대한내과학회지 : 제 81 권제 3 호 2011 만성신질환환자에서의갑상선기능저하증빈도 국립의료원신장내과 이다현 전용덕 이승훈 문가슬 나수지 차혁환 Prevalence of Hypothyroidism in Patients with Chronic Kidney Disease Da Hyen Lee, Young Deok Jeon, Seung Hun Lee, Ga Seul Mun, Su Sie Na, and Huk Hwan Cha Department of Nephrology, National Medical Center, Seoul, Korea Background/Aims: Primary thyroid disease is prevalent in chronic renal disease, especially in patients requiring chronic dialysis. However, the relationship between kidney function and the prevalence of primary thyroid disease has not been studied in Korea, a nation where the dietary iodine intake is excessive. Methods: Retrospective data from 2201 consecutive adult patients who visited a health promotion center over the last 5 years were analyzed; specifically, 54 patients with chronic kidney disease not requiring hemodialysis and 64 adults treated with hemodialysis. The glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease equation. Multivariable logistic regression was used to evaluate the independent association between the prevalence of primary hypothyroidism and estimated GFR. Results: The prevalence of overt hypothyroidism increased from 0.5% at an estimated GFR > 90 ml/min/1.73 m 2 to 6.3% in end-stage renal disease requiring chronic dialysis (p < 0.001 for trend). Compared with participants with an estimated GFR > 60 ml/min/1.73 m 2, those with an estimated GFR < 60 ml/min per 1.73 m 2 had an increased odds of overt hypothyroidism after adjusting for age, gender, fasting blood glucose (FBS), and the total cholesterol (TC) and triglyceride (TG) concentrations. Conclusions: These findings suggest that overt primary hypothyroidism is relatively common (6.3%) among persons with chronic kidney disease requiring chronic dialysis, and it is independently associated with a progressively lower estimated GFR. (Korean J Med 2011;81:334-339) Keywords: Chronic renal insufficiency; Hypothyroidism 서 만성신부전은점진적인신장기능상실을특징으로하는질 론 환이다. 전세계적으로유병률이증가하고있으며삶의질, 경제적비용이라는측면에서주목받고있다 [1]. 미국에서는이미 2005년투석또는신이식을받은환자가 500,000명으로보고되 Received: 2011. 4. 12 Revised: 2011. 4. 27 Accepted: 2011. 6. 20 Correspondence to Young Deok Jeon, M.D. Department of Nephrology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul 100-799, Korea Tel: +82-2-2260-7558, Fax: +82-2-2262-4755, E-mail: ydjeon62@hotmail.com - 334 -
