LOW TRIIODOTHYRONINE (T3) SYNDROME IN ACUTE HEART FAILURE AND ASSOCIATION WITH SHORT-TERM OUTCOME

Methods: 176 patients diagnosed as acute HF fulfilling inclusion criteria were enrolled. Serum fT3, fT4, and thyroid-stimulating hormone were measured. Patients were followed up and length of hospital stay, need for inotropes, mechanical ventilation, and intensive care unit (ICU) facility were compared with thyroid function tests. End points were discharge or death. Data were entered into structured pro forma and analyzed. Results: There was a statistically significant association between need for ICU/high dependency unit (HDU) facility care and T3 status ( χ 2 =27.82; p<0.001). There was a statistically significant association between the need for mechanical ventilation with the levels of T3 ( χ 2 =16.14; p<0.001). There is a statistically significant difference in mean T3 among the patients who expired and patients who were discharged (2.31±0.74 vs. 1.71±0.66; p=0.019). Conclusion: Low T3 correlated with a higher rate of ICU/HDU admissions (53.5% vs. 14.7%, p<0.001) and an increased need for invasive mechanical ventilation (35.6% vs. 9.3%, p<0.001). Low T3 syndrome is frequently found in patients with acute HF and is associated with a poor short-term outcome in terms of need for intensive care and mechanical ventilation.


INTRODUCTION
Heart failure (HF) is a clinical syndrome characterized by symptoms (dyspnea, orthopnea, and lower limb swelling) and signs (elevated jugular venous pressure and pulmonary congestion) often caused by a structural and/or functional cardiac abnormality resulting in reduced cardiac output and/or elevated intracardiac pressures [1]. Incidence of HF is rapidly growing in developed and developing countries. It is also associated with frequent hospitalizations, increased health-care expenditure and it is a major cause of morbidity and mortality worldwide [2,3].
The thyroid hormone is well known for regulating numerous bodily processes [4]. The hypothalamic-pituitary-thyroid axis is a selfregulatory circuit comprised of the thyroid gland, anterior pituitary gland, and hypothalamus. Thyroxine, also known as tetraiodothyronine (T4), and triiodothyronine are the primary hormones produced by the thyroid gland (T3). Low thyroid hormone levels, particularly low serum T3 levels, are frequently observed in patients with nonthyroidal diseases, such as cardiac disorders. In euthyroid patients with HF, changes in peripheral thyroid hormone concentration and metabolism can occur. Low-T3 (triiodothyronine) syndrome is the most common alteration of thyroid function in HF, characterized by a decrease in serum total T3 and free T3, with normal levels of thyroxine and thyrotropin [5]. These changes have primarily been attributed to a decrease in the 5'-monodeiodination of diiodothyronine and reverse triiodothyronine. Free triiodothyronine typically decreases when the total triiodothyronine concentration is significantly reduced. A common interpretation of this low-T3 syndrome is that it is an adaptive, compensatory, and advantageous response that reduces energy consumption in diseased states.
In studies of hospitalized patients with HF, low T3 syndrome was independently associated with higher all-cause mortality, an increased length of hospital stay, higher rates of intensive care unit admission and an increased need for invasive mechanical ventilation. Thyroid function test is easily available in all hospitals. By assessing fT3 status, we can predict the outcome of patients with HF and improve outcome in acute HF patients.

Study tool
Structured Pro forma.

Inclusion criteria
Patients diagnosed with acute HF, admitted to the Department of General Medicine, Government Medical College, Kottayam.

Exclusion criteria
The following criteria were excluded from the study: • Patients with documented thyroid disease.
• Patients with documented liver disease, malignancy, chronic kidney disease, and chronic Obstructive Airway Disease. • Patients with present or past history of trauma, brain injury within 3 months. • Patients who had ischemic stroke, intracranial hemorrhage within 3 months. • Patients taking medications causing thyroid dysfunction, such as glucocorticoids, amiodarone, lithium, and tyrosine kinase inhibitors. • Pregnant patients.

Study procedure
After getting clearance from the institutional review board and written informed consent from the patient or immediate relatives, the selected patients diagnosed to have acute HF were taken for study. A history was taken, and previous records were analyzed in detail. A detailed clinical examination was done. The diagnosis of HF was made based on modified Framingham criteria. Investigations including thyroid function test, renal function test, liver function test, and electrocardiogram were done at the time or within 24 h of admission. The serum levels of thyroid hormones (fT3, fT4, and thyroid-stimulating hormone [TSH]) were measured by Chemiluminescence Immunoassay method (Beckman Coulter Access 2 Immunoassay System). A screening transthoracic echocardiographic evaluation was performed during the course of hospital stay.
Patients were followed up in ward/intensive care unit (ICU). Their length of hospital stay, need for inotropes, need for mechanical ventilation, and need for ICU facility were noted. End points of study were either discharge from the hospital or death of the patient.

