Review ISSN 1975-7425(Print) / ISSN: 2288-016X(Online) Korean J Urogenit Tract Infect Inflamm 2013;8(1):7-12 만성전립선염의유발및악화인자 정홍 건국대학교의학전문대학원비뇨기과 Chronic Prostatitis/Chronic Pelvic Pain Syndrome: What Are the Starting and Worsening Factors? Hong Chung Department of Urology, School of Medicine, Konkuk University, Chungju, Korea Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in the absence of any identifiable pathology such as cancer, curable infection, or anatomic abnormalities is defined as urologic pain or discomfort in the pelvic region, associated with urinary symptoms and/or sexual dysfunction, lasting for at least 3 of the previous 6 months. However, etiologic factors of CP/CPPS remain unknown. The traditional marker of inflammation, namely white blood cells in prostatic fluids, dose not correlate with the predominant symptom of pelvic pain. The role of normal bacterial flora in prostate in inciting the inflammatory response has also been reconsidered. Nanobacterial infection might be an important etiologic factor of type III prostatitis. An imbalance toward increased proinflammatory and decreased anti-inflammatory cytokines has been implicated, and its correlation with pelvic pain has also been observed to some extent. Pelvic pain also correlates with the neurotrophin (nerve growth factor) implicated in neurogenic inflammation and central sensitization. Finally, psychological stress may produce measurable biochemical changes and affect other processes. Here, the author reviewed the existing literature on etiology involved in the mechanisms of CP/CPPS. Keywords: Etiology; Prostatitis; Recurrence Copyright 2013, Korean Association of Urogenital Tract Infection and Inflammation. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution n-commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 2 March, 2013 Revised: 26 March, 2013 Accepted: 6 April, 2013 Correspondence to: Hong Chung Department of Urology, Konkuk University Chungju Hospital, School of Medicine, Konkuk University, 82, Gugwon-daero, Chungju 380-704, Korea Tel: +82-43-840-8270, Fax: +82-43-848-4722 E-mail: chunghong@kku.ac.kr potential conflict of interest relevant to this article was reported. 서론 만성전립선염 / 만성골반통증후군 (chronic prostatitis/chronic pelvic pain syndrome, CP/CPPS) 에대한관심이고조되고있으나병인이명확히밝혀져있지않고치료가다양하다. 특히초기약물치료후증상호전을보이는경우가많으나, 증상재발이흔하여완치를기대하기는어려운질환이다. 또한재발방지를위하여증상호전후에도환자스스로관리가중요하게여겨지고있다. 이는증상발생및재발하는 CP/CPPS 에대한명확한원인및그치료방법에대해서현재까지알려져있지않기때문이다. 1 CP/CPPS는 50세이하의남성에서가장흔한전립선질환으로개원비뇨기과환자의 25-30% 정도가 CP/CPPS 로추정될만큼높은유병률을가지고있는질환이다. 2,3 7
