Euthyroid sick syndrome in psychiatric inpatients

Euthyroid Sick Syndrome in Psychiatric Inpatients Shahla Nader, M. Dhyanne Warner, Suzanne Doyle, and Cecilia A. Peabody

Numerous disorders are associated with euthyroid sick syndrome (ESS). This retrospective study examines the incidence and circumstances of ESS among 3188 psychiatric inpatients. There were 324 patients (10.2%) who met strictly defined criteria for ESS. Of these, 95 were hyperthyroxinemic (HT), 6 were hypothyroxinemic, 179 had mildly elevated thyroid-stimulating hormone (HTSH), and 47 had suppressed TSH. All were classified by DSM-III-R discharge diagnoses, encompassing five categories. X2 tests of significance of the 95 HT and 179 HTSH subjects revealed the following: 1) no relationship with age or gender; 2) the frequencies of HT and HTSH differed significantly (p < .05 and p < .01, respectively) across the five psychiatric categories; 3) HT frequency was highest in mood disorders (HT in mood versus others p < .02); and 4) HTSH frequency was highest in substance abuse (HTSH in substance abuse versus others p < .02). In conclusion, ESS is common in psychiatric inpatients, especially HT and HTSH; pathophysiologic mechanisms may vary according to psychiatric diagnosis. © 1996 Society of Biological Psychiatry Key Words: Euthyroid sick, thyroid, pituitary, substance abuse, mood disorder, schizophrenia BIOL PSYCHIATRY 1996;40:1288--1293

Introduction Patients with nonthyroidal illnesses often have abnormal thyroid function tests (TFTs). These changes can be associated with a euthyroid clinical state but may reflect alterations in thyroid function. Thus, in the euthyroid sick syndrome (ESS) ill patients exhibit abnormal thyroid function tests in the absence of true disease of the hypothalamus, pituitary, or thyroid. Numerous disorders, notably serious acute illness, caloric deprivation, infection,

From the Department of Medicine (SN) and Psychiatry (SD), University of Texas Medical School, Houston, TX; Department of Psychiatry, Stanford, Palo Alto, CA (MDW); and Menlo Park VA Medical Center, Menlo Park. CA (CAP). Address reprint requests to Shahla Nader, MD, 6431 Fannin, Suite 3.204, Houston. TX 77030. Received July 5. 1995; revised November 21, 1995.

© 1996 Society of Biological Psychiatry

renal disease, and liver disease have been associated with ESS, as have acute psychiatric disorders (Wartofsky and Burman 1982; Lambert et al 1987). In most of these conditions, there is a state of low thyroxinemia, but in some, especially liver disease and psychiatric disorders, a state of hyperthyroxinemia has been frequently reported (Zalogo and O'Brian 1985; Lambert et al 1987). Maes et al (1993) reported significantly higher free thyroxin concentrations in melancholic depressed subjects than in controlled subjects or those with minor or simple major depression, and the levels were significantly correlated with the severity of illness. In addition, there is increasing evidence of disturbances of thyrotroph function (Chopra et al 1990) or abnormal thyroid stimulating hormone (TSH) concentrations (Joffe and Levitt 1992). The present study examines the incidence and circumstances of ESS among a large group of psychiatric inpatients. 0006-3223/96/$15.00 SSDI 0006-3223(95)00626-5

Euthyroid Sick in Psychiatric Inpatients

Method Patients A retrospective review of 4377 admissions of adult patients (> 18 years) admitted to a 250-bed state/county psychiatric hospital was conducted from May 1989 through December 1990. Screening admission TFTs, including thyroxine (T4), triiodothyronine resin uptake (T3U), TSH, and calculated free T 4 index (FTI), were routinely ordered on all admissions, and blood samples were collected upon admission (any time of day). Of the 4377 admission, 714 were excluded because they represented readmissions, and another 475 patients were excluded for refusing blood work or incomplete TFTs. The remaining 3188 cases were evaluated as to the frequency and pattern of abnormal TFTs, thyroid disease incidence and prevalence, and association of these with specific psychiatric disorders, age, and gender. This current report focuses on ESS in this population, while a prior report extensively described the other areas evaluated (Warner et al 1993).

