청소년기기능성자궁출혈과관련된철결핍성빈혈의치료 가천의과학대학교의학전문대학원소아과학교실, 1 산부인과학교실 이상선ㆍ황선태ㆍ남기룡ㆍ차한ㆍ이지성 1 ㆍ전인상 Management of Iron Deficiency Anemia Associated with Dysfunctional Uterine Bleeding in the Adolescent Females Sang Seon Lee, M.D., Seon Tae Hwang, M.D., Ki Lyong Nam, M.D., Hann Tchah, M.D., Ji Sung Lee, M.D. 1 and In-sang Jeon, M.D. Departments of Pediatrics, 1 Obstetrics and Gynecology, Graduate School of Medicine, Gachon University of Medicine and Science, Incheon, Korea Purpose: To investigate hematologic features and the appropriate management in Korean adolescent females with dysfunctional uterine bleeding (DUB) and iron deficiency anemia (IDA) we performed this study. Methods: We investigated retrospectively the initial complete blood count (CBC) profiles and the changes of the hemoglobin levels after iron only therapy or iron/hormone combination therapy in 23 adolescent girls (a group of 15 patients treated with oral iron only and another group of 8 patients treated with oral iron/hormone) with DUB and IDA. Results: A statistically significant correlation was observed between the increase of hemoglobin level and treatments in both groups. The increase of hemoglobin levels in group treated with iron only were inconsecutive in comparison with the consecutive increase of hemoglobin level in group treated with iron/hormone combination therapy during the subsequent six month follow-up. On the comparison of increase of hemoglobin level in two groups, the differences were statistically insignificant at 14, 30, 60 days after treatment but statistically significant at 90, 120, 150 days. Conclusion: Iron/hormone combination therapy was more effective than iron only for consecutive increase of hemoglobin level in Korean adolescent females with DUB and IDA. (Clin Pediatr Hematol Oncol 2010;17:1 8) Key Words: Adolescent, Dysfunctional uterine bleeding, Iron deficiency anemia, Oral iron supplement, Hormone therapy 서 책임저자 : 전인상, 인천시남동구구월동 1198 가천의과학대학교길병원소아청소년과, 405-760 Tel: 032-460-8382, Fax: 032-460-3224 E-mail: isjeon@gilhospital.com 론 비정상자궁출혈은출혈성질환, 감염, 임신관 련합병증같은질환이나생식기병변과같은기질적원인에의한자궁출혈과특별한기질적원인없이내분비학적원인에의해나타나는기능성자궁출혈로나눌수있다 1-3). 청소년기에나타나는비정상자궁출현은대부분이기능성자궁출혈에의한것으로이러한출혈은초경을경험한청소년기여성에게신체적, 심리적영향을준다 4,5). 기능성자궁출혈의정의에대한여러논란이있으 임상소아혈액종양제 17 권제 1 호 2010 1
2 이상선ㆍ황선태ㆍ남기룡등 나대체적으로무배란성자궁출혈과과다월경과같은배란성자궁출혈을포함하여말한다 1,6,7). 청소년기기능성자궁출혈은시상하부-뇌하수체- 난소축의미성숙에의하여나타나는것으로알려져있다 3,7). 특히최근에는영양상태가양호해지면서초경의조기화, 서양화된식습관과다이어트에의한식이의불균형, 스포츠활동의증가, 학업등에의한스트레스로인해청소년기기능성자궁출혈이증가하고있다 8). 청소년기의기능성자궁출혈은적절한치료가이루어지지않을경우자궁내막증식증, 자궁내막암, 유방암을일으킬수있고심한경우불임이될수도있다 9). 이러한여성질환이외에도지속적인자궁출혈은철결핍성빈혈을일으킬수있 다 10,11). 청소년기는급격한성장이이루어지는시기로비정상적인자궁출혈은빈혈을더유발할수있으며이시기의철분결핍은정상적인성장과발달을이루는데장애가된다 12). 그러나청소년기의비정상적인자궁출혈은임상적중요성에도불구하고이에대한연구는미흡한실정이다. 기능성자궁출혈을보이는청소년기여성의철분상태및적절한치료에대해알아보기위해본연구를시행하였다. 대상및방법가천의대길병원소아청소년과및산부인과에서 2007년 6월부터 2009년 5월까지 2년동안기능 Fig. 1. Enrollment and Outcomes.
