Medical management of haemorrhagic hereditary telangiectasia in adult patients

G Model

ARTICLE IN PRESS Med Clin (Barc). 2019;xxx(xx):xxx–xxx

www.elsevier.es/medicinaclinica

Review

Medical management of haemorrhagic hereditary telangiectasia in adult patients夽 Antoni Riera-Mestre a,b,c,∗ , Jesús Ribas a,d , José Castellote a,c,e a

Unidad de Telangiectasia Hemorrágica Hereditaria, Hospital Universitari de Bellvitge–IDIBELL, L’Hospitalet de LLobregat, Barcelona, Spain Servicio de Medicina Interna, Hospital Universitari de Bellvitge–IDIBELL, L’Hospitalet de LLobregat, Barcelona, Spain Facultad de Medicina y Ciencias de la Salud, Universitat de Barcelona, Barcelona, Spain d Servicio de Neumología, Hospital Universitari de Bellvitge–IDIBELL, L’Hospitalet de LLobregat, Barcelona, Spain e Unidad de Hepatología y Trasplante hepático, Servicio de Aparato Digestivo, Hospital Universitari de Bellvitge–IDIBELL, L’Hospitalet de LLobregat, Barcelona, Spain b c

a r t i c l e

i n f o

Article history: Received 26 August 2018 Accepted 27 September 2018 Available online xxx Keywords: Haemorrhagic hereditary telangiectasia Rare diseases Vascular malformation

a b s t r a c t Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant inherited Rare Disease that causes a systemic anomalous vascular overgrowth. The approach and follow-up of these patients should be from multidisciplinary units. Its diagnosis is carried out according to Curac¸ao clinical Criteria. Telangiectasia in the nasal mucosa cause recurrent epistaxis, the main symptom of HHT and difficult to control. The three types of hepatic shunting, hepatic artery to hepatic vein, hepatic artery to portal vein or to portal vein to hepatic vein, can cause high-output heart failure, portal hypertension or porto-systemic encephalopathy, respectively. These types of vascular involvement can be established using computerized tomography. Pulmonary arteriovenous fistula should be screened for all HHT patients by contrast echocardiography. The main objective is to review the management of epistaxis, liver and lung involvement of the adult patient with HHT. ˜ S.L.U. All rights reserved. © 2018 Elsevier Espana,

Tratamiento de la telangiectasia hemorrágica hereditaria en el paciente adulto r e s u m e n Palabras clave: Telangiectasia hemorrágica hereditaria Enfermedades minoritarias Malformación vascular

La telangiectasia hemorrágica hereditaria es una enfermedad minoritaria con herencia autosómica dominante que ocasiona un crecimiento vascular anómalo de forma sistémica. El abordaje y seguimiento de estos pacientes debería hacerse desde unidades multidisciplinares. Su diagnóstico es clínico según los criterios de Curac¸ao. Las telangiectasias en la mucosa nasal ocasionan epistaxis recurrentes, principal síntoma de esta enfermedad y de difícil control. Los 3 patrones de afectación hepática, comunicaciones entre arteria hepática y venas suprahepáticas, entre arteria hepática y vena porta o entre vena porta y venas suprahepáticas pueden causar insuficiencia cardiaca por hiperaflujo, hipertensión portal o encefalopatía hepática, respectivamente. Estos tipos de afectación vascular se pueden establecer mediante tomografía computarizada. Se debe realizar un cribado de fístulas arteriovenosas pulmonares a todos los pacientes mediante una ecocardiografía con contraste. Nuestro principal objetivo es realizar una revisión del manejo de las epistaxis, afectación hepática y pulmonar del paciente adulto con telangiectasia hemorrágica hereditaria. ˜ S.L.U. Todos los derechos reservados. © 2018 Elsevier Espana,

夽 Please cite this article as: Riera-Mestre A, Ribas J, Castellote J. Tratamiento de la telangiectasia hemorrágica hereditaria en el paciente adulto. Med Clin (Barc). 2019. https://doi.org/10.1016/j.medcli.2018.09.015 ∗ Corresponding author. E-mail address: [email protected] (A. Riera-Mestre). ˜ S.L.U. All rights reserved. 2387-0206/© 2018 Elsevier Espana,

