Thyroid Hormone Abnormalities in Euthyroid Patients with Chronic Kidney disease in Abuja, Nigeria

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1 Advances in Biomedical Sciences 2018; 3(4): Thyroid Hormone Abnormalities in Euthyroid Patients with Chronic Kidney disease in Abuja, Nigeria Mathias Abiodun Emokpae *, Best Ubebe, Joan Oghogho Osunbor Department of Medical Laboratory Science, School of Basic Medical Sciences, College of Medical Sciences, University of Benin, Benin City, Nigeria address * Corresponding author To cite this article Mathias Abiodun Emokpae, Best Ubebe, Joan Oghogho Osunbor. Thyroid Hormone Abnormalities in Euthyroid Patients with Chronic Kidney disease in Abuja, Nigeria. Advances in Biomedical Sciences. Vol. 3, No. 4, 2018, pp Received: August 7, 2018; Accepted: August 17, 2018; Published: September 1, 2018 Abstract Introduction: Chronic Kidney disease (CKD) has emerged as a global health challenge and is associated with cardiovascular diseases and increase healthcare expenditure in most countries. Thyroid gland regulates several physiological functions of the body including that of the kidney and any disorder of the kidney may impact on thyroid function. Studies on thyroid hormone abnormalities in patients with non-dialysis CKD are scarce in our setting. Objective: This study seeks to determine the pattern of thyroid hormone abnormalities in non-dialysis CKD patients attending renal clinics in Abuja metropolis. Methods: Serum thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH), urea and creatinine were analyzed in 65 adult patients with CKD and 60 control subjects by Enzyme linked Immunoabsorbent assay and Selectra ProS auto analyzer respectively. Estimated glomerular filtration rate was calculated using Cockcroft-Gault formula. Results: Thyroid hormone abnormalities were observed in 38 (58.5%) subjects with CKD while 27 (41.5%) had euthyroid status. The pattern of thyroid abnormalities observed were sick euthyroid syndrome 17 (26.1%), subclinical hypothyroidism 8 (12.3%), hypothyroidism 7 (10.8%) and hyperthyroidism 9 (9.2%). Serum creatinine correlated negatively with T4 (r = -0348; p<0.001) and positively with TSH (r = 0.286; p = 0.02). Conclusion: Thyroid function tests evaluation may be considered in some patients with CKD but careful interpretation of results is needed. Keywords Chronic Kidney Disease, Thyroid Dysfunction, Thyroid Hormones 1. Introduction Chronic Kidney disease (CKD) has emerged as a global health challenge and is associated with cardiovascular disease, heart failure and increase healthcare expenditure in most countries [1-2]. Thyroid gland regulates several physiological functions of the body. The thyroid hormones have modulating actions on water and electrolytes metabolism, protein synthesis, development and control of many other important hormones. Dysfunction of the thyroid gland can affect the production of the thyroid hormones, which may be associated with several pathologies in the body [3]. The interactions between kidney and thyroid functions are known for years [2-3]. Whereas thyroid hormones are vital for growth and development of the kidney, maintenance of water electrolyte homeostasis, the kidney is involved in the metabolism and elimination of thyroid hormones from the circulation [4]. A decline in renal function is associated with alteration in the production, secretion, metabolism and excretion of thyroid hormones. Changes in thyroid hormone status have been reported in patients with CKD and the prevalence of thyroid dysfunction was shown to increase with severity of CKD [5-6]. Studies have reported that thyroid hormone profile is altered in patients with CKD mainly in the stage 5 CKD and the commonest thyroid dysfunction being low triiodothyronine (T3), low thyroxine (T4) and normal thyroid stimulating hormone levels [3-4].

