Prevalence and Pattern of Sick Euthyroid Syndrome in Acute and Chronic Non-thyroidal Illness — Its Relationship with Severity and Outcome of the Disorder

Original Article
Prevalence and Pattern of Sick Euthyroid Syndrome in Acute and Chronic Non-thyroidal Illness — Its Relationship with Severity and Outcome of the Disorder AH Zargar*, MA Ganie*, SR Masoodi*, BA Laway*, MI Bashir*, AI Wani*, M Salahuddin+
Abstract Background: Non-thyroidal illness is a common cause of alterations in thyroid hormone economy in absence of underlying intrinsic thyroid disorder. Objective: To study the prevalence and pattern of alterations in thyroid hormone economy in various non-thyroidal illnesses in our region and also to correlate these alterations with the severity and outcome of the non-thyroidal illness. Material and Methods: We analyzed circulating T3, T4, TSH in 382 patients with non-thyroidal illness (285 acute and 97 acute on chronic) and correlated the alterations with severity and outcome of the non-thyroidal disorder. The patients had one or more organ failure at the time of enrollment to the study. The hormones were estimated at the onset of sickness, and at 3rd and 24th week. T3, T4 and TSH in 75 age and sex matched euthyroid subjects were taken as controls. Results: T3 (mean + SEM) was significantly reduced at the onset of illness, in both acute and chronic patient groups (1.61+ 0.05 nmol/l) compared to that in the controls (3.17+ 0.06 nmol/l). In spite of clinical improvement in most instances, T3 continued to remain low in the 3rd week (1.49+ 0.11 nmol/l) but increased (2.14+ 0.09 nmol/l) in 24th week. Low T3 was found in 93 (32.6%) cases with acute illness in 20 (20.6%) cases with chronic illness. A combination of low T3 and T4 was found in 35 (12.3%) of cases with acute and 15 (15.5%) with chronic illness. Although serum TSH showed noticeable fall and rise in some individuals, no significant difference in mean TSH was observed during any period of illness compared to that in the controls. Severity of illness correlated with decrease in T3 (r=0.58) and T4 (r=0.38). A low T3 and T4 with low or undetectable TSH were associated with increased mortality. At the onset of acute illness low T3 was seen in 113 (29.6%, low T3 -low T4 in 50 (13.1%), high T4 in 28 (7.3%) lowT3-lowT4- low TSH in 10 (2.6%) and low T4 alone in 4 (1%) patients. Fifty one (13.4%) of our patients demonstrated alterations in TSH in presence of normal T3 and T4-26 patients had decreased TSH while as 25 had increased TSH. Of 118 patients who followed at 24 weeks, 11(9.3%) had low T3, 7(5.9%) had low T3- low T4 and 13 (11%) had elevated TSH. Conclusion: Pattern and prevalence of sick euthyroid syndrome in this part of the world, a recognized iodine deficient region, appears to be similar to that reported elsewhere. Important finding in our study was higher percentage of TSH elevation, which we believe to reflect the underlying iodine deficiency state of our community. Besides a significant number of subjects persisted with alterations in thyroid functions even after 6 months of therapy.
Though the severity of thyroid hormone derangement correlated with severity of sickness, the derangement was similar in
*Department of Endocrinology and +Immunology, Sher-i- kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir. Received : 19.3.2001; Revised : 11.9.2001; Re-revised : 21.3.2002; Accepted : 28.7.2002
28 www.japi.org © JAPI • VOL. 52 • JANUARY 2004
acute vs. acute on chronic non-thyroidal illnesses. ©
INTRODUCTION
Thyroid hormones maintain optimal metabolism and normal function of various organs. The normal thyroid hormone
economy (kinetics and dynamics) is regulated by suprathyroidal and intrathyroidal mechanisms and any tilt in the regulation may lead to alterations in the thyroid hormone function. Multiple alterations are known to occur in nonthyroidal illnesses (NTI) of varying severity. Most prominent of the changes are decrease in serum T3 and increased rT3 leading to ‘low T3 syndrome’.1 However, more appropriate terms is ‘sick euthyroid syndrome’ (SES)2 since not only T3 but all other parameters, including T4 and TSH are often affected in NTI. The SES has also been described in liver disease,3 renal failure,4 after stress or surgery,5, in elderly sick,6 and after ingestion of drugs like amiodarone,7 corticosteroids,8 and propranolol.9 The magnitude of changes in serum T3 and T4 do not depend on the type of illness but on its severity.10 With progression in severity, serum T3 continues to fall to very low values in critical illness while serum T4 are normal, low or elevated. Most of the previous reports have generally been on small number of patients.3-9 Hence this study was undertaken in a big cohort of patients with disorders of various systems with a significant number being followed up to 24 weeks.
