9/24/2015 Thyroid function in nonthyroidal illness Official reprint from UpToDate® www.uptodate.com ©2015 UpToDate® Thyroid function in nonthyroidal illness Author Section Editor Deputy Editor Douglas S Ross, MD David S Cooper, MD Jean E Mulder, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2015. | This topic last updated: Jul 24, 2013. INTRODUCTION — Assessment of thyroid function in patients with nonthyroidal illness is difficult, especially among those hospitalized in an intensive care unit. Many of them have low serum concentrations of both thyroxine (T4) and triiodothyronine (T3) and their serum thyrotropin (TSH) concentration also may be low. Previously, these patients were thought to be euthyroid, and the term euthyroid­sick syndrome was used to describe the laboratory abnormalities [1]. However, there is some evidence that these patients may have acquired transient central hypothyroidism [1]. Despite these abnormalities, treatment of these patients with thyroid hormone, while controversial, appears to be of little benefit, and may be harmful [2]. It is possible that the changes in thyroid function during severe illness are protective in that they prevent excessive tissue catabolism [2]. This topic will review the changes in thyroid hormone and TSH metabolism that can occur in patients with nonthyroidal illness. The utility of the different tests to assess thyroid function is discussed separately. (See "Laboratory assessment of thyroid function".) There are two important general principles [3]: Thyroid function should not be assessed in seriously ill patients unless there is a strong suspicion of thyroid dysfunction. When thyroid dysfunction is suspected in critically ill patients, measurement of serum TSH alone is inadequate for the evaluation of thyroid function. LOW SERUM T3 — The majority of hospitalized patients have low serum T3 concentrations, as do some outpatients who are ill (figure 1). Unlike T4, which is produced solely within the thyroid, 80 percent of circulating T3 is produced by the peripheral 5'­deiodination of T4 to T3, a reaction catalyzed by 5'­monodeiodinases in organs such as the liver and kidney (figure 2). 5'­monodeiodination decreases whenever caloric intake is low and in any nonthyroidal illness, even mild illness [4]. Liver and skeletal muscle biopsies obtained within minutes after death from intensive care unit patients demonstrate reduced 5'­monodeiodinase activity and increased 5­monodeiodinase activity (which converts T4 to rT3, see below) [5,6]. Patients with fatal illness have low tissue T4 and T3 concentrations [7,8]. Several mechanisms can contribute to the inhibition of 5'­monodeiodination and therefore to the low serum T3 concentrations in patients with nonthyroidal illness. They are: High endogenous serum cortisol concentrations and exogenous glucocorticoid therapy [9]. Circulating inhibitors of deiodinase activity, such as free (non­esterified) fatty acids [10]. Treatment with drugs that inhibit 5'­monodeiodinase activity such as amiodarone and high doses of propranolol. Cytokines (such as tumor necrosis factor, interferon­alfa, NF­kB, and interleukin­6) [11­14]. Serum samples from patients with nonthyroidal illness impair uptake of T4 into cultured rat hepatocytes, thereby reducing the availability of substrate for conversion to T3 [15]. When to measure — The presence of decreased 5'­monodeiodinase activity is often not recognized, because http://www.uptodate.com.ucsf.idm.oclc.org/contents/thyroid­function­in­nonthyroidal­illness?topicKey=ENDO%2F7817&elapsedTimeMs=1&source=search_re… 1/8 9/24/2015 Thyroid function in nonthyroidal illness measurement of serum T3 is rarely utilized as a screening test for thyroid function (nor should it be). It is, however, useful to measure serum T3 in hospitalized patients who have a low serum TSH concentration in whom the differential diagnosis is hyperthyroidism versus nonthyroidal illness (as an example, in a sick patient with paroxysmal atrial fibrillation). The serum T3 value should be high (or high­normal) in hyperthyroidism, but low (or low­normal) in nonthyroidal illness. Rarely, a very sick patient with hyperthyroidism will have a low serum T3 concentration. (See "Diagnosis of hyperthyroidism", section on 'Critically ill patients'.) Reverse T3 — Reverse T3 (rT3) is the product of 5­monodeiodination of T4 (type III T4­5­deiodinase) (figure 2). The clearance of reverse T3 to diiodothyronine (T2) is reduced in nonthyroidal illness because of inhibition of the 5'­monodeiodinase activity [16]. As a result, serum rT3 concentrations are high in patients with nonthyroidal illnesses (figure 1), except in those with renal failure [17,18] and some with AIDS [19,20]. (See "Thyroid hormone