2 35 Mathias Abiodun Emokpae et al.: Thyroid Hormone Abnormalities in Euthyroid Patients with Chronic Kidney disease in Abuja, Nigeria Some authors have observed that thyroid functions were normal in earlier stages of renal disease indicating that the low serum T3 and T4 levels were common in advanced disease [4]. Even though thyroid dysfunction has been associated with CKD, no recommendation is available regarding the treatment of subtle or mild thyroid abnormalities among individuals with CKD not requiring dialysis [7]. These thyroid abnormalities could act as risk factors for adverse health outcomes such as cardiovascular diseases and could accelerate kidney disease progression [8]. Early identification and treatment of thyroid dysfunction in subjects with renal insufficiency or those at risk of thyroid dysfunction is important for survival and improve quality of life especially in resource limited setting like ours [9]. The previously reported thyroid hormone abnormalities among patients with CKD are inconsistent. Whereas studies among Asians and Caucasians indicated low T3 and T4 with normal or increased TSH, recent study among Africans (Ghanaian) with non-dialysis CKD showed higher T3 and T4 but not TSH which were associated with the incidence of CKD and egfr decline [7]. In addition, information on thyroid hormone abnormalities in patients with CKD or renal insufficiency that has not progressed to end stage renal disease (stage 5 CKD) and not requiring dialysis is few in our setting. This study was therefore designed to bridge this gap. The proportion and the pattern of thyroid hormone abnormalities among patients with non-dialysis CKD patients are not known. This study seeks to determine the pattern of thyroid hormone abnormalities in non-dialysis CKD patients attending renal clinics in Abuja metropolis. 2. Methods 2.1. Study Design and Subjects This is a case control study of 65 non-dialysis patients with renal insufficiency attending renal clinics of Asokoro District Hospital and Wuse District Hospital in Abuja. They do not have previous history of thyroid dysfunction and 60 apparently healthy control subjects were recruited for the study. All the study participants were non-dialysis dependent patients with CKD and were assessed for thyroid function. A semi-structured questionnaire was administered to each patient at enrollment to obtain demographic data, full clinical history including diabetes status, hypertension and poly cystic kidney disease Inclusion and Exclusion Criteria All participants with clinical and laboratory evidence of CKD such as symptoms of ureamia for at least 3months, elevated serum urea, serum creatinine, below normal estimated glomerular filtration rate (egfr), anaemia, urine specific gravity and changes in serum electrolytes were included in the study. Patients with history of thyroid disorders and other conditions such as acute illness, recent surgery, trauma or burns and those taking drugs altering thyroid profile like amiodarone, steroids, dopamine, phenytoin, estrogen pills and iodine containing drugs as well as those who did not give consent were excluded Ethical Consideration Informed consent was obtained from all participants prior to their inclusion in the study. Ethical approval was sought and obtained from the Health Research Ethics Committee of Federal Capital Territory, Abuja (code: EHREC/2016/01/84/ , dated 24/10/2016) Definition of Cases Chronic Kidney disease was defined as the presence of kidney damage or decreased kidney function characterized by abnormal albumin excretion and decreased estimated glomerular filtration rate (egfr) of 90mL/min/1.73m 2 that have persisted for more than 3 months with proteinuria. The egfr was calculated using Cockcroft-Gault formula [10]. Proteinuria refers to the presence in urine of protein by dipstick urinalysis reading of +1. The stages of non-dialysis dependent renal disease (stages 2-4) were defined according to the American National Kidney Foundation as follows: stage 2:eGFR 60-89mL/min/1.73m 2, stage 3:eGFR 30-50mL/min/m 2, and stage 4:eGFR 15-29mL/min/1.73m 2 [12] Specimen Collection Five milliliters of whole blood was collected from antecubital vein of the subjects into plain sterile containers. The blood sample was allowed to clot and serum separated after centrifugation at 3000rpm for 10 minutes. The serum was then stored at -20 C prior to analysis for triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) using ELISA techniques and reagent supplied by Accubind (Monobind Inc. Lake Forest, USA). Serum creatinine and urea were analyzed using Selectra ProS chemistry autoanalyzer, Puteaux, France and reagents supplied by ELITech group, Rotterdam, Netherlands. Thyroid dysfunction was considered if a participant s thyroid hormone level was outside the recommended reference ranges (T3= nmol/L; T4=56-139nmol/L; TSH= µIU/mL). Sub-clinical hypothyroidism was defined as TSH levels higher than the upper limit of reference range with T3 and T4 levels within normal reference range Statistical Analysis Graphpad Prism (version 7.0; Graphpad Software, San Diego, California, USA) was used for statistical analysis. Error bars were reported as mean±standard deviation. The mean values of the measured parameters were compared between cases and control group using student s t-test. Oneway analysis of variance (ANOVA) and post hoc multiple comparison was performed to compare the different patterns of thyroid abnormalities. Pearson correlation coefficient was used to determine the association between thyroid hormone levels and serum creatinine and egfr. A p-value of <0.05 was considered statistically significant.