청소년기기능성자궁출혈과관련된철결핍성빈혈의치료 3 성자궁출혈로진단받고전혈구검사및철분상태를알아보는검사가시행된청소년중빈혈이있고각종치료를받았던 36예를대상으로병록지검토를통한후향적분석을하였다. 자궁출혈을일으킬수있는기질적원인에의한출혈을본연구에서제외하기위하여정확한문진과이학적검사가시행되었고의심이되는경우에는경직장초음파검사및호르몬검사를시행한경우로한정하였다. 이러한과정을걸쳐자궁출혈을일으킬수있는기질적원인을완전히배제한예만을대상으로하였다. 대상환아 36명에서철분단독치 료가시행된예는 20예, 호르몬단독치료가시행된예가 6예, 철분및호르몬병합요법이시행된예가 10예였다. 철분치료는절대철 (elemental iron) 6 mg/kg 투여하였다. 투여된호르몬제재의성분은 Yasmin R (ethinyl estradiol/drospirenone), Myvlar R (ethinyl estradiol/gestodene), Cycrin R (methroxypregesterone), Provera R (methroxypregesterone) 였다. 치료를시작한 36예중 6개월간외래추적관찰이가능하였던경우는철분단독치료 15예, 철분및호르몬병합요법이시행된예가 8예의총 23예로호르몬단독치료한경우는모두추적 Table 1. Demographic Characteristics of the Patients at the Time of Diagnosis Case No. Age at Diagnosis (years) Body weight (kg) Hemoglobin (g/dl) Hct (%) MCV (fl) Reticulocyte (%) Iron (μg/dl) TIBC (μg/dl) Ferritin (ng/dl) 1 16.4 52.0 11.6 35.5 78.7 1.6 60 422 4.96 2 16.3 43.0 9.9 34.5 68.6 1.2 72 409 5.39 3 14.3 58.0 6.0 23.6 59.8 1.4 85 512 7.66 4 13.9 59.0 5.5 19.9 60.0 1.5 23 486 2.69 5 15.5 48.0 7.2 23.4 71.7 1.3 11 451 1.01 6 12.4 39.0 9.2 29.0 72.3 1.7 16 456 0.01 7 13.5 49.0 7.5 26.7 59.9 1.1 19 577 1.03 8 13.8 42.0 5.2 17.9 70.8 2.9 10 492 2.58 9 15.7 51.0 5.9 22.9 70.6 2.5 67 451 7.44 10 13.0 49.0 6.9 23.5 58.4 2.5 33 463 15.75 11 16.7 52.5 11.2 35.3 76.2 1.0 58 438 19.69 12 16.3 42.0 9.6 32.2 66.3 0.5 37 471 3.99 13 10.7 43.0 9.8 32.1 75.4 0.8 73 510 5.31 14 15.2 45.5 4.8 17.6 2.2 15 409 0.5 15 16.8 57.0 11.6 35.1 79.6 1.1 37 467 1.89 16 12.1 43.0 7.8 25.8 66.6 2.4 25 558 7.66 17 13.1 45.0 10.0 31.9 75.8 1.5 19 404 2.40 18 13.2 50.0 4.5 17.9 60.5 1.6 10 574 0.11 19 14.2 50.0 7.8 23.3 82.6 1.7 38 482 2.55 20 14.8 46.0 5.0 15.1 82.1 1.8 27 530 0.67 21 14.8 47.0 5.8 17.8 77.7 2.2 33 492 4.34 22 15.3 70.0 5.0 16.3 67.7 2.4 8 463 1.52 23 13.4 38.5 3.0 12.0 58.4 4.1 10 454 0.13 Mean 14.4±1.6 48.7±7.3 7.4±2.5 24.8±7.3 70.0±8.0 1.8±0.8 34.1±23.6 4.3±1.8 477.0±49.4
4 이상선ㆍ황선태ㆍ남기룡등 관찰이이루어지지못했다 (Fig. 1). 이들 23예를대상으로혈색소, 적혈구용적률, 평균적혈구용적, 망상적혈구를조사하였고치료후혈색소변화를분석하였다. 전체 23예중빈혈이심하여수혈이시행되었던 9예에서는수혈후시행된전혈구검사를치료시작점으로하여혈색소의변화를분석하였다. 빈혈의정의는홍에의한한국소아의빈혈수치를진단기준으로하였다. 통계분석은 SPSS R (Ver. 18.0, IBM Company, Chicago, Illinois) 를사용하였다. 연속변수는평균값 ± 표준편차로표시하였으며, 비교분석은 Mann-Whitney-U test를사용하였다. P value가 0.05 미만인경우통계적으로유의하다고판정하였다. 결과 1) 환자의특성본연구의대상환자는총 23명으로진단당시연령은 10세에서 18세로평균연령은 14.4±1.6세, 평균체중은 48.7±7.3 kg이었다. 진단시평균혈색소는 7.4±2.5 g/dl, 평균적혈구용적률은 24.8± 7.3%, 평균적혈구용적의평균은 70.0±8.0 fl이었으며, 평균망상적혈구는 1.8±0.8% 이었다. 