很少有系统性疾病具有多种心肺表现,例如遗传性出血性毛细血管炎(HHT),也称为Osler病或Rendu -Osler -Osler -Weber综合征。HHT是最常见的遗传疾病之一,患病率为5,000–10,000,并且与至少五个不同基因的突变有关,包括内og和活化受体受体样激酶(ALK)-1,两者都属于转化生长因子(TGF)-β的受体超家族1. Alk-1 and endoglin are abundantly expressed on endothelial cells and are involved in mediating the cellular effects of TGF-β and other members of the TGF-β superfamily. Loss-of-function mutations in the genes encoding for Alk-1 or endoglin cause the clinical syndrome of HHT, which is characterised by vascular dysplasia. The cardinal clinical features of HHT include mucocutaneous telangiectases, often prominently visible on the lips and tongue, and arteriovenous malformations (AVMs), which can involve several organs, such as liver, brain and lungs. Pulmonologists will encounter three main manifestations of HHT: pulmonary arterial hypertension; high cardiac output failure in the setting of large AVMs in the liver; and pulmonary AVMs. A forthcoming article by Faughnan等.2, as part of the欧洲呼吸杂志’s(ERJ) current series on pulmonary hypertension2–7, will review the cardiopulmonary manifestations of HHT in detail.
Pulmonary arterial hypertension and liver AVMs are predominantly seen in patients with Alk-1 mutations (also called HHT type 2)8. Isolated pulmonary arterial hypertension in patients with HHT is clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension, a disease that has been linked to mutations in another TGF-β superfamily receptor, termed bone morphogenetic protein receptor-II9. Many patients with HHT type 2, however, present with a distinct clinical picture, characterised by pulmonary hypertension and a state of high cardiac output caused by liver AVMs10. These patients are prone to developing refractory heart failure within weeks to months after presentation. Treating this condition is a major challenge and successful therapy often requires a combined approach, with embolisation of the liver AVMs to bring cardiac output back to a normal level11的药物治疗肺hypertension.
肺AVM是HHT的另一种表现,最常发生在内尾突变患者(HHT 1型)。通过仔细的筛查,包括胸部射线照相,计算机断层扫描和对比度超声心动图,可在多达50%的HHT患者中发现肺AVM(图1⇓)12. These AVMs originate from the pulmonary rather than the bronchial arteries and are associated with the signs and complications of intrapulmonary right-to-left shunts. Smaller pulmonary AVMs are often clinically silent until the patients present with neurological catastrophes, such as ischaemic strokes or brain abscesses. Larger pulmonary AVMs can result in hypoxaemia and reduced exercise capacity. Rarely, patients present with massive haemoptysis or rupture as life-threatening complications of pulmonary AVMs. However, all these problems are preventable, as embolotherapy offers a safe and effective means of sealing pulmonary AVMs before they cause irreversible problems. Thus, screening HHT patients for pulmonary AVMs should be advocated. In a recent study, Shovlin等.13研究了305例HHT患者,其中绝大多数(n = 219; 72%)患有肺AVM。这些患者中几乎有80%没有呼吸道症状,几乎一半的AVM是通过筛查程序不仅涉及受影响患者而且是其家人的筛查程序。此外,有74个(34%)患有神经系统事件,i.e.a stroke or a brain abscess, underscoring the magnitude of the problem. In contrast, not a single neurological event occurred in those patients in whom all visible pulmonary AVMs had been successfully treated by embolotherapy. These data provide a strong argument for establishing screening programmes and pre-emptive treatment strategies in HHT patients.
However, given the fact that HHT patients are prone to develop pulmonary hypertension, there is concern that embolisation of pulmonary AVMs increases pulmonary artery pressure, which could have devastating consequences in patients presenting with established pulmonary hypertension. In the present issue of theERJ, Shovlin等.14present somewhat reassuring data derived from 143 patients with pulmonary AVMs (of whom 131,i.e.92%,接受了栓塞处理。没有患者会出现正确的心力衰竭迹象,并且没有一种情况下肺动脉压的迹象显着升高。
Does this mean that worsening pulmonary hypertension is not a matter of concern when pulmonary AVMs are embolised in patients with HHT? Certainly not! While the study by Shovlin等.14presents unique data, its main shortcoming is that it did not include patients with advanced pulmonary hypertension and signs of right heart failure. In fact, four patients presenting with a diagnosis of severe pulmonary hypertension were not considered candidates for embolotherapy. In addition, the study looked at only pulmonary artery pressures and not at complete haemodynamics. A patient with an elevated pulmonary artery pressure in the setting of a high cardiac output (i.e.with low pulmonary vascular resistance) will probably tolerate embolisation of pulmonary AVMs, whereas the same procedure may be detrimental in a patient with similar pulmonary artery pressures but a low cardiac output (i.e.a high pulmonary vascular resistance). In the latter patient, embolisation of pulmonary AVMs may result in a critical increase in right ventricular afterload15. Thus, from the studies by Shovlin and co-workers13,14,我们可以相信,在大多数HHT患者中,栓塞疗法是治疗肺AVM的安全有效手段,但我们仍然不知道这对于患有严重肺动脉高压的患者的子集是否也是如此。
然而,重要的信息可以从肖夫林和同事的研究中得出13,14:遗传性出血性毛细血管扩张患者常见肺动脉畸形畸形很常见,但通常在临床上保持沉默。筛查患者及其在存在肺动脉畸形的情况下的亲属确实有所作为,因为可以提供安全有效的干预措施,以防止发生毁灭性的并发症。因此,下次我们在嘴唇上(或其他地方)遇到患者时,我们应该仔细观察。
Statement of interest
None declared.
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