Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis

doi:10.21203/rs.3.rs-21868/v1

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Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis

https://doi.org/10.21203/rs.3.rs-21868/v1

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published 01 Sep, 2020

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Background: Sick euthyroid syndrome is frequent in children admitted with diabetic ketoacidosis (DKA). This study evaluates the interplay of various metabolic factors with occurrence of deranged thyroid function tests in children admitted for management of DKA.

Methods: 194 children admitted for management of DKA were selected from hospital records. Children on thyroxine replacement or those with overt hypothyroidism or anti-TPO antibody positive were excluded. Tests for liver function, renal function, lipid profile, serum osmolarity, thyroid function, c-peptide levels, and glycosylated hemoglobin were done for all. Children were divided into a euthyroid group (n=88) and an euthyroid sick syndrome（ESS）group (n=106).

Results:The ESS group had a higher WBC, PG, β-HB, TG, AG, and HbA1c and lower HCO3-, PA, and ALB levels compared with the euthyroid group (P<0.05). FT3 levels were significantly correlated to β-HB, HCO3-, AG, PA, and HbA1c. (r=-0.642, 0.681, -0.377, 0.581, -0.309, respectively; P<0.01) FT4 levels were significantly correlated to β-HB, HCO3-, and ALB levels (r=-0.489, 0.338, 0.529, respectively; P<0.01). TSH levels were significantly affected by HCO3^– only (r=-0.28; P<0.01). HCO3^– level was the most important factor deciding adjudication to euthyroid or ESS group on logistic regression analysis (OR=0.844, P=0.004, 95%CI=0.751-0.948).

Conclusions: Lower levels of free thyroid hormones and occurrence of ESS is associated with a higher degree of acidosis in children admitted with DKA. Lower levels of markers of nutrition such as serum albumin and pre-albumin levels are associated with lower levels of free thyroid hormone concentrations in children with DKA.

Endocrinology & Metabolism

diabetes

thyroid function

metabolic changes

T1DM

children

Type 1 diabetes (T1DM) is a common autoimmune disorder affecting children under the age of 18 years although no age group is exempt. It is commonly associated with other autoimmune disorders like celiac sprue and autoimmune hypothyroidism. Absolute insulin deficiency is a sine qua non of T1DM and hence hospital admissions for both hypoglycemic and hyperglycemic emergencies are frequent.

The number people living with T1DM is estimated to reach 5 million by 2050 in US [1]. The incidence rate of T1DM is higher in developed countries of the Western hemisphere, such as UK, Switzerland, and US, whereas the incidence rate is reportedly lower in Asian countries such as China. Prevalence of diabetic ketoacidosis (DKA) is relatively high in China in spite of a lower incidence of T1DM as compared with the developed countries of the Western hemisphere [2]. DKA may be the presenting feature at diagnosis in up to 50% patients with T1DM. DKA in children is associated with a high morbidity and mortality, especially in children less than 5 years of age [3].

Euthyroid sick syndrome (ESS), also known as non-thyroidal illness syndrome, is a transient derangement in thyroid function tests characterized by low free T3 levels. ESS is reportedly associated with a higher risk of mortality among critically ill patients admitted with myocardial infarction, sepsis, trauma, and chronic kidney disease.

Previous studies have shown that patients with ESS tend to be more critically ill compared to those with normal thyroid function. Moreover, poor glycemic control is also associated with a lower level of free T3. ESS in children with T1DM connotes a poor metabolic millieu and has been recognized as a predictor of poor prognosis of T1DM[4]. Studies show that ESS is common in children with DKA [5]. The potential mechanisms in children with T1DM could be (but not limited to) deranged regulation of the hypothalamic-pituitary-thyroid axis, effect of inflammatory cytokines, or consequence of oxidative stress [6].

A study by Hu et al showed that children with T1DM diagnosed with DKA and were found to have ESS had a higher level of HbA1c, anion gap, and plasma glucose, whilst having a lower level of bicarbonate in comparison with those without ESS [7]. However, it was a retrospective case-control study, which is potentially susceptible to recall and selection bias.

