uncontrolled studies, case reports, or preclinical models. Examples include the VEGF inhibitor pazopanib and the immunosuppressive agents sirolimus and interferon [56-60]. It has been suggested that their use should be restricted to selected, consenting individuals in randomized trials conducted at experienced HHT centers, due to the lack of evidence for benefit from randomized trials, potential side effects, and lack of long-term safety and efficacy data [61]. Further ENT options recommended in international guidelines Other directed therapies include septodermoplasty and/or unilateral or bilateral surgical closure of the nostrils [31,62-67]. These invasive treatments are almost always used in patients who have also received laser therapy and/or cauterization [27,31]. Young's procedure (bilateral surgical closure of the nostrils) has not been evaluated in a randomized trial, but as published in a series of 100 cases, many seen by us in subsequent years, it can have remarkable long-term success in alleviating major nosebleeds and reversing transfusion dependency, as long as there is complete closure of nasal flow [68]. However, a small proportion of patients cannot tolerate the procedure and request reversal, and a larger number decline as they are concerned about the implication of anosmia and mouth breathing. Some patients have been treated with submucosal injection of bevacizumab at the time of laser therapy; long-term results of this approach are awaited [69,70]. Tamoxifen and other non-guideline approaches Additional elements that can be incorporated as part of general care include: Dietary changes for prevention HHT nosebleeds usually come in clusters and vary in severity over a lifetime. A proportion of people with HHT (we estimate approximately one in https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 12/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate three) may be able to identify dietary triggers of nosebleeds that can be avoided without detrimentally impacting their lifestyle [27,62,71]. We suggest keeping a food diary of items ingested in the hours immediately prior to an unusually severe bleed to aid identification of potential precipitants. Avoidance of over-the-counter supplements Caution with over-the-counter dietary supplements offers another opportunity to avoid potential precipitants. An example is fish oil supplements, for which antiplatelet activity is not generally appreciated [72]. (See "Fish oil: Physiologic effects and administration".) For individuals who require systemic therapy, the 2020 International HHT Guideline discussions did not incorporate tamoxifen (with evidence from randomized trials) and the two European Medicines Agency (EMA)-recommended drugs raloxifene and thalidomide. Tamoxifen A 2018 meta-analysis of eight randomized placebo-controlled trials demonstrated that only tamoxifen was superior to placebo, reducing both the frequency and the severity of epistaxis [28]. Tamoxifen appears to be well tolerated, has evidence of efficacy from a double-blind, randomized controlled trial, and is our first treatment of choice when a systemic agent is used for treating epistaxis. In a 2018 meta-analysis of randomized, placebo-controlled trials, tamoxifen was the only systemic agent shown to be superior to placebo; it reduced epistaxis severity and frequency [28]. Tamoxifen also has a favorable side effect profile compared with tranexamic acid, bevacizumab, and raloxifene (wider HHT population use of raloxifene is awaited). However, tamoxifen would not be recommended for someone with a prior history of VTE, atrial fibrillation, or similar higher risk-factor status for venous or arterial thromboembolism. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) A benefit from tamoxifen was demonstrated in a 2009 trial that randomly assigned 25 individuals with HHT (men and women) to receive placebo or tamoxifen (20 mg daily) for six months [12]. Compared with placebo, tamoxifen was associated with a reduction in epistaxis, based on self-report and nasal endoscopy (improvement in 18 versus 90 percent). Some individuals assigned to tamoxifen also had an improvement in hemoglobin level or reduction in transfusion requirements. In an extended follow-up of patients completing the trial arm, in a total of 46 patients with mean 23.4 months of treatment, there were improvements in bleeding score, quality-of-life score, and hemoglobin concentration; none required blood transfusions [13]. These and other extended follow-up studies, as well as our experience, suggest sustained benefits from tamoxifen, and therapy has been well tolerated [13,23,73]. In contrast to other agents discussed below, we have yet to see VTE developing in HHT patients using tamoxifen [23,73]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 