指南速递 | 2019 意大利内分泌学会（SIE）共识声明：极低热量生酮饮食（VLCKD）在代谢疾病中的管理（下）

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接上文: 2019 意大利内分泌学会（SIE）共识声明：极低热量生酮饮食（VLCKD）在代谢疾病中的管理（中）

译者：刘睿  佛山市妇幼保健院

审校：贾彤 江苏省太仓市妇幼保健计划生育服务中心

极低热量生酮饮食（VLCKD）和男性肥胖相关的性腺功能减退症

推荐建议

•本共识建议患有性腺功能减退症的肥胖男性患者可使用VLCKD减肥，以增加血浆雄激素水平（2ØØØO）。

•本共识建议患有性腺功能减退症的肥胖男性患者可使用VLCKD减肥以改善性功能（2ØØOO）。

证据

轻度性腺功能减退症是一种因血清总睾酮处于低水平而引起的综合症，临床上可以继发于腹型肥胖，也可以独立地预测胰岛素抵抗和糖尿病的发病[151-154]。很少有研究评估快速减肥对肥胖性腺功能减退患者血浆总睾酮和其他性激素水平的影响。两项RCT分别观察了19和51名肥胖的性腺功能减退患者使用了10周VLCKD后，监测指标的变化情况[155,156]，他们发现其总睾酮、性激素结合球蛋白（SHBG）和高密度脂蛋白胆固醇显著提高，而胰岛素[155]、瘦素[155]和甘油三酯明显下降[156]，LH和性功能问卷评分没有变化[156]。与这两项RCT的结果相似，另外两项观察性研究报告在热量限制后，患者的总睾酮、SHBG和游离睾酮计算值均有所提高[157,158]。在VLCKD期间，脱氢表雄酮硫酸盐（DHEA-S）浓度没有显著变化。国际勃起功能指数（IIEF-5）和性欲量表（SDI）评分的均值有明显提高，并且国际前列腺症状量表（IPSS）平均值显著下降[158]。到目前为止，还未有VLCKD对男性生育能力影响的研究。

价值

有一定质量的证据表明，肥胖的性腺机能减退患者使用VLCKD减肥可以提高血浆雄激素水平并改善性功能。目前没有证据说明VLCKD对男性生育能力的影响。

评述

考虑到现有少数研究提供的证据有限，建议肥胖的性腺功能减退患者接受VLCKD减肥计划，以改善性激素血浆浓度和性功能。尽管肥胖对精子参数的负面作用已被明确证实，但并没有研究评估VLCKD在其中的作用[159]。

极低热量生酮饮食（VLCKD）和多囊卵巢综合征

推荐建议

•本共识建议超重/肥胖的多囊卵巢综合征（PCOS）患者对多组分标准化饮食干预无反应时，可通过VLCKD减肥，可改善胰岛素抵抗（2ØOOO）。

•本共识建议超重/肥胖的多囊卵巢综合征（PCOS）患者对多组分标准化饮食干预无反应时，可使用VLCKD减肥，以改善排卵障碍和高雄激素血症（2ØOOO）。

证据

与体重正常的女性相比，超重/肥胖PCOS患者更易发生月经异常、无排卵、不育和代谢异常[160]。特别是胰岛素抵抗，可存在于94％的肥胖PCOS女性，78％的超重PCOS女性和59％的正常体重PCOS女性[161]。胰岛素抵抗在促进或加重雄激素过多症和排卵功能障碍中发挥了重要作用，也经常使肥胖PCOS表型复杂化[160]。此外，肥胖的PCOS女性通常有低度炎症状态的特点，它可以加重胰岛素抵抗和雄激素过多症，参与了该病的病理生理学变化及其代谢并发症发病过程[162]。有高质量的证据表明，饮食控制使体重减轻至少5％可改善肥胖PCOS女性的雄激素过多症、排卵障碍性不孕症和代谢改变[160]。通过标准饮食减重，每个人之间的差异已有大量报道，但预测性的因子还在研究当中[163]。另外，没有确切的证据表明这些指定的能量等效饮食方案在治疗PCOS上优于另一种，即使有也很有限[164]。然而，令人感兴趣的是，在大多数超重/肥胖PCOS女性中，只有低碳水化合物饮食才能降低胰岛素抵抗和循环炎症标志物[165,166]。VLCKD用于治疗肥胖型PCOS的研究很少，但经验证实其有效。事实上，迄今为止只发现了一项非对照预试验研究，其中对11名超重/肥胖的PCOS女性进行了为期24周的VLCKD，但只有5名受试者从头到尾参与了该研究[167]。在24周后评估这5名受试者，研究者发现VLCKD降低了患者的体重（平均降低12％），可使游离睾酮下降（平均降低30％），可降低LH与FSH比值（平均降低36％），重要的是使空腹胰岛素大幅度下降（平均降低54％）。另外，此前患不孕的两名患者亦在饮食干预后成功受孕。

