乙肝病毒慢性感染与维生素D相关性的研究进展
Progress on the Relationship between Chronic Hepatitis B Virus Infection and Vitamin D
DOI: 10.12677/ACM.2022.125605, PDF, HTML, XML, 下载: 370  浏览: 729 
作者: 唐璐琪, 曾维琼：重庆医科大学附属第二医院，重庆
关键词: 乙肝病毒；乙肝病毒慢性感染；维生素D；Hepatitis B Virus； Chronic Hepatitis B Virus Infection； Vitamin D
摘要: 我们已知维生素D的主要功能是维持机体内钙/磷动态平衡及骨骼系统的健康。近年来的研究表明，维生素D还有促分化、促凋亡、抗肿瘤、调节先天性和获得性免疫、清除病毒、抗纤维化等骨骼外作用。乙肝抗病毒治疗为乙肝病毒慢性感染患者带来了良好的预后。肝脏作为维生素D合成过程中的重要器官，参与维生素D的合成的关键步骤。越来越多研究发现维生素D与乙肝病毒感染的相关性，本文就维生素D与乙肝病毒慢性感染相互作用的最新研究进展作如下综述。
Abstract: We already know that the main function of vitamin D is to maintain the dynamic balance of calci-um/phosphorus in the body and the health of the bone system. In recent years, studies had shown that vitamin D also has extra-skeletal effects such as promoting differentiation, promoting apoptosis, anti-tumor, regulating congenital and acquired immunity, virus clearance, anti-fibrosis and so on. Hepatitis B antiviral therapy has brought a good prognosis for patients with chronic hepatitis B vi-rus infection. As an important organ in the process of vitamin D synthesis, the liver participates in the key steps of vitamin D synthesis. More and more studies had found the correlation between vitamin D and hepatitis B virus infection. This paper reviews the latest research progress on the in-teraction between vitamin D and chronic hepatitis B virus infection.
文章引用：唐璐琪, 曾维琼. 乙肝病毒慢性感染与维生素D相关性的研究进展[J]. 临床医学进展, 2022, 12(5): 4172-4180. https://doi.org/10.12677/ACM.2022.125605

1. 引言

乙肝病毒(HBV)作为噬肝DNA病毒中的一种，能够特异性识别肝细胞上的钠离子–牛黄胆酸–协同转运蛋白(NTCP)受体感染肝细胞 [1]。慢性肝病患者被发现普遍缺乏维生素D [2]，而研究表明肝病的进展和预后与血清维生素D浓度相关 [3]。研究发现，维生素D是影响乙肝病毒水平的独立因素，血清维生素D浓度与血清HBV-DNA水平呈负相关 [4]。乙肝病毒减少了乙肝病毒感染细胞中维生素D受体(VDR)的表达，减少了维生素D对免疫防御系统的辅助作用，从而降低了抑制病毒复制的效果 [5] [6]。维生素D可通过影响HBVDNA水平影响患者免疫状态 [7] [8]。随着维生素D与乙肝病毒感染的相关性越来越多地被发现，维生素D与HBV慢性感染之间的关系值得深入探讨。

2. 维生素D的合成与代谢

维生素D是一种脂溶性类固醇激素，主要形式包括来源于植物的维生素D2和来源于动物的维生素D3。人体内的维生素D仅少量来源于食物，主要由皮肤中的7-脱氢胆固醇经紫外线照射后生成。在紫外线中UVB的作用下，表皮的7-脱氢胆固醇转变为维生素D3，其在小肠经胆汁酸吸收，与维生素D结合蛋白(DBP)结合，被转运到肝脏，经肝脏线粒体细胞内的25-羟化酶作用生成25(OH)D3 (钙二醇)，其再与DBP结合被转运到肾脏近端小管，经1-α羟化酶作用转变为1,25(OH)2D3 (骨化三醇)，活性维生素D即骨化三醇，通过结合维生素D应答基因启动子区域的维生素D应答元件(VDRE)上的维生素D受体/类维生素X受体(RXR)复合物引发其转录作用 [9]。人体内1,25(OH)2D3的合成是受到严格调控的，皮肤和饮食摄入的维生素D总量对于大部分人群是安全的 [10]。在机体内血液中活性维生素D的供应量是有严格监控机制的，以甲状旁腺激素(PTH)、成纤维细胞生长因子23(FGF23)和“VDR感受器”形成的调节环路扮演着重要的角色，它们的协同作用确保了维生素D激素合成量能稳定在合理的范围，避免了活性维生素D的过度生产和供应 [11] [12]。

