Tiroides en Critico 2015 Lancet

7232019 Tiroides en Critico 2015 Lancet

httpslidepdfcomreaderfulltiroides-en-critico-2015-lancet 110wwwthelancetcomdiabetes-endocrinology Published online June 11 2015 httpdxdoiorg101016S2213-8587(15)00225-9 1

Series

Endocrine and metabolic considerations in critically ill

patients 4

Thyroid function in critically ill patients

Eric Fliers Antonio C Bianco Lies Langouche Anita Boelen

Patients in the intensive care unit (ICU) typically present with decreased concentrations of plasma tri-iodothyroninelow thyroxine and normal range or slightly decreased concentration of thyroid-stimulating hormone This ensembleof changes is collectively known as non-thyroidal illness syndrome (NTIS) The extent of NTIS is associated withprognosis but no proof exists for causality of this association Initially NTIS is a consequence of the acute phaseresponse to systemic illness and macronutrient restriction which might be beneficial Pathogenesis of NTIS in long-term critical illness is more complex and includes suppression of hypothalamic thyrotropin-releasing hormone

accounting for persistently reduced secretion of thyroid-stimulating hormone despite low plasma thyroid hormone Insome cases distinguishing between NTIS and severe hypothyroidism which is a rare primary cause for admission tothe ICU can be diffi cult Infusion of hypothalamic-releasing factors can reactivate the thyroid axis in patients withNTIS inducing an anabolic response Whether this approach has a clinical benefit in terms of outcome is unknownIn this Series paper we discuss diagnostic aspects pathogenesis and implications of NTIS as well as its distinctionfrom severe primary thyroid disorders in patients in the ICU

IntroductionThe hypothalamicndashpituitaryndashthyroid (HPT) axis iscontrolled by a classic endocrine feedback loop Thyro-tropin-releasing hormone (TRH) is released at the levelof the hypothalamus which stimulates the anteriorpituitary to secrete thyroid-stimulating hormone (TSH)

In turn TSH drives the thyroid gland to release thyroidhormones The prohormone thyroxine (T4 ) is convertedin peripheral tissues to the active hormone tri-iodothyronine (T3) Hypothalamic TRH neurons wereidentified as determinants of thyroid hormone setpointregulation more than three decades ago and thisdiscovery was followed by thyroid hormone receptor(TR) β being shown to have a key role in thyroid hormonenegative feedback at the level of both the hypothalamusand anterior pituitary Thus the HPT axis was assumedto have a fixed setpoint aiming at individuallydetermined serum concentrations of thyroid hormones1 However studies2 have shown that these serumconcentrations can be variable and adaptive in response

to environmental factors including nutrient availabilityand inflammatory stimuli

Substantial changes in plasma concentrations ofthyroid hormones have been noted in a range ofdiseases characterised by clearly decreased plasma T3low plasma T4 and increased plasma reverse T3 (rT3)concentrations Despite low T3 and T4 TSH is typicallymaintained within its normal range or is slightlydecreased This ensemble of changes in thyroidfunction tests is collectively known as the non-thyroidalillness syndrome (NTIS)3 In this Series paper we focuson the presentation pathogenesis metabolicconsequences and clinical management of thyroiddysfunction in critically ill patients The distinctionbetween NTIS and primary thyroid disorders in patients

in the intensive care unit (ICU) can sometimes bediffi cult which will also be briefly discussed

Non-thyroidal illnessIn both human beings and rodents illness decreasesserum concentrations of thyroid hormones without a

concomitant rise in serum TSH This effect represents adeviation from normal negative feedback regulation inthe HPT axis If a similar drop in serum T3 and T4 happened in the context of primary hypothyroidismserum TSH would be substantially increased and thepatient would need thyroid hormone replacementtherapy The combination of low serum T3 and serumTSH within the reference range in the context of illnessis called NTIS34 Several different names have been usedto refer to NTIS including sick euthyroid syndrome andlow T3 syndrome5 (suggesting low plasma T3 as the mostconsistent and striking change) in this Series paper wewill use the term NTIS

Very rapidly after the onset of acute stress such as

from myocardial infarction or surgery serum T 3 con-centrations decrease In patients undergoing abdominalsurgery a fall in serum T3 was noted within 2 h after thestart of surgery6 NTIS has been reported in patientswith acute and chronic illnesses including infectiousdiseases cardiovascular and gastrointestinal diseasescancer burns and trauma4 Serum T3 further decreasesas the severity of disease progresses This change isshown in the reported correlations between the fall inserum T3 concentrations and the size of a myocardialinfarction the increase in serum creatinine in renalinsuffi ciency and also burn severity4 Therefore thescale of the decrease in plasma concentrations of thyroidhormone generally represents the severity of thedisorder and as a result is associated with prognosis In

Lancet Diabetes Endocrinol 2015

Published Online

June 11 2015

httpdxdoiorg101016

S2213-8587(15)00225-9

This is the fourth in a Series of

four papers about endocrine and

metabolic considerations in

critically ill patients

Department of Endocrinology

and Metabolism Academic

Medical Centre University of

Amsterdam AZ Amsterdam

Netherlands (Prof E Fliers MD

A Boelen PhD) Division of

Endocrinology and

Metabolism Rush University

Medical Center Chicago IL

USA (Prof A C Bianco MD) and

Laboratory of Intensive Care

Medicine Department of

Cellular and Molecular

Medicine University of Leuven

Leuven Belgium(L Langouche PhD)

Correspondence to

Dr Anita Boelen Department of

Endocrinology and Metabolism

Academic Medical Centre

University of Amsterdam

1105 AZ Amsterdam

Netherlands

aboelenamcuvanl


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a study7 with patients in the ICU the sensitivity and

specificity in predicting mortality were 75 and 80respectively for serum T4 less than 40 nmolL Forcombined low serum T4 and high serum cortisol thesenumbers were even highermdashie 100 and 81Likewise low T3 was shown to be a strong predictor ofmortality in patients with heart disease8

NTIS is present in most if not all critically illpatientsmdashie patients with any life-threatening disorderthat requires support of vital organ function andwithout which death would be imminent9 Thuscritically ill patients who need long-term treatment inthe ICU typically show decreased plasma T3 and T4 concentrations An absent TSH response in this contextpoints to profoundly altered feedback regulation of the

HPT axis10 Although the normal TSH concentration inthe presence of low plasma T3 has been interpreted as

suggesting a euthyroid status this assumption has not

been substantiated by data Common changes inplasma thyroid hormone ranges that can be easilyassessed in the clinical setting are the result of changesin the central regulation of the thyroid axis includingdecreased TSH pulsatility10 Moreover several changestake place in the peripheral components of the thyroidaxis that vary according to the tissue and the severity ofillness11 Peripheral changes include but are not limitedto changes in the concentrations of thyroid hormonebinding proteins and transporters in expression andactivity of thyroid hormone deiodinases and inexpression of thyroid hormone receptors3 Changes inthyroid characteristics that are similar but not identicalto those reported during NTIS occur in response to

fasting in healthy individuals12 NTIS in response tofasting in healthy people is regarded as adaptive and

RCT Participants Intervention (duration) Main outcomes Beneficial or positive

(endpoints)

Harmful

Children after cardiopulmonary

bypass surgery age range from

2 days to 10middot4 years (n=40)15

Yes Children 2 microgkg IV of T3 given on day 1 after

surgery and 1 microgkg given on day 2

for 12 days

Cardiac function ICU

measures

Yes No

Premature newborns born after

lt37 days of gestation (n=100)16

No Children LT4 (25 microgday) plus T3 (5 microgday)

given orally

Mortality Yes No


lt32 weeks of gestation (n=49)17

Yes Children LT4 10 microgkg (IV) or 20 microgkg

(through nasogastric tube) for

21 days

Chronic lung disease

death CNS damage sepsis

No No

Children lt18 years with

cessation of neurologicalfunction during assessment for

organ recovery (n=171)18

No Children Weight-based LT4 bolus followed

by infusion

Vasopressor score Yes No

Protracted critical illness

(n=14)10

Yes Adults TRH (1 microgkg per h) IV for 5 days

plus GHRP-2 (1 microgkg per h) IV for

5 days

GH and TSH secretion

biochemical anabolism

and catabolism variables

Yes No

Critical illness (n=76)19 Yes Adults GHRP-2 alone or in combination

with TRH and GHRH (each peptide

1 microgkg per h)

