Review Article Abnormalities of Thyroid Hormone Metabolism during Systemic …downloads.hindawi.com/journals/ije/2016/2157583.pdf · 2019-07-30 · in hormone conversion predominate

Review ArticleAbnormalities of Thyroid Hormone Metabolismduring Systemic Illness The Low T3 Syndrome inDifferent Clinical Settings

Arnaldo Moura Neto and Denise Engelbrecht Zantut-Wittmann

Division of Endocrinology Department of Clinical Medicine Faculty of Medical Sciences University of CampinasCampinas SP Brazil

Correspondence should be addressed to Arnaldo Moura Neto arnaldomouranetogmailcom

Received 5 June 2016 Revised 18 August 2016 Accepted 15 September 2016

Academic Editor Giuseppe Damante

Copyright copy 2016 A Moura Neto and D E Zantut-Wittmann This is an open access article distributed under the CreativeCommons Attribution License which permits unrestricted use distribution and reproduction in any medium provided theoriginal work is properly cited

Thyroid hormone abnormalities are common in critically ill patients For over three decades a mild form of these abnormalitieshas been described in patients with several diseases under outpatient careThese alterations in thyroid hormone economy are a partof the nonthyroidal illness and keep an important relationship with prognosis in most cases The main feature of this syndrome isa fall in free triiodothyronine (T3) levels with normal thyrotropin (TSH) Free thyroxin (T4) and reverse T3 levels vary accordingto the underlying disease The importance of recognizing this condition in such patients is evident to physicians practicing in avariety of specialties especially general medicine to avoid misdiagnosing the much more common primary thyroid dysfunctionsand indicating treatments that are often not beneficial This review focuses on the most common chronic diseases already knownto present with alterations in serum thyroid hormone levels A short review of the common pathophysiology of the nonthyroidalillness is followed by the clinical and laboratorial presentation in each condition Finally a clinical case vignette and a brief summaryon the evidence about treatment of the nonthyroidal illness and on the future research topics to be addressed are presented

1 Introduction

The low T3 (triiodothyronine) syndrome also known asthe euthyroid sick syndrome or the nonthyroidal illnesssyndrome (NTIS) was initially described in the 1970s Itrepresents a state of alterations in thyroid hormone (TH)economy classically present in critically ill patients particu-larly those admitted to intensive care units [1] These abnor-malities are by definition not related to intrinsic diseases ofthe hypothalamus-pituitary-thyroid axis but rather representimbalances in thyroid hormone productionmetabolism andaction [2]

The hallmark of this syndrome is a fall in serum T3levels that may be accompanied by a drop in serum thyroxine(T4) levels Serum thyrotropin (TSH) is usually normal butmay be slightly increased or even decreased In the recentdecades the syndrome has also been described in patientswith chronic conditions and under outpatient care [3ndash8]The

importance of recognizing this condition in such patients isevident to physicians practicing in a variety of specialtiesespecially general medicine in order to avoid misdiagnosingthe much more common primary thyroid dysfunctions andindicating treatments that are often not beneficial

2 Laboratorial Presentation

Much information about the pathophysiology and the mainlaboratorial abnormalities of NTIS is derived from animalmodels or patients admitted to the intensive care unit Insuch patients TH abnormalities usually show two distincttemporal phases In the first phase acute modifications inperipheral thyroid hormone metabolism predominate Inthe second phase disturbances of neuroendocrine originpredominate [9]

In patients under ambulatory care the presentation oftencarries components of both phases The fall in T3 levels

Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2016 Article ID 2157583 9 pageshttpdxdoiorg10115520162157583

2 International Journal of Endocrinology

is always present and the diagnosis should be suspectedif low T3 presents concurrently with low or normal TSHThere is often a rise in reverse T3 (rT3) levels as welland the decrease in T3rT3 relationship is considered themost sensitive parameter for diagnosis of NTIS [10] This issomewhat complicated in routine clinical care because rT3is not part of thyroid hormone profiles The value of freeT4 measurements in NTIS is a matter of debate as resultsare strongly influenced by the laboratorial method employed[11] The association between TH and prognosis is conservedamong various noncritical conditions [4 12 13] The mainlaboratorial abnormalities that may be identified in the mostcommon clinical situations associated with NTIS will bediscussed in the appropriate sections below

3 Pathophysiology

In patients with noncritical diseases peripheral abnormalitiesin hormone conversion predominate The abnormalities arebetter reflected by the relations T3rT3 and FT3rT3 cor-roborating the action of peripheral mechanisms favouringdecreased thyroid hormone activation and increased inacti-vation [14 15]

The peripheral metabolism of TH is determined by theaction of the three selenodeiodinases (D1 D2 and D3)that catalyse the interconversion of different iodothyroninesStudies in critically ill patients have shown decreased activityof D1 in liver and skeletal muscle [14] increasedD2 activity inskeletal muscle [16] and increased activity of D3 in patientswith acute myocardial infarction [15] The diminished pro-duction of T3 from T4 resultant of low D1 activity combinedwith increased rT3 production from increased D3 activitygenerates the classical pattern of low T3 and increased rT3while also explainingwhy in some conditions higher T4 levelsmay be found [17]

Additionally abnormal production of thyroid bindingglobulin (TBG) is a potential cause for thyroid hormonealterations in patients with NTIS especially if total T3 orT4 is being measured Usually patients with NTIS have lowTBG levels [18] In some cases such as nephrotic syndromemassive protein loss can be a contributor for this [8] Diseasesthat affect the liver and patients with HIVmay show elevatedTBG levels that wouldmake the interpretation of laboratorialdata more difficult [19 20] The advent of free T3 measure-ment almost eliminated this trouble since even conditionswith high TBG levels show low serum free T3 during NTIS[21] Patients treated with proinflammatory cytokines alsoshow decreased TBG levels which are normalized after druginterruption [22]

Proinflammatory cytokines are often elevated in NTISand have been demonstrated to correlate inversely withthyroid hormone levels in the critically ill [23 24] as well asin patients with chronic diseases [4 17 25]

Furthermore these cytokines are possibly implicated inthe suppression of hypothalamic-pituitary axis often seenin NTIS [25] Production of thyrotropin release hormone(TRH) mRNA is decreased in patients with NTIS but notin those who died of immediate external causes [26] In-creased pituitary activity of D2 has been demonstrated [16]

and may be a contributor for this abnormality [27] More T3produced locally by this enzyme could render the pituitaryeuthyroid even in face of a generalized hypothyroid statewith low circulating levels of T3 [27ndash29] Since most chronicambulatory diseases carry a strong inflammatory componentit is very likely that many (if not all) of these mechanismsare present in these situations The relationship betweenproinflammatory cytokines and thyroid hormone levels hasbeen shown in patients with chronic obstructive pulmonarydiseases and diabetes mellitus [4 17 30]