synthesis and physiology".) When to measure — Measurement of serum rT3 is occasionally useful in hospitalized patients to distinguish between nonthyroidal illness and central hypothyroidism; the values are low in the latter patients because of low production of the substrate (T4) for rT3. In patients with mild hypothyroidism, however, serum rT3 concentrations may be normal or even slightly high [21], limiting its usefulness. Thyroxine sulfate (T4S) is also elevated in critical nonthyroidal illness and correlates with reduced hepatic 5'­ monodeiodination [7]. LOW SERUM T4 — From 15 to 20 percent of hospitalized patients and up to 50 percent of patients in intensive care units have low serum T4 concentrations (low T4 syndrome) (figure 1). The concentrations are low primarily because of reductions in the serum concentrations of one or more of the three thyroid hormone­binding proteins: thyroxine­binding globulin (TBG), transthyretin (TTR, or thyroxine­binding prealbumin [TBPA]), and albumin. Since TBG is the major binding protein, low serum T4 values are likely the result of decreased production of normal TBG or production of TBG that binds T4 poorly because it is abnormally glycosylated or is cleaved in the circulation [22]. Free T4 — Small reductions in binding proteins should not alter serum free T4 index or direct free T4 values, and these values are usually normal in patients whose illness is not severe. However, when the concentrations of binding proteins are very low, the T3­resin uptake test (and therefore the calculated thyroid hormone­binding ratio) fails to correct for the binding­protein deficiency adequately, and the serum free T4 index is low (figure 1) [23]. The effects of non­thyroidal illness and drugs on "direct" free T4 measurements may be method dependent and result in low values (or occasionally spuriously high values), leading one expert in this field to conclude: "Despite the theoretical attraction of measuring the concentration of free or biologically active hormone, it remains uncertain whether current free T4 methodology is any improvement over an uncontentious measurement of total T4" [24]. The different thyroid function tests are reviewed elsewhere. (See "Laboratory assessment of thyroid function".) An additional problem occurs in patients with more critical illness because some of them have circulating substances that inhibit T4 binding to the binding proteins (see below). The result is a further reduction in serum total T4 concentrations, and frequently low serum free T4 concentrations [25] and low serum free T4 index values. However, the serum free T4 fraction measured by equilibrium dialysis may be normal or even slightly high in these patients [26]. In one study, as an example, none of 25 patients with nonthyroid illness had a low serum concentration of free T4 by equilibrium dialysis [27]. Possible contributing factors for decreased T4 and free T4: inhibitors of T4 binding — Controversy exists as to the cause and importance of inhibitors of T4 binding to its binding proteins in patients with nonthyroidal illness [26]. Some data support the possibility that high serum free fatty acid concentrations inhibit T4 binding to serum proteins [28,29]. Serum free fatty acid, particularly oleic acid concentrations, may be high in critically ill patients [30], and their effect on T4 binding may be increased because of hypoalbuminemia, because albumin is the major carrier of free fatty acids in serum [31]. However, this phenomenon may be an in vitro effect of fatty acids released during collection and transport of the serum sample [32]. Inhibitors may also interfere with the T3­resin uptake test by interacting with the solid matrices used in the test [33]. http://www.uptodate.com.ucsf.idm.oclc.org/contents/thyroid­function­in­nonthyroidal­illness?topicKey=ENDO%2F7817&elapsedTimeMs=1&source=search_re… 2/8 9/24/2015 Thyroid function in nonthyroidal illness Transient central hypothyroidism — Patients with severe nonthyroidal illness may have acquired transient central hypothyroidism [1]. This suggestion is supported by the following observations: A prospective study evaluated changes in thyroid function in patients undergoing bone marrow transplantation: serum TSH concentrations fell coincident with declines in serum T4 concentrations [34]. A study of critically ill patients recovering from nonthyroidal illness demonstrated that a rise in serum TSH concentration (which transiently reached supranormal values in some patients) preceded normalization of serum T4 concentrations [35]. Patients with nonthyroidal illness, similar to those with central hypothyroidism from other causes, have a blunted nocturnal rise in serum TSH concentrations, but usually have