진단시평균혈청철은 34.1±23.6μg/dL, 평균혈청페리틴은 4.3±1.8 ng/ml, 평균총철결합능은 477.0± 49.4μg/dL였다 (Table 1). 2) 두군의비교철분제재단독요법을받은대상환자와철분및호르몬병합요법을받은환자사이의치료시작시두집단간의평균연령, 평균체중, 평균혈색소, 평균적혈구용적률, 평균적혈구용적의평균, 평균혈청페리틴, 평균혈청철, 평균총철결합능의차이는없었다 (Table 2). 3) 철분제재단독요법을받은환자의혈색소변화경구철분제재단독복용한 15예의치료시작일, 14일, 30일, 60일, 90일, 120일, 150일의혈색소는각각 8.5±2.2 g/dl, 9.4±1.7 g/dl, 10.3±1.7 g/dl, 11.5±1.6 g/dl, 11.1±1.4 g/dl, 11.9±1.1 g/dl, 12.6± 1.0 g/dl이었다 (Fig. 2). Table 2. Demographic Features of the Adolescent Girls with Dysfunctional Uterine Bleeding and Iron Deficiency Anemia Treatment for anemia Iron only (n=15) Iron and Hormone (n=8) P value Age (years) 14.3±1.9 14.6±1.1 0.672 BWt (kg) 48.0±6.8 49.9±8.5 0.726 Hemoglobin 8.5±2.2 8.8±0.8 0.183 (g/dl) Hct (%) 27.0±7.2 20.5±5.6 0.484 MCV (fl) 71.0±6.8 77.2±9.2 0.069 Reticulocyte (%) 1.7±0.9 1.9±0.6 0.362 Iron (μg/dl) 39.0±27.0 25.1±12.3 0.674 TIBC (μg/dl) 472.5±50.6 485.5±49.2 0.889 Ferritin (ng/dl) 4.7±4.9 1.9±0.6 0.207 Fig. 2. Changes of hemoglobin level after iron supplement therapy in fifteen girls with dysfunctional uterine bleeding and iron deficiency anemia.
청소년기기능성자궁출혈과관련된철결핍성빈혈의치료 5 4) 철분및호르몬병합요법을받은환자의혈색소변화철분및호르몬병합요법을받은환자의 8예의치료시작일, 14일, 30일, 60일, 90일, 120일, 150일 의혈색소는각각 8.8±0.8 g/dl, 9.7±0.5 g/dl, 10.8±0.6 g/dl, 11.9±0.4 g/dl, 12.7±0.2 g/dl, 13.1± 0.3 g/dl, 13.5±0.3 g/dl이었다 (Fig. 3). 5) 철분제재단독요법과철분및호르몬병합요법간의혈색소증가비교 경구철분제재단독요법을받은군과철분및 Table 3. Comparison of Hemoglobin Level After Iron Only Therapy and Iron with Hormone Therapy Hemoglobin (g/dl) Iron (n=15) Iron and hormone (n=8) P value Fig. 3. Changes of hemoglobin level after iron supplement with hormone therapy in eight girls with dysfunctional uterine bleeding and iron deficiency anemia. D0 8.5±2.2 8.8±0.8 0.183 D14 9.4±1.7 9.7±0.5 0.207 D30 10.3±1.7 10.8±0.6 0.161 D60 11.5±1.6 11.9±0.4 0.092 D90 11.1±1.4 12.7±0.2 0.025 D120 11.9±1.1 13.1±0.3 0.028 D150 12.6±1.0 13.5±0.3 0.017 Fig. 4. Outcomes of girls with dysfunctional uterine bleeding and iron deficiency anemia. (A) Rate of hemoglobin level over 12.0 g/dl per time in fifteen patients treated with iron supplement only. Values in whole bar (, ) and black protion ( ) indicated the total subjects and thesubjects who showed hemoglobin level over 12.0 g/dl, respectively. (B) Rate of hemoglobin level over 12.0 g/dl per time in eight patients treated with iron supplement and hormone. Values in whole bar (, ) and black protion ( ) indicated the total subjects and thesubjects who showed hemoglobin level over 12.0 g/dl, respectively.
