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通讯作者:

聂静(1967-),女,北京人,博士生导师,主要从事慢性肾脏病发病机制和防治策略的应用基础研究。E-mail:niejing@smu.edu.cn

中图分类号:R589.7,R459.3

文献标识码:A

文章编号:2096-8965(2021)04-0034-07

DOI:10.12287/j.issn.2096-8965.20210405

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目录contents

    摘要

    高尿酸血症是由于体内嘌呤代谢紊乱导致的代谢性疾病。我国高尿酸血症患病率高达13.3%。高尿酸血症不仅是痛风最重要的危险因素,也与多个重要靶器官损害密切相关。目前临床上使用的降尿酸药物存在一定的副作用且大多治疗成本较高。营养素是维持人体基本功能必不可少的物质。研究发现,叶酸、维生素C、血清磷、血清镁等营养素与高尿酸血症发生风险呈负相关,提示营养治疗可能是防治高尿酸血症的潜在策略。本文对高尿酸血症的发病机制、并发症及治疗进展进行综述。

    Abstract

    Hyperuricemia is a metabolic disease caused by a disorder of purine metabolism. The prevalence of hyperuricemia is about 13.3% in Chinese adults. Hyperuricemia is not only the most important risk factor for gout, but also closely associated with target organs damage. The uric acid-lowering drugs currently used in clinical practice have certain side effects and most of them are costly to treat. Nutrients are essential for the maintenance of basic body functions. Studies have found that nutrients such as folic acid, vitamin C, serum phosphorus, and se‐ rum magnesium are negatively associated with the risk of hyperuricemia, suggesting that nutritional therapy may be a potential strategy to prevent and treat hyperuricemia.This article provides a review of the pathogenesis, com‐ plications, and treatment advances of hyperuricemia.

    关键词

    尿酸高尿酸血症营养素

    Keywords

    Uric acidHyperuricemiaNutrition

  • 高尿酸血症是嘌呤代谢紊乱引起的代谢异常综合征。根据中国高尿酸血症与痛风诊疗指南 (2019),无论男性还是女性,非同日2次血尿酸水平超过420 μmol/L (7mg/dL),即可诊断为高尿酸血症[1]。没有痛风发作的高尿酸血症称为无症状性高尿酸血症。近年来,随着经济的快速发展和生活方式的改变,我国高尿酸血症的发病率呈明显上升且年轻化趋势。2015年的荟萃分析显示,中国成人高尿酸血症的患病率高达13.3%,约有1.7亿高尿酸血症患者[2]。高尿酸血症不仅是痛风的关键危险因素,也与肾脏疾病、高血压、糖尿病、心血管疾病等密切相关[3]。因此,高尿酸血症已成为一个日益严重的公共卫生问题。有效地降低尿酸水平是降低痛风发生风险及预防合并症发生发展的关键。大部分患者需要长期甚至终生降尿酸药物治疗。然而,长期使用降尿酸药物成本较高且具有一定的副作用。因此,积极寻求安全、价廉、有效的防治尿酸升高的策略具有重要的临床和公共卫生意义。近年来,随着临床营养学的快速发展及临床工作者对营养学的重视,营养治疗在临床工作中的作用日益凸显。研究发现,营养素水平与高尿酸血症的发生风险相关,提示营养治疗可能是防治高尿酸血症的潜在策略。

  • 1 高尿酸血症的发病机制

  • 尿酸是嘌呤化合物代谢的最终产物,主要以尿酸盐阴离子的形式存在于循环中。尿酸通常不能通过食物直接摄取,主要由膳食性及内源合成性嘌呤化合物在肝脏中的黄嘌呤氧化酶作用下代谢生成[4]。膳食性来源约占嘌呤来源的20%,摄入富含嘌呤的食物如动物内脏、海鲜、浓汤、酒类尤其啤酒等可引起体内尿酸生成增加。内源性来源嘌呤约占80%,由人体内氨基酸、核苷酸类等物质通过从头合成途径以及游离的核苷酸补救合成途径而产生。人体内的尿酸约2/3经肾脏排泄,1/3经胆道和肠道排泄[4]。在正常生理和正常嘌呤饮食状态下,人体内每天尿酸的产生和排泄保持动态平衡,维持血尿酸在正常水平。当高嘌呤饮食、恶性肿瘤、癫痫发作、过度运动等引起尿酸生成过多,肾脏疾病引起尿酸排泄障碍时,尿酸代谢平衡被打破导致高尿酸血症的发生。大约90%的高尿酸血症是由肾脏尿酸排泄效能下降所致[5]

