Nonthyroidal Illness Syndrome

Wilmar M. Wiersinga

Greet Van Den Berghe

Changes in the regulation of the hypothalamic–pituitary–thyroid axis and in thyroid hormone transport and metabolism are common in patients with nonthyroidal illness, collectively known as the nonthyroidal illness syndrome (NTIS). Illness in this context comprises virtually all nonthyroidal disorders, surgical and nonsurgical trauma, and inadequate caloric intake. Many patients with nonthyroidal illness also receive drugs that affect thyroid hormone regulation and metabolism, but for the sake of clarity pharmacologic interference is not considered an intrinsic part of NTIS.

The effects of illness are not confined to the thyroid axis; in fact, illness induces changes in many neuroendocrine systems (Fig. 11C.1). The changes in thyroid function are therefore only one component of the neuroendocrine response to illness and can be viewed as part of the general adaptation to stress (1). Whereas the acute stress response is considered beneficial, this is not necessarily true for the response in prolonged critical illness.

NTIS is sometimes referred to as the “sick euthyroid syndrome.” This name is less appropriate because it is unclear if patients are really euthyroid in all target tissues of thyroid hormone. NTIS occurs in humans and animals, and has been reviewed extensively (2,3,4,5,6); NTIS in animals is discussed here only to clarify aspects for which human data are lacking. Although NTIS is heterogeneous, as most evident from particular changes in patients with specific disease entities, the majority of illnesses induce a rather uniform pattern of changes.

Description of Nonthyroidal Illness Syndrome

Changes in Serum Thyroid Hormone and Thyrotropin Concentrations

NTIS in the Acute Phase of Illness

Within hours of the onset of acute stress (such as sepsis, surgery, myocardial infarction, or trauma) serum concentrations of triiodothyronine (T₃) decrease and that of reverse triiodothyronine (rT₃) increase (7,8,9). The fall in T₃ and rise of rT₃ are the most common changes in NTIS, often referred to as the low T₃ syndrome. Few studies describe in detail the very early stages of NTIS. In patients who underwent elective abdominal surgery, a small significant increase of serum thyrotropin (TSH) occurs peaking at 0.5 hours after skin incision and lasting for 2 hours, followed by a transient 20% increase of serum total and free thyroxine (FT₄); a sustained fall in total and free triiodothyronine (FT₃) and rise of rT₃ is observed as of 2 and 6 hours, respectively (10). The data support the sequence of events depicted in Fig. 11C.1.

NTIS in the Chronic Phase of Illness

The low serum T₃/high rT₃ pattern is found in patients with most acute and chronic illnesses, including infectious diseases, infiltrative and metabolic disorders, cardiovascular diseases, pulmonary diseases, gastrointestinal diseases, cancer, burns, and trauma (5,11,12). In general, serum FT₃ falls to a lesser extent than does total T₃. Serum rT₃ increases to supranormal values in patients with mild illness and does not increase much more in patients with more severe illness. In contrast, serum T₃ decreases further as the severity of illness increases (Fig. 11C.2). Serum T₃ concentrations are low or even undetectable in patients with critical illness, and can remain persistently low in patients with chronic illnesses. The severity of the illness is in general reflected by the magnitude of the changes in serum T₃ and rT₃. For example, there is an inverse relationship between serum T₃ and glycosylated hemoglobin values in diabetes mellitus, between serum T₃ and serum creatinine in renal insufficiency, and between serum T₃ and burn severity (13). Similarly, the size of myocardial infarction is inversely related to the fall in serum T₃ and directly related to the rise in serum rT₃ (8).

Figure 11C.1 Simplified concept of the pituitary-dependent changes during the course of critical illness. In the acute phase, anterior pituitary secretion is essentially maintained or amplified, whereas anabolic target hormones are inactivated. Cortisol secretion is elevated in concert with ACTH. In the chronic phase anterior pituitary secretion appears uniformly suppressed in relation to reduced circulating levels of target organ hormones, with cortisol being a notable exception. In the recovery phase, anterior pituitary sensitivity to reduced feedback control is restored. (From Van den Berghe G, de Zegher F, Bouillon R. Acute and prolonged critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 1998;83:1827–1834, with permission.)

