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SICK EUTHYROID SYNDROME - DR. MUNIRA DILAWER GHEEWALA NORMAL THYROID HORMONE SECRETION T3 – metabolically active hormone – exerts its action via binding to chromatin bound nuclear receptors and regulating gene transcription. Half lives of circulating T4 – 5 to 8 days T3 – 1.3 to 3 days. Both T4 and T3 circulate in serum as bound hormones to several proteins synthesized by the liver Thyroxine Binding Globulin is the predominant transport protein (binds 80% of circulating serum thyroid hormone.) Affinity of T4 is 10 times more than T3. Hence circulating levels of T4 are higher than T3. Other serum binding proteins – transthyretin (15% of T4, but little of T3), prealbumin. 41% of T4 is converted to T3, 38% to rT3, 21% is metabolized by other pathways like conjugation in liver and excretion in bile. 10% of circulating T3 is secreted directly by thyroid while >80% of T3 is from conversion from T4 in peripheral tissues. FREE HORMONE CONCEPT Only the free hormone present in the circulation has any metabolic effect. Under the regulation of pituitary, overall thyroid function is affected when there are any changes in free hormone concentrations. Changes in either the concentrations of binding proteins or the binding affinity of thyroid hormone to the serum-binding proteins, have significant effects on the total serum thyroid hormone levels due to the high degree of binding of T4 and T3 to these proteins. Despite these changes, this does not necessarily translate into thyroid dysfunction. SICK EUTHYROID SYNDROME Severe illness, Caloric deprivation, Physical trauma, Physiological stress may result in, 1. Altered regulation of TSH secretion TSH decreases markedly at 24-48 hrs, then tends to return to normal 2. Peripheral conversion of T3 to rT3 inhibitor of peripheral 5-monodeiodination - cortisol, starvation 3. Protein binding of thyroid hormones There are circulating inhibitors of thyroid hormone binding to TBG's Artefactual decrease in resin uptake of T3 & the FTI is also low 4. FT4 levels are low/normal & plasma t½b ~ 1-5 days 5. Euthyroid state is maintained by increased tissue T3 receptors CHANGES IN CRITICALLY ILL PATIENT These 1. 2. 3. changes occur due to : Alterations in peripheral metabolism of thyroid Alterations in TSH regulation Alterations in binding of thyroid hormone to TBG. PATHOPHYSIOLOGY Cytokines De-iodination. Inhibition of TSH, Type 1 deiodinase, Factors inhibiting binding of T4 to TBG ROLE OF CYTOKINES IN PATHOPHYSIOLOGY OF SICK EUTHYROID DISEASE TNF-α, IL-1, and IL-6 concentrations are increased in systemic illness and are implicated as mediators of endotoxemia-induced shock, fever, and metabolic acidosis. Serum concentrations of these cytokines have shown to be inversely proportional to serum T3 concentrations in children (IL-6 and TNF-α);postoperative patients (IL-6); hospitalized patients, including those with acute myocardial infarction (IL-6) and after bone marrow transplant (IL-6 and TNF-α); and nursing home patients (TNF-α). TNF-α causes an acute decrease in both serum T3 and TSH concentrations and a rise in serum rT3 concentrations. Several components of the thyroid hormone synthesis pathway are down-regulated by cytokines directly on the level of thyrocyte, eventually leading to decreased secretion of T4 and T3. DEIODINATION 1. T YPE 1 DEIODINASE T4 to T3 is by sequential monodeiodination. Removal of outer ring iodine by type 1 iodothyronine 5’ deiodinase (type1 deiodinase, D1). It is the “activating” metabolic pathway. Type 1 deiodinase found abundantly in liver, kidney, and thyroid. Upregulated in hyperthyroidism and downregulated in hypothyroid. Nonthyroidal illness induces a marked decrease in liver type 1 deiodinase mRNA expression and its activity in critically ill patients Peripheral deiodination of T4 to T3 is impaired in critically ill, secondary to decreased activity of type 1 deiodinase enzyme, which deiodinates T4 to T3. 2. T YPE 2 DEIODINASE Type 2 deiodinase enzyme is localized in the endoplasmic reticulum of the cells and deiodinates T4 into biologically active T3. Type 2 deiodinase is the main enzyme involved in the production of tissue T3 and is largely involved in local thyroid hormone metabolism. There is a major role of type 2 deiodinase in the central part of hypothalamic-pituitary-thyroid axis that is altered during illness. 