Studies on the interplay between DKA, ESS, and various metabolic parameters like hyperglycemia, hyperketosis, acidosis, and other acute phase reactants are sparse. In this study, we aim to evaluate the metabolic parameters like leukocyte count, blood biochemistry, liver function, kidney function, blood lipid, and C-peptide levels in relation to risk of deranged thyroid function among children with T1DM admitted for management of DKA or acute hyperglycemia.

2.1. Patient recruitment and exclusion criteria: This is a retrospective case-control study undertaken in the Pediatric Department of Shandong Provincial Hospital affiliated to Shandong University in Shandong, China. We enrolled children with newly diagnosed (or already suffering from) T1DM admitted to the hospital for management of DKA or acute hyperglycemia between January 2014 and August 2019. Ethical approval was obtained from the Ethical Committee of Shandong Provincial Hospital. Study participants and parents of minors provided signed informed consent at the moment they admitted to the hospital..

T1DM was diagnosed based on the American Diabetes Association criteria [8]. The criteria for diagnosing DKA was blood glucose (BG) >11 mmol/L, venous pH <7.3, or bicarbonate <15 mmol/L. A diagnosis of DK was made, if blood sugar was more than 11 mmol/L, urine ketones were positive, but venous pH ≥7.3 or serum bicarbonate level was normal (≥15mmol/L) [9]. Euthyroidism was defined when levels of thyroid function tests were within the reference ranges. ESS was defined when FT3 and/or FT4 levels were decreased and TSH levels were normal or decreased.[7,10,11]

A total of 237 children patients were screened. All children under the age of 18 years admitted for management of DKA (either newly diagnosed or already on insulin) were included in the trial. Children with overt hypothyroidism, on thyroid medications, or those with other types of diabetes like pancreatic diabetes or juvenile type 2 diabetes, morbid obesity, or on anti hyperglycemic agents other than insulin were excluded from the trial. Children on steroids or any such medication that could significantly affect thyroid function tests were also excluded from the analyses. Children with other critical organ illness like those with rheumatic heart disease, heart failure, nephrotic syndrome, celiac sprue, or chronic kidney disease as well as those who were anti-TPO antibody positive were also excluded.

A total of 194 children qualified for the final analysis. 88 children were adjudicated to the euthyroid group, and 106 children were adjudicated to the ESS group.

2.2. Laboratory assays: All samples for laboratory analysis were taken before commencing initial therapy. Serum biochemical analysis including electrolytes, renal function tests, lipid profile, and liver function tests were measured using an automatic biochemistry analyzer (AU5400, Beckman Coulter, Tokyo, Japan). Glycosylated hemoglobin (HbA1c) was measured by high-performance liquid chromatography (HLC-723G7, Tosoh Corporation, Tokyo, Japan). Thyroid function tests were measured using an automated chemi-luminescent immunoassay system (Advia Centaur, Siemens, Munich, Germany). The intra-assay and inter-assay coefficients of variation were <6% for all parameters. Serum C-peptide (C-p) level was measured by chemi-luminescent immunometric assay (Cobas E170, Roche Diagnostics, Mannheim, Germany).

2.3. Statistical methods: Normally distributed data is represented as mean ± standard deviation (SD). Non parametric and skewed data is represented as median (interquartile range). Chi-squared test was used to compare rates and proportions. Two-tailed student t-tests was used to compare normally distributed data between two groups and Mann-Whitney Rank sum test was used to compare non parametric skewed data between the two groups. Pearson and Spearman correlation tests were applied to evaluate associations between parametric and nonparametric data, respectively. Multiple linear regression analysis was done to detect variables which had an independent affect on thyroid function tests. Logistic regression analysis was done using thyroid function status as a binary variable to determine which factors independently influenced the placement of a subject in a particular group. All analysis was performed on Statistical Package for Social Sciences version 25.0 (SPSS Inc. Chicago, IL, USA). A p-value <0.05 was considered statistically significant.