8 Hong Chung Fig. 1. Interplay of immunological, endocrine, neurological and psychological factors in development of CP/CPPS and proposed mechanisms. CP/CPPS: chronic prostatitis/chronic pelvic pain syndrome, NGF: nerve growth factor, IFN-γ: interferon-γ, IL: interleukin, TNF-α: tumor necrosis factor (adapted from Pontari and Ruggieri. J Urol 2008;179(5 Suppl):S61-7, with permission of Elsevier). 6 임상적으로전립선염은전립선에의하여유발되는증상을일으키는복합적인질환을지칭하며, 전립선염의범위는급성세균성전립선염부터만성세균성전립선염, 전립선염증을포함하지않는만성비세균성전립선염, 혹은증상을호소하지않는무증상전립선염까지그형태가다양하다. 과거에는전립선염의원인으로반복되는회음부의손상이나과도한성생활등으로생각하기도하였으며, 이후각각분류하였던비세균성전립선염과전립선통은구별이명확하지않은한계점이있었다. 실제세균성전립선염의경우전체전립선염환자의 10% 이하로보고되고있어, 4 전립선의감염을증명할수있는경우는비교적드물다. 이러한이유로근래에비세균성만성전립선염을 CP/CPPS 로통합하여 type III로분류하고있고, 이는전체전립선염의 90% 이상을차지하고있다. CP/CPPS는전립선마사지후분비액 (expressed prostatic secretion, ), 전립선마사지후소변 (voided bladder 3, VB3) 또는정액의백혈구유무에따라염증성만성골반통증후군 (type IIIA) 과비염증성만성골반통증후군 (type IIIB) 으로나누고있다. 5 현재까지 CP/CPSS 의병인으로감염, 자가면역질환, 신경질환및정신질환등여러원인이거론되고있으며, 재발에대한원인은명확하지않다. 많은 CP/CPPS 환자에서항생제투여가효과를보인다는점과통상적인배양검사에서확인이어려운세균이나바이러스감염이있을수있다는점등에서미생물에의한감염이중요한역할을할것으로추정되고있다. 또한 cytokines, urinary nerve growth factor (NGF) 등의변화, 배뇨장애등도전립선염의발생및재발에 관여할것으로생각된다 (Fig. 1). 6 이에보고된문헌고찰을통하여 CP/CPPS 의발생및악화에관여하는요인에대하여살펴보고자한다. 본 론 1. 세균 (Bacteria) 많은 CP/CPPS 환자에서항생제투여후증상의호전을보인다는점과통상적인배양검사에서확인이어려운세균이나바이러스감염이있을수있다는점등에서미생물에의한감염이중요한요인중하나일것으로추정된다. 7-10 최근의연구에서 Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Neisseria gonorrhoease, Trichomonas vaginalis, Ureaplasma urealyticum 등의잠복미생물이중합효소연쇄반응 (polymerase chain reaction, PCR) 을통해 CP/CPPS의환자에서확인된바있다. 11,12 그러나모든 CP/CPPS 환자에서검출되는것은아니며, 연관성이없다는보고도있어논란이있다. 13 Shen 등 14 은 100-500 nm 크기의 nanobacteria가 CP/CPPS 원인일가능성을제시하였으며, 백서를이용한전립선염모델에서대조군에비하여 nanobacteria를투여한군에서병리학적변화와함께시간에따른 tumor necrosis factor (TNF)-α와 interleukin (IL)-1β 의증가를보여임상에서검출이어려운 nanobacteria 가 type III 만성전립선염의원인이될수있다고하였다. 근래에 Shoskes 등 15 은과거치료에반응하지않는 16명의환자를대상으로
만성전립선염의유발및악화인자 9 하여 tetracycline 3개월투여시 12명 (80%) 에서 National Institutes of Health chronic prostatitis symptom index 증상점수가 25% 이상호전을보였으며, 이중 8명에서는 50% 이상의호전을보였다. 또한 Zhou 등 16 은 48명을대상으로위약대조군연구에서 tetracycline 의투여시 3개월투여군의증상호전과함께 및 VB3의 nanobacteria가초기 62.5% 에서 16.7% 로감소함을확인하였다. 이들의연구에서 tetracycline 의투여는통상적인치료에도재발하거나혹은반응하지않는 type III 만성전립선염환자에서 nanobateria가주요원인이될수있으며, tetracycline 의투여로재발을줄일수있을것으로기대된다. 