3. T YPE 3 DEIODINASE Type 3 deiodinase is present in the plasma membrane of cells and can be considered as the major thyroid hormone–inactivating enzyme, as it catalyzes innerring deiodination of both T4 and T3, resulting in the production of biologically inactive rT3 and rT2. Removal of the iodine by type 3 deiodinase D3 leads to formation of reverse T3→ “inactivating” pathway. Type 3 deiodinase is expressed in brain, skin, placenta and chorionic membranes. Increased type 3 deiodinase activity is observed in severely ill patients. In acute illness – acute inhibition of D1 resulting in impairment of T4 to T3 conversion. ↓ Acute decrease in T3 production Also there is increased deiodination by D3 resulting in increased levels of rT3. TSH levels are initially normal early in acute illness. They often fall as the illness progresses due to effects of inhibitory factors. INHIBITION OF TSH, T YPE 1 DEIODINASE, FACTORS INHIBITING BINDING OF T4 TO TBG 1. FACTORS THAT DECREASE D1 ACTIVITY Acute and chronic illness Caloric deprivation Malnutrition Glucocorticoids ß- blockers Oral cholecystographic agents (iopanoic acid, sodium ipodate.) Amiodarone Propylthiouracil Fatty acids Fetal/ neonatal period Selenium deficiency Cytokines (IL-1, IL-6). 2. FACTORS THAT ALTER TSH SECRETION Increase Chlorpromazine Cimetidine Domperidone Dopamine antagonists Haloperidol Iodide Lithium Metoclopramide Sulfapyridine Radiographic contrast agents Decrease Acute & chronic illness Adrenergic agonists Caloric restriction Carbamazepine Clofibrate Cyproheptidine Dopamine and dopamine agonist Endogenous depression Glucocorticoids Insulin like growth factor-1 agents Opiates Phenytoin Somatostatin Serotonin Surgical stress 3. FACTORS AFFECTING BINDING TO T4 TO TBG Increase Estrogen Methadone Clofibrate 5-fluorouracil Heroin Tamoxifen Raloxifen Liver disease Porphyria HIV infection inherited Decrease Glucocorticoids Androgen L-asparaginase Salicylates Mefenamic acid Antiseizure medication (phenytoin, tegretol) Furosemide Heparin Inherited Acute illness Non-esterified free fatty STAGES OF SICK THYROID SYNDROME Low T3 state High T4 Low T4 Recovery state SPECIFIC ILLNESSES 1. CALORIC DEFICIENCY: Most, if not all, non-thyroidal illness is associated with decreased caloric intake, catabolism, and/or malnutrition. Caloric deprivation is the most common inhibitory factor of type 1 5′-deiodinase. The decrease in serum T3 levels may possibly be an adaptive response in order to preserve the total body protein stores. Restoring the serum T3 to normal during starvation results in a marked increase in urinary nitrogen excretion. Thus, the inhibition of T4 to T3 conversion in starvation can be viewed as a condition of adaptive hypothyroidism. 2. HIV INFECTION A progressive increase in TBG levels is commonly observed and T4 levels rarely decrease below the normal range. Serum T3 levels remain in the normal range despite progression of the HIV infection and are only mildly decreased in the critically ill AIDS patient, suggesting that these “inappropriately normal” T3 levels play a role in the wasting and weight loss seen in the terminal phases of this disease. In contrast to T4 levels in the sick euthyroid syndrome, it is the decreased serum T3 levels in AIDS patients admitted to the ICU with Pneumocystis carinii infections that correlate with increased mortality. 3. LIVER DISEASES Individuals suffering from acute and chronic hepatocellular dysfunction often have marked elevations in total T4 levels similar to those seen in patients with thyrotoxicosis. T3 levels are also higher than expected with illness and tend to fall late in the course of terminal liver disease. The etiology of these increased thyroid hormone concentrations is the increased discharge of TBG following destruction of hepatocytes. Free hormone measurements remain in the normal range. Low T4 levels are seen in patients with cirrhosis and associated with increased mortality. 