3.1. Baseline clinical and laboratory characteristics: The baseline demographic and clinical characteristics of enrolled children are shown in Table 1. There was no statistically significant difference in mean age, gender ratio, and BMI between the euthyroid and EES groups. Levels of WBC, PG, HbA1c, β-HB, AG, and TG levels were significantly higher in the EES group than in the euthyroid group whereas serum HCO3- levels and PA levels were significantly lower in the EES group than in the euthyroid group (p-value <0.05).

Table 1. Baseline clinical and laboratory characteristics in DK/DKA children

Variables	Thyroid function		Z/T/c²	P
Variables	Euthyroidism	ESS	Z/T/c²	P
Gender (male/female)	50/38	59/47	0.03	0.871
Age (years)	7.16±4.24	7.42±4.27	0.416	0.678
BMI (kg/m²)	16.93±3.19	15.80±3.07	-1.589	0.116
WBC (×10⁹/L)	7.25 (6.15~9.82)	10.72 (7.82~16.9)	-5.316	<0.001*
PG (mmol/L)	19.13 (14.97~27.8)	21.77 (16.89~29.46)	-3.222	0.001*
BUN (mmol/L)	5.35 (4.48~6.35)	4.95 (3.93~6.75)	-0.372	0.71
Cr (umol/L)	31.3 (23.55~48.63)	34.05 (25.15~45.64)	-0.765	0.444
β-HB (mmol/L)	2.92 (1.61~5.22)	6.52 (4.28~8.46)	-7.375	<0.001*
K⁺(mmol/L)	4.25 (3.8~4.6)	4.2 (3.5~4.63)	-1.403	0.161
Na⁺(mmol/L)	133.42±4.72	131.02±5.28	3.309	0.001*
Cl^-(mmol/L)	99.3 (96~103)	101 (96~106.15)	-1.256	0.209
HCO3^-(mmol/L)	19.15 (16.4~21.9)	9.55 (6.63~14.75)	-7.946	<0.001*
OSM (mOsm/L)	284.39 (279~289.03)	280.02 (272.05~286.49)	-0.978	0.328
AG (mmol/L)	19.2 (17.2~22.15)	22.97 (19.65~27.53)	-4.857	<0.001*
ALT (U/L)	14 (12~18.25)	14 (10~17.75)	-0.746	0.456
PA (mg/L)	123.93 (99.39~151)	93.88 (71.97~123.7)	-5.748	<0.001*
ALB (g/L)	39.76±4.58	37.58±5.53	2.809	0.006*
GLO (g/L)	23.1（20.08~26.78)	22.4 (19.3~25.95)	-1.594	0.111
TC (mmol/L)	4.4（3.77~5.06)	4.14（3.67~5.24)	-0.267	0.789
HDL (mmol/L)	1.15（0.96~1.44)	1.13（0.94~1.36)	-0.769	0.442
LDL (mmol/L)	2.51（2.06~2.99)	2.54（1.94~3.11)	-0.594	0.553
TG (mmol/L)	0.97（0.69~1.31)	1.34（0.91~2.19)	-3.724	<0.001*
HbA1c (%)	11.42±2.49	12.62±2.15	-3.593	<0.001*
C-p (ng/ml)	0.19（0.09~0.46)	0.19（0~0.34)	-1.294	0.196

*P＜0.05

3.2 Correlation and multiple linear regression analysis:

3.2.1 Correlating and independent influencing factors of FT3: FT3 levels positively correlated with levels of serum Na+, HCO3-, PA, K+, ALB, GLO, and HDL but negatively correlated with WBC, PG, β-HB, AG, TG, and HbA1c. There was no significant correlation between levels of FT3 and levels of BUN, Cr, Cl-, OSM, ALT, TC, LDL, and C-p (P>0.05) data not shown). Variables showing significant correlation were subjected to multivariate linear regression analysis, which showed that levels of β-HB, HCO3-, AG, PA, and HbA1c independently affected FT3 levels (Table 2). The correlations between these independent variables and FT3 is shown in the scatter plot on Figure 1 (r=-0.642, 0.681, -0.377, 0.581, -0.309, respectively; P＜0.01)

