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Abstract
Primary hypothyroidism is observed in adult patients with chronic kidney disease (CKD) though described scantily in the pediatric population. The primary objective of this study was to detect the prevalence of hypothyroidism in children (1-18 years) with CKD as assessed by thyroid profile. This cross-sectional study was conducted in the department of pediatrics of a tertiary care teaching hospital between January 2016 and January 2017. Clinical examination and biochemical investigations were performed for children with CKD aged 1 -18 years. Sixty-five children (51 boys, 43 CKD Stages 1-3) with a mean [standard deviation (SD)] age of 7.9 (3.2) years were enrolled. Overall, 17 (26.2%) had thyroid dysfunction; nine (13.8%) had subclinical hypothyroidism, three (4.6%) overt hypothyroidism, and five (7.7%) had isolated low T3 levels. The prevalence of hypothyroidism increased from 20.9% in CKD Stages 1-3 to 40.9% in Stages 4-5 of CKD; P = 0.09. The mean (SD) height SD scores were lower in those with hypothyroidism than with normal thyroid function [−1.02 (1.69) and −1.89 (1.12), P = 0.003, respectively], lowest at -2.79 (0.65) in overt hypothyroidism. A significant proportion of children with CKD manifest with hypothyroidism who have more profound growth failure. It may be prudent to screen CKD patients for thyroid dysfunction.
Introduction 
Primary hypothyroidism is commonly observed in adult patients with chronic kidney disease (CKD). There is an impaired excretion of iodide by the kidneys leading to higher blood levels and increase in inorganic iodide pool leading to decreased thyroid hormone production with falling glomerular filtration rate (GFR).[1] Patients with CKD also have chronic metabolic acidosis and protein malnutrition which affects iodothyronine deiodination leading to low plasma T3 levels due to decreased survival of T3 and reduced peripheral conversion of T4 to T3.
CKD predisposes to growth failure due to anemia, metabolic acidosis, bone mineral disease, and growth hormone resistance.[2] Besides, a co-existence of hypothyroidism may further affect growth in children. While studies on the prevalence of hypothyroidism in CKD have been done in adults, the literature in the pediatric age group is scant. These studies have shown an inverse relationship between the GFR and risk of hypothyroidism, with the prevalence of hypothyroidism ranging between 20% and 30% in adults with different stages of CKD.[3],[4],[5]
While all other factors such as metabolic acidosis, anemia, and bone mineral disease are screened for in children with CKD, there is no protocol for screening of thyroid functions. This study was aimed at identifying thyroid dysfunction in children with CKD.
Methods This cross-sectional study was conducted in the department of pediatrics of a tertiary care teaching hospital located in the northern part of India between January 2016 and January 2017. All children between the ages of 1 and 18 years detected with CKD and being followed up in a pediatric nephrology clinic or admitted to pediatric wards were included in this study. Children previously diagnosed with hypothyroidism and syndromes associated with both CKD and hypothyroidism (Down syndrome and Turner syndrome) were excluded from the study. Informed consent and assent was obtained from caregivers/patients enrolled in the study. The study protocol was approved by the institute’s ethical committee. The sample size calculated with a population prevalence of 20% for hypothyroidism in children with CKD with a 95% confidence level and 10% absolute precision was 64.[3] Hence, 65 subjects were enrolled in the study.
A pre-tested pro forma was filled which included baseline information, cause of CKD, history of hypothyroidism, and radiological findings. A history related to hypothyroidism included inquiry about cold intolerance, constipation, dry skin, hair fall, and recent weight gain. The examination included anthropometry, general physical examination, and examination of the thyroid gland in a sitting position. Anthropometric assessment and interpretation was done according to the reference standards, and standard deviation scores (SDS) for weight and height were calculated.[6],[7] All the subjects at the time of enrolment were on iron, calcium carbonate, active Vitamin D analogs, and sodium bicarbonate for the management of the underlying CKD.
Six milliliters of venous blood sample was collected in a fasting state from all children under aseptic precautions for the estimation of hemoglobin, blood urea, serum creatinine, serum calcium, phosphorus, and alkaline phosphatase levels; blood gas analysis, lipid profile and thyroid function test were also done. The estimated GFR (eGFR) was calculated using the modified Schwartz formula.[8] The thyroid-stimulating hormone (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) were estimated using the electrochemiluminescence method by Cobas Autoanalyzer using competition principle and T3, T4, and TSH specific antibody.[9] The normal values for fT3 after adjusting for age were taken between 2.0 and 4.4 pg/mL, for fT4 0.93 and 1.7 ng/dL, and TSH values between 0.270 and 5.20 mIU/mL. Overt hypothyroidism was defined as low fT4/fT3 with elevated TSH levels, subclinical hypothyroidism as TSH between 5 and 10 mIU/mL with normal fT4/fT3 and low fT3 syndrome where only fT3 was low.
Statistical Analysis Data were analyzed using software IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA). A comparison of two subgroups of early (Stages 1−3) and late (Stages 4 and 5) of CKD was done. Descriptive statistics were used for quantitative variables. Independent Student’s t-test and ANOVA were used for comparing the groups with continuous data and Chi-square for categorical data, and a 5% probability (P <0.05) was considered statistically significant.