4. CARDIAC DISEASES Cardiac contractility, systolic time intervals, and heart rate are all increased in thyrotoxicosis and decreased in hypothyroidism. A significant inverse relationship between free T3 and global oxygen consumption has been demonstrated after coronary artery bypass grafting with and without cardiopulmonary bypass. In contrast to other medical illnesses where serum T4 levels are correlated with prognosis, serum T3 concentrations are a negative prognostic factor in patients with congestive heart failure and with coronary artery disease MANAGEMENT Evaluation Diagnosis Prognosis Treatment EVALUATION Primary 1. 2. 1. 2. tests : Sensitive thyrotropin assay : lower limit of 0.01 to 0.03 mU per L which is 20-30 fold lower than lower limit of normal range – improved sensitivity. Serum T4 assays: free T4 index, free T4, free T3 which represent estimates of the free hormone concentration. Secondary tests: Serum T3 & rT3 assay : done only if thyrotoxicosis is clinically suspected. Serum thyroid autoantibodies: Antibodies to thyroglobulin and thyroid peroxidase Imaging : Functional analysis of thyroid using radioisotope I123 in patients suspected with thyrotoxicosis. Anatomical studies like USG, CT, MRI, Isotopic imaging are rarely used in critically ill patients. DIAGNOSIS Single best test to screen for thyroid dysfunction is either free T4 index or the free T4, realizing subtle changes in thyroid function. Assessment of the TSH & FT4 or free T4 index values in the context of the duration, severity, and stage of illness of the patient will allow the correct diagnosis in most patients. E.g. : a mildly elevated TSH coupled with a low free T4 index or free T4 is more likely to indicate primary hypothyroidism early in an acute illness as opposed to the same values obtained during the recovery phase of the illness. If the diagnosis is still unclear, measurement of thyroid antibodies is helpful as a marker of intrinsic thyroid disease and increases the sensitivity of both the free T4 index or free T4 and the TSH. PROGNOSIS Both serum T4 and serum T3 concentrations have been associated as negative indicators of prognosis when they are low. A direct relationship exists between low serum T4 levels and poor outcomes in critically ill patient. In acutely ill older patients with non-thyroidal illness syndrome, mortality rate was significantly higher, with an inverse relationship between free T3 values and death rate. In patients on mechanical ventilation, patients with low free T3 had higher mortality rate and longer duration of mechanical ventilation and ICU length of stay . In different types of cardiac disease the prognostic value of low T3 is poor, including coronary artery disease and chronic heart failure. TREATMENT General ICU patients : No benefit of L-T4 on general medical patients ,patients with acute renal failure , or renal transplant . No benefit of L-T3 on burn patients. Premature infants : No benefit of L-T4 on developmental indices of premature infants at 26–28 weeks’ gestation. Possible beneficial effect of L-T4 on infants of at 25–26 weeks’ gestation but possible deleterious effects on infants of 27–30 weeks’ gestation . No benefit of L-T3. Meta-analysis shows no significant effects of thyroid hormone treatment of premature infants. Cardiac surgery patients : Small studies suggest improved hemodynamic parameters with L-T3. Large trials show no benefit of L-T3 noted in patients undergoing cardiac bypass. Possible improvement in hemodynamic parameters and hospital stay with L-T3 in children undergoing cardiac surgery. Cardiac donors: Variable results on the effects of LT3 in preserving function of normal hearts in brain-dead cardiac donors prior to transplantation. Possible benefits of L-T3 in improving function of impaired hearts prior to transplant, potentially increasing the pool of organs available for transplantation. Consensus conferences recommend the use of L-T3 as part of the hormonal resuscitation in donors whose cardiac ejection fraction is < 45%. Congestive heart failure : Small uncontrolled study suggested short term L-T4 therapy increased cardiac output and functional capacity and decreased systemic vascular resistance . Improved hemodynamic parameters and neurohumoral profiles with short term intravenous L-T3 infusion, possibly requiring supra physiologic concentrations