Synchrony among GH

TSH and PRL release

Yes No

Critical illness (n=40)20 Yes Adults Combinations of GHRH GHRP-2

(both 1 microgkg) TRH (200 microg) given

as bolus time interval 6 h

Serum GH TSH T3 and T4

concentrations

Yes No


(n=20)21

Yes Adults Combinations of GHRH GHRP-2

and TRH start with bolus (1 microgkg)

followed by 1 microgkg per h (for

two consecutive nights)

Serum hormone

concentrations

Yes No

Protracted critical illness(n=33)22

Yes Adults Combinations of GHRH GHRP-2and TRH (1 microgkg per h of each)

GnRH (0middot1 microgkg per 90 min) for

5 days

Serum hormone andmetabolic marker

concentrations

Yes No

Elective coronary bypass surgery

(n=80)23

Yes Adults T3 (125 microgday) orally (7 days

pre-operative until discharge)

Haemodynamic data

morbidity mortality

Yes (haemodynamic

values)

No (morbidity

mortality)

No

Burn injury (n=36)24 Yes Adults T3 (200 microgday) orally or via

nasogastric tube in four divided

doses until wounds healed

Mortality resting

metabolic rate

No No

Coronary bypass surgery

(n=60)25

Yes Adults T3 (0middot8 microgkg) IV for 6 h Operative outcome

morbidity mortality

No No


(n=100)26

Yes Adults T3 (20 microg12 h) oral (48 h) Serum T3 haemodynamic

variables morbidity

No No

(Table continues on next page)



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Series

beneficial because it reduces energy expenditure torestrict catabolism via decreased thyroid hormoneaction

Whether NTIS in response to critical illnesses shouldbe seen as an adaptive mechanism such as instarvation or rather as a maladaptive mechanism isunknown On the one hand a seemingly logicalassumption is that a reduction in serum T 3 woulddecrease thyroid hormone action in important T 3 targetorgans such as the liver and muscles thereby affectingmetabolism that might be beneficial in critically illpatients On the other hand patients with extendedcritical illness show clear symptoms and signs thatresemble those noted in patients with hypothyroidism

including impaired consciousness myocardialfunction hypothermia neuropathy muscle weaknessatrophy of the skin and hair loss which together mightimpede recovery1314 Although the hypothesis that NTISin patients in the ICU could be maladaptive has beenextensively discussed9 surprisingly few clinical studies(some being randomised controlled trials [RCTs]) aimedat modulating NTIS to improve clinical outcome havebeen reported With some clinical intervention studiesirrespective of their design the riskndashbenefit ratio mightseem favourable with most patients showing a benefitand only a few showing harm (table) but this ratio hasnot been formally analysed when only RCTs withclinically relevant outcome measures such as mortalityor morbidity are taken into account

Pathogenesis of NTISHPT axis feedback regulation and local thyroid hormonemetabolismSevere illness induces large changes in thyroidhormone economy resulting in a downregulation ofthe HPT axis both at the hypothalamic and pituitarylevels with an associated decrease in circulating thyroidhormone concentrations3 This finding points tosubstantial changes to the negative feedback regulationin the HPT axis during NTIS2 In people centraldownregulation of the HPT axis during NTIS wassupported by the observation in autopsy samples ofdecreased TRH gene expression in the hypothalamicparaventricular nucleus TRH mRNA expression in the

paraventricular nucleus showed a positive correlationwith antemortem concentrations of plasma TSH andT3

33 Additionally simultaneous changes in livermetabolism of thyroid hormone contribute to thecharacteristic changes in thyroid hormone plasmaconcentrations low plasma T3 and high plasma rT3normal or low to normal plasma TSH and low plasmaT4 during severe illness3

Although the mechanisms associated with theseseemingly paradoxical HPT axis changes are notcompletely understood findings from animal studiesusing various NTIS models have elucidated someaspects of NTIS pathogenesis NTIS induces specificchanges in enzymes associated with thyroid hormonemetabolism (deiodinases type 1 [D1] 2 [D2] and 3 [D3])


(endpoints)

Harmful

(Continued from previous page)

High risk valvular heart surgery

(n=50)27

Yes Adults T3 (20 microg12 h) orally (24 h) Vasopressor need Yes No

Patients in the ICU with low T4

concentrations (n=23)28

Yes Adults 1middot5 microgkg bodyweight LT4 IV

(2 weeks)

Mortality No No

Acute renal failure (n=59)29 Yes Adults LT4 infusion 150 microg20 mL every

12 h for 48 h

Percentage dialysis

percentage recovery

mortality

No Possibly

(increased

mortality)

Idiopathic dilated

cardiomyopathy (n=20)30

Yes Adults 100 microgday of LT4 for 3 months Cardiac performance Yes No

Congestive heart failure

(n=86)31

Yes Adults Thyroid hormone analogue DIPTA

two per day maximum dose

360 mgday

Composite congestive

heart failure endpoints

No Yes

Non-thyroidal illness syndrome

after major trauma (n=31)32

Yes Adults Selenium (500 microgday) with or

without vitamin E and zincsupplementvs placebo (5 days)

Serum selenium levels T4

levels duration ofmechanical ventilation

Yes (T4 and selenium

plasmaconcentrations)

uncertain (ventilation)

No

Patients with sepsis in the ICU

(n=40)17

Yes Adults High dose selenium (158 microgday for

3 days) followed by standard dose

selenium-selenite (31middot6 microgday)

Serum selenium

concentrations oxidative

damage values need for

renal replacement therapy

No No

Whether trial showed overall beneficial and positive outcomes or harmful effects was defined by the authors on the basis of results reported RCT=randomised controlled trial

IV=intravenous T3=tri-iodothyronine ICU=intensive care unit LT4=levothyroxine TRH=thyrotropin-releasing hormone GHRP=growth hormone-releasing peptide

GH=growth hormone TSH=thyroid-stimulating hormone GHRH=growth hormone-releasing hormone PRL=prolactin T4=thyroxine GnRH=gonadotropin-releasing

hormone DIPTA=di-iodothyropropionic acid

Table Overview of clinical studies reporting interventions in patients with non-thyroidal illness syndrome




Series

thyroid hormone transporters and thyroid hormone

receptors (TRα and TRβ)

3

For example induction ofacute inflammation in rodents by a single peripheralinjection of bacterial endotoxin or lipopolysaccharidestimulates D2 mRNA expression in tanycytes lining thethird ventricle in the hypothalamus3435 This D2upregulation is followed by an increased localconversion of T4 to T3 which subsequently lowers TRHmRNA expression in the paraventricular nucleus asnoted in people (figure 1)333637 Although an increase in

D2 activity has not yet been proven experiments in an

in-vitro co-culture system showed that glial D2modulates T3 concentrations and gene expression inneighbouring neurons38 Thus inflammation inhibitshypophysiotropic TRH neurons probably via increasedD2 activity thereby accounting for hypothalamicdownregulation of the HPT axis during NTIS

The liver is one of the key metabolising organs of thyroidhormone It expresses the thyroid hormone transportersmonocarboxylate transporter 8 (MCT8) and MCT10 bothD1 and D3 (although D3 is expressed at very low con-centrations in a healthy liver) TRβ1 and TRα1 Figure 2shows a detailed overview of cellular thyroid hormonemetabolism Although liver-expressed D1 contributesabout only 20 of the circulating T3 in man47 this enzymersquos

involvement in NTIS pathogenesis has been extensivelystudied48 Investigations showed reduced liver D1 mRNAexpression and enzyme activity in people during illnesssuggesting a role for liver-expressed D1 in the pathogenesisof illness-induced changes in plasma T3 and rT3

48

Critical illnesses that include a substantial hypoxia orischaemia component show a large increase in thyroidhormone catabolism via induction of D3 This effectwas shown originally in post-mortem tissues of patientsfrom the ICU49 and later in a series of animal modelsincluding in models for myocardial50 and braininfarction38 Thus induction of D3 during NTIS intissues that do not normally express or express onlyvery little D3 is likely to greatly contribute to theabnormalities in thyroid economy reported duringischaemic injury51

