT8 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0 Muscle * * * P < 0.05 Mebis L et al, EJE 2009

16 General Conclusions (1) nucleus D2 D1, D2 D3 MCT8 TR r D3 D1, D2 D2 cytoplasm MCT10 Compensatory changes during prolonged critical illness? = An argument pro treatment?

17 Study 3: Changes in the central component of the HPT-axis Fliers E, et al. Decreased TRH gene expression in patients with chronic non-thyroidal illness JCEM 1997; 82:

18 Central regulation of the HPT axis Local hyperthyroidism? + neuroendocrine dysfunction TRH T TRH TSH Healthy Critically ill PVN D1, D2 D3, D1 r TRH TRH D3, D1 D1,D2

19 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron Astrocyte/tanycyte

20 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Astrocyte/tanycyte

21 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Astrocyte/tanycyte

22 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Astrocyte/tanycyte

23 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Astrocyte/tanycyte

24 TH transporters in the hypothalamus Healthy Critically ill MCT8 MCT10 OATP1C P = 0.16 P = 0.04 P = TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Mebis et al. Crit Care 2009

04 0.02 0.00 P = NS D2 Critically ill D3 activity (fmol/min/mg) 2,0 1,8 P = NS D2 1,6 1.

25 D2 and D3 in Rabbit Hypothalamus Healthy Critically ill Relative D2 mrna D2 activity (fmol/min/mg) Healthy P = P = NS D2 Critically ill D3 activity (fmol/min/mg) 2,0 1,8 P = NS D2 1,6 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s 1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 Mebis et al. Crit Care 2009

26 TH tissue content of the hypothalamus Healthy Critically ill content Hypothalamus (pmol/g) content Hypothalamus (pmol/g) 7 P = P = TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Mebis et al. Crit Care 2009

27 TR expression in the hypothalamus Healthy Critically ill TRalfa1 TRalfa2 TRbeta1 TRbeta2 1.2 P = NS P = NS P = NS P = NS TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Mebis et al. Crit Care 2009

28 Thyroid hormone pathway in the hypothalamus D3 bloodvessel OATP1C1 D2 MCT8/10 TR s TRH neuron 1. TH transporters 2. TH metabolism by D2/D3 3. TH tissue content 4. TR s Astrocyte/tanycyte

29 General Conclusions (2) + neuroendocrine dysfunction TRH T TRH TSH D1, D2 D3, D1 Other mechanisms for TRH repression? D3, D1 r D1,D2

30 Acknowledgments Intensive Care Medicine Greet Van den Berghe Lies Langouche Yves Debaveye & Björn Ellger Sarah Derde en Eric-Jan Ververs Sarah VP, Ilse, Yoo-Mee, Marijke, Hilke, Jan, Annelies, Ine, Leslie Research Group Comparative Endocrinology Veerle M Darras International collaborators Theo J Visser, Rotterdam, Nl Eric Fliers, Amsterdam, Nl Funding bodies Fund for Scientific Research, Flanders, Belgium Research Fund of the Catholic University of Leuven

Illness-induced changes in thyroid hormone metabolism: focus on the tissue level

R E V I E W Illness-induced changes in thyroid hormone metabolism: focus on the tissue level J. Kwakkel*, E. Fliers, A. Boelen Department of Endocrinology & Metabolism, Academic Medical Center, University