评述

虽然我们只有初步证据表明VLCKD在超重/肥胖PCOS女性中有积极作用，但已有明确的机制支持应用这种饮食疗法的合理性。然而，考虑到收集到的证据有限，建议对多组分标准化饮食无反应的肥胖型PCOS患者制定个体化的VLCKD减肥计划。需要进一步充分开展对照研究来确定VLCKD对PCOS各种临床表现的有益疗效，并确定这些效应是否可归因于体重减轻或特定的饮食方法。

极低热量生酮饮食（VLCKD）在更年期肥胖女性中的应用

推荐建议

•考虑到绝经过渡期的女性发生心脏代谢性疾病风险增加，本共识建议处于这一时期的肥胖女性可使用VLCKD (2ØOOO)。

证据

绝经的定义是为最后一次月经之后的临床状态，既往月经规律的女性在月经停止12个月后可得到回顾性地诊断。它反映卵巢功能完全或几乎完全永久性停止[168]。绝经过渡期发生在绝经之前，其特征在于月经周期长度和出血模式发生了变化[168]。

女性在绝经后发生心血管疾病的风险显著增加。实际上，绝经过渡期的特征是发生体脂沉积，脂及和脂蛋白升高，血管重塑和出现炎症改变，这些不利于健康的变化参与了动脉粥样硬化进程[169]。新出现的研究结果发现了预测绝经后女性发生心血管疾病风险可能有效的新的标志物，即：心外膜脂肪（epicaridial fat）和更高的HDL-胆固醇水平，这些指标在这类人群中似乎不具有心脏保护作用。此外，血管舒缩症状被认为直接参与心血管疾病的病理生理学，是代表内皮功能障碍和动脉硬化的标志物[170]。最初研究者认为由于肥胖是可引起外周芳香化酶增加，所以理论上对血管舒缩症状具有保护作用。然而，最近的调查表明，BMI和腰围与绝经早期的潮热症状出现呈正相关，与绝经晚期潮热症状的发生率呈负相关[171]。最后，体脂和血管舒缩症状之间的关系可能会随着年龄的增长而改变，在绝经过渡期时，肥胖是一个风险因素，因发生潮热时脂肪组织会阻挡散热，而在绝经后，卵巢不再产生雌激素，肥胖则具有保护作用[172]。

评述

关于减重和血管舒缩症状关系的相关数据非常有限。在最近一项对照预试验研究中，经问卷调查发现随机化分组至减重的女性较对照组更能减少其潮热的发生[172]。现在缺乏关于VLCKD减轻绝经期体重，减少血管舒缩症状和降低心血管发生风险的文献报道。在绝经女性中使用VLCKD的理由可能源于酮体可降低肾上腺素能张力[147]，并有益于促进代谢[30]。这是一个值得进一步探讨的领域。

极低热量生酮饮食（VLCKD）在肥胖儿童中的应用

推荐建议

•患癫痫的肥胖儿童因联合治疗导致体重大幅度增加时，应考虑使用VLCKD（1ØØØØ）。

•重度肥胖患儿伴有严重胰岛素抵抗和/或其他合并症，并且对一般饮食方案无反应时，应考虑VLCKD（12周）作为二线治疗方案（1ØØØO）。

•本共识推荐应该对重度肥胖儿童使用VLCKD后的进行长期随访，随访内容包括体重维持，生长发育，骨自然生长和心血管病危险因素（1ØØØØ）。

经典或改良方式的生酮饮食方案在过去几十年中被广泛用于治疗多种儿科疾病，如难治性癫痫和GLUT-1缺乏症。因此也在儿童中首次报道了不良事件和主要的短期和长期并发症。尽管癫痫患者儿发生营养缺乏的风险较高，但生酮饮食在2岁以下的癫痫婴儿中是有效的并且有良好的耐受性。应特别注意他们可能会出现生长发育和骨生长的损害或延迟，尤其是幼儿。有一项研究的随访工作超过了10年，其结果显示生酮包含不增加颈动脉内膜中层厚度，也不增加一般的心血管疾病发生风险[173]。VLCKD应该建议应用于因联合治疗导致体重快速增长的患儿[174,175]。

