趙 健, 田 浩, 姚定康
(第二軍醫(yī)大學(xué)長(zhǎng)征醫(yī)院 內(nèi)科學(xué)教研室, 上海 200003)
原發(fā)性膽汁性膽管炎并發(fā)骨質(zhì)疏松的研究現(xiàn)狀
趙 健, 田 浩, 姚定康
(第二軍醫(yī)大學(xué)長(zhǎng)征醫(yī)院 內(nèi)科學(xué)教研室, 上海 200003)
骨質(zhì)疏松是原發(fā)性膽汁性膽管炎的常見并發(fā)癥,發(fā)病率高,骨折風(fēng)險(xiǎn)大,其發(fā)病機(jī)制尚不明確。回顧了PBC發(fā)病機(jī)制與治療的最新進(jìn)展,研究表明其病因復(fù)雜,與多種因素引起的骨質(zhì)吸收增加、成骨作用減少等相關(guān)。雖然已有多種藥物應(yīng)用于臨床,但目前最有效的治療藥物是雙膦酸鹽,未來(lái)還需要更多長(zhǎng)期的系統(tǒng)性研究以明確其療效與對(duì)骨折事件的影響。
膽管炎; 骨質(zhì)疏松; 綜述
原發(fā)性膽汁性膽管炎(PBC)是一種以肝內(nèi)小膽管進(jìn)行性、非化膿性炎癥為病理表現(xiàn)的慢性肝內(nèi)膽汁淤積性肝病,血清抗線粒體抗體陽(yáng)性是其特征性標(biāo)志物[1]。該病多發(fā)生于中老年女性,多數(shù)患者表現(xiàn)為乏力、瘙癢等癥狀。PBC可引起多種并發(fā)癥,骨代謝障礙是其中一個(gè)常見并發(fā)癥,且近年來(lái)也越來(lái)越受到重視[2]。由于以骨質(zhì)疏松為代表的骨代謝障礙會(huì)增加PBC人群的骨折發(fā)生率和患者病死率以及相應(yīng)的經(jīng)濟(jì)負(fù)擔(dān),因此研究PBC相關(guān)骨病具有重要的現(xiàn)實(shí)意義,本文就PBC并發(fā)骨質(zhì)疏松的流行病學(xué)、發(fā)病機(jī)制及其處理的研究進(jìn)展做一綜述。
與其它骨代謝障礙分類相似,PBC相關(guān)的骨代謝障礙根據(jù)骨密度(bone mineral density,BMD)降低程度可分為骨質(zhì)軟化與骨質(zhì)疏松[3]。根據(jù)世界衛(wèi)生組織的診斷標(biāo)準(zhǔn):采用雙能X線吸收法測(cè)量腰椎、髖部或股骨頸的BMD,并與年輕人和同齡人的參考值進(jìn)行比較。骨質(zhì)軟化定義為:BMD低于正常年輕成年人平均值1~2.5 SD(-2.5 SD 正常的骨質(zhì)代謝是持續(xù)性的骨質(zhì)重構(gòu),需要成骨作用與破骨作用之間的平衡。而骨質(zhì)重構(gòu)過(guò)程很大程度上是由破骨細(xì)胞抑制因子(osteoclastogenesis inhibitory factor,OPG)、核因子κB受體活化因子(receptor activator for nuclear factor-κB,RANK)、核因子κB受體活化因子配體(receptor activator for nuclear factor-κ B ligand,RANKL)等分子調(diào)控。RANKL位于成骨細(xì)胞膜表面,其與RANK相結(jié)合可強(qiáng)效激活破骨細(xì)胞活動(dòng),從而引起骨質(zhì)吸收。同時(shí),由肝臟產(chǎn)生的OPG與RANKL相結(jié)合,從而競(jìng)爭(zhēng)抑制RANK以減弱破骨作用[9]。雌激素能夠通過(guò)抑制破骨細(xì)胞活動(dòng)而影響骨質(zhì)代謝,其機(jī)理是增加OPG的表達(dá)與破骨細(xì)胞的凋亡。對(duì)于絕經(jīng)后的女性,雌激素水平迅速下降,6~10年期間可使骨量減少達(dá)30%[10]。目前對(duì)PBC引起骨質(zhì)疏松的機(jī)理尚未完全研究透徹,并存在較多爭(zhēng)議,但主要觀點(diǎn)是骨質(zhì)吸收增加與成骨減少共同導(dǎo)致了骨質(zhì)疏松的發(fā)生。 2.1 骨質(zhì)吸收增加 PBC患者最顯著的表現(xiàn)之一是肝內(nèi)膽汁淤積導(dǎo)致膽汁分泌減少,而理論上膽汁分泌減少會(huì)影響包括維生素D在內(nèi)的脂溶性維生素的吸收,繼而影響鈣磷的代謝,引發(fā)繼發(fā)性甲旁亢和成骨作用減弱。