6 이상선ㆍ황선태ㆍ남기룡등 호르몬병합요법을받은군간의혈색소증가비교에서치료시작처음 14일, 30일, 60일까지는두군간에통계학적으로유의한차이가없었다 ( 각각, P=0.21, 0.16, 0.09). 그러나치료시작후 90일, 120일, 150일의두군간의혈색소증가차이는통계적으로유의하였다 ( 각각, P=0.03, 0.03, 0.02) (Table 3). 6) 철분제재단독요법과철분및호르몬병합요법간의혈색소정상화비교철분제재단독요법후 14일, 30일, 60일, 90일, 120일, 150일까지혈색소가정상인환자는 6.7%, 26.7%, 33.3%, 26.7%, 60.0%, 80.0% 였고, 철분및호르몬병합요법후 14일, 30일에서혈색소가정상인환자는없었으나 60일, 90일, 120일, 150일까지혈색소가정상인환자는 50%, 100%, 100%, 100% 였다 (Fig. 4). 고찰시상하부-뇌하수체-난소축 (Hypothalamus-pituitary-ovarian axis) 을통해이루어지는정상적인호르몬의분비와기능의균형에의해정상적인월경이일어난다 3). 그러나청소년기여성에서초경이후첫 18개월에서 24개월사이 ( 길게는 5년까지 ) 시상하부-뇌하수체-난소축의성숙이지연되면서무배란성주기가지속되어성인과는다른월경형태를보이며월경주기가규칙적이지못하거나그양이일정하지못하다 2,13). 초경자체가사춘기소녀에게신체적, 심리적영향을주는데이러한불규칙한자궁출혈은사춘기소녀에게심리적으로큰부담을준다 1,14). 그뿐아니라자궁출혈은사춘기여성에게빈혈을일으킨다. 청소년기자궁출혈의대부분은특별한기질적원인없이내분비학적이상에의해나타나는기능성자궁출혈이다 15). 청소년기기능성자궁출혈은병적인상태라기보다는성숙해가는단계에서시상하부-뇌하수체-난소축의미성숙에의해발생하는것으로하나의질병으로보기에는문제가있 으며그정의도다양하며진단자체에도어려움이있다 5). 청소년기여성에서정확한월경력을얻기가어렵고또한골반검진, 질초음파등진료접근성이용이하지않다. 본논문에서는기능성자궁출혈의정의로무배란성과배란성을구별하지않았으며정확한병력과이학적소견및검사 ( 경직장초음파검사및호르몬검사 ) 를통해진단이된경우만을한정하였다 1,6). 청소년기여성에서기능성자궁출혈에대한통계와연구가부족하지만, 기능성자궁출혈을포함하는비정상자궁출혈을 70% 가넘는여학생이경험하며, 더욱이과도한월경으로불편을호소하는여성이 30% 가넘는것으로알려져있다 4,14). 특히최근에는영양상태의호전등에의해초경이빨라지면서기능성자궁출혈의빈도는늘어날것으로생각되나이에대한정확한통계는아직없는상태이다. 본연구에서도이러한기준에합당한예로 2년동안 36예가있었지만, 이시기에자궁출혈을호소한청소년기여성이 3배이상많았던점을고려하면실제로더많은환자가있었을것으로추측된다. 청소년기기능성자궁출혈은성숙해가는과정에겪는한단계라고할수있으나자궁출혈에대한적절한치료가이루어지지않으면자궁내막증식증, 자궁내막암, 유방암을일으킬수있고심한경우불임의원인이되기도한다 9). 부인과적문제이외에불규칙적인자궁출혈은사춘기소녀에게심리적부담이되며정상적인성인이되는데장애가될수도있다. 본연구에서는대상환자의진단시평균연령이 14.4세로급속한성장이이루어지는청소년기전반에서중반에걸친시기로불규칙적인자궁출혈은정상적인성장과발달을이루는데신체적, 정신적으로지장을줄수있어이에대한적절한치료가필요함을알수있었다. 청소년기는급격한성장이이루어지는시기로철결핍성빈혈이흔하게일어난다. 더욱이비정상적인자궁출혈이동반될경우에는철결핍성빈혈의발생위험은더증가한다. 또한월경력만을갖고자궁출혈정도를객관적으로평가할수없