Figure 11C.2 Serum thyroid hormone concentrations (filled circle, triiodothyronine (T₃); open circle, reverse T₃ (rT₃); open triangle, thyroxine (T₄); upside down open triangle, free T₄ index; closed triangle, free T₄, measured by equilibrium dialysis) in 504 newly hospitalized patients, divided as follows: Group I, all values within the normal reference range; group II, serum rT₃ values high but serum T₃ and T₄ values normal; group III, serum T₃ values low but serum T₄ values normal; group IV, serum T₃ and T₄ values low. The hospitalization days are given as median days for the survivors. (From Docter R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499–518, with permission.)

Patients with mild to moderate nonthyroidal illnesses usually have normal serum total and free T₄ concentrations. Some severely ill patients have low serum T₄ (Fig. 11C.2), and serum T₄ concentrations are inversely correlated with the mortality rate. There has been uncertainty about serum FT₄ concentrations in NTIS; the results vary depending on the assay method (see Chapter 13A). The issue is complicated by the decrease in serum T₄-binding proteins that may occur in severe nonthyroidal illnesses. Furthermore, the serum of some patients with nonthyroidal illness contains substances that inhibit the binding of T₄ to serum binding proteins (14). On the basis of the most accurate assays, it appears that most patients with nonthyroidal illness have serum FT₄ within the normal reference range (15,16).

Serum TSH is usually normal in NTIS. However, some critically ill patients who have low serum T₄ concentrations also have low serum TSH indicative of a poor prognosis (17), although TSH is rarely as low as in patients with thyrotoxicosis. The serum TSH response to thyrotropin-releasing hormone (TRH) is usually proportional to baseline TSH. Critically ill patients are often treated with dopamine infusions or high doses of glucocorticoids, both of which lower serum TSH. The prevalence of low TSH in NTIS is rather low. In patients admitted to an intensive care unit who underwent invasive mechanical ventilation, low TSH was observed in 7%, low FT₄ in 24%, and low FT₃ in 79% (18).

NTIS in the Recovery Phase of Illness

During recovery of illness a rapid rise of total and free T₄ can be observed, associated with a marked increase in serum TSH. TSH concentrations may rise transiently above the upper normal limit in some patients, but rarely exceed the value of 10 mU/L. The TSH rise consistently precedes the T₄ rise, suggesting an essential role of TSH in the return of T₄ to normal. Normalization of serum T₃ also occurs after the TSH rise (19,20).

Figure 11C.3 Effect of nonthyroidal illness on serum concentrations, metabolic clearance rate (MCR), and production rate (PR) of triiodothyronine (T₃) and reverse T₃ (rT₃; expressed as a percentage of the values in normal subjects). (From Doctor R, Krenning EP, de Jong M, et al. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 1993;39:499–518, with permission.)

NTIS and Nutrition

Fasting induces a fall in serum T₃ and rise in serum rT₃ within 24 to 36 hours, and the values return rapidly to baseline upon refeeding (21,22). The composition of the food is relevant: Refeeding with glucose is more effective in restoring normal values than refeeding with equicaloric amounts of protein or fat (11,23,24). Serum T₄ does not change during fasting in healthy subjects, but decreases in patients with protein-calorie malnutrition (25). Serum TSH falls during fasting. To which extent nutritional deficiencies contribute to NTIS in critically ill patients, is unclear.

Figure 11C.4 Serum TSH concentrations measured at frequent intervals for 24 hours in (top) 8 normal subjects before and after fasting for 60 hours, and (bottom) in 21 patients with nonthyroidal illness and 6 patients with central hypothyroidism caused by a pituitary adenoma. (From Romijn JA, Adriaanse R, Brabant G, et al. Pulsatile secretion of thyrotropin during fasting: a decrease of thyrotropin pulse amplitude. J Clin Endocrinol Metab 1990;70:1631–1636; Adriaanse R, Romijn JA, Brabant G, et al. Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1313–1317, with permission.)