MEDCLE-4665; No. of Pages 7

G Model

ARTICLE IN PRESS

2

A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

Introduction Hereditary haemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu disease has an incidence of 1/5000–8000 inhabitants and has been classified as a rare disease (ORPHA: 774).1,2 Despite being an autosomal dominant genetic disorder, its diagnosis is clinical, according to the Curac¸ao criteria3 (Table 1). More than 800 mutations have been reported in more than 5 genes, but most of them are located in the ENG gene, which encodes for endoglin, or the ACVRL1 gene, which encodes for activin.4 Both proteins are part of the transforming growth factor ␤ (TGF-␤) family, involved in vascular signaling pathways, influencing the counterregulation of angiogenesis.5 Thus, changes in these proteins give rise to abnormal vascular growth. Mutations in the ENG gene define type I HHT, with a higher rate of pulmonary arteriovenous fistulas (PAVFs), whereas mutations in ACVRL1 define type II HHT, with a higher prevalence of liver involvement.6,7 Since it is a germline disease, vascular involvement can occur in any organ, although it mainly involves lungs and liver. This involvement is located both in the microvessels, in the form of telangiectasias, and in the form of vascular malformations (VMs) in larger vessels.3,4 Telangiectasia is the characteristic lesion of the HHT and is an aberrant connection of the capillary bed.8 Telangiectasias predominate in the pulp of fingers and mucous membranes, particularly in the nasal mucosa, causing recurrent epistaxis, the main symptom of this disease. Screening test is recommended for early detection of the potential VMs, and proper treatment and follow-up.6,7 Given its systemic involvement, its approach from multidisciplinary units is recommended. HHT penetrance increases with age and shows an inter and intrafamilial clinical variability.4,7 Its onset is usually in the form of epistaxis at the beginning of the second decade of life, with vascular involvement progressing until the fourth decade.9 This is the reason why pediatric age patients might not meet the Curac¸ao criteria, requiring a genetic study for their diagnosis.3,7 However, brain VMs show a different performance, since they are present from birth, reason why screening in asymptomatic adult patients is controversial.7,10 On the other hand, gastrointestinal impairment is the latest manifestation, since it begins on the 5th or 6th decade of life.11 Its examination is recommended only in those patients with anemia disproportionate to epistaxis.7 This peculiar form of involvement, the systemic nature of HHT, its low prevalence and its great clinical variability make the management of this disease complex. The purpose of this study is to monitor the management of the most relevant vascular disease in adult patients with HHT, specifically, regarding epistaxis, liver and lung involvement. Epistaxis Epistaxis is the most frequent clinical manifestation of HHT.7,12 It is recurrent and variable in duration, intensity and frequency. Approximately half of the patients suffer from epistaxis before the Table 1 Criteria of Curac¸ao. Criterion

Description

Epistaxis Telangiectasias

Spontaneous and recurrent Multiple, in characteristic sites: lips, oral cavity, fingers, nostrils GI telangiectasias, pulmonary, hepatic, cerebral or spinal arteriovenous malformations First-degree relative with HHT according to these criteria

Visceral injuries Family history.

GI: gastrointestinal; HHT: hereditary haemorrhagic telangiectasia. Source: Ola et al.5

age of 10 and it affects almost all of them throughout their lives.7,12 It is the most significant symptom associated with poor quality of life, and one of the main causes of urgent medical consultation.13 In the first study of the only registry of HHT patients in Spain, called RiHHTa (computerized registry of HHT), with 141 patients, 22% required blood transfusions and 35.5% visited the emergency department for epistaxis.14 Urgent assistance should be a scenario for the early diagnosis of HHT, where the patients are asked about their history of recurrent epistaxis, family history and digital or the oral cavity telangiectasias. These 3 Curac¸ao criteria would define a final diagnosis of HHT.3 The approach to epistaxis should include an assessment of the severity of nosebleeds, an assessment of its consequences (especially preventing iron deficiency and chronic anemia) and follow-up in a multidisciplinary unit, which should include an otolaryngologist.7 For the clinical evaluation and follow-up of patients, the use of tools to quantify epistaxis, such as the Epistaxis Severity Score (ESS), is useful.15 It is a simple and easy-to-apply scale available online, which refers to different aspects of epistaxis in the last 3 months.

Treatment Training the patient is essential, both in nasal hygiene and in using preventive therapies or in taking action in case of bleeding episodes. These guidelines should be provided in writing in every center.16 As preventive measures of epistaxis, humidification is recommended as a therapy to help preserve a healthy mucosa. This prevents nose scabs and the telangiectasia damage caused by airflow. In case of acute epistaxis requiring plugging, we should not use any non-resorbable materials, given the recurrence of bleeding when the plug is removed. Various medical therapies have been recommended for the treatment of chronic epistaxis, tested in a small number of patients and with different results. Oral tranexamic acid, an antifibrinolytic agent, seems to reduce the length of epistaxis but not its recurrence.17 Hormonal treatments with topical estrogens (such as estriol 0.1%) or systemic estrogens (such as oral contraceptives or selective estrogen receptor modulators) have been shown to improve various aspects of epistaxis.18,19 Estrogens induce a reversible metaplasia of the ciliated columnar epithelial cells of the nasal mucosa to a keratinized squamous epithelium, with greater capacity to protect telangiectasias.18 Evidence is also available on the use of bevacizumab, a monoclonal antibody with antiangiogenic activity that inhibits the activity of vascular endothelial growth factor. Although some of these studies, with a small number of patients, showed some clinical advantages regarding the administration of submucosal or spray topical bevacizumab, in 2 recent randomized clinical trials with a greater number of patients, the epistaxis improvement was not better than with placebo.20–22 For all these reasons, today its use in epistaxis is not recommended.23 Oral thalidomide 50–150 mg/day decreased the severity of epistaxis according to the ESS as well as the need for transfusions within 6 months.24 Thalidomide inhibits the endothelial cell proliferation and migration, stabilizing the blood vessels, which prevents from bleeding. Despite this, its evidence is very limited, with a small number of patients and it is not free from adverse effects.25 Recently, in telangiectasias of patients with type 2 HHT an increase in the activity of the enzyme phosphoinositide 3-kinase has been detected. Thus, the use of the mammalian target of rapamycin (mTOR) inhibitors has been proved to be beneficial in a mouse model.26,27 The potential benefit when using mTOR inhibitor drugs (sirolimus or everolimus) in the treatment of epistaxis or larger VMs in other organs of HHT patients has not been verified yet.

