Bevacizumab to treat complicated liver vascular malformations in hereditary hemorrhagic telangiectasia: A word of caution

We read with interest the article by Mitchell et al.1 dealing with bevacizumab treatment of a patient with hereditary hemorrhagic telangiectasia (HHT), cardiac failure, and portal hypertension due to severe liver vascular malformations (VMs). The treatment reversed the need for liver transplantation. Despite the undoubtedly inspiring value of this report for future research examining the potential of antiangiogenic drugs in HHT, an appropriate scenario for the use of bevacizumab in the treatment of complicated liver VMs must be clearly detailed. Important data, which are essential for judging both therapeutic decisions and the treatment outcome, are missing from the case description. The assessment of the patient's hemodynamic condition should have included a cardiac rhythm description, right heart catheterization data, and pulmonary pressures and vascular resistances. Right heart catheterization should always be performed in patients with HHT who are being evaluated for liver transplantation.2 The patient therapy description is also unsatisfactory. For example, which diuretics at what dosages were used, what other drugs in addition to beta-blockers were used, and whether anemia was appropriately corrected all remain unclear. High-output heart failure complicating liver VMs in HHT responds most significantly to intensive medical therapy. This therapy should include the correction of anemia, salt restriction, diuretics, antihypertensive agents, antiarrhythmic agents, and digoxin as clinically indicated. Complications of portal hypertension (in this case, ascites) should be treated as recommended in patients with cirrhosis.2 Invasive therapies, however, which may be either palliative (eg, transarterial embolization of liver VMs) or curative (eg, liver transplantation), are not current treatment options for advanced symptomatic liver VMs and should be considered only in patients who have failed to respond to intensive medical therapy.2 A critical issue to be carefully weighed regarding the use of bevacizumab is its nonnegligible toxicity. Toxicity may potentially cause substantial worsening of an HHT patient's condition, inducing cardiac failure and a tendency to bleed due to the genetic disease itself. Across trials, the most serious and sometimes fatal bevacizumab toxicities include gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome, and congestive heart failure.3 Authors have reported the persistence of bevacizumab effects at 6-month follow-up visits. However, revascularization following the withdrawal of anti–vascular endothelial growth factor therapy in a mouse xenotransplantation model suggests that anti-angiogenic therapy should be continuous to avoid vessel regrowth4 and, in the specific case, VM re-formation. Altogether, the use of bevacizumab as a bridge therapy to liver transplantation, as proposed by the authors, seems to be questionable. Because of unpredictable bevacizumab efficacy, surgeons may face patients under anti-angiogenic treatment who require emergency liver transplantation; this could present problems with respect to angiogenesis-dependent phenomena such as wound repair and healing of anastomoses. Thus, caution seems indispensable in considering the effects of bevacizumab in this case. Elisabetta Buscarini*, Guido Manfredi*, Alessandro Zambelli*, * Gastroenterology Department Center for the Diagnosis, Therapy, and Surveillance of Hereditary Hemorrhagic Telangiectasia Crema, Italy.