3 Advances in Biomedical Sciences 2018; 3(4): Results Table 1 shows the comparison of the measured parameters between CKD subjects and controls. Serum urea, creatinine and TSH were significantly higher (p<0.001) in renal impaired subjects than control subjects. On the other hand, serum T3 (p=0.006), T4 and egfr (p<0.001) were significantly lower in CKD subjects than controls. Table 1. Comparison of thyroid hormone levels among chronic kidney disease subjects and controls. Parameters (Reference range) CKD patients (n=65) Controls (n=60) P-value Age (Years) 56.2± ± Serum Urea (mmol/l)( ) 26.1± ± Serum Creat (µmol/l)(80-133) 910 ± ± egfr (ml/min/1.73m 2 )( 90) 58.32± ± T3 (nmol/l)( ) 1.7 ± ± T4 (nmol/l)(56-139) 88.5 ± ± TSH (µiu/ml)( ) 5.13 ± ± egfr=estimated glomerular filtration rate; T3=triiodothyronine, T4=thyroxine; TSH=thyroid stimulating hormone; serum creat= serum creatinine; reference range in parenthesis. Table 2 shows the pattern of thyroid hormone abnormalities among non-dialysis CKD patients. It indicates that 27 (41.5%) had euthyroid status while the following thyroid dysfunction were observed; 17 (26.1%) euthyroid sick syndrome, 8 (12.3%) sub-clinical hypothyroidism, 7 (10.8%) hypothyroidism and 6 (9.2%) hyperthyroidism. Subjects with hyperthyroidism had significantly higher (p=0.05) urea concentration when compared to subjects in the euthyroid state and other observed thyroid abnormalities. Creatinine level and egfr were not significantly different among the patients of different thyroid function states. Subjects with hyperthyroidism had a significantly higher (p<0.001) T3 when compared with hypothyroidism subjects, subclinical hypothyroidism, euthyroid sick syndrome and euthyroid subjects. Subjects with hypothyroidism had a significantly lower (p<0.001) T3 levels when compared with subclinical hypothyroidism and euthyroid subjects. Similarly, subjects with euthyroid sick syndrome had a significantly lower (p<0.001) T3 when compared with euthyroid state. Subjects with subclinical hypothyroidism had significantly higher (p<0.001) T3 when compared to subjects with euthyroid sick syndrome. There was a significant increase in T4 concentration in subjects with hyperthyroidism compared to hypothyroidism, subclinical hypothyroidism, euthyroid sick syndrome and euthyroid subjects (p<0.001). Subjects with hypothyroidism had significantly lower T4 concentration compared with subclinical hypothyroidism, euthyroid sick syndrome and euthyroid subjects (p<0.001). The mean TSH level was significantly lower in subjects with hyperthyroidism compared to hypothyroidism, subclinical hypothyroidism, euthyroid sick syndrome and euthyroid subjects (p<0.001). Subjects with hypothyroidism had significantly higher TSH concentration compared to euthyroid sick syndrome subjects and euthyroid state (p<0.001). Subjects with subclinical hypothyroidism also had a significantly higher concentration of TSH when compared to euthyroid sick syndrome subjects and euthyroid state (p<0.001). Table 2. Pattern of thyroid hormone abnormalities in non-dialysis Chronic Kidney Disease. Euthyroid Sick Subclinical Hypothyroidism Parameters (Reference Euthyroid Hyperthyroidism Syndrome Hypothyroidism range) N = 27 (41.5%) N = 17 (26.1%) N = 8 (12.3%) N = 7 (10.8%) N = 6 (9.2%) P value Urea (mmol/l)( ) 23.7± ± ± ± ±1.65 c 0.05 Creatinine (µmol/l)(80 133) 924± ±92.7 a 932± 64.8 a 813± 89.9 a 905±43.9 a 0.94 egfr (ml/min/1.73m 2 ( 90) 58.2± ±6.1 a 56.3±6.8 a 56.9±8.0 