NTIS part of the acute phase responseSeveral clinical studies done more than 20 years agoshowed a clear association between the changes in thyroidhormone metabolism and the activation of variousproinflammatory cytokines5253 Cytokines are importantmediators of the acute phase response affecting feverleucocytosis the release of stress hormones and theproduction of acute phase proteins Cytokines are alsoable to affect the expression of many proteins connectedwith thyroid hormone metabolism and are causally

involved in the pathogenesis of NTIS54 Lipopolysaccharidestimulation of a range of cells results in a stronginflammatory response characterised by the productionof various cytokines including tumour necrosis factor α(TNFα) interleukin 1 and interleukin 6 For the inductionof cytokines the activation of inflammatory signallingpathways including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and activator protein1 is mandatory55 Activation of NFκB was shown to playan important part in the upregulation of D2 inhypothalamic tanycytes during inflammation5657 D1 isalso sensitive to cytokines D1 expression in a liver cellline decreases upon interleukin 1β stimulation and thisresponse can be abolished by simultaneous inhibition ofNFκB and activator protein 158 In summary cytokines

Neuron

TRH

TRβ

D2uarr

Tanycyte

Inflammation

Hypothalamus

T4rarrT3uarr

T3

NFκB

D2 promoter

Figure 983089 Schematic representation of hypothalamic thyroid hormone

signalling during inflammation

Inflammation activates the NFκB pathway in tanycytes specialised cells lining the

third ventricle Tanycytes express D2 the main T3 producing enzyme in the brain

the promoter of which contains NFκB responsive elements Binding of NFκB

increases D2 expression and activity and this stimulates the conversion of T4 into

T3 T3 will enter adjacent neurons and bind to neuronal TRβ thereby regulating

transcriptional activity of TRH T3=tri-iodothyronine TRβ=thyroid hormone

receptor β TRH=thyrotropin-releasing hormone NFκB=nuclear factor kappa-light-

chain-enhancer of activated B cells D2=deiodinase type 2 T4=thyroxine

T4

T4 T4

T4

T4

T4

T4

T4

T4

T3

T3

T3

T3

T3

T3

T3

T3

T3

Blood vessel

T3 target gene

TRE

RXR TRD3

D3D2

D2

Nucleus

rT3

rT2

Cell

Figure 983090 Schematic representation of cellular thyroid hormone metabolism

Cellular entry of thyroid hormones is necessary for intracellular conversion and for T3 to exerts its actions in the nucleus

Two categories of thyroid hormone transporters have been noted the organic anion transporters and the aminoacid

transporters139ndash41 Once transported into the cell thyroid hormones (T 4 and T3) can be metabolised by outer or inner ring

deiodination through the iodothyronine deiodinases These enzymes belong to a selenocysteine containing enzyme

family and comprise three types type 1 (D1) 2 (D2) and type 3 (D3) 42 D1 is able to deiodinate the inner ring and outer

rings of T4 as well as the outer ring of rT3 D1 is expressed in the liver kidney thyroid and pituitary and localised in the

plasma membrane4344 D2 is localised in the endoplasmic reticulum and deiodinates T4 into the biologically active T3 D2

is the main enzyme involved in the production of tissue T3 and therefore heavily involved in local thyroid hormone

metabolism4546 D3 is localised in the plasma membrane and can be viewed as the major thyroid hormone inactivating

enzyme as it catalyses inner-ring deiodination of both T4 and T3 exclusively resulting in the production of biologically

inactive rT3 and rT2 respectively47 The balance between D2 and D3 determines the availability of cellular T 3 which enters

the nucleus and binds to the nuclear receptor complex (RXR and TR) T 3 exerts its nuclear actions via the RXR and TR

complex that binds to thyroid hormone response elements in target genes TR complex regulates transcriptional

activity of T3-target genes TR=thyroid hormone receptor T3=tri-iodothyronine T4=thyroxine rT3=reverse T3 rT4=reverseT4 RXR=retinoid-X receptor TRE=thyroid hormone response elements




Series

that are activated as a result of the inflammatory response

are causally associated with the pathogenesis of NTISmaking NTIS part of the acute phase response

Differential effects of illness on thyroid hormone actionin metabolic organsEnergy homeostasis changes dramatically during illnesssince activation of the immune system induces energyexpenditure at the same time as food intake is decreasedAlthough the common view is that NTIS results inoverall downregulation of metabolism in the organism tosave energy investigations have shown great variabilitybetween various key metabolic organs and tissues in theexpression of genes encoding proteins involved inthyroid hormone metabolism3 These tissues include

cells that are now known to be thyroid hormoneresponsive such as granulocytes59 macrophages60 andlung epithelial cells (figure 3)61

Thyroid hormones are important for skeletal musclefunction because a range of genes expressed in the musclesare regulated by T3 Thyroid hormone signalling was shownto be different in skeletal muscle tissue during illnessdepending on the type (eg acute inflammation or bacterialsepsis) and stage (ie acute or long-term) of illness62ndash64 Whether the differential changes in thyroid hormonemetabolism in muscles during illness are clinically relevantis unknown however muscle dysfunction has beenassociated with changes in muscle metabolism of thyroidhormones during extended critical illness65ndash68

Thyroid hormones are now known to target cells andorgans that respond to inflammation by increasing D2 orD3 expression thereby affecting cellular function Forexample stimulation of macrophages with bacterialendotoxin increases D2 expression which is essential forcytokine production and phagocytosis60 Moreovergranulocytes show increased D3 expression wheninfiltrating an infected organ69 A functional role for thisevent was suggested by the finding that the absence ofD3 in mice severely impaired the bacterial clearancecapacity of the host70 Induction of D3 in activatedgranulocytes not only inactivates thyroid hormone butalso yields substantial amounts of iodide that can be used

by the cell for bactericidal and tissue-toxic systems71 Tosummarise the presence of D3 in activated granulocytessuggests a novel and protective role for the deiodinatingenzymes in the defence against acute bacterial infection

Role of nutritionCritical illness is associated with loss of appetite and poororal and enteral nutritional intake72 Because fasting inhealthy individuals induces a similar NTIS response asthat reported in patients who are critically ill 12 decreasedcaloric intake during illness might greatly contribute tothe development of NTIS Fasting induces a decrease inserum thyroid hormones through a multifactorialmechanism and includes a decrease in serum leptin anddownregulation of hypothalamic hypophysiotropic TRH

neurons contributing to persistently low concentrationsof serum TSH (figure 4)74 At the organ level activity ofD1 the enzyme driving the conversion of T4 into thebiologically active T3 and clearing the biologically inactiverT3 is decreased Increased activity of D3 the T3 inactivating enzyme has also been reported75 Findingsfrom three clinical studies that compared patients ondifferent nutritional strategies suggested that decreasedcaloric intake during critical illness is associated withpronounced NTIS76ndash78

In 2011 the large randomised controlled EPaNIC trial79 reported comparisons between two nutritional regimensin 4640 adult patients in the ICU who were at risk ofmalnutrition the early parenteral nutrition groupreceived parenteral nutrition within 48 h of admission tothe ICU (to supplement insuffi cient enteral nutrition)whereas the late parenteral nutrition group did not startthis feeding regimen to supplement enteral nutritionbefore day 8 in the ICU Findings from this study79

showed that toleration of a nutritional deficit during thefirst week of critical illness resulted in fewer complicationsand accelerated recovery than with the earlyadministration of supplemental parenteral nutritionAbility to tolerate a fasting response thus seems to bebeneficial for the patient Of note a subanalysis of theEPaNIC trial80 (280 participants) showed that late feedingreduced complications and accelerated recovery ofpatients with NTIS but also aggravated the changes incirculating concentrations of plasma TSH total T4 T3and the ratio of T3 to rT3 By contrast the opposite wasreported with patients given early feeding80

Thus the peripheral metabolism of T3 is affected bydecreased nutritional intake during acute critical illnessThe subanalysis of the EPaNIC trial80 suggested that the