MATERIAL AND METHODS Study population : Two hundred and eighty five consecutive
patients suffering from acute NTI and 97 patients of acute on chronic NTI, admitted to various departments of SKIMS, were enrolled for this study (Table 1). The inclusion criteria for acutely sick patients were presence of one or more organ failure as defined by modified APACHE-II scoring system for illness.11 The inclusion criteria for chronically sick patients were an acute exacerbation of the underlying or intercurrent sickness needing admission to the hospital. The severity of acute on chronic sickness were defined by APACHE-II scoring system.12 Patients were 20-78 years old with nearly equal proportion from both sexes. Patients with clinical suggestion of intrinsic thyroid disease were excluded from the study. Seventy five healthy, age matched, subjects from both sexes were taken as controls.
Methods : All patients, in addition to clinical assessment, were subjected to baseline investigations including a haemogram, blood urea nitrogen, creatinine, glucose, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, calcium, phosphorus and electrolytes, arterial blood gas analysis, urine examination, 12-lead electrocardiogram and X-ray chest. Blood samples were obtained at the onset, at three weeks and at 24 weeks in acutely ill while in those with chronic sickness, samples were taken at the time of admission and others at three and 24 weeks of followup. One blood sample for T3, T4 and TSH was taken from all controls. T3, T4 and TSH were estimated using specific radioimmunoassay (RIA) kits obtained from Bharat Radiation Isotope Technology (BRIT), Mumbai, India. The
intra-and interassay coefficient of variation was less than 5% and less than 10% respectively. Definitions : Depending upon the changes in T3, T4 and
TSH and their various combinations, various thyroid hormone alterations were categorized into: low T3 syndrome, low T3- low T4 syndrome, low T3-low T4-low TSH (all low), high T4 (normal T3 and TSH), high TSH (normal T3 and T4), low TSH (normal T3 and T4), and low T4 (normal T3 and TSH) variants.
Statistical Analysis : Statistical analysis was performed using the SPSS (Statistical Programme for the Social Sciences, version 6.0) software on an IBM-compatible computer. All the results, unless otherwise noted were expressed as mean ± SEM. In addition to descriptive statistics, various non- parametric tests were used to assess the association between categorical variables and the t-test for comparison among continuous variables. Other methods of statistical analysis included one way analysis of variance (ANOVA) and the multiple linear regression model. A P value of < 0.05 (two- tailed) was considered significant.
RESULTS Of 285 subjects with acute sickness, 32 patients died;
most others recovered fully, but among them, only 95 were
Fig. 1 : Age distribution of patients and controls.
Table 1 : Distribution of cases as per type of illness (system involved)
Illness No. of patients (%) Overall Acute Chronic
Cardiovascular 91 (23.8) 66 (23.1) 25 (25.8) Renal 73 (19.1) 54 (18.9) 19 (19.6) Neurological 34 (8.9) 31 (10.9) 3 (3.1) Malignancy 33 (8.6) 25 (8.8) 8 (8.2) Gastrointestinal 25 (6.6) 18 (6.3) 7 (7.2) Sepsis 18 (4.7) 15 (5.3) 3 (3.1) Chest 17 (4.5) 13 (4.6) 4 (4.1) Haematological 10 (2.6) 6 (2.1) 4 (4.1) Surgery and trauma 10 (2.6) 8 (2.8) 2 (2.1) Poisoning 3 (0.8) 3 (1.1) — Miscellaneous 68 (17.8) 46 (16.1) 22 (22.7)
All illness 382 (100) 285 (100) 97 (100)
© JAPI • VOL. 52 • JANUARY 2004 www.japi.org
Fig. 2 : Overall T3, T4 and TSH in the study population.
available for sample collection at three weeks and 84 patients, at 24 weeks. Of 97 patients with chronic sickness, 47 were available for second sample at three weeks and 34 for third sample at 24th week.
