Homozygous familial hypercholesterolaemia (HoFH) is one of the most extreme forms of hereditary lipoprotein disorders. One only has to refer to the numerous published case reports to gain an appreciation of the dramatic consequences of HoFH. Patients typically experience a first major cardiovascular event during adolescence or early adulthood, and cholesterol levels can be elevated to such an extent that depositions in the form of xanthomata may already be present at birth. Large variation in the phenotypical expression of HoFH does exist, and cases of death and the need for major cardiovascular surgery during early childhood have been described. The implementation of screening programmes for FH and advances in genetics have revealed that HoFH is threeto four-fold more common than the traditional estimate of one in a million. However, much higher rates of up to 1:30 000 have been reported in some populations due to founder effects and consanguinity. The advent of statin therapy and ezetimibe has substantially improved the outcomes for HoFH patients. In the pre-statin era, there was little more that clinicians could do than to advise patients to adhere to a low-fat diet, combined with minimally effective lipidlowering drugs, two interventions with very limited effect on LDL cholesterol levels. In addition, apheresis could be started, or a liver transplantation performed, The statin revolution in the 1990s finally provided the means to change the course of HoFH—no longer did clinicians have to stand by and watch patients succumb to the detrimental consequences of ‘plasma dissolved in cholesterol’. Little over a decade later, in the early 2000s, the introduction of the cholesterol absorption inhibitor ezetimibe presented another addition to the armamentarium in the fight against HoFH. Although clinical trial evidence to demonstrate the placebo-controlled effects of statins and ezetimibe in HoFH is not available for obvious ethical reasons, retrospective analyses comparing event rates before and after introduction of these therapies are revealing. For example, Raal et al. reported a hazard ratio of benefit from therapy of 0.34 for death. Recent years have experienced the second revolution in the pharmacological treatment of dyslipidaemia after statins, in the form of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. These drugs enable the majority of high-risk patients to reach unprecedented low LDL cholesterol levels. The curse of HoFH is, however, that both statins and PCSK9 inhibitors are less effective than in nonHoFH patients because both therapies work by virtue of increased expression of the LDL receptor, which is functionally impaired in HoFH. The magnitude of the achieved LDL reduction with statins and PCSK9 inhibitors depends on residual LDL receptor function— patients without residual function typically do not respond to PCSK9 inhibitors. Nonetheless, for the majority of HoFH patients ( 90%) who do have residual LDL receptor activity, high-dose statins typically reduce LDL cholesterol in HoFH patients by 10–25%, ezetimibe by 10–15%, and PCSK9 inhibitors by 20–30%. These still modest percentages, combined with the observation that HoFH patients typically have untreated LDL cholesterol values >13 mmol/L, make it evident that even the combination of statins, ezetimibe, and PCSK9 inhibitors leaves the majority of patients with unacceptably high lipid levels and a sharply elevated risk of cardiovascular disease. Other treatment options include lipoprotein apheresis, mipomersen, and lomitapide. Even if these treatments are effective, available, and reimbursed, they are cumbersome and have significant side effects. Patients and their physicians therefore face the daunting task of balancing residual cardiovascular risk against the burden of therapy. This makes it all the more clinically relevant to determine whether additional lipid lowering actually improves clinical outcomes for HoFH patients, as is shown for non-HoFH patients. Expert panels have recently taken the position that HoFH patients should ideally be treated to lipid goals similar to other high-risk patients, which is an impossible task with currently available treatment options. These recommendations are now firmly supported by the results of the study by Thompson et al. in the current issue of the journal, which

中文翻译：

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纯合子家族性高胆固醇血症：隧道尽头的光

纯合子家族性高胆固醇血症 (HoFH) 是遗传性脂蛋白疾病的最极端形式之一。人们只需要参考大量已发表的病例报告即可了解 HoFH 的戏剧性后果。患者通常在青春期或成年早期经历第一次重大心血管事件，胆固醇水平可能升高到黄瘤形式的沉积物可能在出生时就已经存在的程度。HoFH 的表型表达确实存在很大差异，并且已经描述了儿童早期死亡和需要进行大心血管手术的病例。FH 筛查计划的实施和遗传学的进步表明，HoFH 的发生率是传统估计的百万分之一的三到四倍。然而，由于创始人效应和血缘关系，在某些人群中报告的比率要高得多，高达 1:30 000。他汀类药物和依折麦布的出现大大改善了 HoFH 患者的预后。在他汀之前的时代，临床医生只能建议患者坚持低脂饮食，并结合最低效的降脂药物，这两种干预措施对 LDL 胆固醇水平的影响非常有限。此外，可以开始血液分离术，或进行肝移植，1990 年代他汀类药物革命终于提供了改变 HoFH 病程的手段——临床医生不再需要袖手旁观，看着患者屈服于“血浆”的有害后果溶于胆固醇'。十多年后，在 2000 年代初，胆固醇吸收抑制剂依泽替米贝的引入为抗击 HoFH 的军备增添了又一​​新成员。尽管由于明显的伦理原因，无法证明他汀类药物和依折麦布在 HoFH 中的安慰剂对照效果的临床试验证据，但比较这些疗法引入前后事件发生率的回顾性分析表明。例如，拉尔等人。据报道，治疗获益的风险比为 0.34。近年来，继他汀类药物之后，血脂异常的药物治疗发生了第二次革命，形式是前蛋白转化酶枯草杆菌蛋白酶/可欣9（PCSK9）抑制剂。这些药物使大多数高危患者能够达到前所未有的低 LDL 胆固醇水平。然而，HoFH 的诅咒是，他汀类药物和 PCSK9 抑制剂均不如非 HoFH 患者有效，因为这两种疗法均通过 LDL 受体表达增加而起作用，而 LDL 受体在 HoFH 中功能受损。他汀类药物和 PCSK9 抑制剂实现的 LDL 降低幅度取决于残留的 LDL 受体功能——没有残留功能的患者通常对 PCSK9 抑制剂没有反应。尽管如此，对于大多数有残留 LDL 受体活性的 HoFH 患者（90%），高剂量他汀类药物通常使 HoFH 患者的 LDL 胆固醇降低 10-25%，依折麦布降低 10-15%，PCSK9 抑制剂降低 20- 30%。这些仍然适度的百分比，再加上观察到的 HoFH 患者通常未经治疗的 LDL 胆固醇值 >13 mmol/L，表明即使他汀类药物、依折麦布、PCSK9 抑制剂使大多数患者的血脂水平高得令人无法接受，心血管疾病的风险急剧升高。其他治疗选择包括脂蛋白单采、米波森和洛美他派。即使这些治疗有效、可用且可报销，但它们很麻烦且具有显着的副作用。因此，患者及其医生面临着平衡残余心血管风险与治疗负担的艰巨任务。这使得确定额外的降脂是否确实改善了 HoFH 患者的临床结果具有更大的临床相关性，如非 HoFH 患者所示。专家小组最近采取的立场是，理想情况下，HoFH 患者应按照与其他高危患者相似的脂质目标进行治疗，这是目前可用的治疗方案不可能完成的任务。这些建议现在得到 Thompson 等人的研究结果的坚定支持。在本期杂志中，