Macrophage

Granulocyte

Muscle

Lungs

Liver

Adipose tissue

D3

D2

D2D2

D2

D1

T3

Figure 983091 Simplified overview of various reported differential effects of NTIS

on deiodinase activities in various tissues

Deiodinase effects probably induce interorgan differences in T3 bioavailability in the

presence of similarly decreased plasma concentrations of T 3 T3=tri-iodothyronine

D1=deiodinase type 1 D2=deiodinase type 2 D3=deiodinase type 3




Series

inactivation of T3 to rT3 as part of the fasting responsemight be a beneficial adaptation during acute illnessTargeting of fasting blood glucose concentrations withintensive insulin treatment in children with criticalillness to 2middot8ndash4middot4 mmolL in infants and 3middot9ndash5middot6 mmolLin children thereby mimicking a fasting responseresulted in improved outcomes81 but at the same timeaggravated peripheral NTIS Use of a multivariate Coxproportional hazard analysis showed that the furtherreduction of T3 and rT3 accounted for part of the therapyimproving patient mortality rates82

Together these findings suggest that thyroid economy isaffected by decreased nutritional intake during acutecritical illness and that the inactivation of T4 to rT3 and T3 to T2 as part of the fasting response might be a beneficialadaptation during acute illness80 Particularly the acuteperipheral inactivation of thyroid hormones by inner-ringdeiodination during critical illness is probably a beneficial

adaptation Indeed the reduced amount of circulatingactive T3 could be interpreted as an attempt by the body todecrease the metabolic rate reduce expenditure of scarceenergy and prevent protein breakdown therebypromoting survival By contrast the central lowering of T4 could be harmful Consistent with this interpretation isthe finding that especially patients who are severely illhave a decrease in circulating T4 concentrations whereasvirtually all patients who are ill have low T3 and high rT3 concentrations already on admission to the ICU62

Diagnosis and management of severe primarythyroid disorders in patients in the ICUThe high prevalence of NTIS in patients in the ICU andthe extent of HPT axis changes in these patients can make

it diffi cult to distinguish NTIS from untreated primary

hypothyroidism Levothyroxine treatment should becontinued during a patientrsquos stay in the ICU in those whoare known to have hypothyroidism Although this practiceseems trivial prescription and continuation of chronictreatment is not always a main focus of care in the ICUsetting Findings from a retrospective chart review study83 in a tertiary referral ICU including 133 patients showedthat thyroid replacement therapy was not prescribed formore than 7 days in 23 (17middot3) patients and omitted inthree (2middot2) Diagnosis of primary hypothyroidism canbe diffi cult in patients who are severely ill and not knownto have hypothyroidism before admission to the ICUbecause serum thyroid hormones especially T3 aredecreased in most patients in the ICU due to NTIS In

patients clinically suspected to have severe hypothyroidismthe most useful test for diagnosis is measurement ofplasma TSH because a normal plasma TSH excludesprimary hypothyroidism In patients with a combinationof primary hypothyroidism and NTIS serum TSHconcentration is still high and responsive to levothyroxinetreatment However of note is that in patients who havehypothyroidism the high serum TSH concentration mightdecrease during the acute phase of illness especially ifdopamine or high doses of glucocorticoids are given Thushigh serum TSH in combination with low serum T 4 isindicative of hypothyroidism although this combinationcan also be seen in patients recovering from NTIS A highserum T

3

to T4

ratio and a low serum rT3

favour thepresence of hypothyroidism since these ratios are reversedin NTIS but the diagnostic accuracy of thesemeasurements is poor4 Especially in patients with long-standing and untreated hypothyroidism cold exposureinfection and vascular accidents might trigger thedevelopment of myxoedema coma This disorder is a life-threatening condition with a high mortality of about 5084 Key clinical features are hypothermia and alteredconsciousness and features of laboratory findings includeraised TSH with low or undetectable T4 and T3

concentrations Of note the presence of NTIS can reducethe extent of TSH increase Active management isimportant for this disorder and depends on the recognition

of the clinical features Treatment of myxoedemacoma aims to replace thyroid hormone treat theunderlying condition and provide supportive careAdditionally stress dose glucocorticoids should be given(eg 100 mg hydrocortisone every 8 h) because concomitantautoimmune primary adrenal insuffi ciency might bepresent especially in patients with hypoglycaemia85

A low serum TSH could suggest thyrotoxicosisespecially if serum free T4 is also high The extent of TSHsuppression is associated with the likelihood ofthyrotoxicosis Combination of suppressed TSH highconcentrations of free T4 and normal T3 concentrationsmight point to the combination of thyrotoxicosis andNTIS and has been referred to as T

4

thyrotoxicosis4 Physical examination (eg for a goitre or proptosis) and the

NTIS and nutritional deficit

D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3

NTIS and early parenteral nutrition

D1 D3

Figure 983092 Schematic representation of the effect of parenteral nutrition

during NTISCritical illness-induced NTIS is characterised by low circulating T3 and raised

concentration of rT3 Low hypothalamic TRH mRNA expression low circulating

TSH and low T4 are also reported during NTIS When early full parenteral

support is used to resolve the caloric deficit the peripheral changes in the

thyroid axis partly normalise but its central suppression does not73 Solid arrows

represent direction of change in concentration or activity = represents

normalisation of concentrations NTIS=non-thyroidal illness syndrome

TRH=thyrotropin-releasing hormone TSH=thyroid-stimulating hormone

T4=thyroxine T3=tri-iodothyronine rT3=reverse T3




Series

presence of thyroid antibodies (antithyroid peroxidase and

thyrotropin binding inhibiting immunoglobulins) mightgive further information about the probability ofthyrotoxicosis In the ICU setting some patients canpresent with decompensated thyrotoxicosis or thyroidstorm which is a life-threatening condition Importantlythyroid hormone concentrations do not distinguishbetween patients with thyroid storm from those withsevere thyrotoxicosis because thyroid storm is a clinicaldiagnosis Classic clinical characteristics of thyroid storminclude fever supraventricular tachycardia gastrointestinalsymptoms and an altered mental state includingconfusion delirium or even coma84 Precipitating factorsinclude surgery parturition and infection Treatmentgenerally requires ICU monitoring and aims to restore

thyroid gland function and at the same time diminishthyroid hormone effects on peripheral tissues with acombination of β blockers thyrostatics intravenousglucocorticoids and eventually a high-dose of iodidecompounds86 In a retrospective cohort study87 of patientsadmitted to hospital with acute thyrotoxicosis the presenceof CNS dysfunction was the only significantly differentclinical feature between patients with thyroid storm andthose with compensated thyrotoxicosis Thus patientswith thyrotoxicosis possible thyroid storm and alteredmentation should be treated aggressively with supportivemeasures and antithyroid drugs87

Treatment and management of NTISWhether interventions aimed at normalising thyroidhormone concentrations in patients with extended criticalillness are beneficial has so far not been satisfactorilyanswered The table contains clinical studies reportinginterventions in patients with NTIS Only a few rathersmall RTCs have assessed the effects of treatment withthyroid hormones in patients with NTIS These trialsreport results obtained in a large range of patient groupsmdasheg patients with acute renal failure29 burn injury24 andcardiac surgery2325ndash27 and those in the ICU with low T4 concentrations28 Furthermore the age of the studypopulation varies greatly in these studies23ndash29 ranging frompremature newborns to children and adults Disease

severity is another variable ranging from critical illness atthe medical ICU to heart surgery in quite healthyparticipants Surprisingly little consistency is present inthe choice of the active study drug since both T 3 (givenorally and intravenously) and levothyroxine have beenused In the context of studies with T4 or T3 of note is thatnormalising thyroid hormone concentrations in serumdoes not necessarily result in normal tissue concentrationsof thyroid hormone This finding was clearly shown in astudy48 of patients who were critically ill and receivedthyroid hormone treatment In these patients increases inliver T3 concentrations after thyroid hormone treatmentwas disproportionally high compared with the increase inserum and muscle T

3

concentrations48 In addition totreatment with thyroid hormones the effect of selenium

on NTIS per se and on clinical outcomes has been

studied

3288

A small RCT

89

investigated the effect ofN-acetylcysteine an antioxidant that restores intracellularglutathione (a cofactor required for D1 catalytic activity) onNTIS N-acetylcysteine administration seemed to preventthe derangement in thyroid hormone concentrations thatcommonly happens in the acute phase of acute myocardialinfarction suggesting that oxidative stress is part of thepathogenesis of NTIS in acute myocardial infarction