3. HBV感染与结局

HBV基因组本为松散的不完全闭合双链DNA，即rcDNA。HBV与NTCP受体高亲和力结合后，通过胞吞作用进入细胞质，并通过内质网等内膜系统被运送至核周，经过核孔复合体将病毒基因组DNA释放到细胞核内。在宿主细胞核内的DNA聚合酶作用于松散的rcDNA，将其不完全闭合的双链补全为共价闭合的环状cccDNA。病毒利用宿主细胞中的RNA聚合酶，以cccDNA为模板进行转录和翻译感染宿主 [13]。当HBV感染患者肝细胞受到炎症或其他损伤时，在如肿瘤坏死因子α (TNF-α)、转化生长因子β (TGF-β)、胰岛素生长因子(IGF-1)等细胞因子的作用下，发生肝星状细胞激活、细胞外基质(主要是I、III、V、XI型胶原)含量明显增加且在基底膜和内膜下沉积等病理变化，导致损伤区域被细胞外基质或纤维瘢痕组织包裹，如这一损伤修复过程持续反复发生，则纤维瘢痕组织越来越多，逐渐形成肝纤维化和肝硬化，甚至进展为肝细胞癌 [14]。

4. HBV慢性感染与维生素D

4.1. HBV感染对维生素D的合成、吸收及代谢的影响

维生素D合成、转运、储存、发挥生物学效应的过程由肝脏直接或间接的参与。HBV感染肝细胞可能从以下几方面影响维生素D合成：1) 肝脏参与7-脱氢胆固醇的合成，而7-脱氢胆固醇作为维生素D的前体，是维生素D合成的原材料 [15]。肝细胞受损时7-脱氢胆固醇的合成受阻；2) 维生素D3、25(OH)D3、1,25(OH)2D3均需通过与DBP结合以在体内进行转运，同时VDR是维生素D发挥生物学效应的关键受体 [9]。肝细胞受到乙肝病毒损伤时，肝脏作为蛋白的主要合成部位，DBP及VDR的合成受阻 [16] [17]。3) 肝细胞参与维生素D合成过程中羟化酶的合成，如CYP2RI、CYP27A1、CYP24A1，慢性HBV感染者体内存在线粒体损伤、羟化酶代谢紊乱、酶的合成受阻等。另外膳食来源的维生素D的吸收可能因门脉高压所致的肠水肿而受阻。在乙型肝炎病毒感染肝细胞的过程中，即因为乙肝病毒导致肝细胞的炎症，导致肝炎-肝硬化-肝癌三部曲的进程中，肝细胞受损，肝脏合成功能受损；另外慢性肝病患者还可能存在包括日照时间不足、维生素D的饮食摄入量不足、药物作用(抗病毒药物、糖皮质激素、影响到维生素D代谢有关的肝细胞色素P450酶的药物)、黄疸存在下维生素D在皮肤中合成受损 [18] 等，最终导致维生素D因多方面原因出现减少。

4.2. 不同乙肝病毒基因型与维生素D

HBV至少有9个基因型(A型至I型) [19]。在国主要以A型、B型、C型、D型等为主。其中，A型易于转为慢性乙型肝炎，B型通常病程轻微，C型易发重症肝病，D型则表现为急性自限型乙型肝炎。研究发现，在控制了潜在的混杂变量后，维生素D和乙肝病毒基因型之间存在关联。与C、D和E、H型相比，A和B型乙肝病毒的维生素D水平明显更高。乙肝病毒A型和B型对聚乙醇型干扰素的临床应答率较高 [20]。侯金林教授等的研究指出基因B型HBV感染患者的维生素D缺乏率高于基因C型HBV感染的慢乙肝患者 [21]，但该方向目前的相关研究较少，需要更多的研究来验证。

4.3. 乙肝抗病毒治疗与维生素D

富马酸替诺福韦(TDF)作为核苷酸类似物逆转录酶抑制剂，是一种有效的乙肝抗病毒治疗药物，其活性成分替诺福韦双磷酸盐可通过直接竞争性地与天然脱氧核糖底物相结合而抑制病毒聚合酶，及通过插人DNA中终止链，从而抑制病毒复制 [22]。TDF非常有效，但它的使用与骨、内分泌和肾脏毒性有关。TDF可升高血清PTH和1,25(OH)2D3，通过改变25(OH)D3与PTH的关系，导致类似于25(OH)D3不足的生理状态，从而导致骨密度的降低 [23]。可能需要更高的25(OH)D3血清浓度目标，以减少甲状旁腺激素和甲状旁腺激素相关的骨吸收，以优化骨骼健康。另一方面，维生素D对氧化应激、脂质代谢和肾素-血管紧张素-醛固酮系统(RAAS)的影响与肾脏和心血管疾病有关。研究指出维生素D缺乏至少部分地通过增加氧化应激、参与肾素-血管紧张素系统和一氧化氮级联反应来加重TDF的肾毒性 [24]。

