대한내과학회지 : 제 76 권제 6 호 2009 증례 08-144 IPSS 검사로진단된 TSH 분비뇌하수체미세선종 1 예 연세대학교원주의과대학 1 내과학교실, 2 신경외과학교실, 3 성균관대학교삼성서울병원건강의학센터 성중경 1 김은미 1 남수민 1 신영구 1 정춘희 1 황금 2 고장현 3 A TSH-secreting pituitary microadenoma diagnosed with inferior petrosal sinus sampling: Case report Joong Kyung Sung, M.D. 1, Eun Mi Kim, M.D. 1, Su Min Nam, M.D. 1, Young Goo Shin, M.D. 1, Choon Hee Chung, M.D. 1, Kum Whang, M.D. 2 and Jang Hyun Koh, M.D. 3 Departments of 1 Internal Medicine and 2 Neurosurgery, Yonsei University Wonju College of Medicine, Wonju, Korea; 3 Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Thyroid stimulating hormone (TSH)-secreting pituitary adenomas are rare tumors of the pituitary gland and represent 1~2% of all pituitary adenomas. A TSH-secreting pituitary adenoma shows as a normal or elevated thyrotropin level in a hyperthyroid patient. We present a 32-year-old woman who was diagnosed with a TSH-secreting pituitary microadenoma. She had a high free T4, with a normal TSH and α-subunit. Bilateral inferior petrosal sinus sampling (IPSS) was done to confirm the α-subunit secreting adenoma, and the concentration of the α-subunit was high on the tumor side. The pituitary microadenoma was removed, and her TSH and free T4 levels decreased to normal. IPSS may help give an accurate diagnosis in the patient with a normal α-subunit. (Korean J Med 76:752-757, 2009) Key Words: α-subunit; Inferior petrosal sinus sampling; Pituitary microadenoma; TSH 서론 1970년 Hamilton 등 1) 이방사면역측정법을이용하여갑상선자극호르몬 (Thyroid stimulating hormone) 의비정상적인과분비가발생하는뇌하수체선종을보고한이후 1980년대에갑상선자극호르몬을정량화하는방법과비정상적인갑상선자극호르몬분비에대한이해가보편화되면서최근들어갑상선자극호르몬을분비하는뇌하수체종양의진단이점차 늘어나고있는추세이다. 하지만이는갑상선기능항진증을유발하는드문질환으로뇌하수체선종의약 1~2% 정도를차지하고있으며국내에서는 10예가보고되었다 2-5). 저자등은갑상선자극호르몬분비뇌하수체미세선종환자에서갑상선자극호르몬유리호르몬 (Thyrotropin Releasing Hormone) 자극검사를양쪽아래바위정맥동굴및말초정맥에서시행하여갑상선자극호르몬및알파소단위 (α-subunit) 를측정하고수술한증례를경험하였기에문헌고찰과함께보고한다. Received: 2008. 5. 19 Accepted: 2008. 7. 11 Correspondence to Jang Koh Koh, M.D., Center for Health Promotion, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Korea E-mail: jangkoh@yahoo.co.kr - 752 -