An unresolved and somewhat controversial issue iswhether there is a place for thyroid hormone treatment inpatients with heart failure Although a failing heart showsmolecular changes partly overlapping with a hypothyroidheart this does not necessarily imply that treatment ofpatients with heart failure and low serum T3 in the setting

of NTIS will improve their disorder8 Although the use ofthyroid hormone treatment in patients with heart failurehas not been adequately studied some trials have reportedencouraging findings A small RCT30 in patients withdilated cardiomyopathy showed beneficial effects ofmedium-term (3 months) levothyroxine treatment oncardiac performance whereas another RCT31 showed thatthe thyroid hormone analogue 35 di-iodothyropropionicacid improved some haemodynamic variables albeitwithout evidence for symptomatic benefit in heart failure

Finally hypothalamic neuropeptides (including com-binations of growth hormone releasing hormone growthhormone releasing peptide 2 gonadotropin releasinghormone and TRH) have been used in patients with long-term critical illness in an attempt to stimulate the anteriorpituitary gland and thereby restore endocrine function interms of plasma concentrations and hormonepulsatility1019ndash22 Overall the RCTs of T3 or T4 in criticalillness have been largely negative in terms of clinicalbenefit (table) However of note is that hypothalamicneuropeptides especially TRH in combination withgrowth hormone releasing peptide 2 given intravenouslycan restore circulating concentrations of thyroid hormoneand TSH pulsatility to a remarkable extent Additionallythis strategy improved overall metabolism includingbone markers and anabolic variables Interpretation ofthese findings as representative of an insuffi cient

hypothalamic drive of pituitary TSH release in protractedcritical illness was supported by a study33 reporting thatdeceased patients with NTIS seemed to have decreasedhypothalamic TRH mRNA expression in theparaventricular nucleus correlating with decreased ante-mortem plasma TSH and T3 concentrations However thestudies undertaken with hypothalamic neuropeptidesconsisted of only small numbers of patients At presentwhether treatment with those neuropeptides offersclinical benefit in terms of morbidity and mortality isunclear In summary no definitive conclusion about theeffectiveness of thyroid hormone treatment in patients inthe ICU with NTIS can yet be made8

Treatment with hypothalamic neuropeptides couldpossibly be harmful The study by Acker and colleagues29




Series

in patients with acute renal failure raised some concern

because of a tendency towards increased mortality aftertreatment with levothyroxine without any beneficialeffect on outcomemdasheg in terms of dialysis need (table)However the reported mortality in the control group ofthis study29 was lower than expected which does notnecessarily justify the interpretation that theintervention was harmful Clearly the reported studieswere not adequately powered to detect clinicallymeaningful differences Finally most of these trialsused rather high doses of either T4 or T3 probablyinducing further suppression of pituitary TSH releaseand altered tissue deiodinase activities Use ofneuropeptides including TRH to stimulate the HPTaxis could be promising in this respect Large RCTs in

well defined patient groups will be needed to investigatepossible positive effects of this approach in terms ofoutcome High priority should be given to RCTscomparing the effect of hypothalamic neuropeptidesincluding TRH with placebo because this approach hasalready been shown to partly normalise concentrationsof serum thyroid hormones and at the same timeimprove metabolic markers10 However these effects

have been shown only in small studies that were not

powered to study clinically relevant outcome measuressuch as mortality or morbidity Another possibility willbe to investigate treatment with recombinant humanTSH because this is a physiological stimulusmdashsimilarto TRHmdashfor thyroid hormone release from the thyroidA pilot study90 showed that once a day low dose (30 microg)TSH treatment in patients with central hypothyroidismwas suffi cient to increase plasma TSH concentrations tothe normal range Furthermore this treatmentimproved patientsrsquo quality of life and sleep behaviour90 Of interest will be to investigate whether this approachcan be used in patients in the ICU with NTIS tonormalise TSH and thyroid hormones and if possiblewhether this approach can improve clinical outcomes

Again these investigations should be done in adequatelypowered randomised placebo-controlled studies

ConclusionsFrom a classic perspective NTIS is a syndrome thatoccurs during various illnesses and is identified bydecreased plasma concentrations of thyroid hormoneswith unclear resulting effects Recent studies have shownthat the changes in thyroid economy during NTISsuggest substantial and complex changes at the level ofthe HPT axis in terms of setpoint regulation and at theorgan level in terms of local metabolism of thyroidhormones (figure 5) Whether the noted changes incritically ill patients are beneficial or harmful in terms ofoutcome probably depends on disease stage and severitythe need for long-term vital support and environmentalfactors (including parenteral nutrition) At present noevidence-based consensus or guideline advocates thyroidhormone treatment of NTIS in patients who are criticallyill Adequately powered RCTs need to be undertaken todefine whether active management of NTISmdasheg withhypothalamic neuropeptides including TRHmdashwill yieldclinical benefit in terms of patient outcome

Contributors

EF AB and LL wrote the manuscript EF AB and ACB revised themanuscript

Declaration of interests

We declare no competing interestsReferences1 Alkemade A Friesema EC Unmehopa UA et al Neuroanatomical

pathways for thyroid hormone feedback in the humanhypothalamus J Clin Endocrinol Metab 2005 90 4322ndash34

2 Fekete C Lechan RM Negative feedback regulation ofhypophysiotropic thyrotropin-releasing hormone (TRH)synthesizing neurons role of neuronal afferents and type 2deiodinase Front Neuroendocrinol 2007 28 97ndash114

3 Boelen A Kwakkel J Fliers E Beyond low plasma T3 local thyroidhormone metabolism during inflammation and infectionEndocr Rev 2011 32 670ndash93

4 Wiersinga WM van den Berghe G Nonthyroidal illness syndromeIn Braverman LE Cooper DS eds Werner amp Ingbarrsquos the thyroida fundamental and clinical text 10th edn Philadelphia LippincottWilliams and Wilkins 2013 203ndash17

5 Wartofsky L Burman KD Alterations in thyroid function in

patients with systemic illness the ldquoeuthyroid sick syndromerdquoEndocr Rev 1982 3 164ndash217

Critical illness Decreased serum TH concentrations

Reduced food intake

Hypothalamic adaptions

Pituitary adaptations

Intrathyroidal changes

Altered tissue TH metabolismresulting in more or less

bioavailability of T3

Figure 983093 Schematic representation of the various changes during critical illness

The scheme is based on both experimental investigations and studies with

people The net result of altered tissue thyroid hormone metabolism could be

beneficial or maladaptive dependent on disease duration and severity

TH=thyroid hormone T3=tri-iodothyronine Solid lines represent a causal

association Dashed lines represent a probable effect

Search strategy and selection criteria

We searched Medline Embase and the Cochrane Central

Register of Controlled Trials for articles published in English

from inception to March 6 2014 with the search terms

ldquocritically ill patientsrdquo ldquointensive carerdquo or ldquosepsisrdquo in

combination with ldquothyroid dysfunctionrdquo ldquoeuthyroid sick

syndromerdquo or ldquothyroid hormonesrdquo References chosen were

selected on the basis of their title




Series

27 Choi YS Kwak YL Kim JC Chun DH Hong SW Shim JKPeri-operative oral triiodothyronine replacement therapy to

prevent postoperative low triiodothyronine state following valvularheart surgery Anaesthesia 2009 64 871ndash77

28 Brent GA Hershman JM Thyroxine therapy in patients withsevere nonthyroidal illnesses and low serum thyroxineconcentration J Clin Endocrinol Metab 1986 63 1ndash8

29 Acker CG Singh AR Flick RP Bernardini J Greenberg AJohnson JP A trial of thyroxine in acute renal failure Kidney Int 2000 57 293ndash98

30 Moruzzi P Doria E Agostoni PG Medium-term effectiveness ofL-thyroxine treatment in idiopathic dilated cardiomyopathyAm J Med 1996 101 461ndash67