An important factor that is worth mentioning is thatpatients with chronic systemic diseases are often undertreatment with several drugs that can affect thyroid hormonemetabolism [31] Among examples of situations where sys-temic diseases that affect TH metabolism coexist with theuse of medications that also alter THmetabolism are patientswith heart or liver diseases taking beta-blockers [32 33] thosewith heart failure receiving amiodarone [34] and patientswith psychiatric conditions under treatment with lithiumandor drugs that affect the hepaticmetabolismofTH [31 35]A discussion on this topic is beyond the scope of this reviewbut this caveat should nonetheless be taken into accountwhen interpreting thyroid function tests in patients withchronic conditions

4 Nonthyroidal Illness in DifferentClinical Settings

NTIS has been reported in a variety of situations even whenpatients are well enough to be seen in an outpatient settingIn this section we review the most common conditionsassociated with abnormalities in thyroid hormone levels thatare compatible with a mild or atypical form of NTIS Table 1summarizes the laboratorial abnormalities found in thesesituations

41 Caloric Deprivation Changes in TH levels during pro-longed fasting are linked to twomain factors changes in basalenergy expenditure and leptin levels

During caloric deprivation the fall in serum T3 is be-lieved to be an adaptative response directed to saving energyand protein for enduring an acute stress stimulus [36] Itresults from peripheral inhibition of T4 metabolism anddecreased TSH response to hypothalamic TRH It has beenshown that in a hypocaloric diet a fall in T3 levels occurs witha simultaneous transient increase in free T4 [37] IncreasedrT3 is observed in the first two weeks followed by normaliza-tion thereafter [38] Normalization of rT3 levels occurred inparallel to decreasedT3 concentrations [39 40]The elevationin serum rT3 levels is related to decreased catabolism bydeiodinases and not increased production from T4 [37]The fall in T3 is a result of decreased conversion from T4Decreased ATP availability during fasting could impair T4uptake by the liver as well as peripheral deiodination Totaland free T4 are within normal concentrations [41]

More recent evidence shows that in addition to a de-creased conversion of T4 to T3 during fasting suppression ofthe hypothalamic-pituitary-thyroid axis is seen [40 42 43]

International Journal of Endocrinology 3

Table 1 Summary of thyroid hormone abnormalities found in noncritically ill patients

Total T3 Free T3 Reverse T3 Total T4 Free T4 TSHCaloric deprivation darr darr uarr darr hArr hArr or darrHeart failure darr darr hArr or uarr hArr or darr hArr hArr or darrHIV infection hArr hArr or darr hArr or darr hArr hArr or darr hArr

Renal diseases darr hArr hArr hArr or darr hArr or uarr hArr

Liver diseases hArr or uarr darr hArr or uarr uarr hArr or darr hArr

Pulmonary diseases hArr darr hArr or uarr hArr hArr hArr

Diabetes mellitus darr darr hArr or uarr darr hArr or uarr hArr

Psychiatric illnesses uarr hArr or uarr hArr uarr hArr or uarr uarr

hArr normaluarr increaseddarr decreased

Leptin is an important factor in this regard because itslevels fall in concert with weight loss [44ndash46] Leptin wasshown to stimulate TSH secretion and this finding may helpto explain the increased TSH levels often found in obeseindividuals [45 46] Patients who have a defective leptinreceptor due to genetic mutations show reduced pituitaryhormone secretion with delayed puberty and diminishedTSH secretion [47] Prevention of the starvation-mediatedfall in leptin levels by administration of exogenous leptin cansignificantly blunt the abnormalities found in TH levels inthis situation [45] It appears that in humans as opposed towhat is seen in animalmodels aminimal serum level of leptinis necessary for adequate pituitary function andmaintenanceof leptin above this threshold prevents the fall in thyroidhormone levels as well as other hormonal axes commonlyseen during prolonged fasting [46] On the other hand somerecent animal models of NTIS have shown that intrahepaticD3 activity is increased independently of autonomic nervefunction [48]

42 HIV Infection HIV infection and NTIS are related notonly by the chronic infection status but also by the catabolicstate resulting from the disease itself and its opportunisticinfections [49ndash51] A fall in serum T3 levels is found inup to 20 of patients carrying the virus and 50 of thoseharbouring an opportunistic infection [20 50 52] Someparticularities are distinctive of this group of patients LowerT3 levels concomitant with high TBG levels are often seen inthis population [53] Additionally TBG levels increase as thedisease progresses but patients with poor prognosis usuallyhave unchanged levels [54] Another interesting findingcharacteristic of this population is low rT3 levels [55] Thelow rT3 usually rises to normal levels upon hospitalizationdue to opportunistic infections [52]

There are several pitfalls other than NTIS that can coexistin a patient with HIV infection when analysing the resultsof thyroid function tests such as thyroid infiltration byopportunistic pathogens (eg P jirovecii) weight loss med-ications and immune reconstitution syndrome [20 52] Theprevalence of antithyroid antibodies although low increasesafter treatment and the consequent immune reconstitutionand may be a potential confounder [56] Thyroid function

abnormalities are more frequent in patients under highlyactive antiretroviral therapy (HAART) The most commonabnormality is subclinical hypothyroidism and FT4 is lowerwhen compared to control subjects In one study HAARTand particularly the use of stavudine were associated withsubclinical hypothyroidism [56]

Weight loss is common in HIV patients and one studyfound that the most malnourished patients presented thelowest serumT3 [51] Patients are as a rule clinically euthyroidand abnormalities in thyroid hormone levels are probably areflection of disease severity [57]

43 Heart Diseases Thyroid hormones are important modu-lators of several cardiac functions such as heart rate cardiacoutput systemic vascular resistance and inotropism [58]Abnormalities in thyroid hormone levels are frequently seenin situations of cardiac ischemia and congestive heart failureand after bypass surgery [59ndash61]

In cases of acute myocardial infarction a fall in T3 T4and TSH levels and an increase in rT3 have been reportedThe relation rT3TT3 is proportional to the severity of thecase [62] The total and free forms of T3 are also low aftercardiac arrest caused by ischemia when compared to patientswith noncomplicated myocardial infarction Furthermorepatients who experienced more prolonged cardiac arrestshowed lower TT3 and FT3 levels than those with shorterresuscitation time [62] Additionally thyroid function testsnormalize after two weeks in patients who fully recover[62] Oxidative stress probably plays a major role in thepathophysiology of thyroid hormone abnormalities in acutemyocardial ischemia as a small clinical trial demonstratedthe ability of an anti-inflammatory medication to preventNTIS in this setting [63]

In congestive heart failure the prevalence of NTIS isaround 18 [60] but can be as high as 23 [64] Patientswith higher severity scores usually developmore pronouncedabnormalities in thyroid function tests than those less symp-tomatic Low T3 concentrations were associated with highermortality rates in patients hospitalized for heart failureand serum free T3 concentrations were stronger predictorsof mortality than established risk factors such as LDL-cholesterol age and left ventricular ejection fraction T3


levels correlated with the New York Heart Association clas-sification system [12]

44 Kidney Diseases Thekidney has an important role in themetabolism and excretion of thyroid hormones Therefore itis not surprising that kidney diseases can cause abnormalitiesin thyroid hormone axis [65]

