DERANGED THYROID HORMONE STATUS IN NON-THYROID ILLNESSES; SICK EUTHYROID SYNDROME
AbstractCritical illness is characterized by multiple andcomplex metabolic, immunological and endocrinealterations1. Abnormalities in thyroid homeostasis alsooccur in variety of non-thyroid illnesses. Changes inthyroid hormone metabolism in critical illnessesappear to reflect a continuum which relates primarilyto the severity of the underlying disorders2,3. Theprevalence of one or more abnormalities of thyroidfunction tests in patients with non thyroidal medicalillnesses has been reported from 40% to 70%4,5. Thecondition is reported in starvation6, sepsis 7, surgery 8,myocardial infarction9, CABG surgery 10, bone marrowtransplantation11, and, in fact, probably any severeillness.Girvent et al12 noted that such changes arehighly prevalent in elderly patients with acute surgicalproblems, and is associated with poor nutrition andhigher sympathetic response. The general hormonalresponse to critical illness involves activation of thepituitary-adrenal axis, inhibition of the pituitarythyroid & pituitary- gonadal axes13. These normalresponses distort standard reference intervals. In caseof the pituitary-thyroid axis, evaluation is furthercomplicated by changes in nutrition and major effectsof medication. Evidence suggests that these patientsmay not really be euthyroid, especially at the tissuelevel14.Based upon the fact that patients with systemicillness are clinically euthyroid, Wartofsky andBunnan15 in 1982 used the term sick euthyroidsyndrome to describe spectrum of thyroidabnormalities associated with non thyroidal illness.Euthyroid Sick Syndrome (ESS) and Non thyroidalillness syndrome (NITS) are terms used alternativelyin the literature16,17.The interpretational difficulty due to NTISleading to mismanagement of co-existing goiter, apathology of sizable incidence in certain geographicaldistribution including Pakistan, is a significantpossibility.Initial data of thyroid function tests fromInstitute of Nuclear Medicine, Oncology andRadiotherapy (INOR), Pakistan is indicative of thisincidence where 51 out of 648 tests on patients withgoiter showed abnormalities of T3, T4, & TSH whichwere un-interpretable18.The most prominent alterations are lowserum triiodothyronine (T3) and elevated reverse T3(rT3), leading to the general term low T3 syndrome.Thyroid-stimulating hormone (TSH), thyroxine (T4),free T4, and free T4 index (FTI) are also affected invariable degrees based on the severity and duration ofthe NTI. As the severity of the NTI increases, bothserum T3 and T4 levels may drop and graduallynormalize as the patient recovers.Serum TSH alterations in euthyroid patientswith non thyroidal illnesses include transientlyreduced or elevated basal TSH values, blunted TSHresponse to TRH, diminished or absent diurnalrhythms of TSH, and altered TSH glycosylation andbioactivity19,20. Slightly decreased serum TSH hasbeen documented in elderly patients20, in healthycentenarians22. Food may also affect TSH secretion23.TSH levels might be considered as a sensitive markerof a lack of thyroid hormone since the concentrationsof TSH sharply increase in primary hypothyroidismeven before serum T4 and T3 fall below the normalreference range (so called sub-clinicalhypothyroidism)24. In NTIS, however, despite thedecrease in serum T3 (and T4 in severe cases), theconcentrations of TSH typically remain within low tonormal range25.Conversely, there is a blunted responseof TSH to thyrotropin-releasing hormone (TRH), andlow TSH levels are associated with poor prognosis26.Taken together, these findings suggest that a majorchange in thyroid hormone set point regulation occursin NTI. Accordingly, prolonged critically ill patientsshow diminished TSH pulsatility, characterized by anabsent nocturnal TSH surge and decreased TSH pulseamplitude27. On occasion, transient TSH elevationoccurs while the patient is still ill. Thepathophysiology of this apparent thyroid glandresistance to TSH is not clear28.Levels of T3 rapidly decrease duringstarvation e.g. post operative period or early in the courseof a critical illness. Low serum total-T3 level has beenrecognized in more than 70% of hospitalized patientswith non-thyroidal illness29. Starvation, and moreprecisely carbohydrate deprivation, appears to rapidlyinhibit deiodination of T4 to T3 by Type 1iodothyronine-deiodinase in the liver, thus inhibitinggeneration of T3, and preventing metabolism ofreverse T3, resulting in low T3 and high reverse T3concentration30. The serum concentration of reverse T3is increased innon-thyroidalillness, except in patients withrenal failure and HIV infection32.Alteration in reverse T3J Ayub Med Coll Abbottabad 2006; 18(4) 2metabolism appear to be disease specific. Both free andtotal reverse T3 levels increase as a result of reducedclearance of reverse T3, however, production rate of rT3remains normal. Reduced metabolic clearance ispredominantly due to decreased activity of the type Iiodothyronine 59-monodeiodinase (5`-MDI) intissues); 5`-MDI de-iodinates T4 to T3 and rT3 to 3,39-diiodothyronine (T2)31. Thus, serum reverse T3levels do not reliably differentiate patients witheuthyroid sick patients, and are not clinically useful32.Increased turnover of T3 and T4 in the hypermetabolic phase of illness may also contribute to lowserum and tissue T3 concentrations2. Total T3, freeT3 levels and T3 daily production rate are decreasedin non-thyroid illness33 while Total T4, free T4 anddaily production rate of T4 is normal in low T3syndrome45.Although the isolated low T3 state usuallyrepresents the mildest form of non-thyroidal illness, themagnitude of the drop in T3 level reflects the severityof illness. A very low serum T3 level has beenassociated with an increased mortality rate in patientswith hepatic cirrhosis, congestive heart failure, andother systemic dis eases35.Serum total T4 levels can be decreased (ie, low T4syndrome) typically inpatients with more chronic andsevere systemic illness36-38. Majority of patients haveserum freeT4 either being normal or slightlydecreased, but occasionally elevated39. This variabilityin free-T4 level reflects both the assay method usedand the underlying illness. As the severity of illness,progresses, there is gradual development of a morecomplex syndrome associated with low T3 and low T4levels that may correlates with the bad prognosis 40. Amarked decrease in serum T4 is associated with a highprobability of death41. Mortality rate in patients withtotal T4 level <3mg/dL was 84%; the mortality rate inpatients with T4 levels between 3 and 5 mg/dL was50%; and for those patients with T4 >5.0 mg/ dL, themortality rate was 15%42,43. Among patients with lowlevels of T4, those with very low T3 levels had theworst survival rate44.High serum total T4 is seen in situationswhere thyroid binding globulin is elevated (acuteintermittent porphyria, chronic hepatitis, and primarybiliary cirrhosis)45. T4 level is elevated, TSH level isnorma l or elevated, and T3 level is normal or high.Heparin, amiodarone and iodinated contrast agentsincrease T4 levels by inhibiting peripheral conversionof T4 to T3. In HIV multiple abnormalities have beendescribed: increased T4 and TBG, decreasedreverseT3, and normal T3 even in the setting of severeillness. Elevated levels of total and free T4 have beenreported in patients with acute psychiatric illness. 46Interpretation of bio-chemical markers ofthyroid disease in patients with goiter presenting withnon-thyroid illness is challenging. As a practicalmatter, the changes in patients with non thyroidalillness must be distinguished from those resultingfrom thyroid disease, which is often rightly suspectedin patients with other illnesses. Clinical evaluation ofthe signs and symptoms of hypothyroidism may beextremely difficult, to discern in a patient in the ICUwho typically has multiple medical problems and maybe receiving medication for sedation. 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