  • 2 高尿酸血症的危害

  • 流行病学研究显示,高尿酸血症不仅是痛风的关键危险因素,还与肾脏损害、高血压、冠心病、糖尿病以及恶性肿瘤等众多疾病密切相关。

  • 2.1 高尿酸血症与肾脏疾病

  • 众所周知,尿酸结晶沉积在肾小管和集合管可阻塞小管及触发炎症导致急性肾损伤[6]。同时,越来越多的研究证实可溶性尿酸盐可通过激活肾素-血管紧张素-醛固酮 (Renin-Angiotensin-Aldoste⁃ rone System,RAAS) 系统、诱导氧化应激和促进炎症反应等机制导致急慢性肾功能损害[7]。此外, Ryu等[8] 发现尿酸通过诱导肾小管细胞的上皮-间质转化促进肾小管间质纤维化。Li等[9] 组织的一项纳入13个队列研究包含190 718名参与者的荟萃分析发现,高尿酸血症显著增加肾功能正常人群慢性肾脏病的发生风险 (RR=2.35,95%CI: 1.59~3.46),且这种关联随随访时间延长而增强。另一项纳入18个队列研究共75 200名患者的荟萃分析显示,与对照组相比,高尿酸血症患者发生急性肾损害的风险增加了1.24倍[10]

  • 2.2 高尿酸血症与高血压

  • 生理水平的尿酸具有清除自由基、促进抗氧化的作用,而过量的尿酸则会促进氧自由基的生成及活性氧的释放从而导致血管内皮损伤。此外,研究发现,尿酸激活RAAS系统,降低一氧化氮生物利用度并增加黄斑部的氧化应激,导致内皮功能障碍和肾血管收缩。进一步发展后,入球小动脉发生病变导致盐敏感型和尿酸非依赖性高血压[7]。一项随访了5年的日本队列研究发现尿酸是高血压前期发展为高血压的危险因素[11]。Grayson等[12] 进行的一项纳入18个前瞻性队列研究的荟萃分析显示,血尿酸水平每升高1mg/dL,发生高血压的风险增加13%。中国脑卒中一级预防研究 (China Stroke Pri⁃ mary Prevention Trial, CSPPT) 的一项事后分析发现,与非高尿酸血症组相比,高尿酸血症组高血压视网膜患病率增加18%[13]

  • 2.3 高尿酸血症与心血管疾病

  • 高尿酸血症是心血管疾病的危险因素。尿酸通过炎症反应、氧化应激、胰岛素抵抗、内皮功能障碍等分子机制促进心血管疾病的发生发展[14]。此外,Li等[15] 发现高尿酸血症通过激活ERK/p38途径直接抑制心肌细胞的活力。多项临床研究也显示血尿酸水平是心血管事件的独立危险因素。一项纳入457 915名受试者的荟萃分析发现尿酸浓度>7.0mg/dL显著增加普通人群患冠心病的风险 (RR=1.206, 95%CI:1.066~1.364)[16]。另一项纳入25 229名疑似或确诊冠状动脉疾病患者的荟萃分析发现,血尿酸浓度每升高1mg/dL,心血管死亡率风险增加12%[17]。Kleber等[18] 进行的孟德尔随机化研究也证实了高尿酸血症与心血管死亡和心源性猝死具有因果关系。