- Joong Kyung Sung, et al. TSH secreting pituitary microadenoma and IPSS - 증례환자 : 박, 여자, 32세주소 : 피로함현병력 : 내원약 4개월전부터의피로함을주소로개인병원에내원하여갑상선기능항진증을진단받고항갑상선제재를복용하던중본원으로의뢰되었다. 과거력 : 특이병력없음. 가족력 : 특이사항없음. 사회력 : 음주및흡연력없음. 이학적소견 : 내원당시혈압 115/62 mmhg, 맥박수 93회 / 분, 호흡수 20회 / 분이었으며체온은 36.5 였다. 청진상심잡음은들리지않았으며호흡음은정상이었다. 목은촉진상경한미만성갑상선종대가있었으며압통은없었다. 검사소견 : 일반혈액검사에서백혈구 7,390/mm 3, 혈색소 13.5 g/l, 혈소판 230,000/mm 3, 적혈구침강속도는 4 mm/hr이었다. 혈청생화학검사에서나트륨 140 meq/l, 칼륨 4.0 meq/l, 염소 107 meq/l, 혈액요소질소 10.1 mg/dl, 크레아티닌 0.8 ng/dl, 칼슘 9.3 mg/dl, 총콜레스테롤 136 mg/dl, 총단백질 7.2 g/dl, 알부민 4.2 g/dl이었다. 갑상선기능검사상 유리 T4 2.78 ( 정상치 : 0.89~1.80) ng/dl, 갑상선자극호르몬 2.63 ( 정상치 : 0.35~5.50) μiu/ml였다. 갑상선자가항체검사상갑상선자극호르몬수용체항체 (TSH-R Ab) 는 4%, 항갑상선과산화효소항체 (antithyroperoxidase antibody) <15 IU/mL 로정상이었다. 알파소단위는 0.75 miu/ml ( 정상치 : 0~0.9 miu/ml) 로정상범위였으며, α-subunit/tsh molar ratio는 2.85 이었다. 복합뇌하수체자극검사 (combined pituitary challenge test) 상성장호르몬은 0.04 ng/ml 미만으로반응이감소되어있었고, 갑상선자극호르몬유리호르몬을투여했을때갑상선자극호르몬은 2.79 μiu/ml에서 2.69 μiu/ml로반응이없었다. 그외다른호르몬의반응은정상을보였다 ( 표 1). 다음으로 octreotide 50 µg을정맥주사한후 30분간격으로 120분동안갑상선자극호르몬과알파소단위를측정하였다. 시간에따라갑상선자극호르몬은부분적으로감소하였으나알파소단위는감소되지않았다 ( 표 2). 측정된말초혈액에서의알파소단위는정상소견을보여중심정맥에서의변화를알아보기위해양쪽아래바위정맥동굴검사 (bilateral inferior petrosal sinus sampling) 을시행하였다. 갑상선자극호르몬유리호르몬을정맥투여한후 15분이지난뒤말초정맥과아래바위정맥동굴에서갑상선자극호르몬과 Table 1. The response of TSH and the α-subunit to thyrotropin-releasing hormone (TRH) stimulation in peripheral sampling Basal 60 min 120 min Preoperative TSH (μiu/ml) 2.79 2.69 2.40 α-subunit (miu/ml) 0.65 0.68 0.81 Molar ratio 2.32 2.52 3.37 Postoperative TSH (μiu/ml) 1.83 1.62 1.41 α-subunit (miu/ml) 0.40 0.63 0.51 Molar ratio 2.18 3.88 3.61 Normal ranges: TSH 0.35~5.50 μiu/ml, α-subunit pre-menopausal women 0~0.9 miu/ml, post-menopausal women 0~1.6 miu/ml, men 0~0.8 miu/ml. Table 2. Octreotide suppression test TSH (μiu/ml) Free α-subunit (miu/ml) Molar ratio 0 min 3.31 0.57 2.47 15 min 2.43 0.49 2.02 30 min 2.40 0.64 2.67 60 min 1.92 0.55 2.86 90 min 1.80 0.62 3.44 120 min 1.67 0.72 4.31-753 -
- 대한내과학회지 : 제 76 권제 6 호통권제 586 호 2009 - Table 3. The response of TSH and the α-subunit to thyrotropin-releasing hormone (TRH) stimulation in IPSS and peripheral sampling TSH (μiu/ml) Free α-subunit (miu/ml) Right Left Right Left Basal sampling IPSS 4.35 2.97 1.89 1.65 Peripheral 1.97 0.72 TRHstimulation (after 15 min) IPSS 4.20 2.75 1.37 1.12 Peripheral 1.95 0.62 IPSS, Inferior petrosal sinus sampling. Figure 1. (Left) Preoperative T1-weighted magnetic resonance imaging (MRI) shows an oval 7.1 8.5 mm low-signal lesion in the right pituitary gland. (Right) Postoperative T1-weighted MRI shows that the mass was removed subtotally and the space was packed with fat. 