Data management and statistical analysis
Data were entered into Microsoft excel and analyzed using IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. IBM Corp. Categorical variables were expressed as frequency (percentage) and continuous variables were expressed in mean and standard deviation. Association of T3 status, outcome variable, and T4 status with categorical variables was done using Pearson Chi-square test. Test for the association of T3 status, outcome variable, and T4 status with the number of days in ICU or hospital was assessed using Mann-Whitney U test. Factors affecting the need for mechanical ventilation were assessed using multiple logistic regression analysis. p<0.05 was considered the threshold for statistical significance.

RESULTS AND OBSERVATIONS
A total of 176 subjects were included in the final analysis.

Inference
Among 176 patients, 101 were males and 75 were females.
The minimum age was 15 and the maximum age was 90 years.
Maximum number of patients was in the age group of 51-60 years (35 males and 22 females).
The prevalence of low T3 syndrome was comparable across all age groups as seen in Graph 1 and Table 1.  Table 2 and Graphs 2 and 3.

Inference
There was no statistical association between gender and T3 status in this population, as seen in Table 3 and Graph 4.

Inference
The mean number of days of hospital stay was 5.09 days with a standard deviation of 1.79. 65 of 176 patients were admitted to either ICU or high dependency unit (HDU). The mean number of ICU/HDU stay among all subjects was 1.00 day. Among patients who were treated in ICU/HDU, the mean number of ICU/HDU stay was 2.70 days. This is seen in Tables 4 and 5, and Graph 5.

Inference
The mean age of patients with Low T3 syndrome was 59.12, with a standard deviation of 11.908. The mean age among patients with normal T3 was 58.05 with a standard deviation of 13.828 (Table 6).
There was no association between age with the T3 status in this population.

Inference
About 53.5% of patients with low T3 syndrome required ICU/HDU admission, whereas only 14.7% of patients with normal T3 were treated in ICU/HDU.

Kumaran and Zachariah
Of 65 patients who required ICU/HDU care, 54 patients (83.07%) patients had Low T3. There was a statistically significant association between ICU/HDU admission and T3 status, with a p<0.001 (Table 7).

Inference
There was no statistically significant association between T3 status and duration of stay in ICU (Table 8).

Inference
Among patients with low T3 syndrome, 35.6% required mechanical ventilation. Among patients with normal T3, only 9.3% required mechanical ventilation. Of 43 patients who required mechanical ventilation, 36 patients (83.7%) were from low T3 group. There was a statistically significant association between the need for mechanical ventilation with the levels of T3, with a p<0.001 (Table 9).
Of 43 patients who required mechanical ventilation, 31 patients were treated with non-invasive ventilation, and 12 patients needed invasive ventilation (Table 10 and Graph 10).
About 13.9% of patients with low T3 syndrome required inotrope support. About 5.3% of patients with normal T3 group required inotrope support. There was no statistically significant association between inotrope requirement and T3 status.

Inference
There is a statistically significant difference in mean T3 among the outcome groups. The T3 value was lower in patients who expired, the p-value being 0.019.
The average length of hospital stay in this study group was 5.09 days with a standard deviation of 1.79 days, which is 5.29±1.85 days in the low T3 group and 4.8±1.65 days in the normal T3 group (Table 11). The median length of hospital stay was 5 and 4 in the low T3 group and the normal T3 group, respectively. No statistical association was found between T3 status and length of hospital stay.

DISCUSSION
In this study, 176 patients with acute HF who met the inclusion criteria, admitted to the General Medicine department of Government Medical College Kottayam were enrolled. A diagnosis of HF was made by Framingham criteria. The thyroid profile was sent at admission.

Kumaran and Zachariah
The mean age of patients in this study was 58.66±12.73 years. The minimum and maximum ages were 15 and 90 years. In the study by Iervasi et al., [6] the mean age of patients with HF was 66±12 years [67]. This is comparable to our study.
In this study, 58.5% were males and 41.5% were females. In the study conducted by Iervasi et al. [6] 56% were males, which is similar to our study.  respectively. The landmark study by Iervasi et al. [6] involving 573 patients with heart disease found a prevalence of 30%. In a study by Zargar et al. [9] the prevalence of sick euthyroid syndrome in chronic non-thyroidal illness was 20.60%. This could be because our study population consisted of patients with acute HF, while the other quoted studies consisted of patients with chronic HF or both acute and chronic HF.
The mean age of patients with Low T3 syndrome was 59.12±11.908 years, whereas the mean age among patients with normal T3 was 58.05±13.828 years. There was no association between age and T3 status in this population as seen in Table 12.
The mean number of days of hospital stay was 5.09±1.79. In a study conducted by Rothberger et al., low T3 correlated with an increased length of stay in the hospital (median 11 vs. 7 days, p<0.001) [11]. In our study, the median duration of hospital stay was 5 versus 4 days in low T3 group and normal T3 group. There was no statistical association between low T3 status with length of hospital stay. The mean duration of hospital stay in patient group with low T3 and normal T3 are 5.3 days and 4.8 days, respectivel (Table 13).