Introduction: Iraqi J Pharm Sci, Vol.19(1) 2010 Chronic renal failure on thyroid hormones 65 The Effect of Chronic Renal Failure on Thyroid Hormones Layla K. Ali *,1 *Nursing Department , Koya Technical Institute Abstract Chronic renal failure (CRF) affects thyroid function in multiple ways, including low circulating thyroid hormone concentration, altered peripheral hormone metabolism, disturbed binding to carrier proteins, possible reduction in tissue thyroid hormone content, and increased iodine store in thyroid glands.The target of study is to find a relationship between chronic renal failure and thyroid function.In addition, we tried to study the effect of CRF on serum creatinine dependent on the level of thyroid hormones (T3 and T4) and thyroid stimulating hormones(TSH). Forty patients with chronic renal failure (20 male, 20 female) were enrolled in this study in addition to forty healthy individual as control group (20 male, 20 female). The age ranged from (25 -65) years. T4, T3, TSH, urea, uric acid and creatinine were measured in each of the two groups. The results revealed statistically significant reduction in T3 and T4 while there is elevation in TSH, urea,uric acid and creatinine in the patients group compared to the control group. Key word : Chronic Renal Failure,Thyroid Hormones. الخالصة لٍت الهزموواث الدرقٍت بطزق مخعددة حخضمه قلت فً حزكٍش هزمون الغدة الدرقٍةت فةً الةد ٌؤثز القصور الكلوي المشمه على فعا حبةةدأ ت حغٍةةز اٌةةم الهزمةةون فةةً ايويةة ت الماٍطٍةةت تترحبالةةق بةةالبزتحٍه الىاقةةس خمالٍةةت اولدةةاة ميةةخو الهزمووةةاث الدرقٍةةت فةةً الدرقٍةت الهةدم مةه الدرااةت اٌ ةاد عالقةت بةٍه القصةورالكلوي المةشمه ايوي ت الماٍطٍت تالبالسما تكذلك سٌادة خةشن الٍةود فةً الغةدة تالغدة الدرقٍت بايضافت الى دراات حاثٍز الدشس الكلوي المشمه اعخمةادا علةى ميةخوٌاث الهزمووةاث الدرقٍةت تالهزمةون المادةش للدرقٍةت " مةه ايحةااك كم موعةت اةٍطزة اعمار الم ةامٍ شلصةا 04مزٌضا" مصابا" بالدشس الكلوي بايضافت الةى 04جمعج الىمادج مه ( اةةةىت حةةة قٍةةةاص هزمووةةةاث الغةةةدة الدرقٍةةةت ثالثةةةً ٌودٌةةةد الاةةةاٌزتوٍه تالااٌزتكيةةةٍه( الهزمةةةون المادةةةش 52 -52حخةةةزاتي بةةةٍه توٍه تالااٌزتكيةٍه للدرقٍت الٍورٌا امم الٍورٌك تالكزٌاحىٍه بٍىج الىخائج تجةود اولدةاة معىةوي فةً كةس مةه ثالثةً ٌودٌةد الاةاٌز فً ٍه تجد ارحداع ملاوظ فً كس مةه الهزمةون المادةش للدرقٍةت الٍورٌةا ةامم الٍورٌةك تالكزٌةاحىٍه فةً مزضةى القصةور الكلةوي مقاروت بايحااك Introduction The thyroid gland produces two major related hormones thyroxine and triiodothyronine, commonly called T4 and T3, respectively, which play essential roles in the complete lack in the processes of metabolism, growth and development in most vertebrate tissue. Complete lack of thyroid secretion usually causes the basal metabolic rate to fall 40 to 50 percent below normal and extreme excesses of thyroid secretion can increase the basal metabolic rate to 60 to 100 percent above normal [1, 2] . Thyroid secretion is controlled primarily by thyroid stimulating hormone (TSH) secreted by the anterior pituitary gland. Small amount of reverse triiodothyronine (rT3) and other compounds are also found in venous blood [1] . The synthesis of the thyroid hormones requires (150 -200 µg) of iodine daily. Most dietary iodide is reduced to iodine before absorption. Iodine after conversion to iodide in stomach is rapidly absorbed from the gastrointestinal tract and distributed in the extra cellular fluid [3] .There are three thyroid hormones binding proteins in human plasma: albumin, with high capacity and low affinity; thyroxine binding globulin (TBG), with low capacity and high affinity, and transthyretin (TTR) with an intermediate capacity [4] . Thyroid