Evaluation Thyroid Function One of the authors, an endocrinologist (SN), retrospectively reviewed all thyroid function test abnormalities and classified them into one of five categories as described below. The patients were not seen by the endocrinologist. For a full description of criteria employed, the reader is referred to our previous publication concerning these 3188 subjects (Warner et al 1993). Although we cannot exclude the possibility of other medical illnesses predisposing to ESS, these patients were all admitted to a psychiatric hospital and were unlikely to have been extremely ill. Patients were classified according to the following categories: 1. Those with newly diagnosed thyroid disease with a) hypothyroidism defined as a TSH --> 15 p~IU/mL on one occasion or a TSH -> 10 p~IU/mL on more than one occasion; or b) hyperthyroidism defined as a TSH < 0.6 ~zlU/mL, FFI > 4.4, and additional evidence such as an abnormal triiodothyronine concentration and/or iodine uptake study. 2. Those with a previous history of thyroid disease based solely on documentation in the medical records, which were carefully scrutinized for goiter, past history of thyroid disease, and thyroid-related medications. Admitting residents had been trained to solicit a history of thyroid disease and to pick up obvious abnormalities on clinical examination. Thyroid scans or thyrotropin-releasing hormone testing

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were not part of the evaluation or exclusion criteria. There were no patients with known pituitary disease likely to have affected thyroid function. . Those with possible thyroid disease with a) hypothyroidism defined as TSH -----10 p~IU/mL but < 15 txIU/mL on one occasion; or b) hyperthyroidism defined as TSH < 0.6 t~IU/mL and FTI in the upper normal range. These cases warranted further followup. 4. Those with abnormal values associated with a) thyroid-altering medications, specifically lithium, phenytoin, androgens, corticosteroids, and carbamazepine; or b) pregnancy, postpartum status, or estrogen replacement. . There were 666 patients with TFT abnormalities who did not fit into any of the above categories. These included 324 patients (10.2%) with presumed ESS as defined below: a) patients with hypothyroxinemic ESS with a low T4, low FTI, and normal TSH; b) patients with hyperthyroxinemic ESS with elevated T4 values, normal T3U, and nonsuppressed TSH (-> 0.6 txUI/mL); c) patients with high-TSH ESS with TSH > 4.6 but < 10 ~xU/mL; and d) patients with low-TSH ESS with TSH < 0.6 t~U/mL and FTI < 4.0.

Psychiatric Diagnoses All patients were additionally classified by their DSMIII-R discharge diagnosis. Psychiatric diagnoses were divided into one of five categories, which included: 1) substance abuse/dependence (SA); 2) mood disorders, including bipolar disorder, major depressive disorder, dysthymia, and cyclothymia (Mood); 3) schizophrenia and schizoaffective disorder (SCZ); 4) dual diagnosis, which included any DSM-III-R axis I diagnosis with a diagnosis of substance abuse/dependence (Dual); and 5) miscellaneous category, which included organic disorders (organic mood syndrome, organic delusional syndrome, organic hallucinosis, and dementia), delusional disorders, anxiety and somatoform disorders, adjustment disorders, and V code for conditions not attributable to a mental disorder (Misc). Semistructured interviews were not used; all cases were reviewed by attending faculty and diagnoses established.

Statistical Methods X2 tests of significance were used to determine the relationship between 1) hyperthyroxinemic ESS; and 2) high-TSH ESS with age, gender, and psychiatric diagnosis.

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Table 1. Frequencies of Hyperthyroxinemic and High-TSH Euthyroid Sick Syndrome by Age and Gender Age

Gender

Group

No.

--< 35 (%)

> 35 (%)

Male (%)

Female (%)

Not HT HT

3093 95

1838 (59) 53 (56)

1255 (41) 42 (44)

1642 (53) 43 (45)

1451 (47) 52 (55)

Not HTSH HTSH

3009 179

1793 (60) 98 (55)

1216 (40) 81 (45)

1591 (53) 94 (53)

1418 (47) 85 (47)

HT = hyperthyroxinemia; HTSH = high thyroid-stimulating hormone. HT relationship with age (-< 35 versus > 35) or gender: not significant. HTSH relationship with age (-< 35 versus > 35) or gender: not significant.

Assay The TFT assays were performed by the National Health Laboratory, Inc., in Houston, Texas. Total s e r u m T 4 and T3U were measured by radioimmunoassay (RIA) (Monobind, Inc., San Diego, CA). The normal range for T 4 is 4.5-12.5 ~g/dL. T 3 resin uptake is an estimate of thyroid hormone binding to plasma proteins, and the normal range is 25-35%. Free thyroxine index (FTI) is calculated by multiplication of T3U by T4, with a normal range of 1.1-4.4; in high or low binding states a normal FTI indicates euthyroidism. TSH was measured with an ultrasensitive TSH double antibody RIA (Nicholas Institute, San Juan Capistrano, CA). The normal range for TSH is 0.6-4.6 ~IU/mL. The interassay coefficients of variation for the three tests were as follows: 7.8-9.4% for T 4, 3.9-6.4% for T3U, and 4.5-6.8% for TSH.