a 57.2±4.2 a 0.82 T3 (nmol/l)( ) 2.24± ±0.02 b 1.94± 0.23 bc 0.472± 0.05 b 3.74±0.13 b T4 (nmol/l)(56 139) 86± ±4.03 a 79±4.3 a, b 49.8±1.82 b, c 172±8.27 b TSH (µiu/ml)( ) 3.71± ±0.28 a 12.2±1.36 b 12.9±1.73 b 0.282±0.01 b a = p>0.05; b =p<0.001; c =p<0.05 Table 3 shows the correlation between serum creatinine, egfr and measured thyroid hormone levels in subjects with CKD. Serum creatinine correlated negatively with T4 (r = , p<0.001) and positively with TSH (r = 0.286, p = 0.02) while egfr correlated positively with T3 (r=0.316, p=0.01). Table 3. Correlation between serum creatinine, estimated Glomerular filtration rate and measured thyroid hormones. Parameters R-value P-value Creatinine vs T < Creatinine vs T Parameters R-value P-value Creatinine vs TSH egfr vs T egfr vs T egfr vs TSH Discussion Chronic kidney disease may adversely impact the thyroid function and the influence of thyroid dysfunction on renal function is associated with the role the kidney plays in the

4 37 Mathias Abiodun Emokpae et al.: Thyroid Hormone Abnormalities in Euthyroid Patients with Chronic Kidney disease in Abuja, Nigeria degradation and elimination of several metabolites including thyroid hormones. Thyroid hormone abnormalities may be observed in patients with CKD and several authors have reported thyroid dysfunctions in patients with CKD on maintenance haemodialysis [4, 13-15]. There are conflicting reports regarding thyroid hormone abnormalities among Africans and Caucasian/Asians with non-dialysis CKD. Generally, in this study we observed significantly lower serum T3 and T4 with higher TSH levels in subjects with CKD than controls. Some 48.5% of subjects with CKD had various types of thyroid hormone abnormalities; euthyroid sick syndrome (26.1%), sub-clinical hypothyroidism (12.3%), hypothyroidism (10.8%) and hyperthyroidism (9.2%) while 41.5% had euthyroid status. The observed significantly lower levels of T3, T4 and higher TSH in this study are partly consistent with previous studies [3-4, 16-17]. The authors reported that serum TSH levels were either normal or elevated while free T3 and free T4 were low or normal. Kannan et al [3] reported that their study participants with CKD had low T3 and T4 while TSH levels were within normal range. Our observation is not consistent with a recent study among Ghanian patients with non-dialysis CKD [7]. The authors reported that TSH levels were not significantly different between CKD patients and clinically euthyroid subjects. Furthermore, free T3 and free T4 were reported to be significantly higher in CKD patients than controls and the levels of the measured parameters were within the normal reference range [7]. It was however explained that the elevated free T3 and free T4 could have been confounded by concomitant comorbidities like hypertension since study has indicated that hyperthyroidism and hypothyroidism are associated with high blood pressure [18]. In this study, we observed that 48.5% of CKD patients had various forms of thyroid abnormalities while 41.5% had euthyroid status. This is consistent with that reported by Kannan et al [3]. They observed that 29/50 (58%) had thyroid profile abnormalities while 21/50 (42%) had normal thyroid profile. The pattern of thyroid abnormalities was however different from the pattern we observed in this study. The authors reported that among the 58% of CKD patients with thyroid abnormalities, 28% had primary hypothyroidism characterised by low T3 level and normal