G Model

ARTICLE IN PRESS A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

3

Hepatic MVs VP SHV

AH SHV Biliary ischemia Heart failure increased flow

Hepatic blood flow disorders

AH VP

Hepatic encephalopathy Portal hypertension

Secondary sclerosing cholangitis

FNH NRH Fig. 1. Pathogenesis of the different hepatic vascular malformations in hereditary haemorrhagic telangiectasia. HA: hepatic artery; FNH: focal nodular hyperplasia; NRH: nodular regenerative hyperplasia; VMs: vascular malformations; SHVs: suprahepatic veins; PV: portal vein.

Regarding invasive treatments, most of them are supported by case series or expert’s opinion. Aethoxysclerol solution for injection, a sclerosing agent used in phlebology, seems to provide an improvement in the severity of epistaxis without any significant side effects.28 Arterial embolization only offers a short-term effect and it is not useful to control chronic epistaxis, since the surrounding blood vessels are enlarged and cause recurrent bleeding.7 From a surgical point of view, the technique with the best results is the modified Young’s procedure.29 Closure of the nasal cavities prevents the airflow from entering the cavities, therefore preventing the turbulent airflow from entering inside the friable telangiectasias. With this procedure, remission of epistaxis has been reported, with improvement of anemia and quality of life, although it implies some side effects such as xerostomia, anosmia and dysgeusia.29,30 Hepatic involvement Vascular hepatic involvement is the most frequent manifestation in HHT, after epistaxis, mostly in type 2 HHT.6,7,31,32 When liver is systematically examined with Doppler ultrasound or multiphase contrast-enhanced computed tomography (CT), this involvement is detected in 41–84% of cases. However, the percentage of patients with symptoms related to liver involvement is below 15%.7,34,35 A scoring system based on 4 variables (age, sex, hemoglobin and alkaline phosphatase) has helped define low and high risk groups of symptomatic hepatic involvement.34 Hepatic involvement of HHT ranges from telangiectasias to larger VMs, and the latter constitute authentic fistulas with a variable flow.31,35 Due to dual blood supply of the liver, 3 different patterns can occur that justify a characteristic clinical feature: connection between the hepatic artery and the suprahepatic veins, between the hepatic artery and the portal vein or between the portal vein and the suprahepatic veins.31,36,37 These 3 types of fistulas can cause high-output heart failure (HF) or due to increased blood flow and/or ischemic cholangitis, portal hypertension (PHT) or hepatic encephalopathy, respectively (Fig. 1).31,36,37 The subtypes of hepatic VMs are not exclusive. Therefore, various clinical manifestations may coexist. High-output HF is the most frequent clinical manifestation and occurs in more than half of the symptomatic cases.31,36,37 It is caused by shunts between the hepatic artery (high pressure) and the suprahepatic veins (low pressure), which leads to a decrease in the systemic vascular resistance. This implies an increase in the cardiac index and a state of hyperdynamic circulation that can lead to HF. The signs and symptoms are those of HF, more frequent in women from their fifth decade of life, although in younger women they can occur during pregnancy.31,37 Anemia associated with HHT and/or the decrease in atrial fibrillation frequently complicate its course or act as its precipitants. Regarding atrial fibrillation, HHT is not an absolute contraindication for anticoagulation. However, if not tolerated, a closure of the left atrial appendage should be considered.14 This type of liver VMs should be diagnosed and

monitored by means of transthoracic echocardiogram (TTE) calculating the cardiac index. Biliary involvement occurs in up to 19% of symptomatic cases.31,37 The bile duct is irrigated by the peribiliary plexus dependent on the hepatic artery. Therefore, shunts that decrease the flow of this artery, such as connections between the hepatic artery and the suprahepatic veins, will lead to hypoperfusion and risk of biliary ischemia. This ischemic process causes the occurrence of necrosis of the biliary epithelium, stenosis and the potential occurrence of bilomas. It occurs almost exclusively in women from their fifth decade of life and is characterized by cholestasis in blood test, pain in right hypochondrium and it may be associated with bacterial cholangitis that aggravates the condition.36,37 Pain tends to be constant and it should alert the clinician about its potential cause. The diagnostic test is magnetic resonance cholangiopancreatography (MRCP), which will show images of stenosis and cystic dilatation of biliary ducts and biliary cysts (bilomas). Endoscopic cholangiopancreatography should not be used because of the risk of bile contamination and subsequent bacterial cholangitis. PHT affects 17–40% of cases with symptomatic liver involvement.31,36,37 In 10–15% of cases, it can be associated with HF. In addition to the shunt between the hepatic artery and the portal vein, a second mechanism is the association with nodular regenerative hyperplasia, non-cirrhotic nodules that occur due to changes in the normal hepatic blood flow. Follow-up is required to detect any potential complications of PHT. More rarely, a few cases of hepatic encephalopathy have been reported.37 The first one occurs in <5% of the symptomatic cases and is due to the portosystemic connection that mixes blood from the portal vein to the suprahepatic veins. As in cirrhosis, it can be associated with a precipitating factor and its treatment is similar. On the other hand, rare cases of mesenteric intestinal ischemia due to poor blood supply in the mesenteric arteries caused by the hepatic artery have been reported.37 The diagnosis of vascular involvement is based on clinical manifestations and imaging tests. Doppler ultrasound can measure the diameter of the hepatic artery and intrahepatic hypervascularization, although the degree of involvement and the subtype of VMs are difficult to determine and depends on the skill of the radiologist.33,38 Multiphase contrast-enhanced CT has become the most sensitive and specific test in the diagnosis of liver involvement and also allows to specify the subtype of predominant shunt and lesions associated with vascular disorders of the liver, such as focal nodular hyperplasia.38,39 It also allows to detect extrahepatic intra-abdominal involvement, present in 10% of patients with HHT in the computerized registry of HHT.14 As hepatic VMs increase with the patient’s age, a screening test for the detection of liver VMs is recommended between the third and fourth decades of life. At an early age, ultrasound might be a proper test to rule out liver involvement, given its availability, non-irradiation and low cost. In symptomatic cases, CT is always recommended.7,9 MRI can be an alternative for the study of hepatic

