be treated [112,113]. A 2016 practice guideline from the EASL and a 2011 observational study involving 154 patients with HHT who had vascular malformations in the liver concluded that in the small proportion (approximately 8 percent) who became symptomatic, medical therapy was beneficial in most [110,111]. For most of the 39 individuals who had a clinical event related to a hepatic AVM, treatment resulted in complete response or stable disease, although eight individuals died of disease complications over the 15-year period of observation. For those who do require treatment, therapy is individualized and should be performed by clinicians with expertise in this area. First-line treatments involve the following, as detailed in selected case series [111,113]: Treatment of high-output heart failure, in a similar way to treatment of heart failure in non- HHT patients, with emphasis on escalating diuretics and correcting anemia [110,111,114]. Iron deficiency anemia was the precipitant of high-output cardiac failure in seven of the eight cases in the largest prospective series [110]. (See "Causes and pathophysiology of high-output heart failure" and "Evaluation and management of anemia and iron deficiency in adults with heart failure".) Treatment of portal hypertension, in a similar way to treatment of portal hypertension in other circumstances. (See "Portal hypertension in adults", section on 'Treatment'.) Antibiotics in case of cholangitis. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management".) The efficacy of these treatments are evaluated within 6 to 12 months, although earlier assessments will be required in individuals with rapid clinical deterioration [111,113]. For complicated liver AVMs that are refractory to first-line treatment, interventions directed at the hepatic arterial bed such as embolization, ligation, or banding of the hepatic artery are generally no longer advised for the majority of patients because of the high rate of complications (including potentially fatal hepatic necrosis) and up to a 20 percent acute mortality rate compared with transplantation [111]; the 10-year survival rate for transplantation is 82.5 percent [115]. Options for severe patients not responding to therapy include bevacizumab and liver transplantation. (See 'Role of bevacizumab for liver AVMs' below and 'Role of liver transplantation' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 23/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Role of bevacizumab for liver AVMs Bevacizumab has observational studies of efficacy and is a first-line choice in many HHT centers in the United States. However, earlier suggestions that this reversed the need for liver transplantation have not been supported by longer-term follow- up studies in those individuals. Bevacizumab is usually reserved for individuals with severe liver disease for which management is ineffective and in many countries where liver transplantation is not possible. It is proposed for older patients (over age 65) who will not meet transplantation criteria (and for patients younger than 65 years who are not medically fit for transplantation) as a "bridge to transplantation" if patients experience a response [113]. The efficacy of bevacizumab in the setting of severe hepatic AVMs was demonstrated in a series of individuals with HHT who had hepatic AVMs and increased cardiac output [38]. Bevacizumab (5 mg/kg intravenously once every 14 days for a total of six doses) was associated with an improvement in cardiac index in 20 of 24 evaluable patients (83 percent); this included cardiac output normalization in five individuals and improvement in 15 others. Additional benefits included resolution of pulmonary hypertension in five of eight (63 percent) and improvement in epistaxis. Case reports and observational studies have also described improvements (in some cases dramatic) in disease manifestations attributable to hepatic AVMs (and pancreatic AVMs) with bevacizumab [38,111,116-118]. Benefits from continued use have been published [119]. Notably, the reported follow-up for these patients has been relatively short compared with the decades-long follow-up post-liver transplantation discussed below (see 'Role of liver transplantation' below). Thrombotic complications of bevacizumab have been reported in individuals with HHT [120]. These and other safety concerns such as those observed in a study from the European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) are discussed above. (See 'Bevacizumab and other systemic antiangiogenic therapies' above.) Role of liver transplantation Liver transplantation in countries where very good long-term survival of HHT patients is reported can be lifesaving for those who develop acute hepatic failure (eg, acute biliary necrosis syndrome), intractable heart failure, or portal hypertension [115,121- 123]. Available data suggest that liver transplantation should be proposed in a timely fashion, before pulmonary resistances become fixed, and taking into account that complicated liver AVMs in HHT represent a model for end-stage liver disease (MELD) exception for transplantation [111,113]. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 24/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate A 2006 series from the European Liver Transplant Registry reported outcomes in 40 individuals with HHT and severe liver disease who underwent liver transplantation [115]. Ten-year actuarial patient and graft survival rates were 82.5 percent. There were seven perioperative deaths, six due to bleeding and one due to heart failure, and one late death (at 11 years) due to chronic rejection. Pulmonary involvement through portopulmonary hypertension is considered a transplant priority and proposed as a MELD exception [124]. Right-heart catheterization to evaluate the severity of pulmonary hypertension prior to transplant is advised [111]. Cerebral lesions Lesions in the cerebral (or spinal) vasculature in individuals with HHT may include telangiectasia, AVMs, and aneurysms. These lesions result in varying degrees of hemorrhagic risk. They may also cause symptoms related to their size or location such as headache, focal neurologic deficit, or seizures; however, the majority of patients will have no complications from cerebral lesions. Significant effort has been invested in trying to identify the patients at higher risk of future complications in whom the known risks of neurologic intervention are more justifiable. Most patients will never have a specific complication from their cerebral AVMs, but for others, the consequences of cerebral AVMs will lead to life-changing or life-limiting consequences. For a small group of patients, symptoms may be used to indicate a higher likelihood of AVM presence, and an AVM that has already bled is usually treated. For highly symptomatic or ruptured cerebral AV shunts for which treatment is appropriate and feasible, therapeutic options include surgical excision, a number of endovascular techniques, or stereotactic radiotherapy. The risks associated with these interventions should not be underestimated [125]. The risk of rupture and details of therapy are discussed separately. (See "Brain arteriovenous malformations", section on 'Acute management issues'.) Management of cerebral lesions that have not bled is complex and should be performed by clinicians with expertise in this area who are aware of the results of the ARUBA (A Randomized trial of Unruptured Brain AVM therapy) trial [126]. The interpretation of this trial and its applicability to the HHT population has remained highly controversial, and in our experience, it is applied differently in Europe and the United States. Across the ERN, cerebral AVMs that have not bled are usually not treated [127]. A 2020 position statement on cerebral screening in HHT published by VASCERN suggested that data do not support routine intervention for unruptured AVMs, acknowledging the controversies that may arise and individual patients may have different preferences [4]. Some clinicians may weigh the risks and benefits differently. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 25/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate The ARUBA trial randomly assigned individuals with a cerebral AVM (not knowingly HHT related) to receive or not to receive an interventional procedure (surgery, embolization, stereotactic radiotherapy) in addition to standard medical therapy [126]. The trial was halted early after accrual of 223 patients when the data and safety monitoring board noted a threefold increased risk of adverse outcomes in the intervention group. At a median follow-up of 33 months, the primary composite endpoint of death or symptomatic stroke was seen in 35 of 114 intervention patients (31 percent) versus 11 of 109 controls (10 percent). Individuals in the intervention group also had worse functional outcomes and a higher risk of hemorrhagic stroke. In a follow-up report that described an additional period of observation (mean follow-up of approximately 50 months total), there were 41 deaths or strokes in the intervention group and 15 deaths or strokes in the medical management group (incidence rate per 100 person-years, 12.3 versus 3.4, respectively) [128]. However, follow-up data were only available for half of the original participants. There is no evidence that the risks associated with cerebral AVMs in HHT are higher or lower than the risks in non-HHT cerebral AVMs [129]. There are other central nervous system vascular malformations that pose a very low risk of hemorrhage and usually no intervention is recommended. (See "Vascular malformations of the central nervous system", section on 'Capillary telangiectasias'.) For the HHT patients with cerebral vascular malformations who do not fall into either of these groups, assessments of the risks and benefits of intervention are based on clinical judgment, which can be highly specific to the individual. SPECIAL POPULATIONS Children Symptomatic children require specialist evaluation and treatment, as discussed in the sections above. It is important that neurologic symptoms are promptly investigated and that parents with HHT are educated about the potential significance of these symptoms or clinical signs of cardiac failure/hydrovenous dysfunction in their children [130]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Sites of large arteriovenous malformations'.) Issues related to screening of asymptomatic children are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Children'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 26/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Pregnancy Case reports have highlighted major complications of