13/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Premenopausal women taking tamoxifen should be aware of the effects on other organ systems. (See "Managing the side effects of tamoxifen and aromatase inhibitors".) Raloxifene Raloxifene is a selective estrogen receptor modulator (SERM) that has received European Medicine Agency (EMA) orphan drug designation for HHT based on a small pilot study [74,75]. There is no evidence from randomized trials in HHT. Raloxifene is associated with an increased risk of VTE events, particularly during the first four months of treatment, and is contraindicated in people with a history of VTE, hepatic impairment, cholestasis, severe renal impairment, unexplained uterine bleeding, or endometrial cancer. Estrogens High-dose estrogens have been beneficial in the setting of gastrointestinal bleeding from AVMs (see 'Gastrointestinal lesions' below); however, we do not use high- dose estrogens due to their side effect profiles, particularly the increased risk of VTE. The 50 mg estradiol dose that was effective in one study is not tolerated by men, and we consider the risk of VTE too great to use systemic estrogens [11]. N-acetylcysteine A pilot study in 43 patients suggested a possible benefit of N- acetylcysteine [76]. Pazopanib A retrospective review of 13 patients who received pazopanib for transfusion- dependent anemia due to HHT bleeding reported that all 13 became transfusion independent, with evidence for reduction in ESS, decreased intravenous iron use, and improvement in hemoglobin [77]. Compared with pretreatment hemoglobin, those treated with pazopanib for 12 months had an increase in their mean hemoglobin by 4.8 g/dL (95% CI 3.6-5.9), from 7.8 to 12.7 g/dL, and decreased mean ESS by 4.77 points (95% CI 3.11-6.44 points; from 2.43 to 7.20 points). As stated by the authors, these findings require confirmation in a randomized trial. Oral itraconazole In an observational assessment of 21 patients treated with oral itraconazole, four discontinued therapy due to side effects; the remaining 17 had a decrease in mean ESS from 6.0 to 3.8 points (IQR decreased from 5.1-7.2 to 3.1-5.2) [78]. Hemoglobin levels did not change significantly. Gastrointestinal lesions Gastrointestinal lesions in HHT are common (seen in up to 20 percent of patients), but in the majority of cases, treatment is not required, as iron deficiency is primarily due to under-replacement of iron losses from nosebleeds. That said, a small population of patients with HHT have very severe, recurrent gastrointestinal bleeding, and some suggest this is more common in patients with SMAD4 HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Individuals with SMAD4 HHT'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 14/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Bleeding gastrointestinal lesions in HHT may be accessible for local therapies administered endoscopically. As for epistaxis, local treatments allow the patient to avoid systemic therapies with potential prothrombotic or other risks. Repeated endoscopic ablation of gastrointestinal lesions may be used to control bleeding in the short term ( picture 1), although the results are not as good as in the non-HHT population [79]. Additionally, local therapies carry a potential risk of causing visceral perforations and other complications. In a 2009 guidance, repeated therapies were therefore not recommended [8]. Embolization and/or surgery has limited success due to recurrent disease but may be useful for emergency control of hemorrhage from discrete lesions. This is also the preferred option for diffuse or endoscopically inaccessible severe gastrointestinal bleeding. Gastrointestinal bleeding requiring frequent endoscopic interventions, transfusions, or iron infusion may be treated with systemic agents, and additional studies are ongoing. (See 'Bevacizumab and other systemic antiangiogenic therapies' above and 'Tamoxifen and other non-guideline approaches' above.) Additional information about management of accessible vascular lesions in the gastrointestinal tract is presented separately. (See "Angiodysplasia of the gastrointestinal tract" and "Argon plasma coagulation in the management of gastrointestinal hemorrhage", section on 'Angiodysplasia'.) Where bleeding from an obscure source is considered (eg, due to iron deficiency anemia or a positive stool guaiac test), under-appreciated epistaxis loss is almost always the cause (see 'Epistaxis' above). The possibility of other hematologic causes of anemia should also be considered. Iron deficiency and iron deficiency anemia Iron deficiency and iron deficiency anemia are common in individuals with HHT. The usual cause is epistaxis due to the vascular lesions of HHT. Other common non-HHT-related causes include heavy menstrual