In nephrotic syndrome when proteinuria is greater than3 g24 hours with concomitant hypoalbuminemia hyperc-holesterolemia and oedema serum T3 concentrations arelow Urinary loss of TBG among other proteins could jus-tify such alterations However on patients with nephroticsyndrome but preserved renal function TBG concentrationsare within normal limits falling only when there is impairedrenal function [8] Reverse T3 is typically normal contrastingwith other situations of NTIS when rT3 is often elevated [8]Free T3 and T4 are usually normal and thyroid hormonesupplementation is reserved only for situations of increasedTSH as a consequence of excessive urinary loss of thyroidhormones or if low T4 is present because of the use of highdose corticosteroids for treatment of nephrotic syndrome [8]

In cases of terminal kidney disease the almost completeloss of renal filtration alters the hypothalamic-pituitary-thyroid axis and causes abnormalities in peripheral thyroidhormone metabolism [65] Like other clinical situationswhere NTIS occur a decrease in T4 conversion to T3 withresultant low serum T3 is seen [66] Similarly to what isobserved in congestive heart failure lower serum T3 levelspredictmortality in patients under haemodialysis [13] SerumrT3 levels are oftennormal as in cases of nephrotic syndromeand conversion of T4 to rT3 is unchanged [8 67] Totaland free T4 are usually within reference ranges or mildlydecreased Free T4 can be mildly elevated in situations ofheparin use to avoid blood clotting in the haemodialysismachine [68] Haemodialysis does not correct the thyroidhormone imbalances of kidney failure but this can beachieved with renal transplantation [65 69]

45 Liver Disease Normal hepatic function is essential toadequate metabolism of thyroid hormones The liver is themain organ responsible for conversion of T4 to T3 (by theaction of type 1 deiodinase) synthesis of TBG T4 uptakeand secondary release of T4 and T3 into the circulationAbnormalities in serum thyroid hormones are frequentlyfound in cases of cirrhosis acute hepatitis and chronic liverdisease [21 70 71]

In cases of cirrhosis the most common finding is lowTT3 and FT3 concomitant to elevated rT3The serum relationTT3rT3 is inversely associated with the severity of thedisease [72] Free T4 may be increased while TT4 can bedecreased due to low TBG and albumin synthesis TSH isusually normal or mildly increased but the patients have aeuthyroid clinical presentation [21]

The alterations found in acute hepatitis are different fromother forms of liver disease Elevated TBG is a consequenceof its hepatic release as an acute phase protein Consequent-ly total T3 and T4 are usually elevated while the free formof thyroid hormones remains within normal range A mild

elevation of rT3 can be found while TSH is most often nor-mal [19]

In chronic liver diseases thyroid hormone imbalancesresemble more those of acute hepatitis than the ones foundin liver cirrhosis Examples of studied liver diseases areprimary biliary cirrhosis and autoimmune hepatitis In theseserum TBG levels are high as are TT4 and TT3 Howeverserum FT3 and FT4 are low [73] Difficulties in hormoneassessments occur due to the fact that both conditions have anautoimmune basis and exclusion of autoimmune thyroiditis iswarranted [7] Noteworthily thyroid hormone abnormalitiesfound in these diseases are not associatedwith prognosis [37]

46 Respiratory Diseases Some authors have found evidenceof NTIS in chronic obstructive pulmonary disease Karadaget al [4] in a study involving 83 patients in stable clinicalcondition 20 with acute exacerbations and 30 healthy indi-viduals observed that patients with stable disease had FT3levels 25 lower than healthy volunteers without differencesin TSH or FT4 The fall in FT3 levels was associated withincreases in interleukin 6 and tumour necrosis factor alphaAcute exacerbations lead to further decreases in FT3 levelsand a small decrease in TSH levels all of which returned tobasal levels after clinical stabilisation

During tuberculosis infection one study showed thatT3 levels are low in more than 50 of the patients withno change in TSH T4 or serum TBG levels After a shortperiod of treatment T3 levels were restored to normality andTBG levels rose to supernormal levels when compared to acontrol group taking prophylactic treatment [74] Althoughthis could have been attributed to drug induced hepatitisonly one patient was diagnosed with the condition

47 Diabetes Mellitus Alterations of thyroid hormone axishave been demonstrated in patients with diabetes mellitus(DM) Some authors found decreased serum TT3 and in afew cases TT4 concomitant to increased rT3 and low orinappropriately normal TSH [75] Comparable abnormalitieshave been found in patients with type 1 DM particularly inthe presence of poor glycaemic control as reflected by higherglycated haemoglobin levels [76ndash78] Similar correlationswere found in patients with type 2 DM especially when theglycated haemoglobin was above 12 [75]

An interesting study conducted by Kabadi [3] in pa-tients with recently diagnosed type 2 DM and glycatedhaemoglobin above 108 found elevated rT3 and low T3levels but these abnormalities were fully reversed uponrestoration of good metabolic control

As both type 2 DM and NTIS present a strong inflam-matory pathogenesis it is not surprising that subclinicalinflammation present in obesity and type 2 DM is correlatedwith serum thyroid hormone levels A recent work has shownthat rT3 waist circumference and high-sensitivity C-reactiveprotein were interrelated in patients with type 2 DM [17] Inanother study a subset of patients with type 2 DM serumrT3 was elevated only in those with previous cardiovasculardisease such as angina or strokeThese were also the patientsshowing the greatest increase in hs-CRP levels [30] In both


studies no relation between HbA1c and thyroid hormoneswas found Therefore poor glycaemic control might notbe solely responsible for thyroid hormone abnormalitiesin patients with DM In fact a recent study found thatabnormalities in FT4rT3 and FT3rT3 ratios in patientswith type 1 and type 2 diabetes were linked to higher serumconcentrations of proinflammatory markers associated withNTIS such as IL-6 [79] while HbA1c was related to higherFT4FT3 only in patients with type 1 diabetes The datasuggests that in diabetesmellitus themain pathophysiologicalprocess may be related to abnormal deiodinase activityAbnormalities in type 2 deiodinase have been related to ahigher incidence of type 2 diabetes [80] and increased insulinresistance [81]

48 Psychiatric Illness Abnormalities in thyroid hormoneprofiles are not uncommon in patients with psychiatricillnesses especially if hospitalization is required The maindisorders associated withNTIS in these patients are posttrau-matic stress disorder schizophrenia and major depression[82ndash84] Psychiatric disorders are unique in that they presenthigh T3 andor TSH levels as opposed to the low thyroidhormone and TSH levels found in other acute and chronicdiseases

In posttraumatic stress disorder patients may presentmild increases in serum total T3 levels but FT3 FT4 andTSH are usually normal [82] In those admitted due tosevere psychosis about 1 in 10 will present thyroid functionabnormalities [83] The most common is high T4 and TSHsimulating the profile of patients with TSH-producing pitu-itary tumours or resistance to thyroid hormone Opposite towhat happens in the latter two conditions thyroid hormonesand TSH usually normalize spontaneously in 7 to 10 days inacute psychosis and a conservative approach is recommendedwhen evaluating such patients [85]