Changes in Thyroid Hormone Kinetics

Kinetic studies of thyroid hormone production and metabolism have been conducted in normal subjects during fasting and in patients with chronic renal failure, cirrhosis, diabetes mellitus, mild illness, and critical illness. The results can be summarized as follows (26). In patients with low serum T₃, the production rate of T₃ is decreased, but its metabolic clearance rate is unchanged. The decrease in T₃ production is due to decreased extrathyroidal deiodination of T₄ to T₃, which normally provides ∼80% of the daily T₃ production (Fig. 11C.3). The fractional rate of transport of T₃ into tissues is unaltered. For rT₃, the production rate is unchanged, but the metabolic clearance rate is decreased, due to decreased extrathyroidal deiodination
of rT₃ to 3,3′-diiodothyronine. For T₄, the metabolic clearance rate is usually normal, but it may be increased in patients with severe illnesses who have low serum T₄, due at least in part to decreased production of one or more serum thyroid hormone–binding proteins. These severely ill patients also tend to have low serum TSH, and may have low T₄ production rates. The fractional rate of transport of T₄ from serum to tissues is reduced to ∼50% of the normal value.

Figure 11C.5 Top: Macroscopic film autoradiograms of hypothalamic sections of two patients, showing the hybridization signal of thyrotropin-releasing hormone (TRH) messenger RNA (mRNA) in the paraventricular nucleus along the wall of the third ventricle. The left panel (A) shows a low-intensity signal of a patient with low serum triiodothyronine (T₃), thyroxine (T₄), and thyrotropin (TSH) concentrations measured <24 hours before death. A high-intensity signal is seen in the right panel (B) of a patient with normal serum concentrations who died from cardiac arrest. Bottom: Relationship between premortem serum TSH or T₃ concentrations and total TRH mRNA in the paraventricular nucleus of 10 patients with nonthyroidal illness. To convert serum T₃ values to ng/dL, multiply by 65.1. (From Fliers E, Guldenaar SEF, Wiersinga WM, et al. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 1997;82:4032–4036, with permission.)

Changes in the Hypothalamic–Pituitary–Thyroid Axis

The failure of serum TSH to increase despite marked reductions in serum T₃ and sometimes T₄, suggests that the sensitivity of TSH secretion to low serum thyroid hormone concentrations is decreased in NTIS. This could be due to changes in the thyrotrophs or due to decreased TRH secretion. Evidence for the latter is a decrease in the amplitude (but not frequency) of the nocturnal pulses of TSH secretion; such decreases in pulse amplitude have been documented during fasting, after surgery, and in a wide variety of nonthyroidal diseases, including chronic renal insufficiency, diabetes mellitus, acute respiratory failure, infections, cancer, and critical illness (27,28). For example, fasting for 60 hours results in disappearance of the nocturnal TSH surge and a 50% reduction in 24-hour mean serum TSH concentrations (Fig. 11C.4). Among patients with nonthyroidal illnesses, the nocturnal TSH surge is decreased in at least half, and the decrease is not closely related to changes in serum T₃ or free T₄ (29). The pattern of 24-hour TSH secretion in these patients is similar to that in central hypothyroidism (Fig. 11C.4). If the abnormal pattern of TSH secretion in NTIS persists for a week or longer, then the T₄ production rate should decrease, as it does in patients with central hypothyroidism.

In a study in deceased patients with nonthyroidal illness, the TRH messenger RNA (mRNA) content in the paraventricular
nucleus was directly correlated with serum TSH and T₃ obtained just before death, but not with serum T₄ or free T₄ (Fig. 11C.5). In another study, the T₃ content of the hypothalamus and anterior pituitary were, respectively, 64% and 46% lower in patients who died as a result of nonthyroidal illness, as compared with patients who died suddenly (30). Furthermore, the TSH that is secreted in patients with nonthyroidal illness is less glycosylated, and therefore less biologically active, than normal, a change that also occurs in patients with overt hypothalamic disease and TRH deficiency (31,32).

Little is known about the function of the thyroid gland itself in NTIS. The increase of serum TSH induced by exogenous TRH or that occurs during recovery from illness is followed by an increase in serum T₃ and T₄, indicating that the thyroid gland can respond normally to TSH. Thyroid weight is lower and thyroid follicular size is reduced in deceased chronically ill patients, as compared with subjects with sudden death (33), possibly related to decreased TSH secretion in severe nonthyroidal illness.