- Da Hyen Lee, et al. Prevalence of hypothyroidism in patient with chronic kidney disease - 었으며 2020년에는 800,000명으로증가될것이라는전망이있다 [2]. 또한이러한추세는영국, 유럽각국에서도보고되고있는바이다 [3]. 만성신부전환자에서는신장기능상실로인한여러대사산물들이체내에축적되어요독증을일으키며요독증으로인해이차적인생리변화및체내기관장애가일어난다. 시상하부-뇌하수체-갑상선의호로몬축이상및말초갑상선호로몬대사장애도요독증의일부로볼수있으며만성신부전환자에서보이는이차적인적응성기능저하증의원인으로생각된다. 흔히발견되는만성신부전환자에서의이차적인적응성기능저하증 (sick euthyroid syndrome) 은혈청 T4, T3, free T4, free T3의감소로알려져있다. 이러한이차적인갑상선기능변화는과도한기아상태에서나타나는생리적변화와마찬가지로에너지소비량을줄이고단백질대사를줄이는것을목적으로하는일종의인체의적절한반응으로해석하는견해도있다 [4]. 이차적인적응성기능저하증 (sick euthyroid syndrome) 외에도만성신질환에서는원발성갑상선질환 ( 갑상선기능저하증, 갑상선결절, 갑상선종, 갑상선암 ) 의빈도가정상인보다높다는사실은여러역학조사에서이미밝혀진바이다 [5]. 최근에는갑상선기능저하증빈도가신기능저하에반비례하여증가한다는연구결과도있었다 [6]. 아이오딘과다섭취국으로알려진한국에서도투석환자에서의갑상선기능저하증빈도 [7] 및신이식, 투석후의갑상선기능변화에 [8] 대한연구가이루어졌지만신기능저하에따른갑상선기능저하증의빈도에대해서는아직연구된바없다. 이에본연구는국립중앙의료원내원중갑상선검사와신기능검사를받은환자를대상으로사구체여과율에따른갑상선호로몬변화및갑상선기능저하증의빈도를알아보고자하였다. 대상및방법대상 2006년 1월부터 2010년 6월까지국립중앙의료원종합검진센터에서검진을받은환자 2201명, 최근 3년간신장내과외래에서갑상선검사를받은투석이요구되지않는만성신부전환자 54명, 인공신장실에서투석치료를받고최근 2 개월내입원이요구되는급성또는만성질환및악성종양의증거가없는만성신부전환자 64명, 총 2,319명을대상으로하였다. 방법대상환자는 6시간동안의공복상태를유지한후정맥혈을채혈하였고, 채혈즉시혈청을분리하여검사를시행하였다. 혈청 T3, Free T4, TSH, creatinine, total cholesterol, triglyceride, HDL-cholesterol, glucose 기저치를측정하였고, 투석환자는투석직전에채혈하였다. 혈청 T3, Free T4, TSH (T3-CTK, ft4-ctk, TSH-CTK, DiaSorin, Saluggia, Italy) 치는각각방사선면역측정법 (radioimmuno assay, RIA), 면역방사계수측정법 (immunoradiometric assay, IRMA) 으로검사하였으며 creatinine, glucose, total cholesterol, HDL, triglyceride치는 UniCel DxC 800 synchron clinical System (BECKMAN COULTER, Brea, California, USA) 를이용하여 enzymatic 방법으로측정되었다. 신장기능과갑상선질환의분류신장기능은추정사구체여과율 (MDRD-estimated glomerular filtration rate) 수치에따라서분류하였다 [GFR (ml/min/1.73 m 2 ) = 186 (serum creatinine [mg/dl]) 1.154 (age [years]) 0.203 (0.742 if female) (1.21 if African American)]. 추정사구체여과율에따라 90 ml/min/1.73 m 2 이상을 I군, 60 ml/min/1.73 m 2 이상 90 ml/min/1.73 m 2 미만을 II군, 60 ml/min/1.73 m 2 미만을 III군, 투석을받고있는만성신부전환자 IV군으로분류하였다. 갑상선기능검사참고치는 T3 80-200 ng/dl, Free T4 7.8-19.4 pg/ml, TSH 0.3-4 ml/u 이었다. 갑상선기능검사수치에따라 TSH 4 ml/u, 7.8 pg/ml free T4 < 19.4 pg/ml 를만족시키는환자를불현성갑상선저하증 (subclinical hypothyroidism) [10,11], TSH 4 ml/u, free T4 < 7.8 pg/ml 를만족시키는환자를명백한갑상선저하증 (overt hypothyroidism) 으로정하였다 [9]. 통계통계분석은 SPSS 18.0.0 을이용하였다. 연속형자료는평균 ± 표준편차를이용하였고, 범주형자료는빈도 ( 백분율 ) 를이용하여요약하였다. 연속변수의비교는 ANOVA test를이용하였고, 범주변수의비교는 chi-sqaure test를이용하였 - 335 -
- 대한내과학회지 : 제 81 권제 3 호통권제 613 호 2011 - 으며 odd ratio 는 multiple logistic regression analysis 이용하여분석하였다. p 값은 0.05 미만인경우를통계적으로유의하다고정의하였다. 결과대상환자들의평균나이는 49.45 ± 13.16세 (19-84세) 였으며이중여성이 1,008명 (43.4%) 남성이 1,311명 (56.5%) 이었다. 평균추정사구체여과율은 91.09 ± 26.96 ml/min/1.73 m 2 (3.54-235.14 ml/min/1.73 m 2 ), 평균 T3는 147.98 ± 28.75 ng/dl (11.01-614.00 ng/dl), 평균 free T4는 12.35 ± 3.16 pg/ml (0.97-61.30 pg/ml), 평균 TSH는 2.52 ± 3.50 ml/u (0.01-124 ml/u) 이었다. 갑상선기능검사상불현성갑상선기능저하증환자는 248명 (10.7%), 명백한갑상선기능저하증환자는 19명 (0.8%), 정상환자는 2,052명 (88.5%) 이었다. 