알파소단위를측정하였다. 검사결과갑상선자극호르몬은아래바위정맥동굴검사와말초정맥검사에서갑상선자극호르몬유리호르몬에반응하지않았다. 알파소단위의기저치는말초정맥검사보다아래바위정맥동굴검사에서증가되었으나갑상선자극호르몬유리호르몬에는반응하지않았다 ( 표 3). 방사선소견 : 내원시시행한갑상선동위원소검사에서방사선요오드주사 2시간후섭취율은 11.32%, 24시간후섭취율은 33.56% 로정상이었으며갑상선초음파검사에서우엽에 0.5 cm 크기의작은낭종이발견된것이외에특이소견은없었다. 뇌하수체자기공명영상에서뇌하수체의우측에저강도를나타내는 7.1 8.5 mm 크기의종괴가관찰되었고, 주변의오른쪽경동맥및해면정맥동으로의침습이의심되었다 ( 그림 1). PET-CT 검사에서오른쪽뇌하수체에서 FDG 섭취율이약하게증가하여뇌하수체종양이의심되었다 ( 그림 2). 임상경과 : TRH 자극검사상말초혈액과아래바위동굴정맥모두에서반응이없어갑상선자극호르몬분비뇌하수체미세선종으로진단하였으며, octreotide억제검사에서는갑상 Figure 2. Positron emission tomography computed tomography (PET-CT) shows mildly increased fluorodeoxyglucose (FDG) uptake in the right pituitary gland. - 754 -
- 성중경외 6 인. IPSS 와 TSH 분비뇌하수체선종 - Figure 3. Pathologically, microscopic examination of the specimen shows loss of the lobular architecture, which was replaced by uniform basophilic cells (left, H&E 400). Methenamine silver stain shows the loss of the fibrous septa of the lobular architecture (middle, 400). There is strong TSH staining on immunohistochemistry (right, TSH stain 400). Table 4. The changes in thyroid hormone Preoperative Postoperative (1 month later) Last follow-up Free T4 (ng/dl) 2.76 1.78 1.44 TSH (μiu/ml) 2.02 1.76 1.59 Normal ranges: Free T4 0.89-1.80 ng/dl, TSH 0.35-5.50 μiu/ml 선자극호르몬이 50% 이상감소하지않고알파소단위는반응을보이지않아 octreotide에대한치료효과가명확하지않을것으로판단하여경접형동접근법 (transsphenoidal approach) 으로종양제거수술을시행하였다. 수술소견상우측의뇌하수체종양은회색과노란색이혼재된모습이었고, 8~9 mm 정도의크기로보였다. 종양제거도중뇌척수액공간의일부가열렸으며종양이오른쪽경동맥및해면정맥동에침습하였기에완전히제거하지못하였다. 제거한종양조직에서 H & E 염색을한경우뇌하수체의소엽구조가소실되어있고한가지의균일하고호염기성 (basophilic) 을보이는세포로대치되어있었다. Methenamine silver 염색에서는소엽구조에서보이는 fibrous septa가소실된모습을더잘관찰할수있었다. 면역조직화학염색에서는종양조직에서갑상선자극호르몬이전반적으로강하게염색되었다 ( 그림 3). 수술후환자는뇌척수액비루등의합병증이관찰되지는않았다. 수술한달뒤에시행한갑상선기능검사상유리 T4는 1.78 ng/dl로, 갑상선자극호르몬은 1.76 μiu/ml로정상이었으며복합뇌하수체자극검사상갑상선자극호르몬은갑상선자극호르몬유리호르몬에반응을보이지않았으나수술전에비해서는전반적으로감소된양상을보였다 ( 표 1). 그외다른호르몬의반응은정상이었다. 수술후시행한 Sella MRI 상이전에보였던종양은현저히감소하였지만아직은조직이남아있었다 ( 그림 1). 마지막검사한유리 T4는 1.44 ng/dl, 갑상선자극호르몬은 1.59 μiu/ ml이며, 향후 Sella MRI 및유리 FT4, 갑상선자극호르몬을추적검사할예정이다 ( 표 4). 고찰갑상선기능항진증의원인으로는자가면역성갑상선질환, 중독성갑상선결절, 아급성갑상선염혹은임파구성갑상선염등에의한것이대부분을차지한다. 부적절한갑상선자극호르몬분비에의한갑상선기능항진증은드문질환으로이는갑상선호르몬에대한뇌하수체의선택적저항에의한경우나뇌하수체의갑상선자극호르몬분비세포의종양성병변으로인하여발생한다 4). 그중종양성병변으로부적절한 TSH 분비에의한갑상선기능항진증은뇌하수체선종이대표적이며이경우뇌하수체선종의약 1~2% 를차지하며국내에서는 10예가보고되었다 2-5). 갑상선자극호르몬분비뇌하수체선종은 85% 이상이거대선종이며약 60% 정도가다양한정도의침습성이있는것으로보고되고있어, 뇌하수체악성종양과같이조기에발견하고치료해야한다 6). 갑상선 - 755 -
