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 a normal serum TSH response to thyrotropin­releasing hormone (TRH) [36].

Abnormalities in TSH glycosylation that may decrease TSH bioactivity have been found in patients with nonthyroidal illness [37], and also in patients with central hypothyroidism [38].

TRH mRNA in the paraventricular nucleus of the hypothalamus was reduced in patients who died with nonthyroidal illness in one report, and was correlated with premortem serum T3 and TSH concentrations [39].

TRH infusion in patients with critical illness raises serum TSH, T4, and T3 concentrations [40].

Infusion of interferon­alfa to eight normal men caused a fall in serum TSH and T3 concentrations as well as a rise in the serum concentrations of rT3 and interleukin­6, thus mimicking the thyroid metabolic changes of serious illness, except that there was no fall in the serum T4 concentration [13].

SERUM TSH — Serum TSH assays that have a detection limit of 0.01 mU/L should be used in assessing thyroid function in critically ill patients [41]. TSH results should be interpreted as follows:

Low but detectable — Almost all patients who have a subnormal but detectable serum TSH concentration (greater than 0.05 mU/L and less than 0.3 mU/L) will be euthyroid when reassessed after recovery from their illness.

Undetectable — In contrast, approximately 75 percent of patients with undetectable serum TSH concentrations (<0.01 mU/L) have hyperthyroidism. (See "Laboratory assessment of thyroid function".)

High — As noted above, some hospitalized patients have transient elevations in serum TSH concentrations (up to 20 mU/L) during recovery from nonthyroidal illness [41]. Few of these patients prove to have hypothyroidism when reevaluated after recovery from their illness. Patients with serum TSH concentrations over 20 mU/L usually have permanent hypothyroidism [42].

EFFECTS OF DRUGS — Hospitalized patients frequently receive medications that have important effects on thyroid function or on thyroid function tests (table 1). Dopamine, dobutamine, glucocorticoids, furosemide, nonsteroidal anti­inflammatory drugs, heparin, anticonvulsants, metformin, and drugs that affect TBG can alter thyroid function tests. (See "Drug interactions with thyroid hormones" and "Euthyroid hyperthyroxinemia and hypothyroxinemia".)

SPECIFIC NONTHYROIDAL ILLNESSES — Several disease states are associated with abnormal thyroid function tests including acute hepatitis, hepatoma, acute intermittent porphyria, acromegaly, nephrotic syndrome, Cushing's syndrome, acute psychosis, and depression. (See "Euthyroid hyperthyroxinemia and hypothyroxinemia" and "Endocrine dysfunction in the nephrotic syndrome".)

Psychiatric illness — Some patients with acute psychiatric illnesses, particularly schizophrenia, have transient elevations in serum T4 concentrations with or without low serum TSH concentrations [43­45]. Patients with severe http://www.uptodate.com.ucsf.idm.oclc.org/contents/thyroid­function­in­nonthyroidal­illness?topicKey=ENDO%2F7817&elapsedTimeMs=1&source=search_re… 3/8 9/24/2015 Thyroid function in nonthyroidal illness depression may have changes similar to those of patients with glucocorticoid excess. (See "Euthyroid hyperthyroxinemia and hypothyroxinemia".)

PROGNOSIS — The magnitude of the changes in thyroid function in patients with nonthyroidal illness varies with the severity of the illness (figure 1). The serum T4 value correlates with outcome; values under 3 have been associated with mortality rates in excess of 85 percent [46]. Similar findings were reported in a randomized trial of early versus late parenteral nutrition in critically ill ICU patients [47]. Tolerating a nutritional deficit for one week was associated with fewer complications and faster recovery from organ failure. The patients who tolerated the nutritional deficit for one week had lower TSH, T4, T3, and T3/rT3 ratios [48]. Lower T3, but higher T4 was associated with a higher likelihood of early alive ICU discharge. These data suggest that inactivation of T4 to T3 conversion during starvation and illness may be a beneficial adaptation, while very low T4 levels in more critically ill patients are associated with deleterious outcomes [48]. (See "Laboratory assessment of thyroid function", section on 'Laboratory tests used to assess thyroid function'.)

TREATMENT

Thyroid hormone replacement — Thyroid hormone replacement has not been shown to be effective for patients with critical illness and low T3 and/or T4, or for patients undergoing cardiopulmonary bypass. The data on thyroid hormone replacement in experimental and clinical conditions are summarized here.

Thyroid hormone during fasting — During fasting, there is an associated decrease in serum T3 concentrations that spares muscle protein. T3 replacement results in increased catabolism with breakdown of skeletal muscle [49,50].

Critical illness — Thyroid hormone replacement does not appear to be beneficial for critically ill patients with low serum T3 and/or low T4 concentrations. In a randomized trial of burn patients with low free T4 index and free T3 index levels, T3 replacement had no effect on mortality or metabolic rate when compared with placebo [51]. In a second trial, administration of T4 to 23 critically ill patients with low serum T4 concentrations did not alter either mortality or outcome [52].

CABG — During and after cardiopulmonary bypass, there is a transient decrease in serum T3 concentrations, which may contribute to postoperative hemodynamic problems [50]. While animal data and anecdotal clinical experience had suggested that T3 repletion might improve outcomes after cardiopulmonary bypass [53,54], clinical trials have not demonstrated such a benefit [55­57]. In a systematic review of 14 randomized trials evaluating the administration of T3 in euthyroid adult patients in the immediate postoperative period (13 cardiac surgery, one renal transplantation), intravenous (IV) T3 administration increased cardiac index [58]. Mortality was not affected by high­dose IV T3 and could not be assessed for low dose IV or oral T3. In one of the trials included in the meta­ analysis, 142 patients with coronary heart disease undergoing coronary artery bypass surgery (CABG) were randomly assigned to intravenous T3 therapy (0.8 mcg/kg bolus followed by an infusion of 0.113 mcg/kg/hour for six hours) at the completion of surgery or placebo [55]. Although the mean cardiac index was higher and systemic vascular resistance was lower in the T3 group compared with placebo, there were no differences in the incidence of arrhythmia, need for inotropic or vasodilator drugs during the 24 hours after surgery, or in perioperative morbidity and mortality.