추정사구체여과율에따른신기능분류는 I 군이 (90 ml/min/1.73 m 2 이상 ) 1,228명, II 군이 (60 ml/min/1.73 m 2 이상 90 ml/min/1.73 m 2 미만 ) 925명, III 군이 (60 ml/min/1.73 m 2 미만 ) 102명, IV 군이 ( 투석을받고있는만성신부전환자 ) 64명이었다. 신기능분류에따른 4개군의특징의보면갑상선기능저하증의위험요소로알려진 age, sex, fasting glucose, triglyceridem total cholesterol, HDL-cholesterol 에서각군간에불균등한분포를보으며 (p value < 0.001), 특히 age, fasting glucsoe가 ESRD로진행할수록증가하는양상을보였다. TSH는 I 군 (2.42 ± 2.00 ml/u), II 군 (2.50 ± 4.40 ml/u) III 군 (3.60 ± 7.02 ml/u), IV 군 (3.06 ± 2.85) 으로 III 군에서유의하게높으며 (p valve: 0.007), free T4는 I 군 (12.25 ± 3.35 pg/ml), II 군 (12.76 ± 2.58 pg/ml), III 군 (12.13 ± 4.50 pg/ml), IV 군 (8.94 ± 2.02 pg/ml), T3는 I 군 (151.47 ± 29.41 ng/dl), II 군 (149.63 ± 22.63 ng/dl) III 군 (122.79 ± 34.26 ng/dl), IV 군 (97.35 ± 16.55 ng/dl) 으로 IV 군에서유의하게낮았다 (p value < 0.001). 불현성갑상선기능저하증은 I 군에서 135명 (11.0%), II 군에서 89명 (9.6%), III 군에서 16명 (15.3%), IV 군에서 8명 (12.5%) 으로각군간에유의한차이점은보이지않았다 (p value: 0.250). 하지만명백한갑상선기능저하증은 I 군에서 6명 (0.5%), II 군에서 5명 (0.5%), III 군에서 4명 (3.9%), IV 군에서 4명 (6.3%) 으로추정사구체여과율에따른유병률이선형관계를보이고있었다 (p value < 0.001, Fig. 1). 갑상선기능저하증의위험인자로알려진나이, 고지혈증 (total cholesterol, triglyceride), 당뇨 (fasting glucose), 성별과함께사구체여과율을다중회귀분석한결과나이 (60세 < vs. 60세 ) 에따른명백한갑상선기증저하증위험도는 1.625 (p value = 0.330), 성별 (male vs. female) 에따른위험도는 2.773 (p value = 0.042), fasting glucose (< 126 mg/dl vs. 126 mg/dl) 에따른위험도는 0.585 (p value = 0.499), total cholesterol (< 240 mg/dl vs. 240 mg/dl) 에따른위험도는 0.385 (p value = 0.362), triglyceride (< 200 mg/dl vs. 200 mg/dl) 에따른위험도는 0.821 (p value = 0.797), 사구체여과율 (> 60 ml/ min/1.73 m 2 vs. 60 ml/min/1.73 m 2 ) 에따른위험도는 9.002 (p value < 0.001), 사구체여과율 (per unit increased) 에따른위험도는 0.981 (p value 0.010) 으로사구체여과율과성별이유의하게연관성있는것으로나타났다 (Table 1). 6.30% 3.90% Figure 1. Prevalence of hypothyroidism. 0.50% 0.50% Table 1. Determinants of overt hypothyroidism in the multiple logistic regression analysis Independent variables Odds ratio (±95% CI) p value Age (60 < vs. 60) 1.625 (0.600-4.397) 0.330 FBS (< 126 vs. 126) 0.585 (0.124-2.762) 0.499 TG (< 200 vs. 200) 0.821 (0.182-3.709) 0.797 TC (< 240 vs. 240) 0.385 (0.050-2.994) 0.362 GFR (60 > vs. 60) 9.002 (3.124-25.211) <0.001 GFR (per unit increased) 0.981 (0.966-0.995) 0.010 Sex (male vs. female) 2.773 (1.037-7.411) 0.042-336 -