Patients with major depression may have TSH and T4concentrations within the normal range although showinghigher levels when compared to matched controls as well aslow TRH-stimulated TSH levels [84] These may be a resultof diminished TRH mRNA expression in the hypothalamus

5 Treatment

Treatment of thyroid hormone abnormalities in patients withNTIS is as controversial as its physiological interpretationFew clinical studies are available to assess thyroid hormonereplacement in this situation and almost all were conductedin critically ill patients

One study assessed the effects of replacement with150mcgday of thyroxine in four doses divided in 2 days inpatients with acute renal failure The only difference encoun-tered was in TSH levels and the treated group showed highermortality [86]

Of particular interest are the studies conducted in patientswith heart diseases subjected to coronary revasculariza-tion which showed increases in cardiac output and lesserneed for vasopressors during recovery but no other effects[87] Patients with advanced heart failure responded to

T3 administration with decreases in serum norepinephrinealdosterone and atrial natriuretic peptide aswell as decreasedheart rate and improved left ventricular function withoutmajor side effects [88] It is noteworthy that treating systemicinflammation can also prevent the abnormalities typical ofNTIS as was demonstrated in a recent study in patients withacute myocardial ischemia [63]

Thyroid hormone replacement in NTIS prevents the TSHelevation that is expected in the recovery phase of the originaldisease [89] Since decreased conversion of T4 to T3 is presentin most cases of NTIS some authors have advocated that iftreatment is warranted it should include T3 or a combinationof T4 and T3 [90]

It is possible that treatment in acute situations wheredecreased T3 is believed to be a proper adaptative responseto stressmay be harmful while thyroid hormone replacementin conditions of chronic low T3 may be beneficial especiallyin patients with heart diseases However it is noteworthy thatthere are no randomized controlled clinical trials assessingthe effects of thyroid hormone supplementation in suchsituations and treatment of these patients is therefore notrecommended

6 Conclusion and Future Perspectives

Thyroid hormone abnormalities characterizing NTIS in dif-ferent clinical setting are complex and have a multifactorialoriginThere is considerable variation in laboratorial presen-tation depending on the original disease As is observed inpatients with acute and more severe diseases the intensityof thyroid hormone imbalances in patients with chronicdiseases represents the severity of the underlying diseaseand keeps an intimate correlation with the prognosis inmost cases Thyroid hormone replacement to such patientsis still largely debatable as most studies were conducted inpatients with acute exacerbations Patients with heart diseasesare most likely to benefit from such treatment but thisshould be confirmed in appropriately powered clinical trialsTreatments targeting other aspects of NTIS such as systemicinflammationmay show benefit in preventing the occurrenceof thyroid hormone abnormalities and also warrant furtherresearch

7 Clinical Case

A male patient 61 years old treated for congestive heartfailure since 2008 due to a myocardial infarction had for thelast 6 months experienced progressive worsening of dyspneaand lower limb oedema despite frequent optimization ofhis medication Laboratorial investigation for his worseningsymptoms revealed a TSH of 43 IUL (RV 05ndash45 IUL)free T4 21 pmolL (RV 10ndash23 pmolL) and free T3 25 pmolL(RV 35ndash65 pmolL) Echocardiography showed a dilatedheart a left ventricle ejection fraction of 28 and moderatepulmonary hypertension He was a smoker for 30 yearsand had quit 10 years before Other relevant comorbiditiesincluded hypertension and hypercholesterolemia His lipidpanel and ambulatory blood pressure profile were within


targets His clinician referred him for evaluation of a possiblehypothyroidism that could be contributing for the deteriora-tion of cardiac function as well as evaluation for treatment

Initial evaluation yielded negative antithyroid antibodiesand a magnetic resonance image of his pituitary revealedno abnormalities The low free T3 concomitant with normalFT4 and TSH was interpreted as a form of NTIS in thispatient and as a marker of poor prognosis given the historyof heart failure and rapid progressing symptoms in the lastmonths Treatment with T3 was considered but as there isno conclusive evidence that treatmentwith thyroid hormonescould improve the condition or even survival it was decidedfor observation and recommended for further investigationinto the cause of cardiac decompensation

Coronary angiography revealed no new obstructions andthe patient had no signs or laboratorial evidence of infectionsEventually a computed tomography revealed a pulmonaryembolism as the cause for his worsening symptoms Thepatient was admitted for initiation of anticoagulant treatmentand showed progressive clinical improvement until discharge7 days later At the end of anticoagulant treatment his dysp-nea was back to previous levels and the echocardiography-estimated right ventricle systolic pressure had improvedA new thyroid function test was ordered and showedTSH 41 IUL FT4 17 pmolL and FT3 31 pmolL Despitethe increase in serum FT3 after treatment of pulmonaryembolism its levels remained below normal values probablydue to the long term irreversible heart failure

Competing Interests

The authors have nothing to disclose

Acknowledgments

This work received funding of FAPESP (Sao Paulo ResearchSupport Foundation Grant no 201303295-1)

References

[1] L Mebis and G van den Berghe ldquoThyroid axis function anddysfunction in critical illnessrdquo Best Practice amp Research ClinicalEndocrinology amp Metabolism vol 25 no 5 pp 745ndash757 2011

[2] A Moura Neto Relation of thyroid hormone abnormalities withsubclinical inflammatory activity in patients with type 1 andtype 2 diabetes mellitus [PhD thesis] Universidade Estadual deCampinas Sao Paulo Brazil 2016

[3] U M Kabadi ldquoImpaired pituitary thyrotroph function in un-controlled type II diabetesmellitus normalization on recoveryrdquoThe Journal of Clinical Endocrinology ampMetabolism vol 59 no3 pp 521ndash525 1984

[4] F Karadag H Ozcan A B Karul M Yilmaz and O CildagldquoCorrelates of non-thyroidal illness syndrome in chronicobstructive pulmonary diseaserdquo Respiratory Medicine vol 101no 7 pp 1439ndash1446 2007

[5] P Vexiau P Perez-Castiglioni G Socie et al ldquoThe lsquoeuthyroidsick syndromersquo incidence risk factors and prognostic valuesoon after allogeneic bone marrow transplantationrdquo BritishJournal of Haematology vol 85 no 4 pp 778ndash782 1993

[6] M O Connell D C Robbins C Bogardus A G Burger andE Danforth Jr ldquoThe interaction of free fatty acids in radioim-munoassays for reverse triiodothyronine Radioimmunoassaysfor Reverse Triiodothyroninerdquo Journal of Clinical Endocrinologyand Metabolism vol 55 no 3 pp 577ndash582 1982

[7] G H Elta R A Sepersky M J Goldberg C M Connors K BMiller andMM Kaplan ldquoIncreased incidence of hypothyroid-ism in primary biliary cirrhosisrdquoDigestiveDiseases and Sciencesvol 28 no 11 pp 971ndash975 1983