Results Of the 3188 patients, there were 324 (10.2%) with ESS as defined above. Only 6 had hypothyroxinemic ESS. Three of these patients were diagnosed with substance abuse disorders; 1 had a mood disorder, 1 was schizophrenic, and 1 had an undefined disorder that was classified in the miscellaneous psychiatric category. No further analyses were performed on these 6 subjects. There were 95 patients with hyperthyroxinemic ESS and 179 with high-TSH ESS (> 4.6 but < 10.0 IxU/mL), 3 of whom were also hyperthyroxinemic. Frequencies of hyperthyroxinemic and high-TSH ESS by age and gender are summarized in Table 1. Although there is a significant dependence of thyroid diagnosis on increasing age and female gender (McLarty et al 1978; Larsen and Ingbar 1985), we found no significant relationship between either hyperthyroxinemic or high-TSH ESS and age or gender. The relationship between hyperthyroxinemic and highTSH ESS and psychiatric diagnosis was first examined across all five psychiatric categories, and then by contrasting each disorder alone with the remaining psychiatric

Table 2. Frequencies of Hyperthyroxinemic and High-TSH Euthyroid Sick Syndrome by Psychiatric Diagnoses Group

No.

Mood

SCZ

SA

Dual

Miscellaneous

Not HT HT

3093 95

690 31

480 17

847 15

340 12

736 20

Not HTSH HTSH

3009 179

692 29

476 21

800 62

338 14

703 53

SCZ = schizophrenia; SA = substance abuse; HT ~ hyperthyroxinemia; HTSH = high thyroid-stimulating hormone. I-IT differences across the five diagnostic categories p < .05. HTSH differences across the five diagnostic categories p < .01. HT relationship with mood versus all other diagnoses p <7 .02. HTSH relationship with SA versus all other diagnoses p <7 .02.

diagnoses. Although the frequencies of hyperthyroxinemic and high-TSH ESS differed significantly (p < .05 for hyperthyroxinemia, p < .01 for high TSH) across the five psychiatric categories, it was the contrast between mood disorders and all other psychiatric conditions that provided the strongest evidence of relationship with hyperthyroxinemic ESS (p < .02) and between substance abuse and all other diagnoses with high-TSH ESS (p < .02). These cross-tabulations are summarized in Table 2, and graphically depicted in Figure 1. There were 47 (1.5% of total patients) with low-TSH ESS ( < 0.6 p~U/mL), in all of whom the FTI was well within the normal range. Their psychiatric diagnoses were categorized as follows: mood disorders (13), schizophrenia (9), substance abuse (14), dual diagnosis (8), and miscellaneous (3). Serum TSH was within the normal range in 92 of the 95 hyperthyroxinemic ESS subjects. It was slightly elevated in the remaining 3 (6.7, 4.8, and 5.7 txlU/mL, respectively). Twenty-one of these 95 patients had repeat TFTs performed in the first few weeks following their admission. In 18 of these 21 patients (86%), the hyperthyroxinemia had normalized; in 3 the T 4 remained high. Two of these 3 subjects with sustained elevations of T 4 had a repeat TSH measured; in both cases it was normal on initial testing and upon repeat.

Discussion We have previously noted (Warner et al 1993) that 25% of our psychiatric inpatients exhibited a TFT abnormality, and 0.5% were found to have newly diagnosed thyroid disease based on screening TFTs, with an overall prevalence of thyroid disease of 2.5%. We also found previously a significant association between mood disorders and thyroid disease separate from the influence of age or gender. The focus of the present report was to investigate the frequency and pattern of ESS (using strictly defined criteria) in this population. While 10.2% could be classi-

Euthyroid Sick in Psychiatric Inpatients

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PERCENT WITH HYPERTHYROXINEMIA

{HT) BY D I A G N O S I S

10 p

9

E R

8

C E N T

7 6 5

W I T H

4 3 2

H T

1 0 SUBSTANCE ABU6E

MISCRLANEOL~

SCHIZOPI"IRE~IA

DUAL DIAGNOSIS

MOOD CISORDB~S

Figure l. Percent of psychiatric inpatients with hyperthyroxinemic or high-TSH euthyroid sick syndrome according to psychiatric diagnosis.