- 이다현외 5 인. 만성신질환환자에서의갑상선기능저하증빈도 - 고찰본연구에서신기능에따른갑상선호로몬수치변화는투석치료를받는만성신부전환자에서이차적인적응성기능저하증의전형적인 low T3, T4 양상을보이고있었다. 하지만최근몇몇연구에서언급된사구체여과율에따른점진적인불현성갑상선기능저하증빈도증가소견은관찰되지않았으며명백한갑상선기능저하증빈도만이사구체여과율감소에따라유의하게증가양상을보였다. 명백한갑상선기능저하증은전체인구에서 3% 정도의유병률을보인다. 여러원인이있으나그중아이오딘결핍및자가면역으로인한경우가가장흔하다 [12]. 불현성갑상선기능저하증은 T3, T4의감소를 TSH증가로보상하고있는상태로 TSH가증가되어있으면서 T3, T4는정상범위인경우를말한다. 전체인구에서는 3-8% [13-15], 60세이상의노인및여성에서는 20% 의유병률을보이며대부분의아무증상없이갑상선초음파상에는미만성저에코성갑상선종, 항갑상선항체양성을보이는경우가흔하다 [16-18]. 명백한갑상선기능저하증과마찬가지로아이오딘결핍및자가면역으로인한경우가흔하며그외에약물유발성갑상선염, 방사선치료후갑상선염, 아급성갑상선염, 산후갑상선염등의원인이있다 [19]. 자연경과상명백한갑상선기능저하증, 관상동맥질환, 말초동맥질환과연관있는것으로밝혀졌으며특히내피세포기능, 혈압, 지질대사에영향을주고심혈관계질환의잠재적인위험인자로작용하여그예후와치료여부에대하여연구중이다 [20]. 만성신부전환자에서의갑상선기능이상, 갑상선종, 원발성갑상선기능저하증빈도가높다는것은이미여러연구를통해서밝혀진사실이다 [21-25]. 게다가그중에서는동반된갑상선호로몬이상이만성신부전환자의독립적인심혈관계사망률예측인자라는연구결과도있다 [23-25]. 기저병인으로는아이오딘대사장애, 자가면역성, 갑상선호로몬대사장애및말초감수성변화등여러가설이제기되고있으며최근에는아이오딘배설장애와아이오딘갑상선침착이갑상선종, 원발성갑상선기능저하증빈도증가의원인이라는가설이유력하다. 과도한아이오딘이체내에축적되면일반적으로갑상선기능항진증이유발되나만성질환환자, 신생아, 정상갑상선기능을유지하고있는자가면역성갑상선염환자에서는 Wolff-Chaikoff 효과가계속지속 됨으로써갑상선기능저하증이유발된다 [26]. 또한이러한현상은가역적인상태로아이오딘섭취제한에갑상선기능이회복된다는여러연구결과가있다 [27]. 최근에는사구체여과율에반비례하여갑상선기능저하증의빈도가증가한다는연구들이보고되고있다. Michel 등의연구에서는투석치료가필요없는경한만성신부전에서불현성갑상선기능저하증빈도가증가하였으며뿐만아니라사구체여과율감소에따라불현성갑상선기능저하증빈도가점진적으로증가한다고보고하였다. 하지만 Michel 등의연구에서는투석치료를받고있는만성신부전환자가제외되었으며또한명백한갑상선기능저하증의빈도역시제외되었다 [28]. 이에본연구에서는투석치료를받고있는환자도포함하여갑상선기능저하증을명백한갑상선기능저하증, 불현성갑상선기능저하증두군으로나누어서빈도를구하였다. 본연구는몇가지제한점이있다. 첫째, inulin이나 iothalmate 를이용하여정확한사구체여과율을구하지않고추정사구체여과율을이용하여신기능을추정하였다. 둘째, 갑상선기능저하증의원인조사를위한자가항체측정및요중아이오딘농도등의검사를시행하지않았다. 셋째, 환자들의정확한과거질환 ( 갑상선질환 ) 및현재복용중인갑상선질환약물, 갑상선기능에영향을미칠수있는약물을파악하지못하였다. 넷째, 타연구와비교하여갑상선기능저하증의위험요소인성별비, 나이, 고지혈증, 당뇨등이각군에따라불균등하여이로인해선택바이어스가생길수있다. 결론적으로본연구에서는추정사구체여과율의감소에따른명백한갑상선기능저하증빈도증가소견은관찰되었지만불현성갑상선기능저하증의빈도증가는관찰되지않았다. 본연구는아이오딘과다섭취국으로알려진한국에서사구체여과율에따른원발성갑상선기능저하증빈도를분석하였다는점에서의의를둘수있으며이러한결과는만성신부전환자의초진시에갑상선기능장애가능성을염두에두고진료및검사를진행해야한다는것을의미한다. 하지만본연구는여러가지제한점을가지고있기때문에보다수정된방법의연구가필요하며또한향후만성신부전에동반된갑상선종, 원발성갑상선기능저하증에대한경과및치료여부에대한대규모연구가필요하다. - 337 -
- The Korean Journal of Medicine: Vol. 81, No. 3, 2011 - 요 목적 : 만성신장질환에서원발성갑상선질환 ( 갑상선기능저하증, 갑상선결절, 갑상선종, 갑상선암 ) 빈도가정상인보다높다는사실은여러역학조사에서이미밝혀진바있다. 하지만아이오딘과다섭취국중하나인한국에서신장기능과원발성갑상선질환빈도의정확한관계는아직까지연구된바없다. 방법 : 2007년 1월부터 2010년 6월까지국립중앙의료원건강증진센터를통해검진받은 2201명, 2008년 5월부터 2011 년 5월까지외래에서진료를보았던투석을요하지않는만성신질환환자 54명, 2010년국립중앙의료원인공신장실에서투석을받고있는 64명을대상으로하여추정사구체여과율 (MDRD-estimated glomerular filtration rate) 에따른갑상선기능저하증의빈도를구하였다. 원발성갑상선기능저하증과신기능의정확한관계는이변량로지스틱회귀분석을통하여구하였다. 결과 : 명백한갑상선기능저하증빈도는 GFR > 90 ml/ min/1.73 m 2 환자에서 0.5%, 투석을요하는만성신부전환자에서 6.3% 로증가하는양상을보였으며또한다변량로지스틱회귀분석결과만성신질환환자에서 9.002의오즈비를보였다. 결론 : 명백한갑상선기능저하증의빈도는투석을요하는신부전환자에서흔하며신기능감소에따라증가한다. 약 중심단어 : 만성신부전 ; 갑상선기능저하증 REFERENCES 1. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139:137-147. 2. U.S. Renal Data System. USRDS 2009 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda: National Institute of Diabetes and Digestive and Kidney Diseases, 2007. 3. Kiberd B. The chronic kidney disease epidemic: stepping back and looking forward. J Am Soc Nephrol 2006;17:2967-2973. 