31 Goldman S McCarren M Morkin E et al DITPA(35-Diiodothyropropionic Acid) a thyroid hormone analog totreat heart failure phase II trial veterans affairs cooperative studyCirculation 2009 119 3093ndash100

32 Berger MM Reymond MJ Shenkin A et al Effect of seleniumsupplements on the low T3 syndrome after trauma a randomizedtrial Intensive Care Med 1996 22 575ndash81

33 Fliers E Guldenaar SE Wiersinga WM Swaab DF Decreasedhypothalamic thyrotropin-releasing hormone gene expression inpatients with nonthyroidal illness J Clin Endocrinol Metab 199782 4032ndash36

34 Boelen A Kwakkel J Thijssen-Timmer DC Alkemade A Fliers EWiersinga WM Simultaneous changes in central and peripheralcomponents of the hypothalamus-pituitary-thyroid axis inlipopolysaccharide-induced acute illness in mice J Endocrinol 2004182 315ndash23

35 Fekete C Gereben B Doleschall M et al Lipopolysaccharideinduces type 2 iodothyronine deiodinase in the mediobasalhypothalamus implications for the nonthyroidal illness syndromeEndocrinology 2004 145 1649ndash55

36 Lechan RM Fekete C Feedback regulation of thyrotropin-releasinghormone (TRH) mechanisms for the non-thyroidal illnesssyndrome J Endocrinol Invest 2004 27 (suppl) 105ndash19

37 Fliers E Alkemade A Wiersinga WM Swaab DF Hypothalamic

thyroid hormone feedback in health and disease Prog Brain Res 2006 153 189ndash207

38 Freitas BC Gereben B Castillo M et al Paracrine signaling byglial cell-derived triiodothyronine activates neuronal geneexpression in the rodent brain and human cells J Clin Invest 2010120 2206ndash17

39 Sugiyama D Kusuhara H Taniguchi H et al Functionalcharacterization of rat brain-specific organic anion transporter(Oatp14) at the blood-brain barrier high affi nity transporter forthyroxine J Biol Chem 2003 278 43489ndash95

40 Heuer H Maier MK Iden S et al The monocarboxylate transporter8 linked to human psychomotor retardation is highly expressed inthyroid hormone-sensitive neuron populations Endocrinology 2005146 1701ndash06

41 Visser WE Friesema EC Visser TJ Minireview thyroid hormonetransporters the knowns and the unknowns Mol Endocrinol 201125 1ndash14

42 Koumlhrle J The deiodinase family selenoenzymes regulating thyroid

hormone availability and action Cell Mol Life Sci 2000 57 1853ndash6343 Jakobs TC Schmutzler C Meissner J Koumlhrle J The promoter of the

human type I 5 -deiodinase gene--mapping of the transcription startsite and identification of a DR+4 thyroid-hormone-responsiveelement Eur J Biochem 1997 247 288ndash97

44 Toyoda N Zavacki AM Maia AL Harney JW Larsen PR A novelretinoid X receptor-independent thyroid hormone response elementis present in the human type 1 deiodinase gene Mol Cell Biol 199515 5100ndash12

45 Burmeister LA Pachucki J St Germain DL Thyroid hormonesinhibit type 2 iodothyronine deiodinase in the rat cerebral cortex byboth pre- and posttranslational mechanisms Endocrinology 1997138 5231ndash37

46 Sagar GD Gereben B Callebaut I et al Ubiquitination-inducedconformational change within the deiodinase dimer is a switchregulating enzyme activity Mol Cell Biol 2007 27 4774ndash83

47 Gereben B Zeoumlld A Dentice M Salvatore D Bianco AC Activationand inactivation of thyroid hormone by deiodinases local actionwith general consequences Cell Mol Life Sci 2008 65 570ndash90

6 Michalaki M Vagenakis AG Makri M Kalfarentzos FKyriazopoulou V Dissociation of the early decline in serum T(3)

concentration and serum IL-6 rise and TNFalpha in nonthyroidalillness syndrome induced by abdominal surgery J Clin Endocrinol Metab 2001 86 4198ndash205

7 Arem RTJ Deppe SA Comparison of thyroid hormone and cortisolmeasurements with APACHE II and TISS scoring systems aspredictors of mortality in the medical intensive care unit J Intensive Care Med 1997 12 12ndash17

8 Gerdes AM Iervasi G Thyroid replacement therapy and heartfailure Circulation 2010 122 385ndash93

9 Van den Berghe G Non-thyroidal illness in the ICU a syndromewith different faces Thyroid 2014 24 1456ndash65

10 Van den Berghe G Wouters P Weekers F et al Reactivation ofpituitary hormone release and metabolic improvement by infusionof growth hormone-releasing peptide and thyrotropin-releasinghormone in patients with protracted critical illness J Clin Endocrinol Metab 1999 84 1311ndash23

11 Kaptein EM Kaptein JS Chang EI Egodage PM Nicoloff JTMassry SG Thyroxine transfer and distribution in criticalnonthyroidal illnesses chronic renal failure and chronic ethanolabuse J Clin Endocrinol Metab 1987 65 606ndash16

12 Boelen A Wiersinga WM Fliers E Fasting-induced changes in thehypothalamus-pituitary-thyroid axis Thyroid 2008 18 123ndash29

13 Arem R Wiener GJ Kaplan SG Kim HS Reichlin S Kaplan MMReduced tissue thyroid hormone levels in fatal illness Metabolism 1993 42 1102ndash08

14 Bello G Pennisi MA Montini L et al Nonthyroidal illnesssyndrome and prolonged mechanical ventilation in patientsadmitted to the ICU Chest 2009 135 1448ndash54

15 Bettendorf M Schmidt KG Grulich-Henn J Ulmer HEHeinrich UE Tri-iodothyronine treatment in children after cardiacsurgery a double-blind randomised placebo-controlled studyLancet 2000 356 529ndash34

16 Schoumlnberger W Grimm W Emmrich P Gempp W Reduction ofmortality rate in premature infants by substitution of thyroidhormones Eur J Pediatr 1981 135 245ndash53

17 Smith LM Leake RD Berman N Villanueva S Brasel JA Postnatalthyroxine supplementation in infants less than 32 weeksrsquo gestationeffects on pulmonary morbidity J Perinatol 2000 20 427ndash31

18 Zuppa AF Nadkarni V Davis L et al The effect of a thyroid hormoneinfusion on vasopressor support in critically ill children withcessation of neurologic function Crit Care Med 2004 32 2318ndash22

19 Van den Berghe G Wouters P Bowers CY de Zegher F Bouillon RVeldhuis JD Growth hormone-releasing peptide-2 infusionsynchronizes growth hormone thyrotrophin and prolactin release inprolonged critical illness Eur J Endocrinol 1999 140 17ndash22

20 Van den Berghe G de Zegher F Bowers CY et al Pituitaryresponsiveness to GH-releasing hormone GH-releasing peptide-2and thyrotrophin-releasing hormone in critical illnessClin Endocrinol (Oxf) 1996 45 341ndash51

21 Van den Berghe G de Zegher F Baxter RC et al Neuroendocrinologyof prolonged critical illness effects of exogenous thyrotropin-releasing hormone and its combination with growth hormonesecretagogues J Clin Endocrinol Metab 1998 83 309ndash19

22 Van den Berghe G Baxter RC Weekers F et al The combinedadministration of GH-releasing peptide-2 (GHRP-2) TRH andGnRH to men with prolonged critical illness evokes superiorendocrine and metabolic effects compared to treatment withGHRP-2 alone Clin Endocrinol (Oxf) 2002 56 655ndash69

23 Sirlak M Yazicioglu L Inan MB et al Oral thyroid hormonepretreatment in left ventricular dysfunction Eur J Cardiothorac Surg 2004 26 720ndash25

24 Becker RA Vaughan GM Ziegler MG et al Hypermetabolic lowtriiodothyronine syndrome of burn injury Crit Care Med 198210 870ndash75

25 Guumlden M Akpinar B Sagğbaş E Sanisoğlu I Cakali EBayindir O Effects of intravenous triiodothyronine duringcoronary artery bypass surgery Asian Cardiovasc Thorac Ann 200210 219ndash22