[8] L A Gavin F A McMahon J N Castle and R R CavalierildquoAlterations in serum thyroid hormones and thyroxine-bindingglobulin in patients with nephrosisrdquo The Journal of ClinicalEndocrinology amp Metabolism vol 46 no 1 pp 125ndash130 1978

[9] RDocter E P KrenningMDe Jong andGHennemann ldquoThesick euthyroid syndrome changes in thyroid hormone serumparameters and hormone metabolismrdquo Clinical Endocrinologyvol 39 no 5 pp 499ndash518 1993

[10] R P Peeters P J Wouters H Van Toor E Kaptein T JVisser andGVanDenBerghe ldquoSerum33101584051015840-triiodothyronine(rT3) and 3531015840-triiodothyroninerT3 are prognostic markersin critically ill patients and are associated with postmortemtissue deiodinase activitiesrdquo Journal of Clinical Endocrinologyand Metabolism vol 90 no 8 pp 4559ndash4565 2005

[11] M I Surks K H Hupart C Pan and L E Shapiro ldquoNormalfree thyroxine in critical nonthyroidal illnesses measured byultrafiltration of undiluted serum and equilibrium dialysisrdquoTheJournal of Clinical Endocrinology and Metabolism vol 67 no 5pp 1031ndash1039 1988

[12] G Iervasi A Pingitore P Landi et al ldquoLow-T3 syndromea strong prognostic predictor of death in patients with heartdiseaserdquo Circulation vol 107 no 5 pp 708ndash713 2003

[13] C Zoccali F Mallamaci G Tripepi S Cutrupi and P PizzinildquoLow triiodothyronine and survival in end-stage renal diseaserdquoKidney International vol 70 no 3 pp 523ndash528 2006

[14] R P Peeters P J Wouters E Kaptein H van Toor T J Visserand G Van den Berghe ldquoReduced activation and increasedinactivation of thyroid hormone in tissues of critically illpatientsrdquo The Journal of Clinical Endocrinology amp Metabolismvol 88 no 7 pp 3202ndash3211 2003

[15] A Rodriguez-Perez F Palos-Paz E Kaptein et al ldquoIdentifica-tion of molecular mechanisms related to nonthyroidal illnesssyndrome in skeletal muscle and adipose tissue from patientswith septic shockrdquoClinical Endocrinology vol 68 no 5 pp 821ndash827 2008

[16] L Mebis L Langouche T J Visser and G Van Den BergheldquoBrief report the type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illnessrdquoJournal of Clinical Endocrinology and Metabolism vol 92 no 8pp 3330ndash3333 2007

[17] A Moura Neto M C R Parisi M A Tambascia S MAlegre E J Pavin and D E Zantut-Wittmann ldquoThe influenceof body mass index and low-grade systemic inflammationon thyroid hormone abnormalities in patients with type 2diabetesrdquo Endocrine Journal vol 60 no 7 pp 877ndash884 2013

[18] A Boelen J Kwakkel and E Fliers ldquoBeyond low plasma T3local thyroid hormone metabolism during inflammation andinfectionrdquo Endocrine Reviews vol 32 no 5 pp 670ndash693 2011

[19] D F Gardner R L Carithers Jr and R D Utiger ldquoThyroidfunction tests in patients with acute and resolved hepatitis Bvirus infectionrdquo Annals of Internal Medicine vol 96 no 4 pp450ndash452 1982


[20] M Lambert ldquo7 Thyroid dysfunction in HIV infectionrdquo Bail-lierersquos Clinical Endocrinology and Metabolism vol 8 no 4 pp825ndash835 1994

[21] M Borzio R Caldara F Borzio V Piepoli P Rampini andC Ferrari ldquoThyroid function tests in chronic liver disease evi-dence for multiple abnormalities despite clinical euthyroidismrdquoGut vol 24 no 7 pp 631ndash636 1983

[22] R A Feelders A J G Swaak J A Romijn et al ldquoCharacteristicsof recovery from the euthyroid sick syndrome induced by tumornecrosis factor alpha in cancer patientsrdquo Metabolism Clinicaland Experimental vol 48 no 3 pp 324ndash329 1999

[23] A Boelen M C Platvoet-Ter Schiphorst andWMWiersingaldquoAssociation between serum interleukin-6 and serum 353rsquo-triiodothyronine in nonthyroidal illnessrdquo Journal of ClinicalEndocrinology and Metabolism vol 77 no 6 pp 1695ndash16991993

[24] S M Wajner I M Goemann A L Bueno P R Larsenand A L Maia ldquoIL-6 promotes nonthyroidal illness syndromeby blocking thyroxine activation while promoting thyroidhormone inactivation in human cellsrdquo Journal of ClinicalInvestigation vol 121 no 5 pp 1834ndash1845 2011

[25] J T Nicoloff D A Fisher and M D Appleman Jr ldquoThe role ofglucocorticoids in the regulation of thyroid function in manrdquoThe Journal of Clinical Investigation vol 49 no 10 pp 1922ndash1929 1970

[26] E Fliers S E F Guldenaar W M Wiersinga and D F SwaabldquoDecreased hypothalamic thyrotropin-releasing hormone geneexpression in patients with nonthyroidal illnessrdquoThe Journal ofClinical Endocrinology amp Metabolism vol 82 no 12 pp 4032ndash4036 1997

[27] V S Lim C Passo Y Murata E Ferrari H Nakamura andS Refetoff ldquoReduced triiodothyronine content in liver but notpituitary of the uremic rat model demonstration of changescompatible with thyroid hormone deficiency in liver onlyrdquoEndocrinology vol 114 no 1 pp 280ndash286 1984

[28] C Fekete B Gereben M Doleschall et al ldquoLipopolysaccharideinduces type 2 iodothyronine deiodinase in the mediobasalhypothalamus implications for the nonthyroidal illness syn-dromerdquo Endocrinology vol 145 no 4 pp 1649ndash1655 2004

[29] A Zeold M Doleschall M C Haffner et al ldquoCharacterizationof the nuclear factor-120581B responsiveness of the human dio2generdquo Endocrinology vol 147 no 9 pp 4419ndash4429 2006

[30] A Moura Neto M C R Parisi M A Tambascia E J Pavin SM Alegre andD E Zantut-Wittmann ldquoRelationship of thyroidhormone levels and cardiovascular events in patients with type2 diabetesrdquo Endocrine vol 45 no 1 pp 84ndash91 2014

[31] P G Curran and L J DeGroot ldquoThe effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid glandrdquoEndocrine Reviews vol 12 no 2 pp 135ndash150 1991

[32] W M Wiersinga ldquoPropranolol and thyroid hormone metabo-lismrdquoThyroid vol 1 no 3 pp 273ndash277 1991

[33] M Bernardi R De Palma F Trevisani et al ldquorsquoLow T3 syn-dromersquo in cirrhosis effect of 120573-blockaderdquo American Journal ofGastroenterology vol 84 no 7 pp 727ndash731 1989