4. Amato AA, Santos GM, Neves F de A. Thyroid hormone action in chronic kidney disease. Curr Opin Endocrinol Diabetes Obes 2008;15:459-465, doi: 10.1097/MED.0b013e32830eb85e. 5. Kaptein EM, Quion-Verde H, Chooljian CJ, et al. The thyroid in end-stage renal disease. Medicine (Baltimore) 1988;67:187-197. 6. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int 2005;67:1047-1052. 7. Song IS, Kim KH, Oh SJ, Jung HS, Lee JH, Yoon KI. The effects of hemodialysis and kidney transplantation on the thyroid function in patients with chronic renal failure. Korean J Med 1996;51:79-87. 8. Lee HH, Kim DJ, Kim JA, et al. Change of the thyroid function in continuous ambulatory peritoneal dialysis patients. Korean J Nephrol 2003;22:96-101. 9. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T (4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499. 10. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease, scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-238. 11. Wilson GR, Curry RW Jr. Subclinical thyroid disease. Am Fam Physician 2005;72:1517-1524. 12. Garber JR, Hennessey JV, Lieberman JA 3rd, Morris CM, Talbert RL. Clinical update: managing the challenges of hypothyroidism. J Fam Pract 2006;55:S1-S8. 13. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000; 160:526-534. 14. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7:481-493. 15. Schectman JM, Kallenberg GA, Shumacher RJ, Hirsch RP. Yield of hypothyroidism in symptomatic primary care patients. Arch Intern Med 1989;149:861-864. 16. Helfand M, Crapo LM. Screening for thyroid disease. Ann Intern Med 1990;112:840-849. 17. Bagchi N, Brown TR, Parish RF. Thyroid dysfunction in adults over age 55 years: a study in an urban US community. Arch Intern Med 1990;150:785-787. 18. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA 1979;242:247-250. 19. Papi G, Uberti ED, Betterle C, et al. Subclinical hypothyroidism. Curr Opin Endocrinol Diabetes Obes 2007;14:197-208. 20. Ripoli A, Pingitore A, Favilli B, et al. Does subclinical hypothyroidism affect cardiac pump performance? Evidence from a magnetic resonance imaging study. J Am Coll Cardiol 2005;45:439-445. Erratum in: J Am Coll Cardiol 2005;45:968. 21. Lim VS. Thyroid function in patients with chronic renal failure. Am J Kidney Dis 2001;38(4 Suppl 1):S80-S84. 22. Zoccali C, Tripepi G, Cutrupi S, Pizzini P, Mallamaci F. Low triiodothyronine: a new facet of inflammation in end stage renal disease. J Am Soc Nephrol 2005;16:2789-2795. - 338 -
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