G Model 4

ARTICLE IN PRESS A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

VMs, also if radiological monitoring is required, given its absence of irradiation.7 Treatment Initially, in HF due to increased blood flow and in PHT, we should prescribe the standard therapy for these procedures. In the initial phase of mild ischemic cholangitis with little involvement of the bile duct, ursodeoxycholic acid (15 mg/kg of weight) is recommended, although no scientific data is available to support it. The usefulness of bevacizumab in patients with HF due to increased blood flow has been studied.40 In a non-controlled prospective study in 24 patients, administration of 6 doses of intravenous bevacizumab 5 mg/kg every 14 days showed a normalization of the cardiac index within 3 months in 3 patients, decrease in 17 and no response in 4 patients; at least one adverse reaction likely related to bevacizumab occurred in 20 patients.41 As invasive treatments, in HF due to increased blood flow, shunt reduction techniques have been tested through embolization or ligature of the hepatic artery. In general, they lead to transient improvements, but they are associated with high morbidity and mortality.7 Recently, a surgical technique has been reported to obtain promising results, with no mortality and with acceptable morbidity. It requires banding of the hepatic artery and ligature of some of its branches.42 In severe ischemic cholangitis, without response to ursodeoxycholic acid, occasionally the drainage of the bile duct or bilomas may be required, but the morbidity rate of this procedure is high and it is poorly beneficial, reason why a liver transplant is often required. Arterial embolization in this case is formally contraindicated because it can worsen biliary ischemia. Finally, liver transplantation is the curative treatment of HHT complications. HF due to increased blood flow represents its main indication.43 The timing for the transplant is delicate, and it should be performed when the condition is refractory to intensive and standard medical treatment.44 However, these patients do not acquire high scores in the Model for End-stage Liver Disease, which is used to prioritize the liver transplant waiting list based on creatinine, bilirubin levels, international normalized ratio, sodium and dialysis levels, parameters usually normal in patients with HHT and severe hepatic involvement.44 Therefore, an exception must be made so that they have real probabilities of being transplanted. The results of the liver transplantation are good and comparable to those obtained by other indications. In a recent systematic review of 57 patients, survival at year 10 was 82.5%.43 The disease can recur in the graft, although the incidence of this complication is very low.45 Pulmonary vascular involvement Pulmonary arteriovenous fistulas The PAVFs occur in 15–50% of HHT patients, particularly in patients with type 1 HHT.7 These structurally abnormal vessels cause an abnormal blood flow from the arteries to the pulmonary veins, without passing through the pulmonary capillary filter, giving rise to a right-to-left shunt. In less than 5% of cases, they affect systemic arteries (bronchial or intercostal) instead of pulmonary arteries.46 70–90% of patients with PAVFs are affected by HHT, the remaining being rare cases.47 They consist of an aneurysmal sac and one or more afferent arteries and one or more drainage veins. They can be single or multiple, unilateral or bilateral and simple (a single afferent artery) or complex (≥2 afferent arteries). A minority of patients present a diffuse form of PAVFs with involvement of multiple segmental branches of one lobe or all branches of a lung segment. In patients with HHT, their most frequent location

is the lower lobes (60–95%) and they are multiple in up to 50% of cases.14,46 Most patients are fully asymptomatic, with PAVFs being discovered after a complication or by screening tests. The occurrence or not of signs and symptoms varies depending on the number, size and percentage of cardiac output that flows through the PAVFs.7,47 The presence of PAVFs is associated with a higher prevalence of migraine, frequently getting better after treatment.46 Major PAVF clinical manifestations can be classified into 3 groups:

- Neurological manifestations due to pulmonary capillary filtration. They are the greatest risk of PAVFs and include: brain abscess, ischemic stroke, transient ischemic attack and asymptomatic cerebral infarction. The pulmonary capillary bed is an 8–10 ␮m sieve capable of retaining small fragments of thrombotic or infectious material that can circulate in the venous blood flow. PAVFs alter this filter function and expose patients to the abovementioned neurological complications. In most of these complications, there is no previous diagnosis of HHT or the screening for PAVFs has not been carried out.7,14 In a recent case report, 37 (8.3%) of 445 patients with PAVFs had a brain abscess, almost 80% of them had not been diagnosed with PAVFs and in 37% there was a history of dental disease. A low O2 saturation, a higher transferrin saturation index, intravenous iron therapy, male sex and a history of venous thromboembolic disease were associated with an increased risk of brain abscess.48 - Alteration of gas exchange due to the right-to-left shunt. Up to 80% of patients with PAVFs have no respiratory symptoms.7,46,47 In patients with chronic hypoxemia and normal iron deposits, a secondary polyglobulin that preserves the arterial O2 content is usually observed, which means that patients with severe hypoxemia have no limited tolerance to exertion. PAVFs are mainly present in the lower lobes. Therefore, up to 29% of patients may present orthodeoxia (desaturation with orthostatism) and in a lower percentage, platypnea (dyspnea with orthostatism).49 - Hemorrhage due to vessel rupture. Hemoptysis or hemothorax are rare, with an increased risk during pregnancy.7,16