[34] D D Ascheim and K Hryniewicz ldquoThyroid hormone me-tabolism in patients with congestive heart failure the lowtriiodothyronine staterdquoThyroid vol 12 no 6 pp 511ndash515 2002

[35] M D Hein and I M D Jackson ldquoReview thyroid function inpsychiatric illnessrdquo General Hospital Psychiatry vol 12 no 4pp 232ndash244 1990

[36] D F Gardner M M Kaplan C A Stanley and R D UtigerldquoEffect of tri-iodothyronine replacement on the metabolic andpituitary responses to starvationrdquo The New England Journal ofMedicine vol 300 no 11 pp 579ndash584 1979

[37] LWartofsky andKD Burman ldquoAlterations in thyroid functionin patients with systemic illness the lsquoeuthyroid sick syndromersquordquoEndocrine Reviews vol 3 no 2 pp 164ndash217 1982

[38] S W Spaulding I J Chopra R S Sherwin and S S LyallldquoEffect of caloric restriction and dietary composition on serumT3 and reverse T3 in manrdquoThe Journal of Clinical Endocrinologyamp Metabolism vol 42 no 1 pp 197ndash200 1976

[39] G Hennemann R Docter and E P Krenning ldquoCauses andeffects of the low T3 syndrome during caloric deprivation andnon-thyroidal illness an overviewrdquo Acta Medica Austriaca vol15 no 1 pp 42ndash45 1988

[40] K D Burman R C Smallridge R Osburne et al ldquoNatureof suppressed TSH secretion during undernutrition effect offasting and refeeding on TSH responses to prolonged TRHinfusionsrdquo Metabolism Clinical and Experimental vol 29 no1 pp 46ndash52 1980

[41] A K Suda C S Pittman T Shimizu and J B Chambers JrldquoTheproduction andmetabolismof 3531015840-triiodothyronine and33101584051015840-triiodothyronine in normal and fasting subjectsrdquo TheJournal of Clinical Endocrinology and Metabolism vol 47 no6 pp 1311ndash1319 1978

[42] G C Borst R C Osburne J T OrsquoBrian L P Georges andK D Burman ldquoFasting decreases thyrotropin responsivenessto thyrotropin-releasing hormone a potential cause of misin-terpretation of thyroid function tests in the critically illrdquo TheJournal of Clinical Endocrinology amp Metabolism vol 57 no 2pp 380ndash383 1983

[43] N G Blake D J A Eckland O J F Foster and S LLightman ldquoInhibition of hypothalamic thyrotropin-releasinghormone messenger ribonucleic acid during food deprivationrdquoEndocrinology vol 129 no 5 pp 2714ndash2718 1991

[44] E A Nillni ldquoRegulation of the hypothalamic ThyrotropinReleasing Hormone (TRH) neuron by neuronal and peripheralinputsrdquo Frontiers in Neuroendocrinology vol 31 no 2 pp 134ndash156 2010

[45] G Legradi C H Emerson R S Ahima J S Flier andR M Lechan ldquoLeptin prevents fasting-induced suppressionof prothyrotropin-releasing hormone messenger ribonucleicacid in neurons of the hypothalamic paraventricular nucleusrdquoEndocrinology vol 138 no 6 pp 2569ndash2576 1997

[46] J L Chan K Heist A M DePaoli J D Veldhuis and C SMantzoros ldquoThe role of falling leptin levels in the neuroen-docrine and metabolic adaptation to short-term starvation inhealthy menrdquoThe Journal of Clinical Investigation vol 111 no 9pp 1409ndash1421 2003

[47] K Clement C Vaisse N Lahlou et al ldquoA mutation inthe human leptin receptor gene causes obesity and pituitarydysfunctionrdquo Nature vol 392 no 6674 pp 398ndash401 1998

[48] E M De Vries L Eggels H C Van Beeren et al ldquoFasting-induced changes in hepatic thyroid hormone metabolism inmale rats are independent of autonomic nervous input to theliverrdquo Endocrinology vol 155 no 12 pp 5033ndash5041 2014

[49] G Jain G Devpura and B S Gupta ldquoAbnormalities in thethyroid function tests as surrogate marker of advancing HIVinfection in infected adultsrdquo The Journal of the Association ofPhysicians of India vol 57 no 7 pp 508ndash510 2009


[50] C J Hoffmann and T T Brown ldquoThyroid function abnormal-ities in HIV-infected patientsrdquo Clinical Infectious Diseases vol45 no 4 pp 488ndash494 2007

[51] W Ricarf-Engel J M Fernandez-Real F Gonzalez-Huix MDel Pozo J Mascaro and F Garcıa-Bragado ldquoThe relationbetween thyroid function andnutritional status inHIV-infectedpatientsrdquo Clinical Endocrinology vol 44 no 1 pp 53ndash58 1996

[52] J S LoPresti J C Fried C A Spencer and J T NicoloffldquoUnique alterations of thyroid hormone indices in the acquiredimmunodeficiency syndrome (AIDS)rdquo Annals of InternalMedicine vol 110 no 12 pp 970ndash975 1989

[53] D E Sellmeyer and C Grunfeld ldquoEndocrine and metabolicdisturbances in human immunodeficiency virus infection andthe acquired immune deficiency syndromerdquoEndocrine Reviewsvol 17 no 5 pp 518ndash532 1996

[54] M Lambert F Zech P De Nayer J Jamez and B VandercamldquoElevation of serum thyroxine-binding globulin (but not ofcortisol-binding globulin and sex hormone-binding globulin)associated with the progression of human immunodeficiencyvirus infectionrdquo The American Journal of Medicine vol 89 no6 pp 748ndash751 1990

[55] C Grunfeld M Pang W Doerrler et al ldquoIndices of thy-roid function and weight loss in human immunodeficiencyvirus infection and the acquired immunodeficiency syndromerdquoMetabolism Clinical and Experimental vol 42 no 10 pp 1270ndash1276 1993

[56] G Madeddu A Spanu F Chessa et al ldquoThyroid function inhuman immunodeficiency virus patients treated with highlyactive antiretroviral therapy (HAART) a longitudinal studyrdquoClinical Endocrinology vol 64 no 4 pp 375ndash383 2006

[57] A Olivieri M Sorcini P Battisti et al ldquoThyroid hypofunctionrelated with the progression of human immunodeficiency virusinfectionrdquo Journal of Endocrinological Investigation vol 16 no6 pp 407ndash413 1993

[58] R Polikar A G Burger U Scherrer and P Nicod ldquoThe thyroidand the heartrdquo Circulation vol 87 no 5 pp 1435ndash1441 1993

[59] H N Pavlou P A Kliridis A A Panagiotopoulos C PGoritsas and P J Vassilakos ldquoEuthyroid sick syndrome in acuteischemic syndromesrdquo Angiology vol 53 no 6 pp 699ndash7072002