- The Korean Journal of Medicine: Vol. 76, No. 6, 2009 - 자극호르몬분비뇌하수체선종에의한갑상선기능항진증은그레이브스병에서보이는진전, 심계항진, 체중감소, 불안증상등갑상선기능항진증에서보이는일반적인증상이나타나지만안구병증이나피부병증과같은증상은동반되지않는것으로알려져있다 2). 또한혈청갑상선호르몬이상승해있음에도불구하고갑상선자극호르몬이증가되어있거나정상을보이는경우이질환을의심해볼수있다. 특히이질환은갑상선자극호르몬의베타소단위보다는알파소단위의증가가특징적으로일어나므로혈액내알파소단위의증가뿐만아니라 α-subunit/tsh molar ratio가 1보다높은것이특징이며, 이 molar ratio는뇌하수체선종의진단과치료판정및재발등진단과추적관찰에유용하게사용될수있다 7-9). 그러나 1991년 Becker 등 10) 에의해서알파소단위가정상인증례가보고되었으며 1997년국내의곽등 5) 에의해서알파소단위및 α-subunit/tsh molar ratio가정상인증례가보고되었다. 본증례에서도 α-subunit/tsh molar ratio는 1 이상으로높게측정되었으나혈청에서측정한알파소단위는정상범위를보여정확한진단을위해아래바위정맥동굴에서알파소단위및갑상선자극호르몬을측정하였다. 그결과아래바위동굴정맥에서측정한알파소단위는모두혈청의정상범위보다높았고종양이있는오른쪽에서정상인왼쪽보다갑상선자극호르몬및알파소단위의수치가증가되어있었다. 뇌하수체종양에서알파소단위의증가는호르몬분해의감소에기인하는것이아니라뇌하수체선종세포에서의호르몬생성이증가하기때문인것으로알려져있다 11). 하지만미세선종인경우에는호르몬을분비하는양이적기때문에혈중에서측정한알파소단위의농도가정상인경우가있다 12). 갑상선자극호르몬분비뇌하수체선종에서양쪽바위정맥동굴에서알파소단위를측정한증례와그참고값이보고되지않았기때문에본증례에서측정한알파소단위가정상보다높은수치를나타내는것인지확인할수는없었다. 하지만본환자의경우처럼아래바위동굴정맥에서측정한알파소단위가적은농도차이를보이기는하지만병변이있는쪽에서높게나온것으로보아혈청알파소단위가정상인환자에게서아래바위동굴정맥검사방법이정확한진단에도움을줄수있을것으로보인다. 더불어본환자의경우알파소단위의분비가정상임에도 molar ratio 가 1보다증가한것은미세선종에서의갑상선자극호르몬의분비가상대적으로적었기때문인것으로판단된다. 이러한이유로알파소단위가정상인환자에게서갑상선자극호르몬분비뇌하수체선종을배제할수는없을것이다 13). 정상인에서는갑상선자극호르몬유리호르몬에의한알파소단위의반응은기저치보다약 10~15% 정도증가하는것으로되어있으나갑상선자극호르몬분비뇌하수체선종의경우갑상선자극호르몬유리호르몬에대한갑상선자극호르몬의반응은약 85% 정도에서변화가없거나감소되어있고이는뇌하수체선종의자율성에기인한다고볼수있다 14,15). 본환자에서도수술전갑상선자극호르몬유리호르몬에대한반응은말초혈관과아래바위정맥동굴에서채취한갑상선자극호르몬및알파소단위모두에서반응이감소하는것을확인할수있었다 ( 표 3). 하지만수술후에도갑상선자극호르몬유리호르몬자극검사에서갑상선자극호르몬이증가하지않고감소하는것은제거되지않고남아있는종양에의한자율성때문인것으로보인다. 소마토스타틴유도체에의한뇌하수체선종의치료는이미잘알려져있다. 소마토스타틴유도체는아데닐레이트시클라아제 (adenylate cyclase) 를억제하여 camp의생성을억제시킴으로갑상선자극호르몬의분비를억제하거나 camp 와관계없이소마토스타틴이세포막의과분극을유발시킴으로세포내칼슘농도를낮춰서갑상선자극호르몬의분비를억제하는것으로알려져있다 16). 소마토스타틴유도체를사용하는경우연구에따라차이를보이지만대략 55~85% 의환자에서갑상선자극호르몬의감소를보였으며 60~90% 정도의환자에게서알파소단위의감소를보였다 17,18). Socin 등 12) 에따르면뇌하수체종양의크기가 50% 이상으로감소하는경우는 30~40% 였지만, Kuhn 등 19) 은대상자 16명모두에서뇌하수체종양의크기감소를보이지않았던것으로보고하고있다. 이는 in vivo 및 in vitro 연구에서소마토스타틴유도체를투여한경우갑상선자극호르몬분비뇌하수체선종에존재하는수용체개수와분포정도에따라선종의크기나알파소단위의감소가일어나는것으로알려져있기때문이다 18). 본증례에서는 octreotide에대한뇌하수체의반응을확인하기위해 octreotide 50 mg을사용하여억제검사를시행하였다. 갑상선자극호르몬은약 50% 가량기저치보다감소하였지만알파소단위는오히려기저치보다증가하는양상을보여 octreotide에대한뇌하수체종양의반응이없을것으로판단하여수술을시행하였다. Bertherat 등 17) 은 octreotide의투여용량에비례하여아데닐레이트시클라아제의억제가증가한다고보고하였으며, Katznelson 등 18) 은 octreotide 100 mg 투여에반응이없는환자에게 200 mg에서 250 mg까지용량을증가시켰을때알파소단위가감소하였다는증례를보고하였다. 그렇기때문에본환자의경우이 - 756 -