In all patients with HHT, PAVF screening is indicated using a contrast-enhanced transthoracic echocardiogram.7,16 This indication is particularly important in childbearing age women, before pregnancy, to prevent life-threatening complications.7,16 Contrast transthoracic echocardiogram means the intravenous administration of 10 ml of shaken serum (9 ml of saline solution + 0.5 ml of air + 0.5 ml of blood), subsequently evaluating the passage of bubbles to the left ventricle. In our HHT unit we use the modified Barzilai classification, which categorizes 5 grades: 0 (absence of bubbles), 1 (<20 bubbles), 2 (moderate opacity of bubbles in left ventricle), 3 (extensive opacity of bubbles without contacting the endocardium) and 4 (extensive opacity with definition of the left ventricle endocardium).50 In the normal population bubbles should be trapped in the pulmonary capillary filter. However, 10% of healthy people may present grade 1 shunt.51 The late passage of bubbles (after more than 3 cardiac cycles after the administration of the shaken serum) is an intrapulmonary shunt, while the passage between the first and third cycles is an intracardiac shunt. In spite of this, this early passage of bubbles does not fully exclude the presence of functioning PAVFs, since they can coexist with the existence of a permeable foramen ovale. The degree of shunt has been correlated with the number of fistulas, diameter of the afferent artery, cerebral complications and severity of hypoxemia.52,53 The absence of bubble passage or the existence of a grade 1 shunt makes it possible to rule out the existence of visible fistulas in thoracic CT, whereas this test should be performed in patients with

G Model

ARTICLE IN PRESS A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

5

Contrast TTE

CI estimate

sPAP evaluation

PH study If sPAP> 40 mmHg

Measurement of the shunt grade (Barzilai)

Grades 0-1

Grade > 2

Grade > 1

Antibiotic prophylaxis

Contrast chest CT If high CI (> 4.5 l/min/m2) suspect hepatic VM

Exclusion of PAVF with clinical relevance

Embolization of every potential PAVF

Untreated PAVMs

Embolization of every potential PAVF

Contrast TTE Contrast chest CT per year

Contrast chest CT in 3-5 years

If increase in the shunt grade

Fig. 2. Algorithm for the screening, diagnosis, treatment and follow-up of pulmonary arteriovenous fistulas in hereditary haemorrhagic telangiectasia. TTE: transthoracic echocardiogram; PAVFs: pulmonary arteriovenous fistulas; PH: pulmonary hypertension; CI: cardiac index; VMs: vascular malformations; sPAP: systolic pulmonary arterial pressure; CT: computerized tomography.

grade ≥2 to define the number, location and anatomical features of the PAVFs (Fig. 2).51,52 Treatment of pulmonary arteriovenous fistulas and antibiotic prophylaxis Antibiotic prophylaxis should be recommended before procedures with risk of bacteremia (particularly dental, digestive or genitourinary endoscopy) to all patients with contrast TTE, to prevent the development of brain abscesses, whether or not the PAVFs are embolized.7,16 It is recommended that the prophylactic antibiotic guidelines be provided in writing to inform all healthcare professionals of the need for compliance.16 Embolization of all AVPFs is recommended where the procedure is technically possible, regardless of the existence or not of any symptoms.7 Currently, Amplatzer-type intravascular devices are being used, which provide a better occlusion compared to coils.47 With these devices, or with the combination of both, close to 100% occlusion rates and a significant improvement in gas exchange are achieved, with minor complications (transient elevation of creatinine or pleuritic chest pain) hacing been reported in 25% of cases.53 Embolization reduces the risk of neurological complications and improves the quality of life.54 In very selected cases, where embolization has failed or is not feasible (as in the diffuse form of PAVFs), surgical resection might be taken into consideration.7,47,55 Lung transplantation is rarely required in patients with PAVFs.7,55 After PAVF embolization, follow-up should be planned to assess whether reperfusion (15% of cases) or growth of untreated small PAVFs (18% of cases) occur.7 Although the degree of shunt in the contrast TTE can be reduced, after embolization this remains positive in 90% of patients with PAVFs.56 Therefore, contrast thoracic CT should also be recommended in follow-up, 6–12 months after embolization and after 3 years.7 In addition, contrast CT can detect the rare development of systemic afferent arteries after embolization. Contrast transthoracic echocardiogram may be useful during follow-up to detect this situation, and in those patients