Table 11C.1 Similarities and Dissimilarities between Changes in Intermediary Metabolism and Peripheral Tissue Function Tests during Fasting, Hypothyroidism, and Illness

	Fasting	Hypothyroidism	Illness
Resting energy expenditure	↓	↓	↑
Glucose utilization	↓	↓	↑
Proteolysis	↓	↓	↑
Lipolysis	↑	↓	↑
Fat oxidation	↑	↓	↑
Pulse-wave arrival time (QKd)	↑	↑	=
Achilles tendon reflex half-relaxation time	↑	↑	=
Serum angiotensin–converting enzyme		↓	↓
Serum sex hormone–binding globulin		↓	=
Serum osteocalcin		↓	=
Erythrocyte Na⁺, K⁺-ATPase		↑	↑
↑, Increase; ↓, decrease; =, no change; Na⁺, K⁺-ATPase, sodium, potassium-adenosine triphosphatase; QKd, time interval between Q-wave on electrocardiogram and arrival of pulse wave in brachial artery.

Changes in Peripheral Thyroid Hormone Metabolism

Thyroid hormone is taken up in target tissues via thyroid hormone transporters, notably monocarboxylate transporter 8 (MCT8). Intracellular thyroid hormone is deiodinated via three iodothyronine deiodinases: Type 1 (D1) catalyzes inner- and outer-ring monodeiodination, type 2 (D2) catalyzes only outer-ring deiodination (converting its preferred substrate T₄ into T₃), and type 3 (D3) catalyzes only inner-ring monodeiodination (degrading its preferred substrate T₃ into T₂). Bioavailability of the active hormone T₃ for binding to its nuclear T₃
receptors (TR) is thus regulated to a large extent locally (34), and changes in each of these regulatory pathways have been described in NTIS.

In critically ill patients, increased MCT8 but not MCT10 gene expression is observed in liver and skeletal muscle as compared with patients undergoing acute surgical stress (35). MCT8 mRNA was reduced in subcutaneous adipose tissue of patients with septic shock relative to patients undergoing knee or hip surgery (36); its significance is unknown.

In biopsies taken from intensive-care-unit patients immediately after death, liver D1 activity was decreased; D3 activity in liver and skeletal muscle (not detectable in healthy subjects) was induced, particularly in disease states associated with poor tissue perfusion (37). D1 and D3 mRNA levels corresponded with enzyme activities, suggesting regulation at pretranslational levels. Observed changes in D1 and D3 correlated with a low premortem serum T₃/rT₃ ratio. No changes in D1 and D3 mRNA were found in subcutaneous adipose tissue (36). Upregulation of D2 mRNA and activity occurred in skeletal muscle of prolonged, but not acute, critically ill patients (38), possibly in an attempt to reverse longstanding low T₃ levels.

Changes in iodothyronine deiodination in NTIS also affect the serum concentrations of diiodothyronines: 3,5-T₂ becomes elevated but 3,3′-T₂ remains normal (34). Nondeiodinative pathways of iodothyronine degradation are frequently increased in NTI. Sulfated iodothyronines do not bind to TR, and sulfation mediates the rapid and irreversible degradation of iodothyronines by D1. Serum concentrations of T₄ sulfate (T₄S), T₃S, and T₂S are all increased in NTIS (39,40). Liver D1 in critical illness is strongly negatively correlated to serum T₄S and with the T₄S/T₄ ratio, suggesting low D1 activity is involved in the rise of T₄S. There may be increases in the products of ether-link cleavage, such as diiodotyrosine, and in the products of oxidative deamination of the alanine side chain of T₄ and T₃, which are, respectively, tetraiodothyroacetic acid and triiodothyroacetic acid.