- Joong Kyung Sung, et al. TSH secreting pituitary microadenoma and IPSS - 후에재발하는경우 octrotide 치료용량을증량해서사용해볼수있을것으로보인다. 결론적으로뇌하수체미세선종인경우거대선종에비해상대적으로알파소단위의수치가정상으로보고되는경우가많이있으며이경우본증례와같이아래바위정맥동굴검사가갑상선자극호르몬분비뇌하수체미세선종의진단에도움이될것으로생각한다. 요 갑상선자극호르몬분비뇌하수체선종은전체뇌하수체선종의 1~2% 에해당하는드문질환이다. 그중에서도뇌하수체미세선종은호르몬분비량이적기때문에말초정맥에서측정한알파소단위가정상을나타내는경우가많다. 저자들은이러한환자에서아래바위정맥동굴에서갑상선자극호르몬유리호르몬자극검사를시행하여말초혈액과의차이를통해뇌하수체미세선종의진단에효과적으로사용한증례를경험하였기에문헌고찰과함께보고한다. 중심단어 : 뇌하수체미세선종 ; 갑상선자극호르몬 ; 알파소단위 ; 아래바위정맥동굴검사 약 REFERENCES 1) Hamilton GR, Adams LC, Maloof F. Hyperthyroidism due to thyrotropin producing pituitary chromophobe adenoma. N Engl J Med 283:1077-1080, 1970 2) Yoon HJ, Hong DS, Hong KS, Cha BY, Kim YW, Son HY. A case of TSH secreting pituitary tumor. J Korean Soc Endocrinol 1:55-62, 1986 3) Lee KM, Lee EJ, Kim KL, Chung YS, Lee BK, Park SW, Lim SK, Lee HC, Yoon DH, Kim YS, Huh KB. Alpha-subunit secretion of pituitary adenomas. J Korean Soc Endocrinol 8:127-133, 1993 4) Jung JK, Jo JW, Nam MS, Lee KM, Kwon SO, Nam SY, Lee EJ, Kim KL, Lee HC, Huh KB. Reduction in size of TSH secreting pituitary adenoma with octreotide treatment. Korean J Med 48:408-413, 1995 5) Kwak MH, Bae MH, Choi Sn, Lee KJ, Park SJ, Chang MS, Shin SH. A case of thyrotropin-secreting pituitary adenoma with normal alpha-subunit/tsh molar ratio. Korean J Med 53:853-859, 1997 6) Sarlis NJ, Gourgiotis L, Koch CA, Skarulis MC, Brucker-Davis F, Doppman JL, Oldfiled EH, Patronas NJ. MR imaging features of thyrotropin-secreting pituitary adenomas at initial presentation. AJR Am J Roentgenol 181:577-582, 2003 7) Beck-Peccoz P, Brucker-Davis F, Persani L, Smallridge RC, Weintraub BD. Thyrotropin-secreting pituitary tumors. Endocr Rev 17:610-638, 1996 8) Brucker-Davis F, Oldfield EH, Skarulis MC, Doppman JL, Weintraub BD. Thyrotropin-secreting pituitary tumors: diagnostic criteria, thyroid hormone sensitivity, and treatment outcome in 25 patients followed at the National Institutes of Health. J Clin Endocrinol Metab 84:476-486, 1999 