26 Choi YS Shim JK Song JW Song Y Yang SY Kwak YL Effi cacy ofperioperative oral triiodothyronine replacement therapy inpatients undergoing off-pump coronary artery bypass grafting J Cardiothorac Vasc Anesth 2013 27 1218ndash23



10 www thelancet comdiabetes-endocrinology Published online June 11 2015 httpdx doi org10 1016S2213-8587(15)00225-9

Series

48 Peeters RP van der Geyten S Wouters PJ et al Tissue thyroidhormone levels in critical illness J Clin Endocrinol Metab 2005

90 6498ndash50749 Peeters RP Wouters PJ Kaptein E van Toor H Visser TJ

Van den Berghe G Reduced activation and increased inactivation ofthyroid hormone in tissues of critically ill patients J Clin Endocrinol Metab 2003 88 3202ndash11

50 Olivares EL Marassi MP Fortunato RS et al Thyroid functiondisturbance and type 3 iodothyronine deiodinase induction aftermyocardial infarction in rats a time course study Endocrinology 2007 148 4786ndash92

51 Huang SA Bianco AC Reawakened interest in type IIIiodothyronine deiodinase in critical illness and injuryNat Clin Pract Endocrinol Metab 2008 4 148ndash55

52 Mooradian AD Reed RL Osterweil D Schiffman R Scuderi PDecreased serum triiodothyronine is associated with increasedconcentrations of tumor necrosis factor J Clin Endocrinol Metab 1990 71 1239ndash42

53 Chopra IJ Sakane S Teco GN A study of the serum concentrationof tumor necrosis factor-alpha in thyroidal and nonthyroidalillnesses J Clin Endocrinol Metab 1991 72 1113ndash16

54 Pang XP Hershman JM Mirell CJ Pekary AE Impairment ofhypothalamic-pituitary-thyroid function in rats treated with humanrecombinant tumor necrosis factor-alpha (cachectin) Endocrinology 1989 125 76ndash84

55 Paringlsson-McDermott EM OrsquoNeill LA Signal transduction by thelipopolysaccharide receptor Toll-like receptor-4 Immunology 2004113 153ndash62

56 de Vries EM Kwakkel J Eggels L et al NFκB signaling is essentialfor the lipopolysaccharide-induced increase of type 2 deiodinase intanycytes Endocrinology 2014 155 2000ndash08

57 Zeoumlld A Doleschall M Haffner MC et al Characterization of thenuclear factor-kappa B responsiveness of the human dio2 geneEndocrinology 2006 147 4419ndash29

58 Kwakkel J Wiersinga WM Boelen A Differential involvement ofnuclear factor-kappaB and activator protein-1 pathways in theinterleukin-1beta-mediated decrease of deiodinase type 1 and thyroid

hormone receptor beta1 mRNA J Endocrinol 2006 189 37ndash4459 Boelen A Kwakkel J Alkemade A et al Induction of type 3

deiodinase activity in inflammatory cells of mice with chronic localinflammation Endocrinology 2005 146 5128ndash34

60 Kwakkel J Surovtseva OV de Vries EM Stap J Fliers E Boelen AA novel role for the thyroid hormone-activating enzyme type 2deiodinase in the inflammatory response of macrophagesEndocrinology 2014 155 2725ndash34

61 Barca-Mayo O Liao XH DiCosmo C et al Role of type 2 deiodinase inresponse to acute lung injury (ALI) in mice Proc Natl Acad Sci USA 2011 108 E1321ndash29

62 Peeters RP Wouters PJ van Toor H Kaptein E Visser TJVan den Berghe G Serum 33 5 -triiodothyronine (rT3) and353 -triiodothyroninerT3 are prognostic markers in critically illpatients and are associated with postmortem tissue deiodinaseactivities J Clin Endocrinol Metab 2005 90 4559ndash65

63 Kwakkel J van Beeren HC Ackermans MT et al Skeletal muscledeiodinase type 2 regulation during illness in mice J Endocrinol

2009 203 263ndash7064 Rodriguez-Perez A Palos-Paz F Kaptein E et al Identification of

molecular mechanisms related to nonthyroidal illness syndrome inskeletal muscle and adipose tissue from patients with septic shockClin Endocrinol (Oxf) 2008 68 821ndash27

65 Vanhorebeek I De Vos R Mesotten D Wouters PJDe Wolf-Peeters C Van den Berghe G Protection of hepatocytemitochondrial ultrastructure and function by strict blood glucosecontrol with insulin in critically ill patients Lancet 2005 365 53ndash59

66 Weitzel JM Iwen KA Coordination of mitochondrial biogenesis bythyroid hormone Mol Cell Endocrinol 2011 342 1ndash7

67 Harper ME Seifert EL Thyroid hormone effects on mitochondrialenergetics Thyroid 2008 18 145ndash56

68 Moreno M de Lange P Lombardi A Silvestri E Lanni A Goglia FMetabolic effects of thyroid hormone derivatives Thyroid 200818 239ndash53

69 Boelen A Boorsma J Kwakkel J et al Type 3 deiodinase is highlyexpressed in infiltrating neutrophilic granulocytes in response to

acute bacterial infection Thyroid 2008 18 1095ndash10370 Boelen A Kwakkel J Wieland CW St Germain DL Fliers E

Hernandez A Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniaeEndocrinology 2009 150 1984ndash90

71 Klebanoff SJ Iodination of bacteria a bactericidal mechanism J Exp Med 1967 126 1063ndash78

72 Schuumltz P Bally M Stanga Z Keller U Loss of appetite in acutely illmedical inpatients physiological response or therapeutic targetSwiss Med Wkly 2014 144 w13957

73 Casaer MP Van den Berghe G Nutrition in the acute phase ofcritical illness N Engl J Med 2014 370 2450ndash51

74 Fekete C Lechan RM Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditionsEndocr Rev 2014 35 159ndash94

75 Galton VA Hernandez A St Germain DL The 5 -deiodinases are notessential for the fasting-induced decrease in circulating thyroid

hormone levels in male mice possible roles for the type 3 deiodinaseand tissue sequestration of hormone Endocrinology 2014 155 3172ndash81

76 Richmand DA Molitch ME OrsquoDonnell TF Altered thyroidhormone levels in bacterial sepsis the role of nutritional adequacyMetabolism 1980 29 936ndash42

77 Chourdakis M Kraus MM Tzellos T et al Effect of early comparedwith delayed enteral nutrition on endocrine function in patientswith traumatic brain injury an open-labeled randomized trial JPEN J Parenter Enteral Nutr 2012 36 108ndash16

78 Ouchi K Matsubara S Matsuno S Effects of supplementaryparenteral nutrition on thyroid hormone patterns in surgicalpatients with liver cirrhosis Nutrition 1991 7 189ndash92

79 Casaer MP Mesotten D Hermans G et al Early versus lateparenteral nutrition in critically ill adults N Engl J Med 2011365 506ndash17

80 Langouche L Vander Perre S Marques M et al Impact of earlynutrient restriction during critical illness on the nonthyroidalillness syndrome and its relation with outcome a randomized

controlled clinical study J Clin Endocrinol Metab 2013 98 1006ndash1381 Vlasselaers D Milants I Desmet L et al Intensive insulin therapy

for patients in paediatric intensive care a prospective randomisedcontrolled study Lancet 2009 373 547ndash56

82 Gielen M Mesotten D Wouters PJ et al Effect of tight glucosecontrol with insulin on the thyroid axis of critically ill childrenand its rel`ation with outcome J Clin Endocr inol Metab 201297 3569ndash76

83 Barrett NA Jones A Whiteley C Yassin S McKenzie CAManagement of long-term hypothyroidism a potential marker ofquality of medicines reconciliation in the intensive care unitInt J Pharm Pract 2012 20 303ndash06

84 Ringel MD Management of hypothyroidism and hyperthyroidismin the intensive care unit Crit Care Clin 2001 17 59ndash74

85 Fliers E Wiersinga WM Myxedema coma Rev Endocr Metab Disord 2003 4 137ndash41

86 Papi G Corsello SM Pontecorvi A Clinical concepts on thyroidemergencies Front Endocrinol (Lausanne) 2014 5 102

87 Angell TE Lechner MG Nguyen CT Salvato VL Nicoloff JTLoPresti JS Clinical features and hospital outcomes in thyroidstorm a retrospective cohort study J Clin Endocrinol Metab 2015100 451ndash59