[60] C Opasich F Pacini N Ambrosino et al ldquoSick euthyroidsyndrome in patients with moderate-to-severe chronic heartfailurerdquo European Heart Journal vol 17 no 12 pp 1860ndash18661996

[61] FWHolland II P S Brown Jr B DWeintraub andR E ClarkldquoCardiopulmonary bypass and thyroid function a lsquoeuthyroidsick syndromersquordquo The Annals of Thoracic Surgery vol 52 no 1pp 46ndash50 1991

[62] K Iltumur G Olmez Z Ariturk T Taskesen and N ToprakldquoClinical investigation thyroid function test abnormalities incardiac arrest associated with acute coronary syndromerdquo Criti-cal Care vol 9 no 4 pp R416ndashR424 2005

[63] J Vidart S M Wajner R S Leite et al ldquoN-acetylcysteineadministration prevents nonthyroidal illness syndrome inpatients with acutemyocardial infarction a randomized clinicaltrialrdquo Journal of Clinical Endocrinology and Metabolism vol 99no 12 pp 4537ndash4545 2014

[64] N R Manowitz G H Mayor M J Klepper and L J DeG-root ldquoSubclinical hypothyroidism and euthyroid sick syndromein patients with moderate-to-severe congestive heart failurerdquoAmerican Journal of Therapeutics vol 3 no 12 pp 797ndash8011996

[65] E M Kaptein ldquoThyroid hormone metabolism and thyroiddiseases in chronic renal failurerdquo Endocrine Reviews vol 17 no1 pp 45ndash63 1996

[66] M R Wiederkehr J Kalogiros and R Krapf ldquoCorrection ofmetabolic acidosis improves thyroid and growth hormone axesin haemodialysis patientsrdquoNephrology Dialysis Transplantationvol 19 no 5 pp 1190ndash1197 2004

[67] P Nicod A Burger V Staeheli and M B Vallotton ldquoAradioimmunoassay for 33101584051015840 triiodo-L-thyronine in unex-tracted serum method and clinical resultsrdquo Journal of ClinicalEndocrinology andMetabolism vol 42 no 5 pp 823ndash829 1976

[68] D S Silverberg R A Ulan D M Fawcett J B Dossetor MGrace and K Bettcher ldquoEffects of chronic hemodialysis onthyroid function in chronic renal failurerdquo Canadian MedicalAssociation Journal vol 109 no 4 pp 282ndash286 1973

[69] K Alsaran A Sabry H Alshahhat E Babgy and F AlzahranildquoFree thyroxine free triiodothyronine and thyroid-stimulatinghormone before and after hemodialysis in Saudi patients withend-stage renal disease is there any differencerdquo Saudi Journalof Kidney Diseases and Transplantation vol 22 no 5 pp 917ndash921 2011

[70] G P Bianchi M Zoli G Marchesini et al ldquoThyroid gland sizeand function in patients with cirrhosis of the liverrdquo Liver vol 11no 2 pp 71ndash77 1991

[71] R Malik and H Hodgson ldquoThe relationship between thethyroid gland and the liverrdquo Quarterly Journal of Medicine vol95 no 9 pp 559ndash569 2002

[72] K Guven F Kelestimur and M Yucesoy ldquoThyroid func-tion tests in non-alcoholic cirrhotic patients with hepaticencephalopathyrdquo The European Journal of Medicine vol 2 no2 pp 83ndash85 1993

[73] G C Schussler F Schaffner and F Korn ldquoIncreased serum thy-roid hormone binding and decreased free hormone in chronicactive liver diseaserdquo The New England Journal of Medicine vol299 no 10 pp 510ndash515 1978

[74] A R Hill M F J Schmidt and G C Schussler ldquoRapid changesin thyroid function tests upon treatment of tuberculosisrdquoTubercle and Lung Disease vol 76 no 3 pp 223ndash229 1995

[75] J L Schlienger A Anceau G Chabrier M L North and FStephan ldquoEffect of diabetic control on the level of circulatingthyroid hormonesrdquo Diabetologia vol 22 no 6 pp 486ndash4881982

[76] G Radetti F Drei F Franzellin B Pasquino and GMengardaldquoThyroid function in type 1 juvenile diabetes mellitus tendencyto the low T3 syndromerdquoHelvetica Paediatrica Acta vol 40 no6 pp 461ndash466 1985

[77] H Dorchy P Bourdoux and B Lemiere ldquoSubclinical thyroidhormone abnormalities in type I diabetic children and ado-lescents Relationship to metabolic controlrdquo Acta PaediatricaScandinavica vol 74 no 3 pp 386ndash389 1985

[78] HTahirovic VDucic andA Smajic ldquoEuthyroid sick syndromein type I diabetes mellitus in children and adolescentsrdquo ActaPaediatrica Hungarica vol 31 no 1 pp 67ndash73 1991

[79] A Moura Neto M C R Parisi S M Alegre E J Pavin MA Tambascia and D E Zantut-Wittmann ldquoRelation of thyroidhormone abnormalities with subclinical inflammatory activityin patients with type 1 and type 2 diabetes mellitusrdquo Endocrinevol 51 no 1 pp 63ndash71 2016

[80] J M Dora W E Machado J Rheinheimer D Crispim andA L Maia ldquoAssociation of the type 2 deiodinase Thr92Alapolymorphism with type 2 diabetes case-control study and


meta-analysisrdquo European Journal of Endocrinology vol 163 no3 pp 427ndash434 2010

[81] A Marsili C Aguayo-Mazzucato T Chen et al ldquoMice with atargeted deletion of the type 2 deiodinase are insulin resistantand susceptible to diet induced obesityrdquo PLoS ONE vol 6 no6 Article ID e20832 2011

[82] D Karlovic S Marusic and M Martinac ldquoIncrease of serumtriiodothyronine concentration in soldiers with combat-relatedchronic post-traumatic stress disorder with or without alcoholdependencerdquoWiener Klinische Wochenschrift vol 116 no 11-12A pp 385ndash390 2004

[83] S NaderMDWarner S Doyle andC A Peabody ldquoEuthyroidsick syndrome in psychiatric inpatientsrdquo Biological Psychiatryvol 40 no 12 pp 1288ndash1293 1996

[84] F Duval M-C Mokrani J A Monreal-Ortiz et al ldquoCortisolhypersecretion in unipolar major depression with melancholicand psychotic features dopaminergic noradrenergic and thy-roid correlatesrdquo Psychoneuroendocrinology vol 31 no 7 pp876ndash888 2006

[85] R Arem and K Cusi ldquoThyroid function testing in psychiatricillness usefulness and limitationsrdquo Trends in Endocrinology andMetabolism vol 8 no 7 pp 282ndash287 1997

[86] C G Acker A R Singh R P Flick J Bernardini A Greenbergand J P Johnson ldquoA trial of thyroxine in acute renal failurerdquoKidney International vol 57 no 1 pp 293ndash298 2000

[87] J D Klemperer I Klein M Gomez et al ldquoThyroid hormonetreatment after coronary-artery bypass surgeryrdquo The New Eng-land Journal of Medicine vol 333 no 23 pp 1522ndash1527 1995

