门静脉高压是肝硬化患者发生失代偿事件的主要病理生理原因，也是肝功能恶化的主要驱动因素。非选择性β受体阻滞剂（NSBB）作为降低门静脉高压、预防食管胃静脉曲张出血的首选用药在临床得到了广泛应用，且有预防门静脉高压相关所有失代偿事件的应用趋势。

 

第58届欧洲肝脏研究学会年会（EASL2023）暨2023年EASL大会（EASL Congress 2023）上，奥地利维也纳医科大学Thomas Reiberger教授出席了“Meet the experts：NSBB in cirrhosis”专题会议，对第三代NSBB卡维地洛用于肝硬化各阶段的热点争议问题进行了分享和讨论。《国际肝病》现场报道团队特邀Thomas Reiberger教授就相关内容进行专访，内容分享如下。

 

《国际肝病》

非选择性β受体阻滞剂（NSBB）在肝硬化患者有较广泛的应用。能否请您谈谈NSBB近年在临床中的应用，以及指南推荐意见？

 

Thomas Reiberger教授：一般我们会使用Baveno指南，最新的Baveno VII指南最近刚发表在Journal of Hepatology。应优先使用β受体阻滞剂（beta-blockers）进行静脉曲张出血的一级预防，而不是使用套扎法（band ligation），以同时预防静脉曲张出血和其他非出血失代偿事件。因为PREDESCI研究对存在临床显著性门静脉高压的患者进行了随机分组，β受体阻滞剂组和安慰剂组。结果发现，接受β受体阻滞剂治疗的患者失代偿事件发生率显著更低。

 

值得注意的是，该研究主要依靠肝静脉压力梯度（HVPG）的测量。现在的问题是我们是否可以使用非侵入性标志物来识别受益患者。虽然没有强有力的证据，但很多间接证据表明，非侵入性标志物，例如肝硬度值超过25 kPa，也能提示患者存在极高的门静脉高压风险。然而这个肝硬度值临界值在肥胖患者（BMI超过30 kg/m² ）中不适用，在非酒精性脂肪性肝炎（NASH）患者中更为明显，原因目前还不清楚。

 

参考文献：

 

The guidelines that we prefer to use are the so called Baveno guidelines. And the most recent version is the Baveno VII guidelines they were just recently published in the Journal of Hepatology. Beta-blockers should be used for primary prophylaxis of variceal bleeding and preferred over band ligation, because they not only prevent variceal bleeding but also other non-bleeding compensation events. The reason why we know this is because of the PREDESCI study that randomized the patients with clinically significant portal hypertension to either beta-blocker or to no treatment. And we have seen that these patients who were treated with beta blockers showed a lower incidence of compensation events. And to treat Carvedilol also without doing a gastroscopy.

 

So importantly, this study was based on measuring HVPG. The question now is if we could also use non invasive markers to identify the patients who would benefit. There is no strong evidence, but a lot of indirect evidence that you could use non invasive markers, such as a liver stiffness of more than 25 kPa which would also tell you that the patient has a very high likelihood of portal hypertension. One caveat is that this cutoff is not valid in patients with obesity saying that a BMI above 30, most prominent in those with NASH (nonalcoholic steatohepatitis), we don't know.

 

《国际肝病》

卡维地洛是第三代NSBB，相比传统NSBB，例如经典代表普萘洛尔，其有哪些优势？

 

Thomas Reiberger教授：我们更倾向于使用卡维地洛而不是普萘洛尔（Propranolol），因为卡维地洛除了具有β-1和β-2受体阻断活性外，还能阻断α1肾上腺素受体。这个α1肾上腺素受体位于肝窦内，负责血管收缩。因此，如果用卡维地洛阻断α1肾上腺素受体，可以减少窦内血管的收缩，降低肝阻力，增加窦内流量，从而进一步降低门静脉压力。

 

我们在多项研究中观察到，如果从普萘洛尔切换到卡维地洛，可以进一步降低门静脉压力，并提高血流动力学反应率，在一级预防中通常可降低至少10%，而在二级预防中可实现HVPG 20%的降低。实际上我们在这两种情况下都进行了测试，使用卡维地洛可以获得更高的血流动力学反应率，原因很可能是由于额外的α1肾上腺素受体阻滞作用。

 

参考文献：

 

We prefer Carvedilol over Propranolol because Carvedilol, in addition to BETA-1 and BETA-2 blocking activity, also blocks the Alpha one adrenergic receptor. This Alpha one adrenergic receptor is in the liver sinusoid responsible for vessel construction. So if you block on Alpha one adrenergic receptor with Carvedilol, you decrease sinusoidal vessel construction, you decrease hepatic resistance, and that increases sinusoidal flow, and thereby leads to a further decrease in portal pressure.

 

So we have seen this in multiple studies that if you switch from Propranolol to Carvedilol, you could further decrease portal pressure and further increase the hemodynamic response rate, which is usually at least a 10 % decrease in primary prophylaxis and a 20 % decrease in HVPG in secondary prophylaxis. And we have actually tested it in both scenarios, and you achieve a higher rate of thermodynamic response with Carvedilol. And the reason is most likely due to the additional Alpha one adrenergic blockade.