with untreated HHT and PAVFs, since the increase in the degree of shunt will help identify any potential candidates for embolization (Fig. 2).57 Pulmonary hypertension The prevalence of pulmonary hypertension (PH), defined as a mean pulmonary arterial pressure (PAP) ≥25 mm Hg, in patients with HHT, is estimated between 4% and 13%.58 Its occurrence is associated with a worse vital prognosis.58 PH has 2 forms of presentation in the HHT: a postcapillary form, more frequent, in patients with hepatic VMs due to the sustained increase in cardiac output and another, much more rare, which corresponds to a precapillary form of PH, similar to the idiopathic pulmonary arterial hypertension (PAH) form, predominantly in patients with mutations in ACVRL 1.7,46,58 In order to distinguish between the two types of PH, a right cardiac catheterization is required. Post-capillary PH is characterized by a pulmonary capillary pressure (PCP) >15 mm Hg, increased cardiac output and normal or low pulmonary vascular resistance. In patients with PAH, PCP is ≤15 mm Hg, cardiac output is not increased (in fact it is reduced with the progression of the disease) and pulmonary vascular resistance is high. In both types of PH, the symptoms are similar (dyspnea on exertion, fatigue, palpitations, peripheral edema and syncope).58 In any case, the occurrence of dyspnea on exertion and signs of HF in a patient with HHT should always be a sign of alarm and we should proceed to his examination. The basic tool for screening PH is transthoracic echocardiogram. Since contrast transthoracic echocardiogram is indicated in all patients with HHT for the screening of pulmonary PAVFs, it is alos important to estimate systolic PAP and cardiac index, particularly in patients with hepatic VMs (Fig. 2). Treatment The treatment of poscapillary PH with high cardiac output includes salt and diuretics restriction, correction of anemia and treatment of atrial fibrillation.7,58 In patients refractory to

G Model 6

ARTICLE IN PRESS A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

medical treatment, we should consider liver transplantation, which is the only curative option in this context.7 The results of liver transplantation in this population in terms of survival and improvement of cardiac function are positive.43 In patients hemodynamically well characterized, some drugs should be prescribed for the treatment of PAH. Some studies show that the prognosis of this form of HHT-related PAH is worse than in the idiopathic form of PAH.59 We should pay special attention to the small number of patients in whom PAVFs and HP coexist. PAVFs can provide a low resistance discharge path for a right ventricle with high pressure, and their occlusion might trigger an increase in pulmonary vascular resistance that would lead to acute right ventricular failure. Despite this, a study that included 143 patients with PAVFs (92% with HHT) did not detect any variations in mean PAP after embolization, although in this study patients with severe PH were excluded.60 In any case, embolization of PAVFs in patients with PH should be assessed individually at the HHT Unit.46 In conclusion, HHT is a minority disease that causes abnormal vascular growth systemically and, therefore, patients with HHT should be treated at multidisciplinary units. An early diagnosis of the disease and a screening of its vascular manifestations will make it possible to offer the recommended preventive and therapeutic measures. Funding This study has been partially financed by the Carlos III Health Institute through project PI17/00669 (co-financed by the European ¨ Regional Development Fund – ERDF – “A way of making Europe). Conflict of interest None. References 1. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu syndrome): a view from the 21st century. Postgrad Med J. 2003;79:18–24. 2. Portal de información de enfermedades raras y medicamentos huérfanos. [accessed 13 Jun 2018]. Available from: www.orpha.net. 3. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary haemorrhagic telangiectasia (Rendu–Osler–Weber syndrome). Am J Med Genet. 2000;91:66–7. 4. McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary haemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1. 5. Ola R, Dubrac A, Han J, Zhang F, Fang JS, Larrivée B, et al. PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia. Nat Commun. 2016;7:13650. 6. Kroon S, Snijder RJ, Faughnan ME, Mager HJ. Systematic screening in hereditary haemorrhagic telangiectasia: a review. Curr Opin Pulm Med. 2018;24:260–8. 7. Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, et al., HHT Foundation International – Guidelines Working Group. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48:73–87. 8. Braverman IM, Keh A, Jacobson BS. Ultrastructure and three-dimensional organization of the telangiectases of hereditary haemorrhagic telangiectasia. J Invest Dermatol. 1990;95:422–7. 9. Letteboer TG, Mager HJ, Snijder RJ, Lindhout D, Ploos van Amstel HK, Zanen P, et al. Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary haemorrhagic telangiectasia. Am J Med Genet. 2008;146:2733–9. 10. Solomon RA, Connolly ES Jr. Arteriovenous malformations of the brain. N Engl J Med. 2017;376:1859–66. 11. Jackson SB, Villano NP, Benhammou JN, Lewis M, Pisegna JR, Padua D. Gastrointestinal manifestations of hereditary haemorrhagic telangiectasia (HHT): a systematic review of the literature. Dig Dis Sci. 2017;62:2623–30. 12. AAssar OS, Friedman CM, White RI Jr. The natural history of epistaxis in hereditary haemorrhagic telangiectasia. Laryngoscope. 1991;101:977–80. ˜ ˜ ˜ 13. Zarrabeitia R, Farinas-Álvarez C, Santibánez M, Senaris B, Fontalba A, Botella LM, et al. Quality of life in patients with hereditary haemorrhagic.telangiectasia (HHT). Health Qual Life Outcomes. 2017;15:19.