Table 2. Correlating factors of FT3

Variables	B SD		Beta	T	P
WBC	-0.016	0.011	-0.092	-1.417	0.159
PG	-0.003	0.011	-0.021	-0.302	0.763
β-HB	-0.151	0.048	-0.331	-3.116	0.002*
Na⁺	-0.006	0.017	-0.023	-0.351	0.726
K⁺	-0.013	0.102	-0.008	-0.128	0.898
HCO3^-	0.067	0.019	0.342	3.603	＜0.001*
AG	0.042	0.02	0.197	2.161	0.033*
PA	0.011	0.003	0.3	3.961	＜0.001*
ALB	0.02	0.02	0.076	1.04	0.3
GLO	-0.013	0.016	-0.049	-0.815	0.417
HDL	0.113	0.261	0.028	0.434	0.665
TG	-0.069	0.067	-0.064	-1.031	0.305
HbA1c	-0.07	0.034	-0.121	-2.082	0.039*

*P＜0.05

3.2.2 Correlating and independent influencing factors of FT4: FT4 levels positively correlated with serum levels of Na+, HCO3-, PA, ALB, GLO, and HDL but negatively correlated with WBC, PG, β-HB, AG, Cl-, TG, and HbA1c. There was no significant correlation between FT4 levels and BUN, Cr, K+, OSM, ALT, TC, LDL, and C-p (P>0.05), data not shown. Variables showing significant correlation were subjected to multivariate linear regression analysis, which showed that levels of β-HB, HCO3-, and ALB significantly affected FT4 levels (Table 3). The correlations between these variables and FT4 levels is shown in the scatter plot on Figure 2 (r=-0.489, 0.338, 0.529, respectively; P<0.01).

Table 3. Correlating factors of FT4

Variables	B SD		Beta	T	P
WBC	-0.009	0.045	-0.017	-0.199	0.843
PG	0.031	0.043	0.063	0.73	0.467
β-HB	-0.434	0.196	-0.303	-2.216	0.028*
Na⁺	0.095	0.077	0.119	1.237	0.218
HCO3^-	0.156	0.084	0.253	1.849	0.047*
AG	0.07	0.082	0.103	0.848	0.398
PA	0.013	0.011	0.119	1.219	0.225
TG	0.135	0.27	0.04	0.501	0.617
HbA1c	0.036	0.136	0.02	0.268	0.789
Cl^-	-0.07	0.039	-0.158	-1.782	0.077
ALB	0.164	0.078	0.193	2.093	0.038*
GLO	-0.026	0.064	-0.032	-0.413	0.681
HDL	1.338	1.053	0.107	1.271	0.206

*P＜0.05

3.2.3 Correlating and independent influencing factors of TSH: TSH showed positive correlation with levels of Na +, HCO3-, OSM, TC, and LDL but negative correlation with WBC, β–HB, and BUN. There was no significant correlation between TSH and levels of PG, K+, Cl-, Cr, ALT, AG, PA, TG, HbA1c, ALB, GLO, HDL, and C-p (P>0.05), data not shown. Variables which showed significant correlation were subjected to multivariate linear regression analysis, which revealed that only serum HCO3- levels had an independent and significant effect on TSH levels (Table 4). The correlations between serum HCO3^- and TSH levels are shown in the scatter plot on Figure 3 (r=-0.28, P<0.01).