hormone levels are under strict control; this is achieved mainly by feed-back inhibition through: Hypothalamic-pituitary – thyroid axis (HPTA); thyrotrpin – releasing hormone (TRH).l.Thyroid hormone regulation ,thyroid stimulating hormone (TSH) secretion or negative – feed back system on pituitary secretion of (TSH); and factors altering (TSH) secretion ,such as somatostatins dopamine and /or glucocorticoids [5] . Some changes in thyroid function test results are observed in most of the acute and chronic illnesses (i.e. renal diseases, cardiovascular diseases, inflammatory conditions and pulmonary diseases). Alteration in thyroid function test findings may reflect changes in production of thyroid hormone by effects on the thyroid itself, on the hypothalamic - pituitary thyroid – axis, on peripheral tissue metabolism of the hormones, or a combination of these effects [6] . 1Corresponding author E- mail : Nergzkarem@yahoo.com Received : 13/12/2009 Accepted : 27/4/2010 Iraqi J Pharm Sci, Vol.19(1) 2010 Chronic renal failure on thyroid hormones 66 A general conviction exists that patients with thyroid function test abnormalities do not have hypothyroidism despite the low serum hormone levels in blood and low T3 in most of the tissues. Many patients with non- thyroid illness (NTI) also receive drugs-that affect thyroid hormone regulation and metabolism. This discussion does not consider pharmacological interference an intrinsic part of the spectrum of changes in hypothalamic – pituitary thyroid function that occur in (NTI) [6] . Assessment of thyroid function in patients with non- thyroid illness is difficult. Many of them have low serum concentrations of both T4 and T3 and their serum (TSH) concentration may also have been low. Previously, these patients were thought to be eurthyroid, and the term eurthyroid – sick syndrome was used to describe the laboratory abnormalities. It is possible that the changes in thyroid function during severe illness are protective in that they prevent excessive tissue catabolism [7] . There are two important general principles in laboratory assessment of thyroid: thyroid function should not be assessed in seriously ill patients unless there is strong suspicion of thyroid dysfunction. When Thyroid dysfunction is suspected uncritically ill patients, measurement of serum(TSH) alone is inadequate for the evaluation of thyroid function [7]. Chronic kidney disease is defined as either kidney damage or a decreased kidney glomerular filtration rate(GFR) of less than 60 ml / min / 1.73 m 2 for 3 or more months [8] . The causes of the chronic kidney disease could be due to primary and secondary glomerular disease, tubulointerstial disease and vascular disease [9] . Previous studies on thyroid function tests indicate lower thyroid hormone concentration (T3, T4) with normal TSH in heaemodialysed patients compared with normal subjects [10] . Thyroid gland produces T4 but only 20% of the most metabolically active thyroid hormone T3 and 5% to 8% as the calorgenically inactive reverse t3 (rT3) hormone and T4 in tissues such as liver,kidneys and muscles [11] . Haemodialysis employs the process of diffusion across a semi permeable membrane to remove toxic products and excess fluid from the blood, while adding desirable components [12] .The aim of this work is to evaluate thyroid gland function in chronic renal failure patients as an attempt to find a relationship between chronic renal failure and thyroid dysfunction. Materials and Methods -Selection of Subjects &Blood Collection Forty patients with chronic renal failure (20 male, 20 female) were