[88] A Pingitore E Galli A Barison et al ldquoAcute effects of triio-dothyronine (T3) replacement therapy in patients with chronicheart failure and low-T3 syndrome A Randomized Placebo-Controlled Studyrdquo The Journal of Clinical Endocrinology andMetabolism vol 93 no 4 pp 1351ndash1358 2008

[89] G A Brent and J M Hershman ldquoThyroxine therapy in patientswith severe nonthyroidal illnesses and low serum thyroxineconcentrationrdquo Journal of Clinical Endocrinology ampMetabolismvol 63 no 1 pp 1ndash8 1986

[90] L J D Groot ldquoNon-thyroidal illness syndrome is a manifesta-tion of hypothalamic-pituitary dysfunction and in view of cur-rent evidence should be treated with appropriate replacementtherapiesrdquo Critical Care Clinics vol 22 no 1 pp 57ndash86 2006

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


is always present and the diagnosis should be suspectedif low T3 presents concurrently with low or normal TSHThere is often a rise in reverse T3 (rT3) levels as welland the decrease in T3rT3 relationship is considered themost sensitive parameter for diagnosis of NTIS [10] This issomewhat complicated in routine clinical care because rT3is not part of thyroid hormone profiles The value of freeT4 measurements in NTIS is a matter of debate as resultsare strongly influenced by the laboratorial method employed[11] The association between TH and prognosis is conservedamong various noncritical conditions [4 12 13] The mainlaboratorial abnormalities that may be identified in the mostcommon clinical situations associated with NTIS will bediscussed in the appropriate sections below

3 Pathophysiology

In patients with noncritical diseases peripheral abnormalitiesin hormone conversion predominate The abnormalities arebetter reflected by the relations T3rT3 and FT3rT3 cor-roborating the action of peripheral mechanisms favouringdecreased thyroid hormone activation and increased inacti-vation [14 15]

The peripheral metabolism of TH is determined by theaction of the three selenodeiodinases (D1 D2 and D3)that catalyse the interconversion of different iodothyroninesStudies in critically ill patients have shown decreased activityof D1 in liver and skeletal muscle [14] increasedD2 activity inskeletal muscle [16] and increased activity of D3 in patientswith acute myocardial infarction [15] The diminished pro-duction of T3 from T4 resultant of low D1 activity combinedwith increased rT3 production from increased D3 activitygenerates the classical pattern of low T3 and increased rT3while also explainingwhy in some conditions higher T4 levelsmay be found [17]

Additionally abnormal production of thyroid bindingglobulin (TBG) is a potential cause for thyroid hormonealterations in patients with NTIS especially if total T3 orT4 is being measured Usually patients with NTIS have lowTBG levels [18] In some cases such as nephrotic syndromemassive protein loss can be a contributor for this [8] Diseasesthat affect the liver and patients with HIVmay show elevatedTBG levels that wouldmake the interpretation of laboratorialdata more difficult [19 20] The advent of free T3 measure-ment almost eliminated this trouble since even conditionswith high TBG levels show low serum free T3 during NTIS[21] Patients treated with proinflammatory cytokines alsoshow decreased TBG levels which are normalized after druginterruption [22]

Proinflammatory cytokines are often elevated in NTISand have been demonstrated to correlate inversely withthyroid hormone levels in the critically ill [23 24] as well asin patients with chronic diseases [4 17 25]

Furthermore these cytokines are possibly implicated inthe suppression of hypothalamic-pituitary axis often seenin NTIS [25] Production of thyrotropin release hormone(TRH) mRNA is decreased in patients with NTIS but notin those who died of immediate external causes [26] In-creased pituitary activity of D2 has been demonstrated [16]

and may be a contributor for this abnormality [27] More T3produced locally by this enzyme could render the pituitaryeuthyroid even in face of a generalized hypothyroid statewith low circulating levels of T3 [27ndash29] Since most chronicambulatory diseases carry a strong inflammatory componentit is very likely that many (if not all) of these mechanismsare present in these situations The relationship betweenproinflammatory cytokines and thyroid hormone levels hasbeen shown in patients with chronic obstructive pulmonarydiseases and diabetes mellitus [4 17 30]

An important factor that is worth mentioning is thatpatients with chronic systemic diseases are often undertreatment with several drugs that can affect thyroid hormonemetabolism [31] Among examples of situations where sys-temic diseases that affect TH metabolism coexist with theuse of medications that also alter THmetabolism are patientswith heart or liver diseases taking beta-blockers [32 33] thosewith heart failure receiving amiodarone [34] and patientswith psychiatric conditions under treatment with lithiumandor drugs that affect the hepaticmetabolismofTH [31 35]A discussion on this topic is beyond the scope of this reviewbut this caveat should nonetheless be taken into accountwhen interpreting thyroid function tests in patients withchronic conditions

4 Nonthyroidal Illness in DifferentClinical Settings

NTIS has been reported in a variety of situations even whenpatients are well enough to be seen in an outpatient settingIn this section we review the most common conditionsassociated with abnormalities in thyroid hormone levels thatare compatible with a mild or atypical form of NTIS Table 1summarizes the laboratorial abnormalities found in thesesituations

41 Caloric Deprivation Changes in TH levels during pro-longed fasting are linked to twomain factors changes in basalenergy expenditure and leptin levels

During caloric deprivation the fall in serum T3 is be-lieved to be an adaptative response directed to saving energyand protein for enduring an acute stress stimulus [36] Itresults from peripheral inhibition of T4 metabolism anddecreased TSH response to hypothalamic TRH It has beenshown that in a hypocaloric diet a fall in T3 levels occurs witha simultaneous transient increase in free T4 [37] IncreasedrT3 is observed in the first two weeks followed by normaliza-tion thereafter [38] Normalization of rT3 levels occurred inparallel to decreasedT3 concentrations [39 40]The elevationin serum rT3 levels is related to decreased catabolism bydeiodinases and not increased production from T4 [37]The fall in T3 is a result of decreased conversion from T4Decreased ATP availability during fasting could impair T4uptake by the liver as well as peripheral deiodination Totaland free T4 are within normal concentrations [41]

More recent evidence shows that in addition to a de-creased conversion of T4 to T3 during fasting suppression ofthe hypothalamic-pituitary-thyroid axis is seen [40 42 43]






































5 Treatment









7 Clinical Case






Competing Interests


Acknowledgments


References




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















































5 Treatment









7 Clinical Case






Competing Interests


Acknowledgments


References




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




































5 Treatment









7 Clinical Case






Competing Interests


Acknowledgments


References




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















5 Treatment









7 Clinical Case






Competing Interests


Acknowledgments


References




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of




















Competing Interests


Acknowledgments


References




































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Abnormalities of Thyroid Hormone Metabolism during Systemic …downloads.hindawi.com/journals/ije/2016/2157583.pdf · 2019-07-30 · in hormone conversion predominate