그러나근래까지도 nanobacteria에대한검사로 indirect immunofluorescence staining, confocal laser scanning microscopy, transmission electron microscopy 등을사용함에있어임상적으로적용하는데에어려움이있었다. 최근 Kim 등 17 은 CP/CPPS 환자의 에서비교적간단하며, 저렴한비용으로측정이가능한 reverse transcription (RT)-PCR로 nanobacteria의측정을보고하여, 만성전립선염에서임상적적용가능성을제시하였다. 특히국내에서는신종플루등에대한확진검사장비로 RT-PCR 이보편적으로적용되고있는바, 보다쉽게임상적용이가능할것으로생각된다. 그러나, nanobacteria가 CP/CPPS의발생및재발에관여하는지에대해서는추가적인연구가필요할것이다. 2. 염증유발시토카인과염증억제시토카인, 감각및신경인성통증의불균형 (Imbalance of Pro- and Anti- Inflammatory Cytokines, Central Sensitization and Neurogenic Pain) 시토카인 (cytokine) 은수용성신호전달물질로백혈구는물론혈관내피세포, 상피세포등여러세포에서생성되며, 국소적으로면역및염증반응의유발또는조절인자로서역할을한다. IL-1β는백혈구에작용해서다른시토카인들의생산을촉진하고 TNF-α 는숙주의방어기전을담당한다. IL-6 는 T 세포의활성화, 성장, 분화에관여하며, T 세포에서 IL-2 수용체의표현을유도한다. IL-8은염증부위에서호중구를끌어모으는화학주성체로서의역할을하는데, 전립선액의백혈구와관련이있다. 염증유발시토카인인 IL-6 는 CP/CPPS 환자의정액에서치료전에는증가된소견을보이며, 치료후에는감소되는소견을보인다. 18 다른염증유발시토카인인 IL-8 역시전립선의염증동반시에증가되는소견을보이며, 정액내염증세포증가, 사정액감소등과관련이있다. 19,20 TNF-α는염증억제시토카인인 IL-10의생산을유도한다. TNF-α는정상군에비하여 CP/CPPS 환자에서 내증가하고 type IIIA 환자에서 IIIB 보다높게나타난다. 47명의만성전립선염 (type IIIA, IIIB) 환자의 내 IL-10, TNF-α의농도는 12명의대조군에비하여증가하였으나, IL-2 는감소한결과를 Table 1. Cytokines levels in chronic prostatitis/chronic pelvic pain syndrome type IIIB vs. asymptomatic controls Fluid IL-1β IL-2 IL-6 IL-8 IL-10 TNF-α IIIB vs. controls significant increased (p<0.05) References John et al. 25 He et al. 21 Miller et al. 23 He et al. 21 He et al. 21 John et al. 25 IL: interleukin, : expressed prostatic secretion, TNF-α: tumor necrosis factor (TNF)-α. 보였다. 21 Orhan 등 22 은대조군에비하여 type III 환자의정액에서 IL-1β, IL-8, TNF-α는의미있는증가를보인반면, IL-6 는차이를보이지않았다. Miller 등 23,24 의결과에서도 내에 IL-2, IL-10 등이 type III 환자군에서높게관찰되었다. 반면 John 등 25 은 에서 IL-1β 와 TNF-α 는대조군에비하여 type III 에서차이를보이지않았다고하였다 (Table 1). 이들시토카인은 CP/CPPS 증상이있는환자의 혹은정액내에서증가를보인다는결과가주로보고되고있으나, 일부에서는변화가없다는결과도있다. 시토카인은치료후변화되는양상을보이는경우, CP/CPPS의발생및재발, 악화와의연관성외에도치료에대한표지자로서유용성이있을것으로생각된다. 다만증상호전후재발하는경우시토카인의추적관찰에대한연구는추가적으로더필요할것이며, 현재까지의연구결과로는재발과의관련성을판단하기에는어려움이있다. 간질성방광염 (interstitial cystitis) 과 CP/CPPS 의임상양상의유사점이많다. 두질환모두신경인성염증 (neurogenic inflammation), 대식세포 (mast cell) 활성화, 자가면역등이발생과관련이있고, type IIIA의환자에서 pentosan polysulfate의투여시증상호전을보인다는보고도있다. 26 NGF는과민성방광, 방광출구폐쇄, 배뇨근과활동성등의질환상태와연관이있는것으로알려져있다. 간질성방광염이나방광통증후군 (bladder pain syndrome) 환자에서방광이비어있거나혹은통증이없을때보다방광의최대팽창시통증과함께소변내 NGF 증가가보고되고있다. 27 2002년 Miller 등 24 은 내의 NGF 농도는대조군과 CPPS군에서차이를보이지않으나환자의항문주위, 하복부통증과 NGF와의연관성이있음을보고하였다. NGF가염증반응과통증신호전달과정의