DIAGNOSIS P E R C E N T W I T H H i G H TSH ( H T S H ) BY D I A G N O S I S

10 P E R C E N

'9 8 7 6

W I T H H T S H

5 4 3 2 1 0 SUBSTANCE ABU6E

MISCELLANEOUS

SC HIZOPHRI~IA

DUAL DIAGNOSIS M O O D D I ~

DIAGNOSIS

fled as having ESS on admission, the overwhelming majority of these patients had hyperthyroxinemic or highTSH ESS patterns. Interestingly, we found no association between gender or age and these two varieties of ESS. There was, however, a relationship between hyperthyroxinemic ESS and the diagnostic category of mood disorders, and a relationship between substance abuse and high-TSH ESS; to our knowledge, these specific associations have not been previously reported. The frequency of ESS among psychiatric patients has been reported as ranging from 7 to 33% (Cohen and Swigar 1979; Levy et al 1981; Spratt et al 1982; Lambert et al 1987). Our reported frequency of 10.2% may be lower than some estimates, possibly because of the exclusion of any patient on medications known to alter thyroid function or thyroxine binding capacity, as well as exclusion of patients with a prior history of thyroid disease. Hyperthyroxinemic ESS (as opposed to the hypothyroxinemic variety) is seen in mild forms of ESS (Docter et al 1993), and is more commonly associated with psychiatric

disorders (Zalogo and O'Brian 1985; Lambert et al 1987), and this is confirmed by our report. The reason for this is unknown. Redistribution of T 4 o u t of the tissues, particularly the liver, which is the repository of one third of the total pool of T 4 outside the glands, has been proposed, and the possibilities of a temporary resistance of the pituitary thyrotroph to T 4 or a block in T 4 clearance have also been suggested (Cavalieri 1991). In cases of amphetamine use, the hyperthyroxinemia may be due to drug-induced augmentation of TSH secretion (Hein and Jackson 1990). Spratt et al (1982) suggested that in some psychiatric illnesses high circulating phenylethylamine, which is structurally similar to amphetamines, may augment serum T4. Although most studies, including this one, fail to find elevated TSH levels to account for the observed increased T4, the plasma clearance rate of TSH is considerably faster than T 4, and TSH can thus return to normal sooner than T 4. Indeed, in a longitudinal study by Roca et al (1990), TSH was higher on the day of free T 4 index peak than on the day of its nadir, supporting the concept that hypersecretion

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of T 4 may result from centrally mediated TSH hypersecretion. The relatively large number of patients with high-TSH ESS was interesting. Spratt et al (1982) have pointed out that many of the key neurotransmitters in psychiatric disorders, norepinephrine, serotonin, and dopamine, are associated with altered TSH secretion, and, as indicated above, amphetamines may augment TSH secretion. It is quite possible that the mildly elevated TSH seen in many of our patients may relate to such activity, and the finding of significant association between substance abuse and high TSH would support this contention. Although we carefully excluded patients who were on medications well known to effect thyroid function tests, such as lithium and oral contraceptives, psychiatric medications taken by the patient and drugs of substance abuse could also have affected their thyroid function tests, as outlined above and as discussed by Docter et al (1993). We chose to include these patients in the analysis, since the effect of these medications is less well defined. Chopra et al (1990), who have also noted transiently elevated TSH concentrations in many psychiatric patients, raised the possibility of altered glycosylation (and reduced bioactivity) of TSH. Given the frequency of TSH abnormalities, Nicoloff and Spencer (1990) advise us that TSH measurements may provide misleading results relevant to thyroid status in patients hospitalized with acute psychiatric disorders or nonthyroidal illnesses. The 47 patients with suppressed ESS (1.5% of total patients) could be expected on statistical grounds, defined by the confidence limits of the normal range in the reference population. Nonetheless, cytokines and other humoral or local factors produced in illness and during

S. Nader et al

stress may inhibit TSH secretion and impair normal feedback responses (Reichlin 1993; Docter et al 1993). Changes in pulsatile and nocturnal TSH secretion may also account for the observed TSH aberrations in ESS (Adriaanse et al 1993), and interestingly abnormal TSH responses to thyrotropin-releasing hormone have been associated with elevated acute phase plasma proteins in depressed men (Joyce et al 1992). Hypo- and hyperthyroxinemic ESS as well as other isolated TFT abnormalities represent only a transient finding. Spratt et al (1982) have suggested that the frequency of such transient abnormalities of TFTs is so common that any initial screening TFTs should be done 1-2 weeks after admission. Although Maes et al (1994) found that TFTs were unchanged 8 days after initial abnormal values were obtained, most data, including ours (repeat testing in 21 out of 95 hyperthyroxinemic ESS patients showed normalization of T 4 in 18), suggest that these abnormalities appear to normalize within 2 - 4 weeks after admission. Again, the reason for the prevalence of hyperthyroxinemic ESS in psychiatric patients remains largely unknown. In conclusion, we found 10.2% of a large psychiatric population to have hypo- or hyperthyroxinemic and hypoor hyper-TSH ESS. Hyperthyroxinemic ESS and highTSH ESS were the two patterns most commonly seen, accounting for 84% of all patients with ESS.

The authors wish to gratefully acknowledge John Overall, PhD, for his generous advice regarding statistical analysis.

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Euthyroid Sick in Psychiatric Inpatients

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