雖然30年前的研究[11]顯示PBC伴發(fā)骨質(zhì)疏松的患者的血清維生素D水平基本正常,且補(bǔ)充維生素D未見對(duì)BMD有顯著影響。不過(guò)最近的研究[12-14]顯示PBC患者血清的維生素D水平相比對(duì)照呈顯著下降,并隨著疾病進(jìn)展而加重,且治療前的維生素D水平與患者對(duì)熊去氧膽酸的應(yīng)答相關(guān)。此外,由于PBC患者肝功能的下降,肝源OPG產(chǎn)生減少,對(duì)破骨細(xì)胞的抑制減弱,也增加了骨質(zhì)吸收[15]。最后,對(duì)于包括PBC在內(nèi)的自身免疫性肝病患者,激素類藥物是常用的治療藥物。而骨質(zhì)流失引起骨質(zhì)疏松則是糖皮質(zhì)激素長(zhǎng)期使用的并發(fā)癥之一,并已有研究[16]顯示在該類人群中,激素應(yīng)用是骨代謝障礙的危險(xiǎn)因素之一。 2.2 成骨作用減弱 有證據(jù)[17]顯示PBC人群成骨作用減弱,引起低轉(zhuǎn)化性骨質(zhì)疏松。對(duì)膽汁淤積患者進(jìn)行骨活組織檢查,病理結(jié)果顯示成骨活動(dòng)顯著減弱。而肝臟的纖維化可引起特定的包括胰島素樣生長(zhǎng)因子1在內(nèi)的生長(zhǎng)因子減少,引起成骨障礙,減少骨生成。嚴(yán)重的膽汁淤積會(huì)使石膽酸累積,抑制成骨活動(dòng),干擾骨質(zhì)形成的基因調(diào)節(jié)[18]。膽汁淤積還會(huì)引起維生素K缺乏,而維生素K缺乏在體外研究[19]中表明會(huì)減弱成骨作用,增強(qiáng)破骨作用。 需要強(qiáng)調(diào)的是,上述2種機(jī)制并非孤立存在,往往是共同作用的,且傾向于隨著PBC患者肝病的進(jìn)展,2種機(jī)制可以相互改變,且性別不同主導(dǎo)的機(jī)制也可能不同。 3.1 骨質(zhì)疏松的篩查與預(yù)防 美國(guó)胃腸病協(xié)會(huì)指南[3]建議PBC患者被確診時(shí)都應(yīng)進(jìn)行BMD檢查,而其他指南[20]為避免過(guò)度檢查則建議對(duì)膽紅素>3倍正常值上限的患者進(jìn)行BMD檢查。而如果PBC患者已經(jīng)發(fā)生了肝硬化,或接受超過(guò)3個(gè)月的糖皮質(zhì)激素治療,或發(fā)生過(guò)脆性骨折的,則均應(yīng)進(jìn)行檢測(cè)以了解BMD情況并及時(shí)干預(yù)。 PBC患者尤其是絕經(jīng)后女性患者是骨質(zhì)丟失的高危人群,減少或消除促進(jìn)骨質(zhì)減少的相關(guān)危險(xiǎn)因素具有重要的預(yù)防意義。生活方式上應(yīng)注意戒煙、戒酒,增加負(fù)重運(yùn)動(dòng)和平衡飲食。一項(xiàng)對(duì)絕經(jīng)后女性的長(zhǎng)期隨訪研究[21]發(fā)現(xiàn),規(guī)律鍛煉的女性BMD顯著高于對(duì)照組并隨著隨訪期的延長(zhǎng),差異也逐漸加大。飲食方面應(yīng)保證足夠的維生素D和鈣的攝入,為預(yù)防骨質(zhì)流失,對(duì)于50歲以上人群每日應(yīng)至少攝入1200 mg鈣和800單位的維生素D[22]。而對(duì)于部分存在吸收功能障礙的人群如膽汁淤積嚴(yán)重的PBC患者,還應(yīng)適當(dāng)增加攝入量,以維持平衡。一些在肝硬化人群中開展的補(bǔ)充維生素D的研究[23-24]表明,試驗(yàn)組患者的BMD較對(duì)照組有顯著改善,但這些研究的樣本量均較小,未來(lái)在預(yù)防方面尚需更多的研究。 3.2 藥物治療 對(duì)于明確診斷為骨質(zhì)疏松或已經(jīng)發(fā)生與骨質(zhì)減少等相關(guān)性脆性骨折的PBC患者應(yīng)進(jìn)行抗骨質(zhì)疏松治療。此外,T值雖<-1.5但預(yù)期骨折發(fā)生風(fēng)險(xiǎn)高的患者也應(yīng)進(jìn)行合理治療[25]。