bleeding, dietary iron insufficiency, regular blood donation, pregnancy, surgery, and other traumatic events, all of which increase the requirement for iron (the hemorrhage-adjusted iron requirement [HAIR]) [80]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome)", section on 'Iron deficiency'.) Most patients with iron deficiency anemia secondary to blood loss from the vascular lesions of HHT are managed conservatively by repletion of the lost iron. Evidence for responses to 35 mg elemental iron tablets (ferrous gluconate) has been published, and this is our preference for https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 15/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate initial oral dosing for reasons described below [81]. Recommended treatment regimens for iron supplementation and education regarding supplementary ways to improve iron absorption, such as avoiding ingestion of absorption inhibitors such as tea within an hour of iron ingestion based on general population considerations, are discussed separately. If iron absorption is impaired due to concurrent inflammation or disease, and/or bleeding is severe enough, parenteral iron therapy and/or blood transfusions may be required. (See "Treatment of iron deficiency anemia in adults".) HHT patients have important additional considerations relative to the general population: Ongoing blood losses and higher HAIR should be expected in individuals with HHT [80]. Data indicate that treatment of anemia (together with treatment of AVMs) improves epistaxis in approximately one-third of patients with HHT [82]. Importantly, a smaller proportion of HHT patients (approximately 5 percent) report that iron treatments and blood transfusions make their nosebleeds worse [82,83]. We are concerned this may relate to supranormal serum iron concentrations evident in people ingesting iron tablets [72,83] and induction of endothelial injury [83,84], but this awaits clinical confirmation. Additional studies are ongoing. Heavy menstrual bleeding is a very common problem for the female HHT population and can exacerbate iron deficiency. Heavy menstrual bleeding in patients with HHT is generally managed the same as in patients without HHT, though applying the prothrombotic concerns outlined above for systemic therapies (see 'Bevacizumab and other systemic antiangiogenic therapies' above). This information is presented in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".) Iron deficiency is the most common form of anemia in HHT, but as for any population, individuals may also be at risk for concurrent pathologies causing anemia, and these should be evaluated as appropriate for the patient. (See "Diagnostic approach to anemia in adults".) Data from a series of HHT patients with severe anemia out of proportion to calculated hemorrhagic iron losses emphasize that low-grade hemolysis may contribute to severe anemia in HHT [85]. Pulmonary AVMs Potential complications of PAVMs Pulmonary AVMs (PAVMs) are of concern in HHT because patients can develop a number of potentially life-threatening and life-changing cerebral https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 16/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate complications including ischemic stroke caused by a paradoxical embolus to the brain and brain abscess caused by paradoxical septic emboli [86]. As noted, PAVMs affect over half of individuals with HHT. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs'.) Hypoxemia versus hypoxia PAVMs commonly cause hypoxemia (low partial pressure of oxygen [PaO ] and low hemoglobin saturation by oxygen [SaO ]) due to impaired gas 2 2 exchange, though this is usually asymptomatic [87]. These changes are due to hypoxemia and not hypoxia. Individuals with HHT maintain their arterial oxygen content (CaO ), and 2 they do not have the same physiology as patients who have low PaO /SaO due to 2 2 parenchymal lung disease [87]. Standard recommendations for individuals with hypoxic lung disease are not applicable since individuals with hypoxemia due to right to left shunting are not specifically at risk of hypoxic pulmonary hypertension [88]. Two studies evaluating exercise capacity in individuals with HHT-associated PAVMs demonstrated that reduced exercise capacity reflects low hemoglobin and/or airflow limitation rather than hypoxemia [89,90]. Nevertheless, it was a surprise when the evidence on how well airline flights were tolerated was published [91]. Using a retrospective questionnaire-based study, the authors examined in-flight complications and predictors in 145 HHT patients (96 with PAVMs) who reported 3950 flights, totaling 18,943 flight hours. Dyspnea and thrombotic complications were less common than expected and could not be predicted from sea-level oxygen saturations or