  • 2.4 高尿酸血症与糖尿病

  • 长期高尿酸血症可能会诱发糖尿病。尿酸氧化酶基因敲除的雄性小鼠出现胰岛素分泌受损[19]。研究发现,高尿酸血症通过增加活性氧 (Reactive Oxygen Species,ROS) 水平诱导肝脏、肌肉和脂肪胰岛素抵抗[20],以及胰岛 β细胞的功能障碍,包括胰岛素表达和分泌缺陷、糖酵解途径受损[21]。多项流行病学研究也证实了尿酸水平升高增加糖尿病患病风险,但是否存在性别差异仍有争议。Wu等[22] 对4 130名参与者进行平均5.4年的随访后发现,尿酸水平与2型糖尿病发生风险呈线性正相关。来自荷兰的Rotterdam队列研究结果发现,男性人群中尿酸水平与糖尿病发病风险呈正相关,而在女性人群中没有显著相关性[23]。相反,在CSPPT研究中,对1.5万例中国高血压患者中位随访4.5年的数据进行分析后发现,在女性人群中,基线血尿酸水平每升高1个标准差,糖尿病的发生风险增加14%,但男性人群中未发现此现象[24]。同样,另一项来自中国的队列研究也发现尿酸水平变化仅在女性中与糖尿病风险相关[25]

  • 2.5 高尿酸血症与恶性肿瘤

  • 越来越多的证据表明,尿酸具有潜在致癌作用。尿酸晶体通过诱导线粒体和溶酶体功能障碍导致ROS产生和自噬受损,以及激活NLRP3炎症体诱导IL-1β 产生[26]。此外,可溶性尿酸也通过激活MAPK、AKT-mTOR信号通路及抑制AMPK信号通路等多条途径促发炎症反应,还可以改变先天免疫细胞的表观遗传促进持续炎症高反应[27, 28]。尿酸所诱导的这些炎症反应、氧化应激、免疫反应创造了适宜肿瘤发生、发展和转移的微环境。Stevenson等[29] 发现缺乏尿酸氧化酶的小鼠在生长到2岁时超过一半出现肝细胞癌。Yan等[30] 组织的一项荟萃分析显示,尿酸水平升高增加癌症发生率和死亡率的风险。同样,在CSPPT的事后分析中,对20 577例高血压受试者平均随访4.5年后,发现尿酸水平升高与总体肿瘤风险呈正相关关系(HR=1.12,95%CI: 1.03~1.22) [31]

  • 3 高尿酸血症的治疗

  • 3.1 高尿酸血症的治疗现状

  • 降尿酸治疗包括生活干预及药物干预。所有高尿酸血症患者均建议进行生活方式的干预,包括控制体重、规律运动、限制酒精及高嘌呤食物的摄入、鼓励奶制品和新鲜蔬菜的摄入等,而药物干预目前在临床上则重点应用于痛风患者。对于无症状性高尿酸血症患者,欧美指南多不推荐药物干预[32, 33]。而我国建议血尿酸 ≥540umol/L或 ≥480umol/L且有合并症的患者启动药物治疗[1]

  • 目前临床应用的降尿酸药物主要有三类。第一类是尿酸生成抑制剂,通过抑制黄嘌呤氧化酶抑制尿酸合成,代表药物有别嘌醇和非布司他,均为临床一线用药。别嘌醇具有良好的降尿酸效果且价格较低廉,但其具有诱发致死性超敏反应的风险,这种超敏反应与HLA-B*5801基因相关[34]。研究发现,汉族人群携带HLA-B*5801基因的频率高达10%~20%,因此使用别嘌醇之前应进行HLA-B* 5801基因检测[1]。一项来自台湾的回顾性研究发现在伴有肾脏或心血管疾病的无症状高尿酸血症患者中使用别嘌呤醇可显著增加超敏反应的风险[35]。此外,长期使用别嘌醇会引起胃肠道不适、肝功能异常、血液系统损害及增加死亡风险。非布司他降尿酸效果显著,但价格昂贵且具有潜在的心脏相关性死亡风险,建议合并有心脑血管疾病患者慎用[36]。但最近发表在Lancet期刊上的FAST试验结果显示与别嘌呤醇相比,长期使用非布司他不增加心血管事件及相关死亡风险[37]。第二类是促尿酸排泄类药物,通过抑制肾小管重吸收尿酸盐来降低血清尿酸水平,代表药物有苯溴马隆和丙磺舒。此类药物不推荐用于肾结石患者,服用时需大量饮水及碱化尿液。此外,苯溴马隆具有潜在肝毒性,不推荐用于肝病患者[38]。丙磺舒与阿司匹林及其他水杨酸盐同用时降尿酸疗效下降,且可增加抗生素、吲哚美辛等药物血药浓度,其临床应用受到限制[39]。第三类是促尿酸溶解类药,代表药物为拉布立酶,属于重组尿酸氧化酶,价格昂贵,主要用于因化疗引起的高尿酸血症患者,该药的安全性仍需要进一步验证[40]