pregnancy in women with HHT. However, our series of 484 pregnancies in 199 women indicated that the vast majority are able to have a normal pregnancy. This is an important observation, since women with HHT are sometimes led to believe that pregnancy is too dangerous to undertake. That said, a small proportion of women did experience life-threatening complications, even in those who previously had only minor symptoms of HHT. In this series, the following complications were noted [131]: Pulmonary arteriovenous malformation (PAVM) hemorrhage 1.4 percent (95% CI 0.2-2.5) Stroke 1.2 percent (95% CI 0.3-2.2) Maternal deaths 1.0 percent (95% CI 0.1-1.9) Myocardial infarction 0.2 percent (one case) General recommendations for the management of pregnant women with HHT include: All pregnancies in women with HHT should be considered "high risk," and local obstetric services should be alerted to the need for greater than normal vigilance and pre-planning. All pregnant women with HHT should receive written advice on pregnancy management; this is one of European Reference Network (ERN) on Rare Multisystemic Vascular Diseases (VASCERN) HHT's five Outcome Measures defining good practice [3]. There is no evidence of hemorrhage from spinal AVMs in women with HHT who receive epidural anesthesia. Nevertheless, since spinal AVMs affect approximately 1 to 2 percent of HHT patients, some anesthetists will not perform epidural analgesia in HHT mothers unless magnetic resonance imaging (MRI) scans have excluded this possibility. PAVMs will enlarge during pregnancy, and fatal hemorrhage from maternal PAVMs has been described [131,132]. As a result, women with HHT should be screened for PAVMs and treated maximally before pregnancy, although treatment may be safely undertaken in late pregnancy if required [133]. Hemoptysis of any degree or sudden severe dyspnea should be considered a medical emergency, prompting urgent hospitalization and institution of appropriate treatment. In the series described above, hemorrhages occurred in both treated and untreated women, including four women who had previous PAVM embolization at four different institutions [131]. Obstetricians advise that a prolonged second stage of labor should be avoided in women in whom cerebral AVMs have not been excluded. In some countries, it is assumed that cerebral AVMs may be present, and this advice is given to all women with HHT. In others, or https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 27/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate if there would be specific separate recommendations were a cerebral AVM to be found, cerebral magnetic resonance imaging (MRI) is performed in pregnancy. In keeping with the general advice for patients with PAVMs and/or HHT, antibiotic prophylaxis should be provided during delivery [73,105,134]. Anecdotal data suggest that epistaxis may get worse and skin telangiectasia become more prominent during pregnancy; there are no firm data regarding effects on hepatic or cerebral AVMs. The patient should also be made aware that any offspring will have a 50 percent risk of inheriting HHT. Prenatal genetic testing is possible in families where the pathogenic variant has been identified in the family but is not necessary for proper pregnancy and delivery management [127]. Decisions about prenatal genetic testing are the choice of the parents, but discussion of all related issues is appropriate. The usual antenatal scans will be offered, and sonographers aware of the presence of HHT in the family will detect most major AVMs. PROGNOSIS When managed by treatment of nosebleeds, iron deficiency anemia, and screening/treatment for pulmonary arteriovenous malformations (PAVMs), life expectancy in individuals with HHT is normal on a population basis [135]. However, in settings in which optimal management is not pursued on a nationwide basis, life expectancy is modestly reduced. For example, in a 2015 case-control series from a primary care database, 675 individuals with HHT demonstrated a three-year reduction in survival (median age of death of 77 years, compared with 80 years in 6696 age- and sex-matched controls) [136]. An important limitation was that the rates were overall survival rather than disease-specific survival. Causes of death could not be confirmed, but the most frequent serious complications included stroke and heart disease. HHT can be life-limiting on an individual basis. Patients can die in childhood and young-adult life from HHT complications such as cerebral hemorrhage [137,138], pulmonary hemorrhage in pregnancy [131], and cerebral abscess from PAVMs [86,139]. Causes of death in older patients include sepsis and cardiac failure in studies from 2006 and 2018 that surveyed HHT patients asking for causes of death in their deceased relatives [140,141]. A reduced survival of 6.8 years in the affected parent compared with the non-affected parent was identified in the 2006 study, https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 28/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate based on median age at death of 63.2 years (HHT parent) versus 70.0 years (non-HHT parent) [141]. Where HHT does contribute to death, the mean life expectancy reduction has been calculated at 19 years (based on 55 of 73 deceased patients selected because HHT was considered implicated in the cause of