Transcript Thyroid Physiology & Non-Thyroidal Illness Syndrome

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!