Fig. 1 shows the age distribution of patients and controls. The mean ( ± SEM) age was 40.82 ± 0.77 years in patients with acute sickness, 43.27 ± 1.08 years in patients with chronic sickness and 38.33 ± 1.43 years in controls. Patients with diseases of cardiovascular system, renal system, neurological system, gastrointestinal system and malignancies constituted the bulk of the study population (Table 1).
Overall, mean total T3 levels were significantly reduced at the onset of the sickness and continued to be low at three weeks. Even at six months (24 weeks), when it had shown a significant improvement, mean T3 continued to be low in comparison to controls (Fig. 2). Serum T4 and TSH did not show significant differences from controls during the course of the sickness. In patients with NTI, age had no influence on serum thyroid hormone levels. Comparison of total T3, T4 and TSH at onset, three weeks and 24 weeks of acute sickness or acute on chronic sickness between age groups of < 40 years and > 40 years was not statistically significant. A two-tailed t test and P value was used to compare the two groups. Using the same statistical parameters there was no difference in T3, T4 and TSH in control groups of < 40 years and > 40 years. Mean T3 was significantly lower in males as compared to females
at the onset of illness. However, there was no significant difference in mean T4 and TSH between the two sexes. The study results indicate highly significant correlation between severity of sickness and fall of T3 and T4 with a correlation coefficient (r) of 0.58 and 0.38, respectively. In patients with an APACHE score less than 16, T3 had become comparable to that of controls by 24 weeks whereas it continued to be significantly low in patients with an APACHE score of 16 or more (Table 2). Analysis of the data separately for acute and acute on chronic illness showed similar correlation of thyroid hormone alteration with severity of sickness. In both acute as
Table 2 : Influence of severity on thyroid hormone profile (mean ± SEM)
Hormone Group I Group II Group III (APACHE < 16) (APACHE 16-20) (APACHE > 20) p value*
T3 (nmol/l) A (0 wk) 2.29 ± 0.11 1.47 ± 0.12 0.83 ± 0.08 < 0.001 (S) B (3 wks) 2.14 ± 0.17 1.66 ± 0.23 1.21 ± 0.20 0.016 (S) C (24 wks) 2.75 ± 0.18 1.87 ± 0.22 1.74 ± 0.20 0.001 (S) T4 (nmol/l) A (0 wk) 128. 34 ± 5.14 106.22 ± 6.17 88.61 ± 5.40 < 0.001 (S) B (3 wks) 132.33 ± 5.56 71.89 ± 9.65 101.59 ± 9.65 0.083 C (24 wks) 145.19 ± 10.16 116.90 ± 8.87 96.19 ± 8.36 0.002 (S) TSH (mU/l) A (0 wk) 2.84 ± 0.73 2.65 ± 0.53 3.56 ± 0.82 0.640 B (3 wks) 4.35 ± 1.93 3.89 ± 1.16 2.30 ± 0.44 0.527 C (24 wks) 6.82 ± 3.17 2.08 ± 0.47 4.04 ± 1.01 0.181
*Analysis of variance (ANOVA)
Table 3 : Thyroid hormone profile - acute versus chronic (mean ± SEM)
Hormone Non-thyroidal illness Acute Chronic p value
T3 (nmol/l) A (0 wk) 1.55 ± 0.06 1.82 ± 0.12 0.025 (S) B (3 wks) 1.47 ± 0.11 1.55 ± 0.26 0.767 (NS) C (24 wks) 2.15 ± 0.11 2.08 ± 0.17 0.175 (NS) T4 (nmol/l) A (0 wk) 101.94 ± 2.58 104.54 ± 4.39 0.609 (NS) B (3 wks) 99.06 ± 4.82 97.0 ± 7.49 0.837 (NS) C (24 wks) 112.6 ± 4.15 111.42 ± 6.92 8.75 (NS) TSH (mU/l) A (0 wk) 2.72 ± 0.23 2.92 ± 0.61 0.701 (NS) B (3 wks) 3.50 ± 0.62 2.98 ± 0.51 0.672 (NS) C (24 wks) 4.19 ± 0.77 2.88 ± 0.52 0.294 (NS)
S - significant, NS - non-significant
Table 4 : Prevalence of SES at onset of NTI and at follow- up
SES variant 0 week 3 weeks 24 weeks (n=382) (n=142) (n=118)