청소년기기능성자궁출혈과관련된철결핍성빈혈의치료 7 는경우가많아혈액검사가필요하다. Quint 등은기능성자궁출혈을보이는청소년기모든여성에서전혈구검사를해야하며, 급성출혈이있거나혈색소가 10 g/dl 미만인경우에는혈액응고검사를포함해야한다고했다 2). 검사를통해철결핍성빈혈이진단이되면적절한치료가필요하다. 아직이들에대한치료지침은없으나철분제재와호르몬제재를병합하여사용하는것이추천되고있다 16). Quint 등은기능성자궁출혈을보이는청소년기여성의혈색소가 10 g/dl 미만이면자궁출혈유무와상관없이철분및호르몬제재병합요법을시행하고정기적인추적을추천하였다 5). 그러나청소년기여성의호르몬제재에대한복용순응도가낮아치료에어려움이있다 1). 실제로본연구에서호르몬제재만복용한군은모두외래추적이되지않아적절한치료를할수없었다. 또한호르몬제재에대한심한거부감이있는경우에는철분제재만을복용하게하여빈혈치료정도를알아보았다. 기능성자궁출혈을진단받은청소년기여성의상당부분은진단후에도적절한치료를받지못하거나치료를받게되더라도치료에대한충분한평가를하기에어려움이있었다. 본연구에서철분만을복용한 15예와철분과호르몬제재를모두복용한 8예두군에서모두혈색소가상승하였다. 그러나철분만을복용한군에서는대부분의환자에서장기간의철분제재치료로혈색소가지속적으로상승하고정상범위내에서유지되나일부환자에서는철분제재치료에도불구하고외래추적기간중혈색소수치가갑자기떨어지거나혈색소상승이지연되었다. 이는자궁출혈이조절이되지않아상당한양의혈액소실이있는경우지속적인철분공급만으로는빈혈치료가충분히이루어지지않음을의미한다. 호르몬제재복용에어려움이있어철분만을복용하는경우에는추적조사를더자주하여빈혈개선이없으면반드시호르몬제재병합치료를해야할것으로생각된다. 본연구에서철분만을복용한군과철분과호르몬제재를병합 복용한군의혈색소상승은처음 60일까지는통계학적으로유의한차이는없었으나 90일이후의검사에서는병합치료를받은군에서상승효과가높았다. 또한병합치료군에서는지속적인혈색소상승이있었으며혈색소수치가갑자기낮아지는경우도없었다. 본연구에서호르몬단독치료군에대한추적이이루어지지않아각치료제재의치료효과를비교하는데문제가있으나, 청소년기기능성자궁출혈이있으며철결핍성빈혈이동반되면안정적인혈색소상승및자궁출혈의조절을위해철분제재와호르몬제재를병합하여치료하는것이좋을것으로생각된다. 또한, 철분제재는급성자궁출혈을멈추게하는효과는없으나이제재를복용함으로써반복적으로과다자궁출혈이지속되어고갈된체내철분을반드시보충해주어야하며, 더나아가충분한양의저장철을갖게해야한다 17). 요약목적 : 기능성자궁출혈과관련된철결핍성빈혈을가진청소년기여성에서철분상태및적절한치료에대해알아보고자본연구를시행하였다. 방법 : 기능성자궁출혈과관련된철결핍성빈혈을진단받은청소년기여성 23예에서진단시전혈구검사와혈색소, 적혈구용적률, 평균적혈구용적, 망상적혈구를후향적으로조사하였고혈색소의변화를분석하였다. 철분제재단독요법을받은 15예와철분및호르몬병합요법을받은 8 예를대상으로하여두군에서의혈색소변화를비교분석하였다. 결과 : 철분단독요법을받은군과철분및호르몬병합요법을받은군, 모두에서혈색소증가가있었다. 철분및호르몬병합요법을받은군이철분제재단독요법을받은군보다혈색소의증가가일관적이고안정적이었다. 두군에서치료후혈색소증가를비교해볼때, 두군의치료후 14일, 30일, 60일의혈색소증가의차이는통계적
8 이상선ㆍ황선태ㆍ남기룡등 으로의미가없었으나 90일, 120일, 150일의혈색소증가의차이는통계적으로의미가있었다 (P value=0.21, 0.16, 0.09; 0.03, 0.03, 0.02). 결론 : 철분및호르몬병합요법이철분제재단독요법보다청소년기여성의기능성자궁출혈과관련된철결핍성빈혈의치료에더효과적이다. 참고문헌 1. Park HT, Kim YT. Abnormal Uterine Bleeding in Adolescence. J Korean Med Assoc 2009;52:779-86 2. Quint EH, Smith YR. Abnormal Uterine Bleeding in Adolescence. J Midwifery Womens Health 2003;48: 186-91 3. Graydanus D, Omar HA, Tsitsika AK, Patel DR. Menstrual Disorders in Adolescent Females: current concepts. Dis Mon 2009;55:45-113 4. Friberg B, Orno AK, Lindgren A, Lethagen S. Bleeding disorders among young women: a population-based prevalence study. Acta Obstet Gynecol Scand 2006;85:200-6 5. Edmonds