 

《国际肝病》

在未进行内镜检查的情况下，代偿期患者是否可以使用卡维地洛？

 

Thomas Reiberger教授：如果你知道存在静脉曲张，那么推荐使用卡维地洛且非常安全。而如果代偿期患者存在静脉曲张但不使用卡维地洛，则可能会出现问题。可以使用非侵入性标志物来评估，其中最显著的是肝硬度值超过25 kPa，此时可以在没有进行内窥镜检查的情况下对患者使用卡维地洛。另一种选择是脾硬度测量，超过50 kPa的临界值则表示存在门静脉高压的风险高。因此在那些没有进行胃镜检查但脾硬度值超50 kPa的患者中，同样也可以使用卡维地洛。

 

参考文献：

 

If you know that there are varices, you are very safe and it is likely indicated. It would be a problem if you don't use Carvedilol if that there are varices in a compensated patient. However, as I said, non invasive markers could be also used, and the most prominent is a liver stiffness value of more than 25kPa. In this case, you could use Carvedilol also without endoscopy. Another alternative is to measure spleen stiffness, and here the cut off is 50 kPa, where there is a high likelihood of portal hypertension. You could also use Carvedilol in those patients without gastroscopy.

 

《国际肝病》

卡维地洛是否可以用于肝硬化合并腹水且无静脉曲张的患者？

 

Thomas Reiberger教授：对存在腹水但没有静脉曲张的患者使用卡维地洛，超出了出血一级预防的范畴。然而，这些患者由于存在腹水而出现了临床显著性门静脉高压，我个人认为则可继续使用卡维地洛进行治疗。但这并没有证据依据，更多是我的个人专业意见。在这种情况下，我会选择继续治疗，因为即使没有静脉曲张，临床显著性门静脉高压仍然存在。如果同时存在静脉曲张和腹水，则可使用卡维地洛进行治疗。原则上，只要没有副作用，如头晕或低血压，则无需中断卡维地洛。若患者收缩压降至110 mmHg以下，则需要从卡维地洛切换到普萘洛尔。

 

参考文献：

 

If you treat with Carvedilol in patients with an ascites and that there are no varices, you're outside of primary bleeding prophylaxis. However, these patients, because they have a ascites, are still suffering from clinically significant portal hypertension, you would treat or at least I would continue to treat with Carvedilol. But this is not evidence based. This is rather my expert opinion. In this case, I would continue, because clinically significant portal hypertension is still present, even if there are no varices. The other question is, if there are varices and ascites, and you treat with Carvedilol. In principle, you can continue with Carvedilol as long as there is no side effect, which could be dizziness or development of hypotension. In this case, I would recommend that if you measure blood pressure and that drops below 110 systolic blood pressure, you switch from Carvedilol to Propranolol.

 

《国际肝病》

如果失代偿性肝硬化后腹水消失，我们应该停用NSBBs吗？

 

Thomas Reiberger教授：再代偿（Recompensation）定义为腹水消失、至少12个月没有出血以及肝性脑病的消退。我们很庆幸通过有效的抗病毒治疗（主要是乙型和丙型肝炎患者）和戒酒，患者可以实现再代偿。

 

值得注意的是，尽管所有这些治疗表明对病情改善有利，但门静脉高压仍然可能存在。只要存在临床显著性门静脉高压，我们建议继续使用β受体阻滞剂。对于那些有再代偿肝硬化的患者，是否可以使用非侵入性标志物来排除门静脉高压存在仍存在争议。

 

若丙型肝炎患者未出现肝硬化（12 kPa的肝硬度临界值），具有正常的血小板计数，且已出现再代偿，则可以停用β受体阻滞剂。临床实际情况可能是患者继续使用β受体阻滞剂，不过这一般不会对患者造成不利影响。

 

可以考虑对这些患者进行胃镜检查。如果看不到静脉曲张，则可以停用β受体阻滞剂。这是我的个人建议。非侵入性标志物提示肝硬度12 kPa以下、血小板计数正常，或者重复胃镜检查并观察发生静脉曲张消失。如果满足其中任何一个标准，则可安全地停用β受体阻滞剂。

 

参考文献：

 

Recompensation is defined by resolution of an ascites by no more bleeding for at least 12 months and also resolution of hepatic encephalopathy. It's actually quite fortunate that we have seen with effective antiviral therapies. Both with hepatitis b and also hepatitis c and also in patients who stop alcohol drinking that they can actually recompensate.

 

So importantly, while this all indicates a favorable course, portal hypertension can still be present. As long as there is clinically significant portal hypertension, we would recommend continuing the beta blockers. There is the question of non-invasive markers can be used in those patients with recompensated cirrhosis to exclude portal hypertension.

 

There is in hepatitis c patient, a cutoff of 12 kPa in liver stiffness, combined with normal platelet counts, if the patient fulfill this criteria and has recompensated, then you can feel safe and stop the beta blockers. The clinical reality is likely that many patients are continued with beta blockers, which will likely not do any harm. And you may consider doing gastroscopy in these patients.

 

And if you don't see any more varices, then you could also stop the patient from the beta blocker. This is what I would do. Non invasive markers below 12 kPa in liver stiffness, normal platelet counts, or you repeat gastroscopy and see if the varices have disappeared. And if either of these criteria fulfilled, you could safely stop the beta blocker.

 

 

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