In summary, there is no evidence that thyroid hormone replacement is beneficial for patients with critical illness who have low serum T4 or T3 concentrations, or for patients undergoing CABG, whose serum T3 concentrations are known to decrease in the perioperative period. If, however, there is evidence to support a diagnosis of hypothyroidism (such as a TSH over 20 mU/L with low free T4 and/or history, symptoms, and signs of hypothyroidism), cautious administration of thyroid hormone is appropriate.

SUMMARY AND RECOMMENDATIONS

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 thyroxine (T4), free T4, and http://www.uptodate.com.ucsf.idm.oclc.org/contents/thyroid­function­in­nonthyroidal­illness?topicKey=ENDO%2F7817&elapsedTimeMs=1&source=search_re… 4/8 9/24/2015 Thyroid function in nonthyroidal illness triiodothyronine (T3) and their serum thyrotropin (TSH) concentrations may also be low.

When to test

We recommend that thyroid function tests not be measured on seriously ill patients unless there is a strong suspicion of thyroid dysfunction.

What to test

When thyroid dysfunction is suspected in critically ill patients, measurement of serum TSH alone is inadequate for the evaluation of thyroid function. In this case, we suggest measurement of a full thyroid panel including a total T4, a free T4, and a T3. However, the diagnosis may still be in doubt. All methods for assessing free T4 levels are unreliable in severe critical illness; a free T4 by equilibrium dialysis sent to a reference lab would be the least likely to provide spurious results. Some experts argue a total T4 is of similar utility, at considerably less cost.

Treatment

In critically ill patients with low serum T3 and/or low T4 concentrations and no other clinical signs of hypothyroidism, we suggest not treating with thyroid hormone (Grade 2B). (See 'Critical illness' above.)

In previously euthyroid patients undergoing CABG, we recommend not treating with thyroid hormone in the immediate post­operative period (Grade 1A). (See 'CABG' above.)

If there is additional evidence to suggest a diagnosis of hypothyroidism in critically ill patients, we suggest that patients receive thyroid hormone replacement (Grade 2C). In the absence of suspected myxedema coma, repletion should be cautious, beginning with approximately half the expected full replacement dose of levothyroxine. (See "Myxedema coma" and "Treatment of hypothyroidism".)

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Thyroid function tests in nonthyroidal illness

Schematic representation of the changes in thyroid function tests in patients with nonthyroidal illness of increasing severity.

rT3: reverse triiodothyronine; T3: triiodothyronine; T4: thyroxine; TSH: thyroid­stimulating hormone.

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T4 metabolism in nonthyroidal illness

The inhibition of 5'­ monodeiodinase in nonthyroidal illness leads to decreased conversion of T4 to T3 and reduced metabolism of reverse T3.

T2: diiodothyronine; T3: triiodothyronine; T4: thyroxine.

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Drugs that cause hypothyroidism, hyperthyroidism, or changes in thyroid function tests

Drugs causing hypothyroidism

Inhibition of thyroid hormone synthesis and/or release ­ thionamides, lithium, perchlorate, aminoglutethimide, thalidomide, and iodine and iodine­containing drugs including amiodarone, radiographic agents, expectorants (Organidin, Combid), kelp tablets, potassium iodine solutions (SSKI), Betadine douches, topical antiseptics

Decreased absorption of T4 ­ cholestyramine, colestipol, colesevelam, aluminum hydroxide, calcium carbonate, sucralfate, iron sulfate, raloxifene, omeprazole, lansoprazole, and possibly other medications that impair acid secretion, sevelemer, lanthanum carbonate, and chromium; malabsorption syndromes can also diminish T4 absorption

Immune dysregulation ­ interferon­alfa, interleukin­2, ipilimumab, alemtuzumab, pembrolizumab

Suppression of TSH ­ dopamine

Possible destructive thyroiditis ­ sunitinib

Increased type 3 deiodination ­ sorafenib

Increased T4 clearance and suppression of TSH ­ bexarotene

Drugs causing hyperthyroidism

Stimulation of thyroid hormone synthesis and/or release ­ iodine, amiodarone

Immune dysregulation ­ interferon­alfa, interleukin­2, ipilimumab, alemtuzumab, pembrolizumab

Drugs causing abnormal thyroid function tests without thyroid dysfunction

Low serum TBG ­ androgens, danazol, glucocorticoids, slow­release niacin (nicotinic acid), l­ asparaginase

High serum TBG ­ estrogens, tamoxifen, raloxifene, methadone, 5­fluouracil, clofibrate, heroin, mitotane

Decreased T4 binding to TBG ­ salicylates, salsalate, furosemide, heparin (via free fatty acids), certain NSAIDs

Increased T4 clearance ­ phenytoin, carbamazepine, rifampin, phenobarbital

Suppression of TSH secretion ­ dobutamine, glucocorticoids, octreotide

Impaired conversion of T4 to T3 ­ amiodarone, glucocorticoids, contrast agents for oral cholecystography (eg, iopanoic acid), propylthiouracil, propanolol, nadolol

T4: thyroxine; TSH: thyroid­stimulating hormone; TBG: thyroxine­binding globulin; NSAIDs: nonsteroidal anti­inflammatory drugs; T3: triiodothyronine.

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