14. Riera-Mestre A, Mora Luján JM, Sánchez Martínez R, Torralba Cabez ˜ JL, Juyol Rodrigo MC, et al. Registro informatiMA, Patier de la Pena zado de la telangiectasia hemorrágica hereditaria (Registro RiHHTa) en ˜ Espana: objetivos, métodos y resultados preliminares. Rev Clin Esp. 2018, http://dx.doi.org/10.1016/j.rce.2018.07.002. 15. Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagia telangiectasia. Laryngoscope. 2010;120:838–43. 16. Shovlin CL, Buscarini E, Kjeldsen AD, Mager HJ, Sabba C, Droege F, et al. European reference Network for rare vascular diseases (VASCERN) outcome measures for hereditary haemorrhagic telangiectasia. Orphanet J Rare Dis. 2018;13:136. 17. Gaillard S, Dupuis-Girod S, Boutitie F, Rivière S, Morinière S, Hatron PY, et al., ATERO Study Group. Tranexamic acid for epistaxis in hereditary haemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014;12:1494–502. 18. Sadick H, Bergler WF, Oulmi-Kagermann J, Naim R, Sadick M, Hörmann K, et al. Estriol induced squamous metaplasia on the nasal mucosa in patients with hereditary haemorrhagic telangiectasia. Arch Med Res. 2005;36:468–73. 19. Yaniv E, Preis M, Shevro J, Nageris B, Hadar T. Anti-estrogen therapy for hereditary haemorrhagic telangiectasia – a long-term clinical trial. Rhinology. 2011;49:214–6. 20. Riss D, Burian M, Wolf A, Kranebitter V, Kaider A, Arnoldner C. Intranasal submucosal bevacizumab for epistaxis in hereditary haemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial. Head Neck. 2015;37:783–7. 21. Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH, et al. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary haemorrhagic telangiectasia: a randomized clinical trial. JAMA. 2016;316:943–51. 22. Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Bréant V, et al. Effect of bevacizumab nasal spray on epistaxis duration in hereditary haemorrhagic telangectasia: a randomized clinical trial. JAMA. 2016;316:934–42. 23. Halderman AA, Ryan MW, Marple BF, Sindwani R, Reh DD, Poetker DM. Bevacizumab for epistaxis in hereditary haemorrhagic telangiectasia: an evidence-based review. Am J Rhinol Allergy. 2018;32:258–68. 24. Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, et al. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. Lancet Haematol. 2015;2:e465–73. 25. Fang J, Chen X, Zhu B, Ye H, Zhang W, Guan J, et al. Thalidomide for epistaxis in patients with hereditary haemorrhagic telangiectasia: a preliminary study. Otolaryngol Head Neck Surg. 2017;157:217–21. ˜ 26. Alsina-Sanchís E, García-Ibánez Y, Figueiredo AM, Riera-Domingo C, Figueras A, Matias-Guiu X, et al. ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation. Arterioscler Thromb Vasc Biol. 2018;38:1216–29. 27. Castillo SD, Tzouanacou E, Zaw-Thin M, Berenjeno IM, Parker VE, Chivite I, et al. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Sci Transl Med. 2016;8:332ra43. 28. Morais D, Millás T, Zarrabeitia R, Botella LM, Almaraz A. Local sclerother® apy with polydocanol (Aethoxysklerol ) for the treatment of epistaxis in Rendu–Osler–Weber or Hereditary Haemorrhagic Telangiectasia (HHT): 15 years of experience. Rhinology. 2012;50:80–6. 29. Lund VJ, Howard DJ. Closure of the nasal cavities in the treatment of refractory hereditary haemorrhagic telangiectasia. J Laryngol Otol. 1997;111:30–3. 30. Richer SL, Geisthoff UW, Livada N, Ward PD, Johnson L, Mainka A, et al. The young’s procedure for severe epistaxis from hereditary haemorrhagic telangiectasia. Am J Rhinol Allergy. 2012;26:401–4. 31. Khalid SK, Garcia-Tsao G. Hepatic vascular malformations in hereditary haemorrhagic telangiectasia. Semin Liver Dis. 2008;28:247–58. 32. Buscarini E, Leandro G, Conte D, Danesino C, Daina E, Manfredi F, et al. Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary haemorrhagic teleangiectasia. Dig Dis Sci. 2011;56:2166–78. 33. Buonamico P, Suppressa P, Lenato GM, Pasculli G, D’Ovidio F, Memeo M, et al. Liver involvement in a large cohort of patients with hereditary haemorrhagic telangietasia: echo-color-Doppler vs multislice computed tomography study. J Hepatol. 2008;48:811–20. 34. Singh S, Swanson KL, Hatchcock MA, Kremers WK, Pallanch JF, Krowka MJ, et al. Identifying the presence of clinically significant hepatic involvement in hereditary haemorrhagic telangiectasia using a simple scoring system. J Hepatol. 2014;61:124–31. ˜ R, Berzigotti A, García-Criado MÁ, Genescà J, 35. Martín-Llahí M, Albillos A, Banares et al. Vascular diseases of the liver. Clinical Guidelines from the Catalan Society of Digestology and the Spanish Association for the Study of the Liver. Gastroenterol Hepatol. 2017;40:538–80. 36. Garcia-Tsao G, Korzenik JR, Young L, Henderson KJ, Jain D, Byrd B, et al. Liver disease in patients with hereditary haemorrhagic telangiectasia. New Eng J Med. 2000;343:931–6. 37. Garcia-Tsao G. Liver involvement in hereditary haemorrhagic telangiectasia. J Hepatol. 2007;46:499–507. 38. Cavel A, Bleuzen A, Bertrand P, Patat F, Cottier JP. Comparison between Doppler ultrasonography and multiphase detector-row computed tomography in the detection of liver involvement in Rendu–Osler disease. Diagn Interv Imaging. 2016;97:451–9. 39. Brenard R, Chapaux X, Deltenre P, Henrion J, de Maeght S, Hormans Y, et al. Large spectrum of liver vascular lesions including high prevalence of focal nodular hiperplasia in patients with hereditary haemorrhagic telangiectasia: the

G Model

ARTICLE IN PRESS A. Riera-Mestre, J. Ribas and J. Castellote / Med Clin (Barc). 2019;xxx(xx):xxx–xxx

40.