10 Hong Chung 변화에관여하는주요물질로여겨지고있고, 요로생식기계에서요로상피, 평활근, 대식세포등에서분비되는점을생각하였을때 NGF와 CP/CPPS에서통증발생과의연관성이있을것을생각된다. 최근 Watanabe 등 28 의결과에서도 CP/CPPS 환자의통증과 내 NGF 의증가는의미있는상관관계를보여 CP/CPPS 환자에서 내 NGF의증가가의미가있음을보고하였다. 그러나통증의위치에대한언급이없다는점과치료전후에 NGF의변화가없다는점등의문제가있어 CP/CPPS와 NGF와의연관성을이해하기에는한계가있다. 또한 내 NGF의증가가전립선의염증에따른이차적변화인지혹은골반의일반적인통증에의하여발생한이차적증가인지여부에대한명확한판단을내리기는어렵다. 그러므로현재까지보고로는 혹은정액내 NGF 농도측정으로 CP/CPPS의발생, 치료판정및재발을예측평가하는데어려움이있다. CP/CPPS와 NGF의연관성에대한연구는부족하나 NGF가 CP/CPPS 환자에서통증의발생과관련이있을것으로생각된다. 3. 배뇨시비정상적인압력증가 (Dysfunctional High- Pressure Voiding) CP/CPPS 의주요증상중하나는비뇨생식기계를포함하는통증과하부요로증상이다. 통증과하부요로증상은하부요로의폐쇄를유발하는방광경부협착, 요도협착, 배뇨근괄약근부조화및다른배뇨장애에서나타날수있는증상으로 CP/CPPS만의특이증상은아니다. 29-31 하부요로의폐쇄를동반하는경우요역동학검사에서배뇨중압력의증가시요속감소와함께최대요도폐쇄압증가를보이는데, 이는여러연구를통해서 CP/CPPS 환자에서도보고되고있다. 이러한증가된배뇨압은배뇨시전립선내역류를유발하여 CP/CPPS 의발생혹은악화요인이된다. 32,33 소변의전립선으로의역류는전립선의부종과함께만성적인염증을유발하고이는다시배뇨증상을유발하여전립선의염증을악화시키는요인이된다. CP/CPPS 환자에서소변의전립선내역류가발생할것이라는증거로는전립선내결석의성상이요로결석의성상과유사하며, 내크레아티닌과요산이높은농도를유지한다는보고로추정해볼수있다. 34,35 이들배뇨중압력증가와이에따른전립선내로의소변역류는 CP/CPPS의발생및악화요인이되며, 치료에있어알파차단제를투여하는근거가된다. 32 De la Rosette 등 38 은 CP/CPPS 환자 50명과정관수술시행한환자 50명의성격및특성을비교하였을때 CP/CPPS 환자에서성격특성판별점수가더높게나타난바있다. 이들의결과는환자의증상발생에있어정관수술과같은수술적인요인보다심리적인요인이더크게작용할수있음을보여주었다. 특히만성적인허리통증을호소하는환자들이우울증상이나불안감을보이는반면, CP/CPPS 환자들은증상이심할수록주요우울증의증상을보인다. 39 우울증이나남자로서의자존심등이 CP/CPPS 환자의초기발생에관여하고있고, 대규모환자-대조군연구에서도우울증이나공황장애가 CP/CPPS 의환자에게더발생한다는점으로보아심리적인요인은 CP/CPPS의초기발생혹은악화의주요한요인이될것이다. 40,41 또한우울증이나참기어려운고통등의심리적인요인외에도과도한스트레스등도요인이될수있다. 42,43 5. 환경적요인 (Environmental Factors) Lan 등 44 의연구에서고도가높은지역에사는경우고도가낮은지역보다 type IIIA와 IIIB 모두증상이더심하며, IIIA는 TNF-α, IL-6, IL-8, IL-10, IIIB는 IL-8이높게나타났다. 이들결과는 CP/CPPS의발생에있어체질량지수 (body mass index), 직업외에도고도에따른산화스트레스 (oxidative stress) 가 CP/CPPS 의발생에영향을미칠수있음을보여주었다. Hedelin과 Jonsson 45 과 Hedelin 등 46 은 CP/CPPS 환자의통증및증상악화가온도변화와관련성이있으며, 추운날씨에증상이더악화된다고하였다. 추운날씨에통증및증상이악화되는점은골반근육경련과관련이있을것으로생각된다. 결 론 CP/CPPS는비뇨기과외래환자의많은부분을차지하고있으며, 질환의발생및재발에대한원인으로는세균및 nanobacteria, 시토카인의변화, 배뇨이상에의한전립선내로의역류와외적인요인등이관여할것으로생각된다. CP/CPPS 의환자에서초기발생시약물에의하여증상호전을보이더라도재발을방지하기위하여알려진악화요인에대한환자스스로의관리가중요하다. 또한만성질환으로생각되고있는 CP/CPPS의발생및재발인자에대한추가적인연구가필요하다. 4. 심리적인요인 (Psychological Factors) 비뇨기계질환및그외의다른질환에대해서도심리적인요인이환자가느끼는증상발생과악화를보일수있다는연구결과들이있으며, 36,37 심리적인요인은 CP/CPPS 환자의발생이나악화의주요한요인으로생각하여야할것이다. REFERENCES 1. Cho IR. Evaluation and treatment of patients with prostatitis. Korean J Androl 2005;23:1-11. 2. Collins MM, Stafford RS, O'Leary MP, Barry MJ. How common
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