hemoglobin concentrations (anemia) [91]. Where there are concurrent pathologies such as parenchymal lung disease or pulmonary hypertension, standard guidance should be followed; this may include supplemental oxygen in certain settings (as an example, airline flights) or continuously. Where patients with PAVMs have successfully traveled by air on many occasions when hypoxemic, and there is no change in their medical state, we do not prohibit flying, based on published evidence [91]. (See "Assessment of adult patients for air travel" and "Evaluation of patients for supplemental oxygen during air travel".) Silent cerebral infarcts and stroke Silent cerebral infarcts are also a concern; these silent infarcts have been identified on cerebral magnetic resonance images (MRIs) performed for another indication (cerebral AVM screening), emphasizing the risk in individuals with PAVMs [92,93]. In a study from the United States involving 353 individuals with HHT who had brain magnetic resonance imaging (MRI) for any reason, silent cerebral infarcts were more common in individuals with PAVMs than those without PAVMs (overall https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 17/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate prevalence, 10 percent; with PAVMs in 81 percent of the silent infarction patients and 53 percent of the individuals without silent infarction) [93]. In a study from Europe in a group of 29 individuals with PAVMs and no history of stroke, one to five silent infarcts were found in 16 individuals (55 percent) [92]. The most frequently affected sites were the cerebellum (40 percent) and thalamus (14.3 percent), and the age-adjusted odds ratio for an infarct was 21.6 (95% CI: 3.7, 126) [92]. Septic embolism to the brain causing brain abscess is also a risk. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Neurologic'.) Bleeding Occasionally, PAVMs may bleed; this event is rare unless PAVMs have developed a systemic arterial supply (spontaneously or post-treatment), the individual is pregnant, or the individual has pulmonary hypertension. PAVM hemorrhage may lead to hemoptysis or hemothorax. These and other complications of PAVMs are discussed in more detail separately. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary AVMs' and "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults".) PAVM screening PAVMs are present in over half of individuals with HHT. Any relevant symptoms should be investigated. (See "Pulmonary arteriovenous malformations: Clinical features and diagnostic evaluation in adults", section on 'Clinical manifestations'.) The approach to screening is discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'PAVM screening'.) Principles of PAVM management Management of PAVMs should be performed by clinicians with expertise in this area and should include the following, which are in keeping with a 2017 good practice statement from the British Thoracic Society and the European Reference Network for HHT (VASCERN HHT) [3,94]. Individuals with PAVMs should receive prophylactic antibiotics prior to dental procedures, other potentially nonsterile procedures (eg, endoscopy), and surgery, to reduce post- procedural bacteremias implicated in brain abscess pathogenesis [95]. This is one of the five VASCERN HHT Outcome Measures, where good practice is 100 percent of all PAVM patients advised in writing [3,95]. It is also important to maintain good dental care to reduce the risk of bacteremia. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Antibiotic prophylaxis'.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 18/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate For PAVMs of a size amenable to embolization, embolotherapy is recommended based on evidence from observational studies that suggests reduced morbidity and mortality [73,96- 99]. These data are also supported by practice standards from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) and a Cochrane database review [5,99]. Information about the details of the procedure and evidence to support its efficacy in reducing cerebral complications are presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Patients suitable for embolotherapy'.) There are occasional circumstances (eg, severe pulmonary hypertension [PH]) when risk- benefit analyses are generally not in favor of embolization or where surgery may be preferred due to a greater likelihood of complete obliteration of shunting through the lesion [99-101]. Patients with in situ metallic coils and Amplatzer vascular plugs used to treat PAVMs can safely undergo MRI [102]. For PAVMs that are not amenable to embolization anatomically, surgery may occasionally be warranted. While the risks of removing normal lung in an individual likely to have multiple PAVMs may in the past have