enrolled in this study in addition to forty healthy individual as control group (20 male, 20 female). The age ranged from (25 -65) years.To compare the significance of the difference in the mean values in comparison groups, student t - test was applied; P ≤ 0.05 was considered statistically significant. Patients with ischemic heart disease, diabetes mellitus and thyroid disease (such as hypothyroidism, hyperthyroidism and goiter) were excluded [13] . Five ml of venous blood were aspirated from control group and CRF patients at 8:00 - 9: 00 am. Blood samples were collected into plain test tubes and centrifuged after 30 minutes of collection for 10 minutes at 3000 rpm.Serum was frozen at -20 C 0 till used in determination of T3, T4, TSH ,urea , uric acid and creatinine. - Determination of T3, T4 and TSH Total triiodothyronine (tT3), total thyroxin (tT4) and thyroid stimulating hormone (TSH) were evaluated using VIDAS (T3) REF, 30403, VIDAS (T4) REF 304041 and VIDAS (TSH) REF. 30400 from biomerix (France) respectively.The principle of the quantitave determination of T3, T4 and TSH combines an enzyme immunoassay competition method with a final fluorescence detection (EIFA). -Determination of Urea Urea concentration levels were determined in serum by using enables end point enzymatic (Urease – modified Berthelot reaction) in which urease hydrolyzes urea in an alkaline medium.The ammonium ions react with the salicylate and hypochlorite to form a green colored indophenol.The reaction is catalyzed by the sodium nitroprusside [4] . -Determination of Uric Acid Uric acid concentrations were determined by using uricase- peroxidose - chromogen sequence in which hydrogen peroxide is formed and reacts as Tinder type reaction [4] . -Determination of Creatinine Creatinine levels were evaluated according to Jaffes method.The production of orange color after the addition of alkaline picrate. The color is proportional to the concentration of creatinine [4] . Iraqi J Pharm Sci, Vol.19(1) 2010 Chronic renal failure on thyroid hormones 67 Results and Discussion Table (1) shows the (mean ± SD) of T3, T4, TSH, urea, uric acid and creatinine concentrations in sera of patients with chronic renal failure and control group,in which P ≤ 0.05 was considered significant . Table 1: levels of T3, T4, TSH, urea, uric acid and creatinine concentrations in sera of patients with renal failure and control group. This study shows highly significant reduction in T3 and T4 concentration in patients serum with CRF compared to control group (P ≤0.05) . Intensive studies revealed that renal insufficiency affects thyroid function in multiple ways, including altered peripheral hormone metabolism, disturbed binding to proteins, reduction in tissue thyroid hormone content, and iodine accumulation in thyroid gland [14,15] .Another explanation is that the reason for the decrease in T4 could be attributed to multiple factors such as deficiency of thyroxine binding - globin (TBG) [16,17] . In the present study serum TSH was measured in CRF and control groups.CRF group had TSH above normal range. Some authors interpret this TSH elevation as a sign of recovery from a hypothyroid state despite the distortion of TSH in some euthyroid patients with NTI, who have significant elevation of TSH due to underlying primary hypothyroidism [18] . Highly significant elevation was found in urea, uric acid and creatinine in serum of CRF patients compared to control group.Increase in urea in renal failure are caused by impaired ability to excrete proteinaceous catabolites because of marked reduction in glomerular filtration rate(GRF).Increases in serum creatinine are also a result of decreased renal excretion [19] . References 1. Guyton A.C. and Hall J. E.: "Text Book of Medical Physiology",11 th ed, Sanders, Elsevier Inc 1600 John F. kenedy Blvd, Philadelphia,2006, 2-9. 