Low T3 113 (29.6) 40 (28.2) 11 (9.3) Low T3-low T4 50 (13.1) 23 (16.2) 7 (5.9) High T4 28 (7.3) 13 (9.2) 8 (6.8) Low TSH 26 (6.8) 9 (6.3) 6 (5.1) High TSH 25 (6.5) 12 (8.4) 13 (11.0) All low 10 (2.6) 3 (2.1) 5 (4.2) Low T4 4 (1.0) — 1 (0.8)
All variants 256 (67.0)* 100 (70.4)* 51 (43.2)* *c2df2=26.3, P < 0.001
30 www.japi.org © JAPI • VOL. 52 • JANUARY 2004
well as acute on chronic sickness, serum T3 was significantly low at the onset of illness (1.55 ± 0.06, 1.47 ± 0.11 and 2.15 ± 0.11 nmol/l in acute, in 1.81 ± 0.11, 1.55 ± 0.26 and 2.09 ± 0.17 nmol/l in chronic at 0, 3 and 24 weeks, respectively), whereas, T4 and TSH did not show any significant alterations (Table 3).
The incidence of SES at the onset of illness was 67.0% and this was not significantly different at third week of illness (70.4%) but showed a decline at 24 weeks (43.2%) (Table 4).
Overall there was no difference in the incidence of SES between acute and acute on chronic NTI groups (Table 3). However, among acute NTI group a higher percentage had elevated TSH at 24 weeks as compared to acute on chronic NTI (22.7% vs. 8.8%). At the conclusion of the study 38 patients (32 from acute groups and six from chronic group) had expired. Table 5 gives the details of hormone profile of alive and expired patients showing significantly low T3 and T4 at beginning as well as at three weeks in patients who expired.
DISCUSSION This study showed that age has no influence on thyroid
hormone alteration in NTI, which was also concluded in an earlier study.6 A recent study also reported high prevalence of SES in elderly subjects undergoing surgery.13 An earlier report suggested that age does not influence these alterations.14 We observed that T3 and T4 showed a significant fall at the onset of the sickness compared to controls and in spite of the clinical recovery in most of the patients by third week, T3 and T4, demonstrated a further fall and it was only at six months that a significant evidence of recovery could be observed even at six months, although mean T4 became comparable to control values, T3 still remained low, versus that in controls. Interestingly, although TSH showed a significant fall and rise in some individual cases, there was no overall difference in the mean TSH at any period of observation. Analysis of data for acute, and acute events in chronic illnesses showed similar correlation of hormone alteration with severity of sickness. At the onset of sickness, mean T3 was significantly low in patients with acute NTI than with those with acute on chronic NTI (Table 3). This pattern of hormone profile has been by now declared as a consistent feature of SES.2,7,15 The
unusual features of this study are that T3 and T4 continued to be low at three weeks even when clinical recovery had taken place; T3 continued to be low even at six months. In patients with APACHE score of more than 20, serum T3 and T4 was the lowest. This observation is consistent with earlier published data.13
In this study, 29.6% had low T3, 13.1% had low T3-low T4, 7.3% had high T4 alone, 2.6% had low T3-low T4-low TSH, 1% had low T4 alone, and 13.4% patients had abnormality of TSH at the onset of NTI, giving an overall prevalence of 67% of SES, as at first observation, 70.5%, at three weeks, 43.2% at 24 weeks. Earlier studies have documented prevalence of SES from 45% to 84%.16-18