outweighed the benefits, parenchymal-sparing surgical techniques mean this is less of a concern, and at our center, surgery is increasingly offered to selected patients. Lung transplantation has been performed in very occasional cases, but in major HHT/PAVM centers, this has not been considered an option for even the majority of complicated PAVM cases, due to longevity of patients with severe hypoxemia who do not receive lung transplantation. Of five where transplantation was considered and not performed, by 2017, survival ranged from 16 to 27 (median 21) years, with surviving patients restating a preference for their ongoing medical issues [103]. Since that publication, at our institution, one patient has been referred and meets the criteria for lung transplantation; however, they are not actively transplant-listed as their quality of life is considered by the patient and the transplant team to be too high to justify the risks of lung transplantation. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations", section on 'Surgical excision'.) Experts in some countries have recommended filters to prevent paradoxical embolization of particulate material present in an intravenous solution. In other countries such as the United Kingdom, where air embolism is a "never event" (ie, one that should not occur if the available preventive measures have been implemented), insertion of such a filter is considered likely to be detrimental, compared with judicious following of safe practices for intravenous solutions [104]. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 19/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Individuals with PAVMs are generally advised to avoid scuba diving. Having been informed of the additional risks, in our experience, some patients choose to make an informed choice of the level of risk that they would consider acceptable to them. The field is awaiting formal guidance to take into account the one in three of the general population who will also shunt through a patent foramen ovale during a dive. Management of complications of PAVMs (eg, ischemic stroke, brain abscess) is discussed separately. Importantly, brain abscess is often not accompanied by leukocytosis, and a low threshold for making the diagnosis should be used to ensure that there is immediate referral for neurosurgical review and that appropriate intravenous antibiotics are given [73,105]. As noted above, MRI can be performed in patients who have undergone PAVM embolization and should not be delayed in emergency situations [102]. (See "Initial assessment and management of acute stroke" and "Treatment and prognosis of bacterial brain abscess".) Pulmonary hypertension is a separate pathology (usually, pulmonary artery [PA] pressures are low to normal in patients with PAVMs). Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that when pulmonary hypertension was present, it was usually part of a broader picture of hepatic AVMs, anemia, atrial fibrillation, and symptoms [106,107]. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)", section on 'Pulmonary hypertension' and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) Additional discussion of the management of PAVMs is presented separately. (See "Therapeutic approach to adult patients with pulmonary arteriovenous malformations".) Hepatic AVMs Hepatic AVM management has been assisted by the 2020 International HHT Guidelines where the expert panel recommended the following [1]: Screening for liver AVMs in adults with definite or suspected HHT. (See "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs", section on 'Hepatic AVM screening'.) Diagnostic testing in HHT patients with symptoms and/or signs suggestive of complicated liver AVMs (including heart failure, pulmonary hypertension, abnormal cardiac biomarkers, abnormal liver function tests, abdominal pain, portal hypertension, or encephalopathy), using Doppler ultrasound, multiphase contrast CT scan, or contrast abdominal MRI. (See 'Identifying hepatic AVMs and determining need for treatment' below.) https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 20/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Estimation of the prognosis of liver AVMs using available predictors, to identify patients in need of closer monitoring. An intensive first-line management only for patients with complicated and/or symptomatic liver AVMs, tailored to the type of complication(s). (See 'Initial management of hepatic AVMs' below.) Co-management of HHT patients with high-output cardiac failure and pulmonary hypertension by an HHT Center of Excellence and an HHT cardiologist or pulmonary hypertension specialty clinic. Systemic bevacizumab is considered for patients with symptomatic high-output cardiac failure due to liver AVMs for whom first-line management