Results A total of 65 children (78% boys) were enrolled in the study; the mean (SD) age was 7.86 (3.2) years, with majority (72.3%) between 5 and 12 years, 24.6% between 1 and 5 years, and 3.1% between 12 and 18 years. Four (6.2%), 11 (16.9%), 28 (43.1%), 14 (21.5%), and 8 (12.3%) subjects had CKD Stages 1, 2 3, 4, and 5, respectively. Congenital anomalies of the kidney and urinary tract contributed to 96.9% of etiological causes in the cohort. The clinical and laboratory parameters of the subjects categorized according to stages (early and late) of CKD are summarized in [Table 1].
Table 1. Clinical and laboratory parameters in children with chronic kidney disease.Seventeen (26.2 %) children were detected with thyroid dysfunction; nine (13.8%) had subclinical hypothyroidism, three (4.6%) overt hypothyroidism, and low T3 syndrome was found in five (7.7%) patients. The prevalence of hypothyroidism increased with decreasing GFR from 20.9% in Stages 1-3 to 36.4% in Stage 4−5 of CKD; [odds ratio 95% confidence interval, 2.2 (0.69, 6.73), P = 0.09]. A comparison of clinical and biochemical parameters between those with normal and abnormal thyroid function is shown in [Table 2]. Height SDS was most affected in those with overt hypothyroidism [−2.79 (0.65)] than those with subclinical hypothyroidism or low fT3/fT4 [−1.67 (1.21) and −1.56 (0.84)], respectively; P = 0.13. None of the patients had goiter or any clinical signs and symptoms of hypothyroidism.
Table 2. Clinical and laboratory parameters based on thyroid profile.The height SDS positively correlated with eGFR (r = 0.38; P <0.001), hemoglobin (r = 0. 36; P = 0.003), and serum bicarbonate (r = 0. 26; P = 0.04) with nonsignificant negative correlation with TSH (r = -0.16; P = 0.2). Serum TSH, fT3, and fT4 did not show significant correlation with eGFR (r = -0.17, r= 0.12, and r = 0.09, respectively; P >0.05).
Discussion The present study reported a prevalence of hypothyroidism in 26% of children (3−18 years) with CKD. Subclinical hypothyroidism was the most common abnormality, with an increased proportion in CKD Stages 4 and 5. Stature was most affected in overt hypothyroidism.
Reduced deiodinase activity with reduced T3 generation, decreased thyroid-hormone-binding globulin, and a central suppression of hypothalamic pituitary axis may be responsible for hypothyroidism seen in CKD. Hypothyroidism has been previously reported in adults with CKD. A case-control study from Northern India reported a prevalence of low fT3 in 76%, low fT4 in 70%, and elevated TSH in 26% (6% in controls) of 30 undialyzed adult CKD patients. fT3 and fT4 showed a strong correlation with creatinine clearance, unlike TSH.[10] In a study from Iraq on 50 adult patients with CKD, 16 (32%) were diagnosed with hypothyroidism, 56% of which had subclinical hypothyroidism.[3] In another study from India conducted among 358 adult patients with CKD, 56.4% had hypothyroidism, of whom 143 (39.9%) had subclinical hypothyroidism and 59 patients (16.6%) had overt hypothyroidism.[4] A similarly higher proportion of subclinical hypothyroidism was seen in the present study, with a higher proportion in those with advanced stages of CKD. Most children with subclinical hypothyroidism would become euthyroid on follow-up;[11] similar data, however, could not be collected in this study.
While most published studies on hypothyroidism in CKD are among the adult population, we came across only a few in children A study from Mexico that enrolled pediatric patients (<17 years) on at least three months of hemodialysis or peritoneal dialysis reported hypothyroidism in 14 (28%) of the 50 subjects.[12] The subjects enrolled were older (13.4 years) and were on dialysis, unlike our study which enrolled younger patients in all stages of CKD, and none on dialysis. Another study on 24 children with CKD showed thyroid dysfunction in at least 50% of the subjects.[13]
Growth is adversely affected in CKD patients due to uremia, anemia, poor nutrition, acidosis, and poor bone health.[14] Thyroid abnormalities would further compromise skeletal growth in these children, as evident from the present study. An inverse correlation with height SDS and TSH suggests the need for evaluation and monitoring the thyroid status of these children.[12]
The absence of a control group for comparing proportions of hypothyroidism was a limitation in the present study. Also the follow-up data of thyroid functions after supplementation were not available in those with thyroid dysfunction
Based on the results of our study, we conclude that the identification of hypothyroidism in CKD may be prudent, especially in those having more severe growth failure. The optimization of medical management and growth monitoring should be practiced during childhood to improve growth outcomes in these children.
Conflict of interest: None declared.
References 
Correspondence Address:
Mukta Mantan
Department of Pediatrics, Maulana Azad Medical College, New Delhi - 110 002, India.
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.352434
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