DK. Dysfunctional uterine bleeding in Adolescence. Reviews of Gynaecological Practice 2003;3:196-200 6. Lee KS. Pathophysiology and treatment guidelines of dysfunctional uterine bleeding. Korean J Obstert Gynecol 2005;48:1390-401 7. Livingstone M, Fraser I. Mechanisms of abnormal uterine bleeding. Hum Reprod Update 2002;8:60-7 8. Swenne I. Haematological changes and iron status in teenage girls with eating disorders and weight loss-the importance of menstrual status. Acta Paediatr 2007;96:530-3 9. Greydanus DE. Breast and Gynaecologic Disorders. In: Hofmann AD, Greydanus DE, editors. Adolescent Medicine volume Ch.25. 3rd ed. CT: Appleton & Lange. Stamford, 1997:520-65 10. Milman N, Kirchhoff M, Jorgensen T. Iron status markers, serum ferritin and hemoglobin in 1359 danish women in relation to menstruation, hormonal contraception, parity, and postmenopausal hormone treatment. Ann Hematol 1992;65:96-102 11. Milman N, Kirchhoff M. Iron Stores in 1359, 30- to 60-year-old danish women: evaluation by serum ferritin and hemoglobin. Ann Hematol 1992;64:22-7 12. Lim HS, Jeong ES. Iron status of the adolescent females before and after menarche. Korean J Nutr 2003;36:646-52 13. Slap GB. Menstrual Disorders in Adolescence. Best Practice & Research Clinical Obstetrics & Gynaecology 2003;17:75-92 14. Demir SC, Kadayyfcy TO, Vardar MA, Atay Y. Dysfunctional uterine bleeding and other menstrual problems of secondary school students in Adana, Turkey. J Pediatr Adolesc Gynecol 2000;13:171-5 15. Edmonds DK. Dysfunctional uterine bleeding in Adolescence. Baillieres Best Pract Res Clin Obstet Gynaecol 1999;13:239-49 16. Porteous A, Prentice A. Medical management of dysfunctional uterine bleeding. Reviews of Gynaecological Practice 2003;3:81-4 17. Milman N, Clausen J, Byg KE. Iron status in 268 Danish women aged 18 30 years: influence of menstruation, contraceptive method, and iron supplementation. Ann Hematol 1998;77:13-9