death) [140]. We interpret these data for the patient, stating that while HHT can result in early deaths (that medical care strives to reduce), overall life expectancy is surprisingly good in HHT and is increasing with improved medical care. The reason for the good survival figures is that deaths due to HHT seem to be balanced by protection conferred by HHT from common causes of death in the general population such as certain cancers and myocardial infarction [135,142-145]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".) SUMMARY AND RECOMMENDATIONS Epistaxis Epistaxis affects over 95 percent of individuals with hereditary hemorrhagic telangiectasia (HHT) and is the usual cause of iron deficiency anemia. Topical, systemic, and surgical treatments are available. We generally try to avoid toxicity of systemic therapies by using local preventive therapies (nasal humidification, ointments) and dietary changes; however, management is individualized. Expert otorhinological review and management is important and often the only additional treatment required. (See 'Overview' above and 'Epistaxis' above.) Rarely, patients may require systemic therapies such as tamoxifen, tranexamic acid, or bevacizumab if epistaxis is recurrent or localized interventions are insufficient. For these individuals, we continue to suggest tamoxifen (Grade 2C). Other options are reasonable and may be preferred due to their differing side effect profiles or patient preference. Systemic agents are generally avoided in individuals with prior venous thromboembolism (VTE) and should be used with caution if there are additional risk factors for VTE or arterial thromboembolism. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.) Gastrointestinal lesions Gastrointestinal lesions are present in up to 20 percent of patients but rarely require treatment. If bleeding occurs, local therapies may be https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 29/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate administered endoscopically, but gastrointestinal bleeding requiring transfusions or iron administration is often due to multiple lesions and is treated with systemic agents rather than frequent endoscopic interventions. (See 'Gastrointestinal lesions' above and 'Bevacizumab and other systemic antiangiogenic therapies' above.) Iron deficiency Iron deficiency and iron deficiency anemia are common, usually from epistaxis. Most individuals are treated with oral iron, but parenteral iron and/or blood transfusions may be required. (See 'Iron deficiency and iron deficiency anemia' above.) Pulmonary AVMs Pulmonary arteriovenous malformations (PAVMs) are especially concerning because of potentially life-threatening cerebral complications including ischemic stroke caused by a paradoxical embolus to the brain or brain abscess caused by a paradoxical septic embolus or hypoxia. Bleeding leading to hemoptysis or hemothorax is much less common but can occur. (See 'Pulmonary AVMs' above.) We screen all adults with HHT for PAVMs. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.) For PAVMs of a size amenable to embolization, we use embolotherapy, unless there are complications such as significant pulmonary hypertension that require more individualized therapy. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.) Antibiotic prophylaxis is required for all PAVM patients prior to dental and surgical procedures. PAVM management is discussed above and separately. (See 'Principles of PAVM management' above and "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) Hepatic AVMs Hepatic AVMs are usually asymptomatic but can require intense, informed specialist care. In our experience, one major risk is of misdiagnoses as metastases. Symptoms attributable to high-output heart failure (often indolent) are seen in <10 percent of patients; acute presentations with portal hypertension and/or biliary disease are less common. For symptomatic liver involvement, initial treatment includes optimizing cardiac status, iron stores, and emergency management as needed. If intense medical management fails, liver transplantation is the treatment of choice. Bevacizumab may also be helpful for nontransplant candidates. (See 'Hepatic AVMs' above.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 30/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Brain AVMs Management of cerebral lesions is complex. Symptomatic lesions and lesions that have bled are managed by specialized units with neurology expertise. For nonsymptomatic patients, management is more challenging since the ARUBA trial indicated that intervention results in worse outcomes than expectant management in unselected cases. Expertise in this area is required for optimal management. (See 'Cerebral lesions' above and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Cerebral AVM screening'.) Children and pregnancy (See 'Special populations' above.) Prognosis Prognosis is variable. Most patients can expect very good life expectancy, and life expectancy continues to improve. (See 'Prognosis' above.) Diagnosis and routine screening (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Vijeya Ganesan, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Faughnan ME, Mager JJ, Hetts SW, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. 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