Table 4. Correlating factors of TSH

Variables	B SD		Beta	T	P
WBC	-0.009	0.018	-0.053	-0.521	0.603
β-HB	0.043	0.06	0.091	0.704	0.483
Na⁺	0.011	0.022	0.041	0.474	0.637
HCO3^-	0.073	0.025	0.369	2.906	0.004*
BUN	-0.022	0.052	-0.036	-0.422	0.674
OSM	0.006	0.005	0.094	1.138	0.257
TC	0.12	0.259	0.09	0.463	0.644
LDL	0.117	0.346	0.068	0.339	0.735

*P<0.05

3.3 Logistic regression of adjudicated thyroid function group with metabolic covariates：Logistic regression model analysis using the thyroid function subgroup (euthyroid or ESS group) as a non-parametric dependent variable and significantly correlated variables in Table 1 as parametric independent variables revealed that serum HCO3- levels were the only factor that independently and significantly affected thyroid function group adjudication (OR=0.844, P=0.004, 95%CI=0.751-0.948) (Table 5).

Table 5. Logistic regression of adjudicated thyroid function group with metabolic covariates

Variables	B	p-value	Wald	Adjusted p value	OR	95% C.I. for OR
Variables	B	p-value	Wald	Adjusted p value	OR	Inferior	Superior
WBC	0.128	0.062	4.236	0.050	1.136	1.006	1.283
PG	0.007	0.033	0.043	0.836	1.007	0.944	1.074
β-HB	0.153	0.149	1.055	0.304	1.165	0.871	1.558
Na⁺	0.022	0.054	0.161	0.688	1.022	0.92	1.135
HCO3^-	-0.17	0.06	8.151	0.004	0.844	0.751	0.948
AG	-0.023	0.067	0.121	0.728	0.977	0.857	1.114
PA	-0.005	0.008	0.445	0.505	0.995	0.979	1.011
TG	0.228	0.267	0.727	0.394	1.256	0.744	2.119
HbA1c	0.177	0.115	2.357	0.125	1.194	0.952	1.496
ALB	-0.072	0.057	1.628	0.202	0.93	0.832	1.04

Few studies have focused on the interplay of metabolic derangements and deranged free thyroid hormone levels in children with DKA and ESS. Our study shows that children of DKA with ESS had poorer glycemic control as evidenced by higher plasma glucose, higher triglyceride levels, and higher glycosylated hemoglobin. Children with ESS also had a higher degree of acidosis as evidenced by higher levels of anion gap, higher levels of β-HB, and lower levels of bicarbonate. Children with ESS were also more malnourished as evidenced by a lower level of serum albumin and pre-albumin. These proteins also serve as carrier proteins for thyroid hormones and hence could thus affect occurrence of more deranged thyroid function tests during DKA episodes thus signifying a poor reserve of thyroid hormones in the blood. Children in the ESS group had a higher level of WBC signifying either a greater acute phase response or more degree of systemic infection.

Abnormal serum thyroid hormone levels have been well described in patients admitted with acute critical illness, and are often associated with the severity of illness[11-14]. The exact underlying cause for ESS has not yet been elucidated although many hypothesis have been proposed[11]. Multiple factors may contribute to the development of ESS [11,15,16]. In previous research, FT3 and FT4 levels were positively correlated with bicarbonate levels and negatively correlated with HbA1c and AG levels [7]. In the present study, we apprised more number of parameters including some acute phase reactants and nutritional markers in addition to metabolic parameters. The results indicate that many other variables correlate with free thyroid hormone levels. Linear regression analysis confirmed that β-HB and HCO3 levels had an independent influence on both free T4 and free T3 levels while serum pre-albumin levels had an effect on FT3 only and serum albumin levels had an effect on free T4 levels only. It is worth noting that in normal thyroid physiology serum albumin binds to 20% of total T4 circulating in the blood while contributing to only 11% of total T3 in circulation. Hence its correlation with free T4 levels only is not surprising whereas transthyretin (also known as thyroid-binding pre-albumin) has higher affinity to T4 and as such contributes to 11% of circulating bound T4 as opposed to 9% of circulating T3. Therefore, correlation of pre-albumin levels to free T3 levels only is surprising. HCO3^- was the only significant independent influencing factor on TSH.

