Low Triiodothyronine: A New Facet of Inflammation in End-Stage Renal Disease

Materials and Methods

The protocol conformed to the ethical guidelines of our institution, and informed consent was obtained from each participant. The steady-state relationship between thyroid hormones and inflammation was investigated in a survey in 200 hemodialysis patients with ESRD (105 men and 95 women, aged 61 ± 15 yr). These patients were being treated in two dialysis centers that shared the same practice pattern. To be included in the study, patients had to be free of intercurrent illnesses (infectious diseases, cardiocirculatory congestion, cancer, and any other disease requiring hospitalization) and off drugs that may affect the plasma concentration of thyroid hormones. Eighteen patients were excluded from the study because they were taking β-blockers. No patient was taking lithium, amiodarone, or other drugs that may interfere with thyroid function.

Patients were being treated thrice weekly with standard bicarbonate dialysis (138 mmol/L Na, 35 mmol/L HCO₃, 1.5 mmol/L K, 1.25 mmol/L Ca, and 0.75 mmol/L Mg) by cuprophane or semisynthetic membranes (dialysis filters surface area 1.1 to 1.7 m²). Dry weight was targeted in each case to achieve a normotensive edema-free state. The average urea Kt/V in these patients was 1.20 ± 0.26. Seventy-one patients were habitual smokers (22 ± 16 cigarettes/d). A total of 107 patients were on treatment with erythropoietin. Sixty patients were on antihypertensive treatment (48 on monotherapy with angiotensin-converting inhibitors, AT1 antagonists, or calcium channel blockers and 12 on double or triple therapy with various combinations of these drugs).

We formed two control groups: One composed of 31 healthy individuals (recruited from the clinical and laboratory staff and from a series of healthy senior members of an association that supports our institution) who were matched accurately (by 5-yr categories) to patients for gender and age (15 men, 16 women, average age 61 yr). Furthermore, for fT3 measurement only, we formed an additional control group that comprised 262 clinically euthyroid individuals (average age 55 yr; range 20 to 85 yr; 136 men and 126 women) who had normal renal function (creatinine <1.2 mg/dl) and were referred consecutively to an internal medicine clinic for hypertension, gastrointestinal diseases, or osteoporosis.

Results

The main demographic, somatometric, clinical, and biochemical characteristics of patients included in the study are detailed in Table 1. A total of 102 patients had had at least one CV event. In particular, 52 patients had had one CV event (myocardial infarction in six cases, ECG documented anginal episodes in 27 cases, peripheral artery diseases in 12 cases, arrhythmia in three cases, transient ischemic attacks in two cases, and stroke in two case), and the remaining 50 patients had had two or three (n = 43) or more than three (n = 7) CV complications.

Steady-State Relationship between fT3 and Inflammation Markers

Patients who were on chronic hemodialysis (3.3 ± 0.8 pg/ml) had lower fT3 (P < 0.001) than healthy subjects (3.7 ± 1.0 pg/ml) and clinically euthyroid patients with normal renal function (3.6 ± 0.8 pg/ml). fT4 did not differ between hemodialysis patients (1.23 ± 0.25 ng/100 ml) and healthy control subjects (1.25 ± 0.22 ng/100 ml). Fifteen hemodialysis patients (7.5%) had TSH above the upper limit (cutoff 3 mIU/L) of the normal range.

When hemodialysis patients were subdivided into three tertiles on the basis of the plasma IL-6 concentration, it emerged that those in the third tertile were older and had a higher proportion of background CV complications. Patients in the third tertile displayed lower albumin than those in the other two tertiles (Table 1). Remarkably, fT3 was progressively lower from the first tertile of IL-6 onward, and overall 43 and 11% of patients displayed fT3 values <90th percentile of the distribution of fT3 in healthy subjects and clinically euthyroid control patients with normal renal function, respectively. The association between IL-6 and fT3 that emerged in this categorical analysis was confirmed in analyses that considered IL-6 as a continuous variable. Indeed, fT3 correlated inversely with IL-6 as well as with CRP, ICAM-1, and VCAM-1 and directly with albumin (Figure 1). Importantly, associations between fT3 with all inflammation markers but ICAM-1 remained significant also in multiple regression analyses adjusting for demographic variables, risk factors, and other potential confounders (Table 2). Indeed, in this analysis, IL-6, CRP, and VCAM-1 remained independently associated with fT3 (P ≤ 0.004). Of note, a complementary analysis correlating fT3 and previous CV events revealed a graded inverse relationship (P < 0.001) between the number of past CV events and the plasma concentration of fT3 (Figure 2).