The thyroid hormone content of tissues is decreased in NTIS. The mean T₃ concentrations in the cerebral cortex, liver, kidney, and lung were lower by 46% to 76% in patients who died of nonthyroidal illness, as compared with those who died suddenly, but the values in heart and skeletal muscle were similar (30). The mean T₄ concentration in the liver was 66% lower in the patients with nonthyroidal illness, but the values in the cerebral cortex were similar in the two groups. Tissue T₄, T₃, and rT₃ levels in liver and skeletal muscle of critically ill patients are positively correlated with their respective serum levels. Whereas MCT8 expression was not related to the ratio of serum over tissue concentration, tissue rT₃ and T₃/rT₃ ratio were correlated with tissue D1 and D3 activities (41).

There are few data on nuclear thyroid hormone receptors (TR) in NTIS. In liver biopsies from critically ill patients who died in the intensive care unit, the ratio of TRα1/TRα2 mRNA was higher in patients with more severe disease, due to a relative increase of TRα1 mRNA (42). A lower TRβ1 mRNA was found in skeletal muscle and subcutaneous adipose tissue of patients with septic shock in comparison with patients undergoing elective surgery (36). TR expression at the protein level was similar in normal livers and livers from patients with hepatic disease (43).

Figure 11C.6 A schematic diagram of the nonthyroidal illness syndrome (NTIS): Changes and their postulated cause in the hypothalamus–pituitary–thyroid axis and in peripheral thyroid hormone metabolism (for explanation, see text). D1, D2, D3, iodothyronine deiodinase type 1, type 2, and type 3 respectively; GSH, glutathione; IS, indoxyl sulfate; MCR, metabolic clearance rate; NEFA, non-esterified fatty acids; PR, production rate; Se, selenium; TR, thyroid hormone receptor; T₃S, triiodothyronine sulfate; T₄S, thyroxine sulfate.

Most, if not all of the described changes would seem to indicate that nonthyroidal illness leads to reduction in the production of T₃ and to lower bioavailability of T₃ in tissues. This raises the important but still incompletely answered question of what the level of thyroid hormone action is in the tissues of patients with nonthyroidal illness. During fasting, oxygen consumption and protein breakdown decrease, so that energy is saved and organ function may be preserved. The lower T₃ production rate during fasting might contribute to this useful metabolic adaptation; similar changes occur in hypothyroidism. Prolongation of the Achilles tendon reflex relaxation time in patients with anorexia nervosa, and of the pulse-wave arrival time during hypocaloric feeding are compatible with a hypothyroid-like state in undernutrition (Table 11C.1). In contrast, the illness-induced changes in glucose, protein, and fat metabolism are opposite to those that occur in hypothyroidism. Whether the occurrence of the low T₃ syndrome in protracted critical illness can still be viewed as a beneficial adaptation to illness, remains doubtful.

Pathogenesis of Nonthyroidal Illness Syndrome

It has become clear that NTIS is a rather heterogeneous entity. The expression and pathophysiology of NTIS differs between starvation and illness, between acute and chronic stages of illness, and between mild and more severe illness (Fig. 11C.6). Animal models of NTIS have helped enormously to better understand the various pathophysiological mechanisms (for recent reviews see 44 and 45). Although animal models may not always reflect accurately what happens in humans, similarities in pathophysiology between animal and human NTIS are striking. Changes in the hypothalamic–pituitary–thyroid (HPT) axis and in peripheral thyroid hormone metabolism develop independent of each other (46). It follows that the factors mediating the various changes are operative simultaneously both centrally and peripherally.

Pathogenesis of Changes in the Hypothalamic–Pituitary–Thyroid Axis

Hypothalamic TRH and pituitary TSH secretion are under negative feedback control of serum thyroid hormones. The absence of a rise in serum TSH despite low serum T₃ and T₄ concentrations as observed in NTIS thus indicates an altered setpoint of the HPT axis. This is further suggested by the smaller than normal increase in serum TSH in response to small decreases in serum FT₄ and FT₃ induced by administration of inorganic iodide that occurs in patients with nonthyroidal illness (47).