  • 鉴于目前临床应用的降尿酸药物有一定的副作用且大多治疗成本较高,患者依从性差[41],积极寻找安全、廉价、有效的防治高尿酸血症的策略具有重要的临床和公共卫生意义。

  • 3.2 营养素对高尿酸血症防治作用的研究进展

  • 营养素是维持人体生理功能不可缺少的物质。越来越多的证据证实体内营养素水平与高尿酸血症的发生风险相关,提示营养治疗可能是防治高尿酸血症的潜在策略。

  • 3.2.1 叶酸

  • 叶酸又称维生素B9,是人体必需的一种微量营养素。1984年,Lewis等[42] 发现,叶酸及其衍生物能够有效抑制黄嘌呤氧化酶,且其作为黄嘌呤氧化酶抑制剂的抑制能力是别嘌呤醇的2倍。此外,高同型半胱氨酸血症和高尿酸血症之间存在着显著的相关性[43],且高同型半胱氨酸血症在痛风患者中非常普遍[44]。因此,补充叶酸,降低同型半胱氨酸可能是降低尿酸水平,防治高尿酸血症的潜在切入点。

  • 在一项纳入480例中国高血压患者的试验中[45],受试者被随机分为每日服用A:依那普利10mg (对照组);B:依那普利10mg + 0.4mg叶酸 (低叶酸组);C:依那普利10mg + 0.8mg叶酸 (高叶酸组),持续八周。研究结果显示,在基线有高尿酸血症的患者中,治疗八周后,对照组和高叶酸组的尿酸浓度分别下降了28.2 μmol/L和57.0 μmol/L,组间差异显著。CSPPT尿酸子课题[46],纳入15 364例45~75岁的中国高血压基线无高尿酸血症患者,受试者按照1∶1比例随机接受以下两种治疗方法中的一种:每日口服含依那普利10mg和叶酸0.8mg的复方片剂1片 (依那普利叶酸组) 或每日口服单片依那普利片10mg (依那普利组)。中位随访4.4年后,依那普利组受试者的尿酸浓度升高了 (34.7 ± 72.5) μmol/L,而依那普利叶酸组的尿酸浓度仅升高了 (30.7 ± 71.8) μmol/L,组间差异显著。并且,与单独使用依那普利相比,依那普利叶酸组受试者的高尿酸血症控制率提高了31%、新发高尿酸血症的风险降低11%。此外,该研究还发现,叶酸补充在基线同型半胱氨酸较高的受试者中降低尿酸的效果更加明显;同时,叶酸治疗后同型半胱氨酸下降和尿酸下降幅度呈正相关。

  • 以上研究表明,叶酸补充对于防治高尿酸血症具有重要意义,且该作用可能是通过降低同型半胱氨酸引起的。同型半胱氨酸的慢性升高会导致细胞内s-腺苷同型半胱氨酸的升高[47]。作为一种对大多数s-腺苷蛋氨酸依赖的甲基转移酶的有效抑制剂,s-腺苷同型半胱氨酸可引起明显的DNA损伤并释放嘌呤核苷酸[48]。嘌呤核苷酸分解代谢,导致尿酸产生。因此,同型半胱氨酸的降低可能是叶酸发挥其降尿酸作用的一个途径。

  • 3.2.2 维生素C

  • 维生素C是一种高效抗氧化剂,也具有降低血尿酸的作用。Sun等[49] 发现美国成年人维生素C摄入量与高尿酸血症发生风险呈负相关。Huang等[50] 进行的一项随机对照临床试验,将184名非吸烟患者随机分为安慰剂组和补充维生素C (500mg/天) 组,2个月后结果显示,补充维生素C组尿酸水平显著下降了0.5mg/dL。Juraschek等[51] 组织的一项荟萃分析,纳入13个随机对照临床研究,共556名受试者,维生素C补充剂量中位数为500mg/天,结果显示补充维生素C显著降低血清尿酸水平(-0.35mg/dL,95%CI:-0.66~-0.03)。体内试验发现,维生素C增加肾脏对尿酸的清除率,促进尿酸排泄,其机制可能是通过竞争抑制近端小管尿酸重吸收位点减少尿酸重吸收[52]。此外,维生素C的抗氧化作用可以减少氧化应激和炎症,减少细胞损伤从而降低尿酸合成[53]