T4 levels while 20% had both low T3 and low T4 levels. The percentage of patients having low T3 and low T4 levels were reported to gradually increase with decreased GFR [3]. We observed that 26.1% of the study participants had euthyroid sick syndrome and is less than 37/50 (74%) reported previously by Haria and Lunia [19]. It was stated that all severe illnesses including CKD can cause abnormal circulating thyroid hormones in the absence of underlying thyroid disease thus making these measurements potentially misleading. The highest percentage of our study population with abnormal thyroid hormones levels was euthyroid sick syndrome. The reason may be attributed to increased release of cytokine, decrease in total and unbound T3 levels (low T3 syndrome) with normal levels of T4 and TSH. The T4 conversion by peripheral deiodination is impaired. The fluctuation in TSH levels was attributed to the effects of cytokines such as interleukin-12 (IL-12) and IL-18 which are generated in high levels during CKD [20]. Subclinical hypothyroidism is an asymptomatic stage of hypothyroidism (SCH) and can progress to overt hypothyroidism with time. The exact mechanisms of SCH are not clear. It can lead to decrease cardiac output, increase peripheral vascular resistance leading to intra-renal vasoconstriction. It can lead to changes in iodine metabolism and decrease peripheral sensitivity to hormones [21]. Prevalence of 9.5% SCH was previously reported among a large population of CKD patients [22] and was lower than 12.3% observed in our study. We also observed 10.8% hypothyroidism and 9.2% hyperthyroidism in this study. In hypothyroidism, there is decrease cardiac output and enhanced systemic vascular resistance leading to decrease renal blood flow, decrease GFR and increase serum creatinine [18, 23]. On the other hand, hyperthyroidism can result to increase cardiac output and circulating blood volume and creatinine clearance [18]. Aryee et al [7] reported that 2% and 3% of CKD patients and control group had evidence of hypothyroidism while 2% was reported to have SCH. These were however less than 10.8% hypothyroidism and 9.2% hyperthyroidism observed in our study. The physiological benefits of a hypothyroid state in CKD and risk of CKD progression with hyperthyroidism calls for a conservative approach in the management of thyroid hormone abnormalities in CKD [24]. 5. Conclusion Some 48.5% of the non-dialysis CKD subjects had thyroid hormone abnormalities which include sick euthyroid syndrome, subclinical hypothyroidism, hypothyroidism and hyperthyroidism while 41.5% had euthyroid status. Assessment of thyroid hormone profile may be considered in the management and treatment of patients with CKD and careful interpretation of the results is desirable. Acknowledgements We appreciate the contributions of the Physicians, Nurses and Medical Laboratory Scientists of Asokoro District Hospital and Wuse District Hospital towards the completion of this study. Conflict of Interest None declared. References [1] Niemczyk S, Niemczyk L, Romejko-Ciepielewska K. Basic endocrinological disorders in chronic renal failure. Endocrinol Polska. 2012; 63 (3): [2] Singh S, Upadhyay-Dhungel K, Aryal G. Value of calcium and phosphorous in chronic kidney disease patients undergoing hemodialysis: a retrospective study. J Pathol Nepal. 2012; 2:

5 Advances in Biomedical Sciences 2018; 3(4): [3] Kannan A, Sriramakrishnan V, Kannan B, Anandan H. Thyroid Function Abnormalities in patients with chronic kidney disease-a Prospective study. Int J Scient Study 2017; 5 (4): [4] Singh S, Verma A, Aryal G, Thapa S, Khakurel S, Shrestha K. Thyroid hormone profile in patients with chronic kidney disease: A single-centre study. J Nepal Health Res Counc 2016; 14 (34): [5] Rothberg MB, Kehoe ED, Courtemanche AL, Kenosi T, Pekow PS, Brennan MJ et al. Recognition and management of chronic kidney disease in an elderly ambulatory population. J Gen Intern Med. 2008; 23 (8): [6] James MT, Hemmelgarn BR, Tonlelli M. Early recognition and prevention of chronic kidney disease. Lancet. 2010; 375 (9722): [7] Aryee NA, Tagoe EA, Anoma V, Arko-Boham B, Adjei DN. Thyroid hormone Status in Ghanian Patients with chronic Kidney disease. Pan Afr Med J 2018; 29: [8] Hossain M, Shah K, Begum N, Ahmed P, Islam AKMM, Chowdhury NI. Thyroid Functional Status in Chronic Kidney Disease. Bangladesh J Nucl Med, 2015; 18 (2): [9] Foster M, Rawlings AM, Marrett E, Neff D, Willis K, Inker LA, Selvin E. Cardiovascular disease risk factors in chronic kidney disease: Overall burden and rates of treatment and control. Arch Intern Med. 2006; 166 (17): [10] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16 (1): [11] Segarra AB, Ramirez M, Banegas I, Hermoso F, Vargas F, Vives F, et al. Influence of thyroid disorders on kidney angiotensinase activity. Horm Metab Res. 2006; 38: [12] Levey As, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation Practice Guidelines For Chronic Kidney Disease: Evaluation, Classification, and Stratification. Ann Intern Med. 2003; 139: [13] Kayima JK, Otieno LS, Gitau W, Mwai S. Thyroid hormone profile in patients with chronic renal failure on conservative management and regular hemodialysis. East Afr Med J. 1992; 69 (6): [14] Ekart R, Ferjuc A, Furman B, Gerjevic S, Bevc S, Hojs R. Chronic kidney disease progression to end stage renal disease: a single center experience of the role of the underlying kidney disease. Ther Apher Dial. 2013; 17: [15] Zoccali C, Mallamaci F, Tripepi G, Cutrupi S, Pizzini P. Low triiodothyronine and survival in end stage renal disease. Kidney Int. 2006; 70 (3): [16] Chonchol M. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2008; 3 (5): [17] Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P et al. Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med. 2007; 262 (6): [18] Prisant LM, Gujral JS, MulloyAL. Hyperthyroidism: A secondary cause of isolated systolic hypertension. J Clin Hypertens (Greenwich). 2006; 8 (8): [19] Haria J, Lunia M. Sick euthyroid syndrome in chronic kidney disease. J Evol Med Dental Sci 2013; 2 (43): [20] Chopra IJ. Euthyroid Sick Syndrome: Is it a misnomer? J Clin Endocrinol Metab 1997; 82: [21] Zhou JB, Li HB, Yang JK. Subclinical hypothyroidism and the risk of chronic kidney disease in T2D subjects: A case control and dose-response analysis. Medicine (Baltimore) 2017; 96 (15): e6519. [22] Kaptein EM, Quion-Verde H, Chooljian CJ, Tang WW, Friedman PE, Rodriquez HJ, et al. The thyroid in end-stage renal disease. Medicine (Baltimore) 1988; 67: [23] Basu G, Mohapatra A. Interactions between thyroid disorders and kidney disease. Indian J Endocrinol Metab 2012; 16:

Thyroid Function Abnormalities in Patients with Chronic Kidney Disease - A Prospective Study

Original Article Print ISSN: 2321-6379 Online ISSN: 2321-595X DOI: 10.17354/ijss/2017/338 Thyroid Function Abnormalities in Chronic Kidney Disease - A Prospective Study Aarathy Kannan 1, V Sriramakrishnan