尽管生酮饮食是一种儿科医生众所周知的饮食方案，但VLCKD尚未被认为是儿童肥胖的治疗选择。近期发表的关于儿童肥胖管理的指南也未提及VLCKD[176]。研究VLCKD治疗儿童肥胖或2型糖尿病的已发表论文很少见。然而，其中大多数是开放性RCT[177,178]。这些研究观察了100名儿童（7-17岁）显示[179,180]，在采用VLCKD治疗10或16周后，患儿的体重和BMI（从-2.5到-5.6kg/m2）比使用低热量低脂饮食的受试者下降得更为明显。这两种饮食方案在6个月内差异明显，但在12月时便无差异了[179]。另外3项研究使用了Atkins生酮饮食法，没有脂肪和蛋白质的能量限制，将其与其他一般性低碳饮食进行比较。大约300名儿童和青少年（6-18岁）[102,181,182]使用了这一饮食方案，在实施8、12或24周后的生酮饮食后，受试者的体重和BMI（从-3.7到-3.3kg/m 2）比其他低碳方案降幅更大。在给予20名患有2型糖尿病的青少年VLCKD后发现，其可有效降低体重和BMI（-3.2 kg/m2），并维持了2年[183]。

所有这些研究都表明VLCKD可改善肥胖患儿的血压、血脂谱、空腹胰岛素、空腹血糖以及胰岛素敏感性，也可以使2型糖尿病肥胖患儿的糖化血红蛋白下降（-1.4%，也可以不必再使用治疗糖尿病的药物）[102,179-183]。这一方法没有报告严重不良事件，并且依从性很高。但现仍缺少关于其对生长情况影响的研究。

评述

由于这些研究的随访周期较短，生酮饮食方案不同，并且接受治疗患者的例数较少，仍然缺乏有力的证据去全面了解生酮饮食的作用。但是，生酮饮食在短期内减轻体重似乎是有效且安全的。

极低热量生酮饮食（VLCKD）在衰老及神经退行性病变中的应用

推荐建议

•本共识建议将生酮饮食用于与老年人少肌性肥胖和难治性癫痫相关的神经退行性疾病（2ØOOO）。

•本共识建议使用生酮饮食选择性地作为阿尔茨海默病/帕金森病的常规治疗中的辅助方法（2ØOOO）。

•本共识建议选择性地将VLCKD应用于出现少肌性肥胖的老年人（65-75岁）（2ØØØO）。

证据

流行病学观察表明，使用可生酮的含中链甘油三酯饮食可改善阿尔茨海默病（AD）患者的认知功能[184]。

人们普遍认为，脑能量缺乏是AD出现临床症状前的特征，它发生在AD导致的认知衰退之前。在AD和轻度认知障碍（MCI）中可出现局部脑葡萄糖摄取受损[185]。

一些研究表明AD患者的血脑屏障受损，导致一些转运蛋白的表达发生改变，包括葡萄糖转运蛋白的下调。酮体是了大脑葡萄糖的替代能源，因为脑摄取葡萄糖在MCI和AD早期仍然是正常的[186]。在过去几年中，慢性炎症和氧化应激被认为是AD发病的两个关键因素[187]。AD患者使用生酮饮食的益处是可以改善细胞代谢和线粒体功能，诱导能量代谢转变，并且还通过几种神经保护机制减少氧化损伤，调节炎症状态[188]。这些观察结果有助于解释为什么生酮饮食可改善MCI和AD患者的部分认知状况[189]。依赖这种饮食的患者会遭遇到各种问题，长期使用生酮饮食会引起肾结石，胆结石和转氨酶升高，因为饮食当中有大约70％的能量来源于脂肪。此前的研究还报告了与生酮饮食相关的短期不良事件，包括恶心、呕吐、腹泻、疲劳、脱水、胃食管反流和腹痛[189]。然而，最近的数据表明VLCKD可有效降低非老年人（18-65岁）的体重，维持减肥期间的肌肉质量和预防肌少症[18]。因此，若开展的随机研究无年龄限制，VLCKD即可能成为一种治疗老年人（65-75岁）少肌性肥胖的有益策略。