Low serum total T3 is the most common abnormality in NTI. It is observed in about 70% of hospitalized patients,19 but in one study, this was observed in 29.6% only. Low T3 is attributed to decreased peripheral production and for increased T3 metabolic clearance.15 Low T3-low T4 syndrome is observed in severely ill, frequently moribund, patients; 50 (13.1%) of our patients had this variant of SES at the beginning of sickness. At six months, seven patients who followed continued to have low T3 and T4. In addition to 50 patients mentioned above, ten more patients had low T3 and low T4 along with low TSH. The incidence of this variant has been reported as 6.5%14 and 29%.15 Low serum total T4 correlates with bad prognosis.20
Four of our patients had low T4 alone. This small group of patients had a mean APACHE score of 12 indicating that the sickness was not severe. Besides low TSH, factors that may contribute to the low T4 of NTI include abnormalities in TSH secretion, decreased biological activity of TSH and diminished thyroidal response to TSH. One percent of our patients had high T4 variant of SES at the onset of sickness. This variant has been demonstrated in cases of drug therapy and organophosphorus poisoning.16 High serum total T4 is seen in some NTI patients, who have elevated serum concentration of TBG. Two each of our four patients with high T4 had organosphosphorus poisoning and liver disease. Fifty-one of our patients had alterations of TSH alone; 26 (6.8%) of them had decreased TSH whereas 25 (6.5%) had elevated TSH. Unlike T3 and T4 the percentage of patients
Table 5 : Relationship between outcome of NTI and thyroid hormone results
Hormone 0 week 3 weeks Live Dead p value Live Dead p value
T3 (nmol/l) Acute 1.43 ± 0.11 0.56 ± 0.09 < 0.001 (S) 1.72 ± 0.12 0.59 ± 0.15 < 0.001 (S) Chronic 1.49 ± 0.24 0.29 ± 0.15 0.023 (S) 1.72 ± 0.28 0.38 ± 0.19 0.082 (S) Overall 1.45 ± 0.10 0.53 ± 0.08 < 0.001 (S) 1.72 ± 0.11 0.56 ± 0.13 < 0.001 (S) T4 (nmol/l) Acute 104.92 ± 5.02 63.73 ± 6.80 < 0.001 119.07 ± 5.21 58.99 ± 5.63 0.238 (S) Chronic 99.65 ± 11.02 57.46 ± 7.09 0.087 (S) 104.38 ± 8.51 75.58 ± 12.13 < 0.001 (S) Overall 103.68 ± 4.60 62.91 ± 5.97 < 0.01 (S) 105.56 ± 4.48 61.15 ± 5.20 < 0.001 (S) TSH (mU/l) Acute 3.68 ± 0.69 2.20 ± 0.36 0.174 2.99 ± 0.62 5.21 ± 1.70 0.135 Chronic 2.31 ± 0.69 0.78 ± 0.25 0.301 3.07 ± 0.56 2.02 ± 0.45 0.565 Overall 3.38 ± 0.57 2.03 ± 0.33 0.146 3.01 ± 4.49 4.90 ± 1.55 0.132
S - significant
© JAPI • VOL. 52 • JANUARY 2004 www.japi.org
with elevated TSH increased to 8.2% by third week and 11% by 24 weeks. In acute group a higher percentage of patients had elevated TSH at 24 weeks as compared to chronic group (22.7% vs. 8.8%). Many authors have reported a lower mean TSH concentration in a group of NTI patients compared to controls and a higher incidence of suppressed serum TSH values in NTI. The transient increase in TSH during recovery from NTI suggests that TSH is suppressed in an illness.
The pattern of hormone profile described above has by now been declared a consistent feature SES. Most of our patients are from the valley which is a recognized iodine deficient region, thus iodine deficiency per se seems not to influence the prevalence and pattern of euthyroid sick syndrome. The behaviour of thyroid profile of acute NTI was not different from acute on chronic NTI. Severe derangement of either T3 or T4 level was highly correlated with…