Thyroid Physiology & Non-Thyroidal Illness Syndrome

Kristin Clemens PGY 4

Endocrine RoundsFebruary 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-pituitary-thyroid 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 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

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!