Hypophysiotropic TRH neurons in the paraventricular nucleus (PVN) of the hypothalamus are one of the main determinants of the setpoint of the HPT axis (48). These neurons express MCT8, D3 (but not D2), and TR. The thyroid hormone transporters OATP1C1 (organic anion transporting polypeptide 1C1) and D2 are prominently expressed in astrocytes of
the median eminence and the infundibular nucleus (the human homologue of the arcuate nucleus in rodents, located outside the blood–brain barrier). They are also expressed in tanycytes that line the inferolateral borders and floor of the third ventricle. These cells are at the interface of the cerebrospinal fluid and the vascular system through long cytoplasmic projections that contact portal vessels and envelop hypothalamic blood vessels (49,50). It is thought that the prohormone T₄ is taken up in these glial cells and converted via D2 into T₃; T₃ is then transported to TRH neurons in the PVN where it may bind to TR (thereby decreasing TRH) or may be degraded via D3 into T2 (thereby increasing TRH). Glial cell–derived T₃ indeed is capable of activating neuronal gene expression by paracrine signaling (51).

TRH secreting neurons in the PVN are also innervated by two anatomically distinct and functionally antagonistic populations of neurons from the arcuate nucleus: α-melanocyte-stimulating hormone (α-MSH) producing neurons that co-express cocaine and amphetamine-regulated transcript (CART), and neuropeptide Y (NPY) producing neurons that co-express agouti-related protein (AgRP). α-MSH stimulates but NPY and AgRP inhibit firing activity of TRH neurons in the PVN through a postsynaptic mechanism (52).

Hypophysiotropic TRH neurons project to the median eminence where mature TRH peptide is released into the portal capillary system and then binds to TRH receptors in pituitary thyrotrophs, influencing TSH production. Thyrotrophs are capable to further modulation of TSH secretion by converting T₄ into T₃ via D2.

Changes in HPT-axis During Fasting

The adipocyte-derived hormone leptin has been recognized as an important mediator of neuroendocrine changes during illness. Leptin communicates information about long-term energy stores. In starved animals, the fall in serum leptin is associated with a decrease of TRH mRNA in the PVN, and administration of leptin reverses the decrease in TRH mRNA (53). These effects are mediated via the arcuate nucleus, because ablation of the arcuate nucleus prevents the decrease in hypothalamic TRH and serum T₄ during fasting and prevents the reversal of these changes by leptin (54). D2 activity in the mediobasal hypothalamus is upregulated during fasting, dependent on glucocorticoid levels: The D2 increase is prevented in adrenalectomized animals, and restored by glucocorticoid replacement but not by leptin or thyroid hormone administration (55). The release of T₃ from tanycytes during fasting upregulates uncoupling protein 2 in arcuate nucleus neurons, leading to regulation of NPY (56). Leptin receptors are expressed on both αMSH/CART and NPY/AgRP neurons in the arcuate nucleus. It is thought that leptin prevents the inhibitory effect of NPY/AgRP but enhances the stimulatory effect of α-MSH on TRH gene expression in the PVN (57,58). Leptin also directly increases firing activity of TRH neurons in the PVN (52). The low leptin levels in starvation thus indirectly and directly may reduce TRH secretion by the PVN, altering the setpoint of the HPT-axis and explaining the fall in serum TSH.

In humans, however, administration of leptin only partially prevents the starvation-induced decrease in serum TSH, and does not prevent the fall in serum T₃ and rise in rT₃ (59). In subjects with low serum leptin (as in hypothalamic amenorrhea or weight-reduced state), leptin therapy is able to elevate FT₄ and FT₃ to pre-weight-loss levels (60,61).

Changes in HPT-axis During Illness

In animal models of NTIS, acute illness induced by bacterial lipopolysaccharide (62), chronic illness induced by turpentine injection in the hind limb (63), and prolonged critical illness due to burn injury (64) are all associated with an increased D2 activity in the mediobasal hypothalamus (notably in tanycytes), whereas D3 expression is decreased in the PVN (63,65). Together, these local changes in D2 and D3 (which occur independent of the fall in circulating thyroid hormones), will increase T₃ content of TRH neurons in the PVN, explaining the observed decrease in TRH mRNA and in serum TSH. The explanation is in good agreement with human data showing a direct relationship between TRH mRNA in the PVN and serum TSH (Fig. 11C.5). The low or normal hypothalamic T₃ content measured in humans (30) and animals (64) does not necessarily contradict this explanation as the PVN was not harvested selectively.

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