Previous studies have noticed the relationship between acidosis and free thyroid hormones levels[16,17]. Lower T4 and T3 and higher rT3 serum concentrations were found in patients with metabolic acidosis[17]. Rashidi et al found that the lower the pH in DKA patients, the lower levels of FT3[18]. pH may be the most important factor directly or indirectly affecting iodo-thyronine metabolism and its regulation in vitro and in vivo[17]. Our study results were consistent with these studies as we also found metabolic acidosis as reflected by serum bicarbonate levels to be the most important factor correlating with all parameters of thyroid function tests (i.e. FT3, FT4, and TSH).

Many studies have suggested that blood β-HB can rapidly and accurately diagnose DKA/DK in hyperglycemic patients[19,20]. Measurement of blood ketones has been recommended in national guidelines in UK for assessment of response to therapy and in tailoring insulin infusion rat{Dhatariya, 2017 #29}es[21].{Dhatariya, 2017 #29}However, few studies have detected the relationship between β-HB and thyroid function. Boado et al found that β-HB may be capable of inducing a moderate depression of pituitary and plasma TSH in rats.[22] Our study showed a strong negative correlation between levels of β-HB and free thyroid hormone concentrations.

Our study finding that low albumin and pre-albumin levels are associated with low FT4 and FT3 levels, respectively, adds a new dimension to understanding ESS occurrence in children with DKA, and shows that children who were more malnourished had lesser circulating thyroid hormone reservoir and hence were more likely to have ESS and consequently more likely to have severe acidosis.

Elevated WBC has been shown to be significantly correlated with severity of DKA and DK in other studies similar to ours[23,24].This phenomenon is probably associated with an elevated level of active systemic inflammatory response and oxidative stress[23]. In our study, we found that WBC was higher in the ESS group and was negatively correlated with levels of FT3, FT4, and TSH.

Our study had several drawbacks as it was a retrospective study with a small number of participants. We also did not measure reverse T3 levels which are usually elevated in ESS patients. Our study also does not correlate ESS with recovery times and hospital stay duration as well as other parameters of morbidity associated with DKA, for example venous thrombosis and cerebral edema.

Lower levels of free thyroid hormones were found to be associated with higher degree of acidosis and hence with the severity of DKA/DK.

β-HB, beta-hydroxybutyric acid;ALB, albumin;DK, diabetic ketosis；DKA, diabetic ketoacidosis; ESS, euthyroid sick syndrome; GLO, globulin;HbA1c, glycosylated hemoglobin; HDL, high density lipoprotein;LDL, low density lipoprotein; OSM, osmolarity; PA, prealbumin; PG, plasma glucose; TC, total cholesterol; TG, triglyceride; WBC, white blood cell count;

Acknowledgments: The authors thank the staff of the Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University for their cooperation and their permission to conduct this study.

Authors’ contributions: PS collected and analyzed the data, drafted the initial manuscript and reviewed the manuscript. GL conceptualized and designed the study, supervised the conduct of the study. SG helped to collect and analyzed the data, Daogang Qin,Sen Li and Ying Luan critically edited the manuscript. All authors gave their final approval of the version to be published.

Funding： There is no funding source.

Availability of data and materials: The datasets are available from the corresponding author on reasonable request.

Ethics approval and consent to participate: Ethical approval was obtained from the Ethical Committee of Shandong Provincial Hospital. All patients and parents gave their written informed consent after full explanation of the purpose and nature of all procedures used.

Consent for publication: Not applicable.

Competing interests: The authors declare that they have no competing interests.

Authors' Information:

Department of Pediatrics, Shandong Provincial Hospital Affiliated to Shandong University
Department of Pediatrics, Liaocheng People's Hospital
Department of Endocrinology, Liaocheng People's Hospital

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Determinants of deranged thyroid function parameters in children admitted for management of diabetic ketoacidosis

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