PBC患者骨質(zhì)疏松的治療與一般的絕經(jīng)后骨質(zhì)疏松治療方案類似,目前主要有以下幾類藥物。 3.2.1 雙膦酸鹽 雙膦酸鹽是臨床常用的抗骨質(zhì)疏松藥物,包括阿倫膦酸鈉、伊班膦酸鈉等,藥理機(jī)制主要是抑制破骨細(xì)胞活動(dòng),減少骨質(zhì)吸收。既往研究[26]表明,有較強(qiáng)的證據(jù)支持雙膦酸鹽可以顯著降低普通骨質(zhì)疏松人群椎體骨折和周圍骨折的發(fā)生率。類似的是,PBC人群中也有小型研究[27-28]提示經(jīng)雙膦酸鹽治療后,PBC人群的BMD可以得到改善。雖然2011年的一項(xiàng)Cochrane薈萃分析[29]發(fā)現(xiàn),目前尚無(wú)證據(jù)表明雙膦酸鹽可以顯著改善PBC人群的BMD、病死率和骨折風(fēng)險(xiǎn)等指標(biāo)。但最近一項(xiàng)大型RCT研究[30]發(fā)現(xiàn),在PBC并發(fā)骨質(zhì)疏松人群中應(yīng)用雙膦酸鹽治療后,患者腰椎、髖關(guān)節(jié)的BMD均有明顯提升,且在用藥方面每月1次的伊班膦酸鈉相比每周1次的阿侖膦酸鈉可以帶來(lái)更好的患者依從性。但由于該研究隨訪時(shí)程較短,尚無(wú)骨折相關(guān)數(shù)據(jù),未來(lái)還需要更長(zhǎng)時(shí)間的隨訪以明確雙膦酸鹽對(duì)骨折事件的影響。 3.2.2 激素替代療法 雌激素具有很好的抗骨質(zhì)吸收作用,雖然應(yīng)用雌激素會(huì)增加其他方面的風(fēng)險(xiǎn)(如乳腺癌),但激素替代療法確實(shí)可以發(fā)揮減少骨折流失,降低骨折風(fēng)險(xiǎn)的作用。過(guò)去有臨床研究[31-33]表明該療法安全且能夠有效改善PBC患者的BMD,但由于激素替代療法對(duì)患者的預(yù)后無(wú)影響,且反而可能增加多種不良事件發(fā)生率,因此薈萃分析結(jié)果并不支持在PBC人群中使用雌激素替代療法。 3.2.3 選擇性雌激素受體調(diào)節(jié)劑 雷洛昔芬是目前被批準(zhǔn)可用來(lái)治療骨質(zhì)疏松的選擇性雌激素受體調(diào)節(jié)劑,其發(fā)明與應(yīng)用是為了應(yīng)對(duì)激素替代療法的安全性憂慮,總體來(lái)說(shuō)其效果弱于雙膦酸鹽和雌激素。雖然一項(xiàng)僅納入9例女性PBC患者的臨床研究[34]發(fā)現(xiàn)應(yīng)用雷洛昔芬后,患者腰椎的BMD較對(duì)照組有顯著提高,但二者股骨頸的BMD變化并無(wú)顯著性差異,且未報(bào)道骨折相關(guān)數(shù)據(jù),因此尚無(wú)法評(píng)估其在PBC人群中的應(yīng)用價(jià)值。 3.2.4 降鈣素 降鈣素的抗骨質(zhì)吸收作用較弱,其在PBC患者中的應(yīng)用僅見于早前零散的小樣本量研究[35-36],且異質(zhì)性較大,對(duì)PBC患者的BMD也無(wú)顯著影響。 綜上分析,目前僅雙膦酸鹽在PBC骨質(zhì)疏松治療領(lǐng)域最有前景與治療意義。 骨質(zhì)疏松是PBC患者的一種常見并發(fā)癥,患病率較高。隨著肝病進(jìn)展、年齡增長(zhǎng)和膽汁淤積病程延長(zhǎng),骨質(zhì)疏松的發(fā)生風(fēng)險(xiǎn)也逐漸增加。骨質(zhì)疏松的發(fā)生增加了骨折的風(fēng)險(xiǎn),不僅嚴(yán)重影響患者的生活質(zhì)量,還增加了患者的經(jīng)濟(jì)負(fù)擔(dān)和病死率,因此在骨折發(fā)生之前識(shí)別出骨質(zhì)疏松并針對(duì)危險(xiǎn)因素進(jìn)行預(yù)防具有重要意義。對(duì)于已經(jīng)發(fā)生骨質(zhì)疏松的PBC患者,雙膦酸鹽已顯示出較好的抗骨質(zhì)疏松效果,且耐受性較高。但由于在PBC人群中開展的相關(guān)治療研究較少且樣本量有限,目前的治療建議主要是基于絕經(jīng)后女性的研究。未來(lái)尚需要更多針對(duì)PBC人群的基礎(chǔ)與臨床研究,以明確其發(fā)病機(jī)制以及預(yù)防與治療方案。 [1] CAREY EJ, ALI AH, LINDOR KD. 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Longitudinal study on osteodystrophy in primary biliary cirrhosis (PBC) and a pilot study on calcitonin treatment[J]. J Hepatol, 1991, 12(2): 217-223. [36] FLOREANI A, ZAPPALA F, FRIES W, et al. A 3-year pilot study with 1,25-dihydroxyvitamin D, calcium, and calcitonin for severe osteodystrophy in primary biliary cirrhosis[J]. J Clin Gastroenterol, 1997, 24(4): 239-244. 引證本文:ZHAO J, TIAN H, YAO DK. Research advances in primary biliary cholangitis complicated by osteoporosis[J]. J Clin Hepatol, 2017, 33(11): 2226-2229. (in Chinese) 趙健, 田浩, 姚定康. 原發(fā)性膽汁性膽管炎并發(fā)骨質(zhì)疏松的研究現(xiàn)狀[J]. 臨床肝膽病雜志, 2017, 33(11): 2226-2229. (本文編輯:邢翔宇) Researchadvancesinprimarybiliarycholangitiscomplicatedbyosteoporosis ZHAOJian,TIANHao,YAODingkang. (DepartmentofInternalMedicine,ChangzhengHospital,SecondMilitaryMedicalUniversity,Shanghai200003,China) Osteoporosis is a common complication of primary biliary cholangitis (PBC) with a relatively high prevalence rate and a high risk of bone fracture. The pathogenesis of osteoporosis remains unknown. This article reviews the latest advances in the pathogenesis and treatment of osteoporosis in PBC. Studies have shown that osteoporosis in PBC has various causes, including increased bone absorption and reduced bone formation due to many factors. Although many drugs have been used in clinical practice, until now, bisphosphonates are still the most effective drugs. Long-term systematic studies are needed in the future to clarify their effects on fracture in PBC patients. cholangitis; osteoporosis; review R575.7 A 1001-5256(2017)11-2226-04 10.3969/j.issn.1001-5256.2017.11.039 2017-08-18; 2017-09-04。 趙健(1993-),男,主要從事自身免疫性肝病診治方面的研究。 姚定康,電子信箱:czyaodingkang@163.com。2 PBC骨質(zhì)疏松的發(fā)病機(jī)制
3 PBC患者骨質(zhì)疏松的處理與治療
4 結(jié)語(yǔ)