  • 3.2.3 血清磷

  • 磷酸盐参与细胞信号传导、细胞膜运输和DNA合成等许多重要生物过程[54];因此,推测磷和高尿酸血症之间也可能存在联系。Nishida等[55] 发现接近一半的痛风患者出现轻度低磷血症。Yuan等[56] 的研究数据发现抗酸剂会减慢ATP周转率,引起血清磷水平降低,导致血清尿酸水平增高,而长期有氧运动则加速ATP周转率,升高血清磷水平,降低尿酸水平。CSPPT尿酸子课题的一项前瞻性研究,考察了血清磷与高尿酸血症的关联[57]。该研究共纳入10 612名基线尿酸水平正常 (<357 μmol/L) 的高血压受试者,经过4.4年随访,结果表明血清磷与新发高尿酸血症的风险呈显著负相关,血清磷水平每增加一个标准差,新发高尿酸血症风险下降29%,并且在基线tHcy<15 μmol/L的受试者中,风险下降更显著。该研究提示,同时维持适宜血磷水平和补充叶酸降低tHcy水平可能是降低高尿酸血症风险的更有效的策略。磷是核苷酸的组成部分,而核苷酸是构成DNA和RNA的基本成分,因此,低水平的磷可引起明显的DNA损伤,并导致嘌呤核苷酸的释放[54, 58]。磷酸盐被还原时,腺苷脱氨酶促进腺苷一磷酸降解为肌苷单磷酸,进一步加速尿酸的合成[59]

  • 3.2.4 血清镁

  • 镁是人体最重要的营养物质之一,参与广泛的生物化学反应,特别是细胞内的转磷酸化。低镁会导致氧化应激和DNA氧化修饰,引起DNA损伤,释放嘌呤核苷酸,导致尿酸生成增加[60]。Zhang等[61] 发现膳食镁摄入量的增加与美国成人高尿酸血症的患病率降低相关,提示镁在预防高尿酸血症中的潜在作用。Zeng等[62] 研究提示血清镁水平与中国男性高尿酸血症患病率呈负相关。来自CSPPT尿酸子课题的一项前瞻性研究[63] 发现,经过4.3年随访后,血浆镁水平与新发高尿酸血症的发生风险呈负相关,血浆镁水平每增加一个标准差,新发高尿酸血症风险下降15%。该研究提示,维持较高的镁浓度可能是预防和治疗高尿酸血症的重要辅助营养策略。

  • 4 总结和展望

  • 高尿酸血症发病率呈明显上升及年轻化趋势,与众多慢性疾病患病风险及相关死亡风险密切相关,已逐渐成为威胁我国人民健康的重要公共卫生问题。目前临床上应用的降尿酸药物存在一定的副作用且大多治疗成本较高。CSPPT研究是由我国科学家开展的预防脑卒中的临床研究,共纳入20 702名中国原发性高血压患者,进行了长达5年的随访。该研究的事后分析发现,尿酸水平与中国高血压患者视网膜病变患病、肿瘤以及糖尿病风险呈显著正相关。更重要的是,CSPPT研究发现叶酸、血清镁、血清磷等营养素水平与高尿酸血症发生风险呈负相关,提示营养素治疗可能是防治高尿酸血症的潜在策略。营养素补充作为一种安全、廉价的治疗方式,若能进一步证实其疗效及相关机制,明确各营养素的最佳剂量和组合方式,将具有重要的临床和公共卫生价值。

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    • [44] SLOT O.Homocysteine,a marker of cardiovascular disease risk,is markedly elevated in patients with gout[J].Ann Rheum Dis,2013,72(3):457.

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    • [47] ZARIC B L,OBRADOVIC M,BAJIC V,et al.Homoc-ysteine and Hyperhomocysteinaemia[J].Curr Med Chem,2019,26(16):2948-2961.