2. Iwasaki y., Morishita M., Asai M. , Onish: A., Yoshida M., Oiso y. and Inoue k. :Effects of hormones targeting nuclear receptors on transcriptional regulation of the growth hormone gene in the MtT/S rat somatotrope cell line . Neuroendocrinology, 2004, 79, 229 – 236. 3. Andreoli, Bennett, Carpenter:" Cecil Essentials of Medicine", 4 th ed, W. B. Saunders Company, New York,1997,111- 116. 4. Benvenga S.: "The Thyroid, Fundamental of Clinical Text Books", 9 th ed. Le,Utiger RD(Eds),Lippincot Williams and Willkins, Philadelphia ,2005, 97. 5. Zoeller R. T., Tan S.W. and Tyl R. W:"General background on the hypothalamic-pituitary- thyroid(HPT)axis", Crit Rev Toxical. ,2007 ,37 (1-2),11 - 53. 6. Serhat Aytug MD., Lawrence E and Shapiro MD :Euthyroid Sick Syndrome,EMedicine Specialties,Endocriology,Thyroid,2007,18 ,55. 7. Douglas S. Ross:Thyroid Function in non –thyroid Illness,: Up to Date CME, 2007,134,1-7. 8. Levey As, Coresh J and Bake E.:National kidney foundation practice guidelines for chronic kidney disease:evaluation,classification,and stratification, Ann Intern Med.,2003, 139(2),137-147. 9. Chobanian AV, Bakris GL, Black HR, Cushman WC: Green LA and Izzo JL:The seventh report of the joint national committee on prevention, detection, evaluation and treatment of high blood pressure, JAMA,2003, 289 (19),2560 – 2572. 10. Goffin E., Oliveira DBG, Raggatt P. and Evans DB:Assessment of the thyroid function of patients undergoing regular haemodialysis, Nephron.,1993,65, 568– 572. 11. Shamsadini S. , Darvish and Abdollah H.:Blood urea nitrogen and thyroid hormone levels before and after haemodialysid, Health Journal,2006,12,55. 12. Hakim RM and Lazarus JM. :Medical aspects of haemodialysis,In:Brenner BM,Rector FC,eds. The Subjects Control (n=40) Patients (n=40) t -Test T3(ng/ml) 1.55 ± 0.54 0.63±0.05 P ≤ 0.05 T4(µg/ml) 9.13±2.84 3.32±1.99 P ≤ 0.05 TSH ( µIU/ml) 2.41± 0.52 6.22±3.31 P ≤ 0.05 Urea (mg/dl) 35.27±5.94 120.81±20.62 P ≤ 0.05 Uric acid (µmol/L) 300.7± 85.05 1220.6±24.1 P ≤ 0.05 Creatinine (mg/dl) 0.94 ± 0.19 7.42 ±1.94 P ≤ 0.05 Iraqi J Pharm Sci, Vol.19(1) 2010 Chronic renal failure on thyroid hormones 68 kidney.Philadelphia, Saunders ,1986 ,5,1791. 13. Lisandro lrizarry MD. , Nadine A. and Jeffry G.:Toxicity,Thyroid Hormone ,Medicine specialties, Emergency Medicine,Toxicology,2008,65,44-50. 14. Lim Vs:Thyroid function in patients with chronic renalfailure, Am J. kidney Discase,2001,38(1), S80 – S84. 15. Kaptein EM , Quion – Verde H., ChoolJian CJ, Tany ww , Friedman PE , Rodriquez HJ and Massry SG:The thyroid in end –stage renal diseases, Medicine (Baltimore),1988,67,187 – 197. 16. Biff F. palmer : Metabolic disturbances in chronic renal failure,Saudi Journal of Kidney disease and Transplantation,2002,13(3),273-280. 17. Boelen A, Mass MA, Lowik CW., Platvoet MC. and Wiersinga WM:Induced interleukin-6 (IL-6) knock- outmice:A causal role of IL-6 in the Development of the low 3,5,3- triiodothyronine syndrome, Endocrinology,1996,137,5250 – 5254. 18. Michalak M. , Vagenakis AG. , and Makri: M:Dissociation of the early decline in serum (T3) concentration and serum IL-6 rise and TNFalpha in nonthyroidal illness syndrome induced by abdominal Surgery,J. Clin. Endocrinol Metab.,2001,86 (9),4198 – 4205. 19. Shivananda Nayak B.: "Manipal Manual of Clinical Biochemistry", 3 rd ed., Medical publishers LTD., New Delhi,2007,182 – 186.