价值

最近在小鼠中进行的研究有令人兴奋的发现，低碳水化合物生酮饮食（LCKD）通过增加循环中的酮体来预防与年龄相关的认知衰退，并能延长寿命[190,191]。与对照饮食相比，LCKD显着增加了中位寿命和存活率，同时保留了生理功能[190]。另一个研究者表明，循环使用LCKD，每周与对照饮食交替，可以减缓小鼠与年龄相关的认知和记忆衰退，并降低了其中年死亡率[191]。有趣的是，酮体的增加可以改善中枢神经系统的胰岛素抵抗，对于预防2型糖尿病患者的认知下降具有重要的前景[192]。但是，仍然没有足够的证据推荐使用生酮饮食治疗MCI和/或AD和其他痴呆性疾病。

评述

虽然生酮饮食也许可以应用于延迟老年人（> 65岁）MCI和AD的发病或进展，但当下并不推荐将其应用于存在共病、重度少肌症和日常活动严重受损的年老体弱的AD患者，因为目前尚缺乏在这些患者应用中的数据。要尤其关注晚期AD患者可能出现的一些症状，例如吞咽困难和多器官功能失调。因此，需要进一步研究设计针对单一脑病（single-brain diseases）的特定的生酮饮食，并在老年患者中，改善获益和不良效应之间的平衡。

结论和展望

尽管已广泛报道VLCKD在降低体重和减少心血管危险因素方面具有短期和中期收益[18,19,23,24]，但由于缺乏长期随访研究，有些研究者质疑其长期使用的效果。所以探索研究VLCKD长期研究在特定终点（例如心血管和神经退行性疾病）上的潜在益处是很有必要的。一些研究先前已经证明长期使用VLCKD是安全和有效的[17,20,54,55]，但现在仍需要进一步的临床试验。规划此类研究的主要困难在于对长期严格遵守高度限制性饮食有较差的依从性。然而，对于需要在短期内快速减轻体重的患者，例如中重度肥胖和伴有心血管危险因素的患者，VLCKD是一种高效的治疗手段[103]。VLCKD在缓解2型糖尿病病情方面的疗效方面有较大的潜力，特别是在病程较短的肥胖患者中。一旦体重达标，必须继续遵循旨在减肥维持的长期多因素策略，VLCKD也应包括在内，强调全面的生活方式改变计划的重要性，包括行为疗法，营养咨询和体育锻炼[12,14,37]，以及碳水化合物重摄入的特定方案。

一个悬而未决的问题是关于VLCKD理想的持续时间和使用频率。在过去，因没有恰当的医疗监督，使用VLCKD会引起治疗失败和产生多种副作用，导致其被废置多年。应该强调的是，应用VLCKD需要有明确的临床指征，并要在严格的医疗监督下使用。如果治疗结果不令人满意或需要开始新的VLCKD周期，则必须调查并分析先前失败的原因。此外，可能需要根据营养治疗的特定间歇期、患者的特征和临床环境来确定实施VLCKD的特定方案。

专家简介

贾彤

贾彤（网名大狐之舞），硕士研究生，副主任中医师。现就职于江苏省太仓市妇幼保健计划生育服务中心。聘任中国医药教育协会生殖内分泌专业委员会委员、苏州中西医结合生殖委员会委员。

与明玥（太原市妇幼保健院李艳主任）在2015年组建明玥妇科内分泌团队，主持中国妇产科网专栏《妇科内分泌频道》的日常工作，并在妇产科网13个微信及QQ平台进行实时答疑，制作讲课视频约300个，编写病例问答共约500多个，浏览次数高达200万。2015-2018年编著并已出版妇科内分泌系列书籍《妇科内分泌知识轻松学》5本；为全国40000余名专业妇科内分泌医生提供了学习资源和专业指导。

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