5. 维生素D与HBV感染

5.1. 维生素D在HBV感染中的作用

5.1.1. 维生素D的免疫调节作用

1,25(OH)2D3通过VDR调节免疫系统，VDR存在于大多数免疫细胞类型，特别是抗原呈递细胞(APC)，如单核细胞、巨噬细胞和树突状细胞 [25]。1,25(OH)2D3激活VDR表达抗菌肽(AMPs)，如长春新素和β防御素，攻击病原体 [26]。另外VitD3对巨噬细胞和树突状细胞存在抑制作用。VitD3直接作用于Th细胞，在没有APC的情况下，可以促进辅助型T细胞2(Th2)表型的发育，并增强转录因子c-maf和GATA结合蛋白3(GATA-3)的表达。研究结果表明，VitD3在自身免疫性疾病和移植中的有益作用是通过作用于APC来阻止辅助型T细胞1(Th1)反应，同时直接作用于T细胞来促进Th2细胞的发育 [27]。肝抑制后预防性应用维生素D3可减缓移植物损伤，降低排斥反应，保护移植物功能 [28]。

5.1.2. 维生素D的抗纤维化作用

1,25(OH)2D3在体外对肺成纤维细胞和间充质多能细胞有抗纤维化作用 [29] [30]，在体内外大鼠肝纤维化模型中也有抗纤维化作用。1,25(OH)2D3在体外可抑制肝星状细胞(HSC)的增殖，抑制细胞周期素D1、金属蛋白酶组织抑制剂1和胶原Ia1的表达；在体内，1,25(OH)2D3可降低α平滑肌肌动蛋白(α-SMA)的表达和胶原水平，阻止硫代乙酰胺(TAA)所致肝硬化的发生 [16] [31]。然而，维生素D作为一种抗纤维化药物的临床重要性仍有待确定。

5.1.3. 维生素D的抗肿瘤作用

1,25(OH)2D3作用于癌细胞的分子机制已被广泛研究，它通过不同的机制以一种细胞类型特异性的方式干预癌症的发生。除了诱导细胞周期阻滞以减少生长外 [32]，还通过调节促凋亡和抗凋亡基因的表达而引发细胞死亡 [33]。这些效应是通过调节基因转录或通过激活快速的非基因组信号级联来实现的。血管生成和转移通过不同的机制减少 [34] [35] [36]。此外，1,25(OH)2D3的抗炎作用，包括抑制前列腺素(PG)合成 [37]、增加丝裂原活化蛋白激酶磷酸酶5(MPK5)表达 [38] 和抑制NFκB的激活 [39] 等进一步有助于其抗癌作用。与维生素D相关的信号通路，可能作为分子靶向治疗肝癌。依赖于1,25(OH)2D3的脂溶性及肝癌细胞的嗜脂性，从肝内动脉注射大剂量的1,25(OH)2D3在实验条件下对肝癌细胞的生长有明显的抑制作用 [40]。研究数据表明，在各种细胞和动物模型中显示出强大的抗癌活性。在这些临床前研究中看到的令人信服的好处表明，在癌症患者中进行临床试验是必要的。认识到维生素D缺乏并将其补充到最佳水平很可能具有化学预防活性和降低癌症风险的能力。用1,25(OH)2D3或其类似物单独治疗或与活性抗癌药物联合治疗，可能能够防止癌症的发生和/或延缓癌症的进展。

5.1.4. 维生素D的其余作用

此外研究还发现，维生素D缺乏与乙肝疫苗接种后抗体形成不良有关 [41]。全基因组研究确定了影响健康人群血清25(OH)D3水平的遗传变异(位于脱氢胆固醇还原酶附近的rs12785878，DHCR7；位于CYP2R1的rs10741657；位于维生素D结合蛋白GC的rs7041)。25(OH)D3代谢的共同变异与出现低至中度弹性增加的患者的肝脏僵硬有关。虽然易受DHCR7基因型影响的风险很小，但其推测，观察到的硬度差异表明25(OH)D3对肝纤维化的启动而不是进展有更强的影响 [42]。