9) Beck-Peccoz P, Persani L. Medical management of thyrotropinsecreting pituitary adenoma. Pituitary 5:83-88, 2002 10) Beckers A, Abs R, Mahler C, Vandalem JL, Pirens G, Hennen G, Stevenaert A. Thyrotropin-secreting pituitary adenomas: report of seven cases. J Clin Endocrinol Metab 72:477-483, 1991 11) Asa SL, Gerrie BM, Singer W, Horvath E, Kovacs K, Smyth HS. Gonadotropin secretion in vitro by human pituitary null cell adenomas and oncocytomas. J Clin Endocrinol Metab 62:1011-1019, 1986 12) Socin HV, Chanson P, Delemer B, Tabarin A, Rohmer V, Mockel J, Stevenaert A, Becker A. The changing spectrum of TSH-secreting pituitary adenomas: diagnosis and management in 43 patients. Eur J Endocrinol 148:433-442, 2003 13) Ozata M, Oztűrk E, Narin Y, Tayfun C, Azal O, Beyhan Z, Corakҫ i A, Bayhan H, Gűndoğan MA. A case of thyrotropine-secreting pituitary microadenoma with thyrotropin alpha-subunit level. Thyroid 7:441-447, 1997 14) Kourides IA, Weintraub BD, Rosen SW, Ridgway EC, Kliman B, Maloof F. Secretion of alpha subunit of glycoprotein hormones by pituitary adenomas. J Clin Endocrinol Metab 43:97-106, 1976 15) Beck-Peccoz P, Persani L. TSH-induced hyperthyroidism caused by a pituitary tumor. Nat Clin Pract Endocrinol Metab 2:524-528, 2006 16) Takano K, Ajima M, Teramoto A, Hata K, Yamashita N. Mechamism of action of somatostatin on human TSH-secreting adenoma cells. Am J Physiol 268:E558-E564, 1995 17) Bertherat J, Brue T, Enjalbert A, Gunz G, Rasolonjanahary R, Warnet A, Jaquet P, Epelbaum J. Somatostatin receptors on thyrotropin-secreting pituitary adenomas: comparison with the inhibitory effect of octreotide upon in vivo and in vitro hormonal secretions. J Clin Endocrinol Metab 75:540-546, 1992 18) Katznelson L, Oppenheim DS, Coughlin JF, Kliman B, Schoenfeld DA, Klibanski A. Chronic somatostatin analog administration in patients with α-subunit-secreting pituitary tumors. J Clin Endocrinol Metab 75:1318-1325, 1992 19) Kuhn JM, Arlot S, Leferbvre H, Caron P, Cortet-Rudelli C, Archambaud F, Chanson P, Tabarin A, Goth MI, Blumberg J, Catus F, Ispas S, Beck-Peccoz P. Evaluation of the treatment of thyrotropin-secreting pituitary adenoma with a slow relrasing formulation of the somatostatin analog lanreotide. J Clin Endocrinol Metab 85:1487-1491, 2000-757 -