    • [48] LIN H C,SONG T Y,HU M L.S-Adenosylhomocysteine enhances DNA damage through increased β-amyloid formation and inhibition of the DNA-repair enzyme OGG1b in microglial BV-2 cells[J].Toxicology,2011,290(2-3):342-349.

    • [49] SUN Y G,SUN J P,WANG J X,et al.Association between vitamin C intake and risk of hyperuricemia in US adults [J].Asia Pac J Clin Nutr,2018,27(6):1271-1276.

    • [50] HUANG H Y,APPEL L J,CHOI M J,et al.The effects of vitamin C supplementation on serum concentrations of uric acid:results of a randomized controlled trial[J].Arthritis Rheum,2005,52(6):1843-1847.

    • [51] JURASCHEK S P,MILLER E R,GELBER A C.Effect of oral vitamin C supplementation on serum uric acid:a meta-analysis of randomized controlled trials[J].Arthritis Care Res,2011,63(9):1295-1306.

    • [52] BERGER L,GERSON C D,YÜ T F.The effect of ascorbic acid on uric acid excretion with a commentary on the renal handling of ascorbic acid[J].Am J Med,1977,62(1):71-76.

    • [53] GRANGER M,ECK P.Dietary vitamin C in human health [J].Adv Food Nutr Res,2018,83:281-310.

    • [54] TAKEDA E,TAKETANI Y,SAWADA N,et al.The regulation and function of phosphate in the human body [J].BioFactors,2004,21(1-4):345-355.

    • [55] NISHIDA Y,ITO K.Decreased renal phosphate threshold in patients with gout[J].Nephron,1992,62(2):142-144.

    • [56] YUAN S,ZHANG Z W,LI Z L.Antacids' side effect hyperuricaemia could be alleviated by long-term aerobic exercise via accelerating ATP turnover rate[J].Biomed Pharmacother,2018,99:18-24.

    • [57] CAO J J,ZHANG J P,LI Q Q,et al.Serum phosphate and the risk of new-onset hyperuricemia in hypertensive patients[J].Hypertension,2019,74(1):102-110.

    • [58] MAIUOLO J,OPPEDISANO F,GRATTERI S,et al.Regulation of uric acid metabolism and excretion[J].Int J Cardiol,2016,213:8-14.

    • [59] NISHIDA Y,ITO K.Decreased renal phosphate threshold in patients with gout[J].Nephron(2015),1992,62(2):142-144.

    • [60] RUBIN H.Central roles of Mg2+ and MgATP2-in the regulation of protein synthesis and cell proliferation:significance for neoplastic transformation[J].Adv Cancer Res,2005,93:1-58.

    • [61] ZHANG Y Y,QIU H B.Dietary magnesium intake and hyperuricemia among US adults[J].Nutrients,2018,10(3):296.

    • [62] ZENG C,WANG Y L,WEI J,et al.Association between low serum magnesium concentration and hyperuricemia [J].Magnes Res,2015,28(2):56-63.

    • [63] CAO J J,ZHANG J P,ZHANG Y Y,et al.Plasma magnesium and the risk of new-onset hyperuricaemia in hypertensive patients[J].Br J Nutr,2020,124(2):156-163.

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    • [55] NISHIDA Y,ITO K.Decreased renal phosphate threshold in patients with gout[J].Nephron,1992,62(2):142-144.

    • [56] YUAN S,ZHANG Z W,LI Z L.Antacids' side effect hyperuricaemia could be alleviated by long-term aerobic exercise via accelerating ATP turnover rate[J].Biomed Pharmacother,2018,99:18-24.

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    • [61] ZHANG Y Y,QIU H B.Dietary magnesium intake and hyperuricemia among US adults[J].Nutrients,2018,10(3):296.

    • [62] ZENG C,WANG Y L,WEI J,et al.Association between low serum magnesium concentration and hyperuricemia [J].Magnes Res,2015,28(2):56-63.

    • [63] CAO J J,ZHANG J P,ZHANG Y Y,et al.Plasma magnesium and the risk of new-onset hyperuricaemia in hypertensive patients[J].Br J Nutr,2020,124(2):156-163.

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