88 Mishra V Baines M Perry SE et al Effect of seleniumsupplementation on biochemical markers and outcome incritically ill patients Clin Nutr 2007 26 41ndash50

89 Vidart J Wajner SM Leite RS et al N-acetylcysteineadministration prevents nonthyroidal illness syndrome inpatients with acute myocardial infarction a randomized clinicaltrial J Clin Endocrinol Metab 2014 99 4537ndash45

90 Dixit K Iwen A Lehmphul I Hoefig C Koumlhrle J Brabant GTreatment of central hypothyroidism with recombinant humanTSHmdasha pilot study Eur Thyroid J 2013 2 (suppl 1) 75ndash194 P153




Series

a study7 with patients in the ICU the sensitivity and

specificity in predicting mortality were 75 and 80respectively for serum T4 less than 40 nmolL Forcombined low serum T4 and high serum cortisol thesenumbers were even highermdashie 100 and 81Likewise low T3 was shown to be a strong predictor ofmortality in patients with heart disease8

NTIS is present in most if not all critically illpatientsmdashie patients with any life-threatening disorderthat requires support of vital organ function andwithout which death would be imminent9 Thuscritically ill patients who need long-term treatment inthe ICU typically show decreased plasma T3 and T4 concentrations An absent TSH response in this contextpoints to profoundly altered feedback regulation of the

HPT axis10 Although the normal TSH concentration inthe presence of low plasma T3 has been interpreted as

suggesting a euthyroid status this assumption has not

been substantiated by data Common changes inplasma thyroid hormone ranges that can be easilyassessed in the clinical setting are the result of changesin the central regulation of the thyroid axis includingdecreased TSH pulsatility10 Moreover several changestake place in the peripheral components of the thyroidaxis that vary according to the tissue and the severity ofillness11 Peripheral changes include but are not limitedto changes in the concentrations of thyroid hormonebinding proteins and transporters in expression andactivity of thyroid hormone deiodinases and inexpression of thyroid hormone receptors3 Changes inthyroid characteristics that are similar but not identicalto those reported during NTIS occur in response to

fasting in healthy individuals12 NTIS in response tofasting in healthy people is regarded as adaptive and


(endpoints)

Harmful

Children after cardiopulmonary

bypass surgery age range from

2 days to 10middot4 years (n=40)15

Yes Children 2 microgkg IV of T3 given on day 1 after

surgery and 1 microgkg given on day 2

for 12 days

Cardiac function ICU

measures

Yes No


lt37 days of gestation (n=100)16

No Children LT4 (25 microgday) plus T3 (5 microgday)

given orally

Mortality Yes No


lt32 weeks of gestation (n=49)17

Yes Children LT4 10 microgkg (IV) or 20 microgkg

(through nasogastric tube) for

21 days

Chronic lung disease

death CNS damage sepsis

No No

Children lt18 years with

cessation of neurologicalfunction during assessment for

organ recovery (n=171)18

No Children Weight-based LT4 bolus followed

by infusion

Vasopressor score Yes No


(n=14)10

Yes Adults TRH (1 microgkg per h) IV for 5 days

plus GHRP-2 (1 microgkg per h) IV for

5 days

GH and TSH secretion

biochemical anabolism

and catabolism variables

Yes No

Critical illness (n=76)19 Yes Adults GHRP-2 alone or in combination

with TRH and GHRH (each peptide

1 microgkg per h)

Synchrony among GH

TSH and PRL release

Yes No

Critical illness (n=40)20 Yes Adults Combinations of GHRH GHRP-2

(both 1 microgkg) TRH (200 microg) given

as bolus time interval 6 h

Serum GH TSH T3 and T4

concentrations

Yes No


(n=20)21

Yes Adults Combinations of GHRH GHRP-2

and TRH start with bolus (1 microgkg)

followed by 1 microgkg per h (for

two consecutive nights)

Serum hormone

concentrations

Yes No

Protracted critical illness(n=33)22

Yes Adults Combinations of GHRH GHRP-2and TRH (1 microgkg per h of each)

GnRH (0middot1 microgkg per 90 min) for

5 days

Serum hormone andmetabolic marker

concentrations

Yes No

Elective coronary bypass surgery

(n=80)23

Yes Adults T3 (125 microgday) orally (7 days

pre-operative until discharge)

Haemodynamic data

morbidity mortality

Yes (haemodynamic

values)

No (morbidity

mortality)

No

Burn injury (n=36)24 Yes Adults T3 (200 microgday) orally or via

nasogastric tube in four divided

doses until wounds healed

Mortality resting

metabolic rate

No No


(n=60)25

Yes Adults T3 (0middot8 microgkg) IV for 6 h Operative outcome

morbidity mortality

No No


(n=100)26

Yes Adults T3 (20 microg12 h) oral (48 h) Serum T3 haemodynamic

variables morbidity

No No

(Table continues on next page)




Series









(endpoints)

Harmful



(n=50)27





(2 weeks)

Mortality No No


12 h for 48 h

Percentage dialysis

percentage recovery

mortality

No Possibly

(increased

mortality)

Idiopathic dilated




(n=86)31



360 mgday



No Yes










No


(n=40)17




Serum selenium




No No









Series



3






48




Neuron

TRH

TRβ

D2uarr

Tanycyte

Inflammation

Hypothalamus

T4rarrT3uarr

T3

NFκB

D2 promoter











T4

T4 T4

T4

T4

T4

T4

T4

T4

T3

T3

T3

T3

T3

T3

T3

T3

T3

Blood vessel

T3 target gene

TRE

RXR TRD3

D3D2

D2

Nucleus

rT3

rT2

Cell



















Series













Macrophage

Granulocyte

Muscle

Lungs

Liver

Adipose tissue

D3

D2

D2D2

D2

D1

T3









Series








3

to T4






4



D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3


D1 D3














Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series









(endpoints)

Harmful



(n=50)27





(2 weeks)

Mortality No No


12 h for 48 h

Percentage dialysis

percentage recovery

mortality

No Possibly

(increased

mortality)

Idiopathic dilated




(n=86)31



360 mgday



No Yes










No


(n=40)17




Serum selenium




No No









Series



3






48




Neuron

TRH

TRβ

D2uarr

Tanycyte

Inflammation

Hypothalamus

T4rarrT3uarr

T3

NFκB

D2 promoter











T4

T4 T4

T4

T4

T4

T4

T4

T4

T3

T3

T3

T3

T3

T3

T3

T3

T3

Blood vessel

T3 target gene

TRE

RXR TRD3

D3D2

D2

Nucleus

rT3

rT2

Cell



















Series













Macrophage

Granulocyte

Muscle

Lungs

Liver

Adipose tissue

D3

D2

D2D2

D2

D1

T3









Series








3

to T4






4



D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3


D1 D3














Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series



3






48




Neuron

TRH

TRβ

D2uarr

Tanycyte

Inflammation

Hypothalamus

T4rarrT3uarr

T3

NFκB

D2 promoter











T4

T4 T4

T4

T4

T4

T4

T4

T4

T3

T3

T3

T3

T3

T3

T3

T3

T3

Blood vessel

T3 target gene

TRE

RXR TRD3

D3D2

D2

Nucleus

rT3

rT2

Cell



















Series













Macrophage

Granulocyte

Muscle

Lungs

Liver

Adipose tissue

D3

D2

D2D2

D2

D1

T3









Series








3

to T4






4



D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3


D1 D3














Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series













Macrophage

Granulocyte

Muscle

Lungs

Liver

Adipose tissue

D3

D2

D2D2

D2

D1

T3









Series








3

to T4






4



D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3


D1 D3














Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series








3

to T4






4



D1D3

TRH

TSH

T3

T4

rT3

TRH

TSH

T3

T4

rT3


D1 D3














Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series






3



studied

3288

A small RCT

89










Series








Contributors











Reduced food intake























Series


















































Series





















































Series








Contributors











Reduced food intake























Series


















































Series





















































Series


















































Series





















































Series


















































Documents

Tiroides en Critico 2015 Lancet