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Figure 1.

Relationships between free triiodothyronine (fT3) and IL-6, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), and albumin. Data are correlation coefficients and P values.

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Figure 2.

Relationship between plasma fT3 and number of background cardiovascular (CV) complications.

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Table 2.

Multiple regression analysis of plasma fT3^a

Thyroid Hormone Response to Inflammation-Infection in CKD

As shown in Figure 3, at the peak of intercurrent inflammatory processes, both CRP and IL-6 were very high and fell substantially after the resolution of these processes (P < 0.001). fT3 was significantly lower (P = 0.008) at the zenith of inflammation than after its resolution, and the magnitude of such suppression was independent of the GFR (fT3 change versus GFR, r = 0.13, P = 0.62). Likewise, inflammation-induced suppression of fT3 was independent of age, gender, smoking, cholesterol, arterial pressure, hemoglobin, and other variables listed in Table 1 (P ranging from 0.12 to 0.97). No changes were observed in plasma fT4 and TSH.

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Figure 3.

Relationship between acute inflammation/infection (zenith versus nadir) and circulating levels of IL-6, CRP, and fT3. IL-6 and CRP are reported as median and interquartile range and fT3 as mean ± SD.

Discussion

This study shows that thyroid function, as characterized on the basis of the plasma concentration of the active form of the thyroid hormone (fT3), is associated with markers of inflammation and endothelial activation in stable patients with ESRD. This association may entail a causal link because we also found that fT3 is suppressed during inflammatory processes that are triggered by intercurrent infections and that it reverts to normal as inflammation resolves.

Intensive studies in the 1980s and 1990s revealed that renal insufficiency affects thyroid function in multiple ways, including altered peripheral hormone metabolism, disturbed binding to proteins, reduction in tissue thyroid hormone content, and iodine accumulation in thyroid glands (1). Furthermore, uremic patients have a variety of nonrenal, nonthyroidal disorders that affect thyroid hormone metabolism, such as diabetes, infections, and malnutrition, and they are often treated by drugs that interfere with thyroid function (1). In ESRD, both plasma fT3 and T3 are often reduced, and this alteration is attributed to impaired extrathyroidal T4 to T3 conversion, whereas T4 and fT4 are much less frequently depressed in these patients (21). The different behavior of fT4 and fT3 in ESRD may depend on the fact that the depression of T3 is much greater than that of T4 and/or that, T3 being less tightly bound to thyroid-binding globulin than T4, alterations in thyroid hormone binding in ESRD are more apt to disturb the interpretation of T4 assays than those of T3 (2).

The malnutrition-inflammation complex is a major clinical problem in patients with ESRD. This complex is not only the hallmark of a negative protein-energy balance but also a fundamental risk factor implicated in the high mortality and in CV complications of the dialysis population (5–9). Notwithstanding that malnutrition was suspected as a possible cause of disturbed thyroid function in ESRD in 1996 (22), the issue whether inflammation is implicated in low fT3 has received no attention so far. Nonthyroidal illness is a clinical syndrome characterized by a disturbance in thyroid function of increasing severity that may occur in disparate stressful conditions such as starvation/malnutrition, sepsis, surgery, myocardial infarction, and perhaps any severe illness (2). A reduction in plasma fT3 is the most precocious alteration signaling thyroid dysfunction while a more complex syndrome, characterized also by reduced plasma fT4, develops as the severity of illness and the associated malnutrition progress. The association between inflammation markers and thyroid dysfunction in nonthyroidal illness has been investigated intensively, and the hypothesis that cytokines may be instrumental in reducing circulating thyroid hormones now has solid support (2,14,15). Indeed, deranged thyroid function in nonthyroidal illness is currently considered as an acute-phase response generated by activation of a cytokine network, with IL-6 playing a fundamental role (15). High plasma IL-6 is an important feature of nonthyroidal illness, and it is well established that in this syndrome, circulating IL-6 mirrors T3 levels. A causal involvement of IL-6 in nonthyroidal illness is suggested by the observation that chronic administration of this cytokine produces clear-cut suppression of plasma T3 (17). The role of IL-6 in thyroid dysfunction is also supported by data in the IL-6 knockout mice. Indeed, in this experimental model, the administration of bacterial endotoxin causes a much less pronounced reduction in plasma T3 than in wild-type mice (18).