41.

42.

43.

44.

45.

46. 47. 48.

49.

Belgian Registry base don 30 patients. Eur J Gastroenterol Hepatol. 2010;22: 1253–9. Guilhem A, Fargeton AE, Simon AC, Duffau P, Harle JR, Lavigne C, et al. Intravenous bevacizumab in hereditary haemorrhagic telangiectasia: a retrsopective study of 46 patients. PLoS One. 2017;30:e0188943. Dupuis-Girord S, Ginon I, Saurin JM, Marion D, Guillot E, Decullier E, et al. Bevacizumab in patients with hereditary haemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307:948–55. Liu ZC, lu XF, Yang H, Liu HD, Song X, Ning SL, et al. Clinical outcomes of patients with severe hepatic hereditary haemorrhagic telangiectasia after banding of the hepatic artery and banding/ligation of branches of the hepatic artery. Eur J Vasc Endovasc Sur. 2016;51:594–601. Felli E, Addeo P, Failot F, Nappo G, Oncioio C, Bachellier P. Liver transplantation for hereditary haemorrhagic telangiectasia: a systemic review. HPB (Oxford). 2017;19:567–72. Muller YD, Oppliger R, Brequet R, Meyer P, Rubbia-Brandt L, Petignat PA, et al. Hereditary haemorrhagic telangiectasia: to transplant ot not to transplant – is there a right time for liver transplantation? Liver Int. 2016;36:1735–40. Sabba C, Gallitelli M, Longo A, Cariati M, Angelelli G. Orthotopic liver transplantation and hereditary haemorrhagic telangiectasia: do hepatic vascular malformations relapse? A long-term follow up study on two patients. J Hepatol. 2004;41:687–9. Dupuis-Girod S, Cottin V, Shovlin CL. The lung in hereditary haemorrhagic telangiectasia. Respiration. 2017;94:315–30. Shovlin CL. Pulmonary arteriovenous malformations. Am J Respir Crit Care Med. 2014;190:1217–28. Boother EJ, Brownlow S, Tighe HC, Bamford KB, Jackson JE, Shovlin CL. Cerebral abscess associated with odontogenic bacteremias hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations. Clin Infect Dis. 2017;65: 595–603. Santhirapala V, Chamali B, McKernan H, Tighe HC, Williams LC, Springett JT, et al. Orthodeoxia and postural orthostatic tachycardia in patients with pulmonary arteriovenous malformations: a prospective 8-year series. Thorax. 2014;69:1046–7.

7

50. Barzilai B, Waggoner AD, Spessert C, Picus D, Goodenberger D. Two-dimensional contrast echocardiography in the detection and follow-up of congenital pulmonary arteriovenous malformations. Am J Cardiol. 1991;68:1507–10. 51. Velthuis S, Buscarini E, van Gent MWF, Gazzaniga P, Manfredi G, Danesino C, et al. Grade of pulmonary right-to-left shunt on contrast echocardiography and cerebral complications: a striking association. Chest. 2013;144:542–8. ˜ 52. Parra JA, Bueno J, Zarauza J, Farinas-Alvarez C, Cuesta JM, Ortiz P, et al. Graded contrast echocardiography in pulmonary arteriovenous malformations. Eur Respir J. 2010;35:1279–85. 53. Abdel Aal AK, Ibrahim RM, Moustafa AS, Hamed MF, Saddekni S. Persistence of pulmonary arteriovenous malformations after successful embolotherapy with Amplatzer vascular plug: long-term results. Diagn Interv Radiol. 2016;22:358–64. 54. Blivet S, Cobarzan D, Beauchet A, El Hajjam M, Lacombe P, Chinet T. Impact of pulmonary arteriovenous malformations on respiratory-related quality of life in patients with hereditary haemorrhagic telangiectasia. PLoS One. 2014;9:e90937. 55. Bakhos CT, Wang SC, Rosen JM. Contemporary role of minimally invasive thoracic surgery in the management of pulmonary arteriovenous malformations: report of two cases and review of the literature. J Thorac Dis. 2016;8:195–7. 56. Lee WL, Graham AF, Pugash RA, Hutchison SJ, Grande P, Hyland RH, et al. Contrast echocardiography remains positive after treatment of pulmonary arteriovenous malformations. Chest. 2003;123:351–8. 57. Vorselaars VM, Velthuis S, Snijder RJ, Westermann CJ, Vos JA, Mager JJ, et al. Follow-up of pulmonary right-to-left shunt in hereditary haemorrhagic telangiectasia. Eur Respir J. 2016;47:1750–7. 58. Chizinga M, Rudkovskaia AA, Henderson K, Pollak J, Garcia-Tsao G, Young LH, et al. Pulmonary hypertension prevalence and prognosis in a cohort of patients with hereditary haemorrhagic telangiectasia undergoing embolization of pAVMs. Am J Respir Crit Care Med. 2017;196:1353–6. 59. Li W, Xiong CM, Gu Q, Wang XT, Cheng XL, Huang L, et al. The clinical characteristics and long-term prognosis of pulmonary arterial hypertension associated with hereditary haemorrhagic telangiectasia. Pulm Circ. 2018;8:1–11. 60. Shovlin CL, Tighe HC, Davies RJ, Gibbs JSR, Jackson JE. Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure. Eur Respir J. 2008;32:162–9.