5.2. 维生素D结合蛋白与HBV

维生素D结合蛋白(DBP)几乎完全由肝脏合成，属于白蛋白基因家族成员，位于第4号染色体上，与白蛋白和甲胎蛋白有很高的序列同源性 [43]。它具有高度的多态性，有三种常见的亚型，Gc1F、Gc1S和GC2，表现出明显的种族变异 [44]，其中Gc1F亚型对维生素D代谢物的亲和力最高。DBP决定了1a-羟化酶有多少游离的25(OH)D底物，以及有多少游离的1,25(OH)2D3配体可以激活VDR，并影响下游基因的转录。在维生素D的转运和生物利用度中起关键作用的血清DBP水平在肝硬化患者中适度降低 [17] [45]。但一次只有5%的DBP结合位点被维生素D代谢物占据，低水平的DBP需要严重的肝功能障碍才能在慢性肝病中起到显著的维生素D缺乏症的作用 [43]。DPB的另外一个作用是清除坏死细胞释放的细胞外单体肌动蛋白，它以长丝状形式触发凝血，可能与血栓易感性相关。目前的研究结果表明，降低肌动蛋白清除剂DBP的水平可能会潜在地导致在慢性纤维性肝病和肝癌患者中经常观察到的血栓易感性 [46]。另外研究表明DBP具有抗炎和免疫调节功能，但与其作为维生素D载体的作用无关 [47] [48]

5.3. VDR及其基因多态性与HBV

作为一种被1,25(OH)2D3激活的转录因子，VDR直接或间接调节200多个影响细胞增殖、分化、凋亡以及免疫调节和血管生成的基因的表达 [49]。维生素D受体(VDR)是启动1,25(OH)2D3诱导的基因组和非基因组信号通路所必需的，并已被证明在其抗癌活性中发挥关键作用。多项研究表明，当肿瘤疾病阶段进展时，VDR表达逐渐减少，与癌症风险相关的VDR多态性的存在也证明了这一点 [50]。在有VDR基因表达的肝癌细胞系，1,25(OH)2D3可通过与肝癌细胞中表达的VDR结合，作用于特定的DNA序列后，造成细胞阻滞于G0/G1期，特异性阻断细胞由G1期向S期的转化，使处于增殖状态的S期及G2/M期细胞数下降，最终抑制癌细胞增殖，促进细胞凋亡 [32]。目前的研究已表明如人HepG2、Hep 3β肝癌细胞系对1,25(OH)2D3的抑制作用表现出很高的敏感性。而另一种大鼠肝癌细胞株Novikoff几乎完全耐药。其中Novikoff细胞中缺乏功能性VDR受体是由于缺乏VDR基因表达所致，而1,25(OH)2D3对该细胞株和更敏感的肝癌细胞株(尤其是HepG2)的抗增殖作用不同是由于VDR基因表达不同所致 [51]。

目前已发现4个主要的VDR基因多态性位点，即Bsm I (rs1544410)、Apa I (rs7975232)、Taq I (rs731236)和Fok I (rs2228570)酶切位点，分别位于第VIII内含子、第IX外显子和第II外显子上 [52]。VDR基因的多态性可以影响其与1,25(OH)2D3和VDRE的结合亲和力，进而影响转录活性和蛋白质合成 [53]。Apa I和Taq I的变异也与更高的乙肝病毒载量以及更严重的纤维化和坏死性炎症有关 [54]。而且在对隐匿性HBV感染者的研究中发现，免疫系统的易感性和对抗性受到VDR基因外显子9-T/T等位基因的影响 [55]，这表明VDR的基因多态性与HBV感染相关疾病的发生及严重程度相关联。

5.4. 维生素D类似物

众所周知，系统使用1,25(OH)2D3时，高钙血症和高钙尿是主要的副作用 [56]。为了克服这些缺点，人们合成了大量维生素D类似物，这些类似物保留1,25(OH)2D3的大部分非经典作用，而高钙反应的副作用更小。既往研究表明，EB1089在体外抑制癌细胞生长的能力约为1,25(OH)2D3的50~80倍，同时其对体内钙代谢的影响更小 [57]。其他维生素D类似物或结构维生素D激活剂，如马沙骨化醇(OCT)、度骨化醇、侧链单不饱和双键类似物、侧链多不饱和双键类似物等已经被合成出来，并进行着临床前研究。这些化合物可能有望作为癌症和其他疾病的治疗剂 [58]。

6. 展望

维生素D作为基础营养素的一种，多方面地参与了体内的多个过程，我们看到了多种多样关于维生素D的研究，但结局不尽相同，这大概是因为我们暂时无法将每一个奥秘通过单一或者多个因素分析透彻。目前暂时没有对维生素D与慢性乙型肝炎之间相关性的系统性研究，而中国乙型肝炎患者人数众多，这方面的研究成果对解决实际问题意义重大。

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