Studies in patients with hypothyroidism and in the general population revealed consistent and intriguing links between biomarkers of inflammation and thyroid hormones. CRP levels are overtly elevated in patients with either subclinical or clinical hypothyroidism (23). fT4 levels are negatively correlated with those of fibrinogen (24), and it was speculated that downregulation of thyroid function may be a mechanism whereby inflammatory processes induce CV damage. By the same token, fT3 is known to be subnormal in approximately 30% of hospitalized patients with heart failure (4), i.e., a disease associated with high IL-6 plasma levels (25). It has been hypothesized that low fT3 in heart failure may specifically contribute to myocardiopathy, and some advocate the therapeutic use of T3 in patients with subnormal plasma concentration of this hormone (26,27). To our knowledge, our study is the first to investigate the relationship between inflammation markers and thyroid hormones in ESRD. Remarkably, we found consistent and independent inverse associations between IL-6 and CRP and an indicator of endothelial activation/dysfunction (VCAM-1) and fT3 in these patients. Besides these steady-state associations, we found that fT3 was reduced to an important extent during intercurrent inflammatory processes and that this alteration resolved as inflammation faded away. This phenomenon documents that like in other clinical situations, inflammation acutely interferes with thyroid function in patients with CKD and that this interference is fully reversible and independent of the GFR. Homocysteine, another risk factor that has previously been associated with inflammation, is increased in hypothyroidism. In this study, homocysteine was unrelated to IL-6 and CRP or to fT3.

The risk for CV events increases in parallel with IL-6 levels both in the general population (28) and in the ESRD population (10,11). Our finding that low fT3 is closely associated with IL-6 and CRP seems to be of relevance. Individuals with subclinical carotid atherosclerosis display lower fT4 levels than those who present with normal arteries (29), and it is interesting to note that a relationship exists between arterial intima-media thickness and CRP in patients with ESRD (12). Given the potentially important role of low fT3 in CV diseases (30), depressed fT3 in ESRD may be an unsuspected player in the high risk associated with inflammation in these patients, an issue that clearly deserves to be explored in more extensive and specifically designed studies.

Our study has limitations. Although very consistent, the multiple associations between inflammation markers and fT3 may not entail a causal link, and the direction of causality, if any, remains unresolved. In this regard, it is worth noting that the links between inflammation and thyroid function may be complex and perhaps bidirectional. Indeed, lipoprotein(a), a pro-atherogenic protein and an acute-phase reactant that is strongly associated with CRP in ESRD (31), is significantly reduced by d-thyroxin treatment in clinically euthyroid ESRD patients (32). The observation that acute inflammation causes a reversible decrease in fT3 is compatible with the hypothesis that this relationship is causal and that inflammation is the trigger of low fT3 in these patients. However, further studies are needed in steady-state ESRD patients to determine whether pharmacologic interventions aimed at reducing inflammation also determine an increase in fT3 or vice versa. Likewise, the association between markers of endothelial activation and background CV complications and fT3, a most stimulating observation of our study, needs to be confirmed in studies contemplating quantitative measurements of the severity of CV involvement, such as measurement of left ventricular mass, and in prospective studies based on solid outcome measures, e.g., mortality and incident CV complications.