is unsuccessful. For those with refractory high-output cardiac failure, biliary ischemia, or complicated portal hypertension, referral for consideration of liver transplantation is appropriate. (See 'Role of liver transplantation' below.) Liver biopsy should be avoided in any patient with proven or suspected HHT. Hepatic artery embolization be avoided in patients with liver AVMs as it is only a temporizing procedure associated with significant morbidity and mortality. Identifying hepatic AVMs and determining need for treatment Hepatic AVMs are common in HHT, identified in approximately 50 percent of people; they are substantially more prevalent in patients with HHT2 due to pathogenic variants in ACVRL1 [108,109]. Longitudinal series have shown that complications occur at an incidence of 3.6 percent per year and that 1 percent annual mortality is due to hepatic AVMs in HHT [110]. Hepatic AVMs vary in size from small telangiectasia to large AVMs and constitute three separate types of aberrant intrahepatic communications. The most common are between hepatic arteries and hepatic veins. Other types of communications include hepatic-portal shunts (between hepatic arteries and portal veins) and portohepatic shunts (between portal and hepatic veins). Typical symptoms include reduced exercise tolerance, dyspnea, edema, ascites, and/or other consequences from high-output cardiac failure. These symptoms should prompt hepatic imaging to identify these lesions. Despite the high prevalence of hepatic AVMs and the significant symptoms they cause, clinicians often do not suspect that the driving pathology leading to these symptoms is sited in the liver rather than the heart. Thus, diagnosis of hepatic AVMs may be delayed. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 21/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Other challenges related to identifying hepatic AVMs include the following: Such patients usually present to cardiologists, who may focus on a potential cardiac cause of their symptoms. Portal hypertension and its consequences including encephalopathy and varices and symptoms from mesenteric or biliary ischaemia (resulting from blood flow steal) are more likely to result in an acute picture within gastroenterology and hepatology disciplines. (See "Portal hypertension in adults", section on 'Clinical manifestations'.) Symptoms may differ according to the nature of the vascular malformations, particularly whether the portal vein is involved, and whether there is a blood flow steal through arteriovenous (AV) shunts. It may be difficult to separate out the majority of patients who will never require specific treatment of their hepatic AVMs, from the significant minority for whom the consequences of hepatic AVMs will come to dominate the clinical picture and who will require high-level specialist support that needs to be delivered in a timely fashion to intervene at the optimal time [111]. Clinicians may not recognize the importance of correcting anemia, atrial fibrillation, and otherwise modest cardiac pathologies to improve the clinical picture. Longitudinal studies have demonstrated that symptoms of hepatic AVMs can be exacerbated in the presence of concurrent anemia and/or atrial fibrillation [110]. Data from two large series published in 2017 (3176 HHT patients, pulmonary artery hypertension in <2 percent) demonstrated that hepatic AVMs may be accompanied by a constellation of findings including pulmonary hypertension, anemia, atrial fibrillation, and symptoms [106,107]. Hepatic AVMs (and resultant high-output cardiac states) are responsible for the most common form of pulmonary hypertension in HHT [106,107]. These data were reviewed in a consensus statement from the European Association for the Study of the Liver (EASL) and an HHT workshop held in 2017 [111]. Updated guidance from the HHT International Guidelines Committee is awaited. For any HHT patient undergoing imaging of the liver, it is most important for clinicians to be aware of the possibility that hepatic AVMs may occur in individuals with HHT. We are aware of three cases in which hepatic AVMs were initially mistaken for cancer metastases (in one case resulting in a fatal outcome) and of two further cases where liver biopsies (performed without appreciating the presence of AVMs) resulted in catastrophic hemorrhage. https://www.uptodate.com/contents/hereditary-hemorrhagic-telangiectasia-hht-evaluation-and-therapy-for-specific-vascular-lesions/print 22/47 7/5/23, 12:20 PM Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions - UpToDate Initial management of hepatic AVMs International consensus is that all patients with HHT should be offered screening for hepatic AVMs; however, only symptomatic hepatic AVMs should 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