**Gastrointestinal Bleeding in Patients with Hereditary Hemorrhagic Telangiectasia: Risk Factors and Endoscopic Findings**

**José María Mora-Luján 1,2,3, Adriana Iriarte 1,2,3, Esther Alba 1,3,4, Miguel Ánge<sup>l</sup> Sánchez-Corral 1,3,5, Ana Berrozpe 3,6, Pau Cerdà 1,2,3, Francesc Cruellas 1,3,7, Jesús Ribas 1,3,8, Jose Castellote 1,3,6 and Antoni Riera-Mestre 1,2,3,9,\***


Received: 22 November 2019; Accepted: 25 December 2019; Published: 28 December 2019

**Abstract:** Background: We aimed to describe risk factors for gastrointestinal (GI) bleeding and endoscopic findings in patients with hereditary hemorrhagic telangiectasia (HHT). Methods: This is a prospective study from a referral HHT unit. Endoscopic tests were performed when there was suspicion of GI bleeding, and patients were divided as follows: with, without, and with unsuspected GI involvement. Results: 67 (27.9%) patients with, 28 (11.7%) patients without, and 145 (60.4%) with unsuspected GI involvement were included. Age, tobacco use, endoglin (ENG) mutation, and hemoglobin were associated with GI involvement. Telangiectases were mostly in the stomach and duodenum, but 18.5% of patients with normal esophagogastroduodenoscopy (EGD) had GI involvement in video capsule endoscopy (VCE). Telangiectases ≤ 3 mm and ≤10 per location were most common. Among patients with GI disease, those with hemoglobin < 8 g/dL or transfusion requirements (65.7%) were older and had higher epistaxis severity score (ESS) and larger telangiectases (>3 mm). After a mean follow-up of 34.2 months, patients with GI involvement required more transfusions and more emergency department and hospital admissions, with no di fferences in mortality. Conclusions: Risk factors for GI involvement have been identified. Patients with GI involvement and severe anemia had larger telangiectases and higher ESS. VCE should be considered in patients with suspicion of GI bleeding, even if EGD is normal.

**Keywords:** hereditary hemorrhagic telangiectasia; rare diseases; telangiectasis; transforming growth factor-beta (TGF-β); Smad pathway; gastrointestinal bleeding

## **1. Introduction**

Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber syndrome (ORPHA774) is an autosomal dominant rare vascular disease characterized by telangiectases and larger vascular malformations (VMs) [1–3]. HHT can be diagnosed either clinically using the Curaçao criteria (recurrent epistaxis, muco-cutaneous telangiectasia, visceral lesions, and family history) or through a molecular gene test [4–6]. Mutations in endoglin (*ENG*) and activin A receptor type II-like 1 (*ACVRL1*) genes are detected in approximately 90% of cases submitted to molecular diagnosis for clinical suspicion of HHT and cause HHT1 and HHT2, respectively [2,7–9]. Mutations in *SMAD4* (encoding the transcription factor Smad4) have been described in less than 2% of the HHT population [8]. Endoglin (encoded by *ENG*) is an auxiliary co-receptor at the endothelial cell surface that promotes BMP9 signaling through the activin receptor-like kinase 1 (ALK1; encoded by *ACVRL1*) [2]. Both proteins contribute to the signaling hub formed by BMP9-endoglin-ALK1-Smad with a high impact in the angiogenesis process [10].

Telangiectasis is the characteristic lesion in HHT and shows dilated post capillary venules directly connected with dilated arterioles losing the capillary bed [11]. These dilated microvessels are more prone to hemorrhage due to fragile walls and turbulent blood flow, especially those located in mucosae, such as nasal or gastrointestinal (GI). Telangiectasia in nasal mucosae can cause spontaneous, recurrent epistaxis, usually the earliest and most common clinical manifestation of HHT [2,9,12].

Unlike epistaxis or visceral involvement, which occur since adolescence, GI bleeding begins in the fifth or sixth decades of life [4,13]. The prevalence of GI telangiectasia ranges from 13% to 30% in the overall HHT population to more than 90% in HHT patients with anemia [14–20]. In HHT patients, GI bleeding is usually chronic, low degree, and in an intermittent fashion [16,17]. However, clinical presentation can be diverse, with some patients presenting none or mild anemia, while others require periodic transfusions. Although argon plasma coagulation (APC) is the most e ffective endoscopic therapy for active GI bleeding, some patients have either multiple or non-accessible telangiectases for APC and usually require additional or alternative therapies [4,13,16,21]. Therefore, pharmacological treatment, such as with estrogen/progesterone, somatostatin analog octreotide, and bevacizumab, has been considered in these patients. However, these pharmacological therapies have not been well established and are based on either individual case reports or small case series [4,13,16,21,22].

Though GI telangiectasia is included in the visceral lesions defined in the Curaçao criteria, international guidelines only recommend endoscopic study in adult patients with disproportionate anemia to the severity of epistaxis [4,5]. Unfortunately, there is no clear definition for disproportionate anemia, so indication for endoscopic study often depends on physician experience. Though some studies have suggested an association between age or female gender and GI disease, risk factors predisposing GI disease are currently unknown [4,8,13,15,16]. Identifying possible risk factors associated with GI involvement could be useful for HHT clinical management. The objective of the present study is to describe risk factors for GI involvement and to assess endoscopic findings and outcomes in this scenario.

#### **2. Materials and Methods**

#### *2.1. Study Design*

This is a prospective, observational study, which includes all consecutive patients attended in a referral HHT unit in a university hospital from September 2011 to June 2019. This HHT unit attends adult patients from all over Catalonia (Spain), which accounts for seven million inhabitants. During this period, a total of 330 patients were visited in our unit. All patients provided oral consent for participation in the study in accordance with local Ethic Committee requirements. Patients with a definite diagnosis according to the Curaçao criteria (meeting ≥ 3 criteria) or a positive genetic study were included [4–6]. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines for observational cohort studies [23].

The main objective was to describe risk factors for GI involvement among patients with definite or molecular diagnosis of HHT. Secondary objectives were to compare endoscopic findings among patients with GI involvement according to clinical severity and to assess clinical outcomes according to GI involvement.

#### *2.2. Assessment of Gastrointestinal Involvement*

Suggestive symptoms/signs of GI involvement were defined as either the presence of overt upper or lower GI bleeding or the presence of anemia thatis disproportionate to the severity of epistaxis [4]. Endoscopic study (GIF-Q165; Olympus, Hamburg, Germany) was performed when suggestive symptoms/signs of GI involvement were present. In patients with active or recently bleeding telangiectases, treatment with APC was performed. A video capsule endoscopy (VCE) (PillCamSB 3; Medtronic, Yokneam, Israel) study was mostly performed in patients with persistent anemia after APC treatment.

Endoscopic study was defined as positive when HHT suggestive telangiectasia was found in the GI tract. Normal endoscopic study or non-suggestive findings of HHT were defined as a negative study. Using these criteria and according to GI disease, three groups were established: (a) GI involvement: patients with positive endoscopic study; (b) no GI involvement: patients with negative endoscopic study; (c) unsuspected GI involvement: patients without suggestive symptoms/signs of GI bleeding and no endoscopic study performed.

Among patients with GI involvement, telangiectases were classified according to their number (few: ≤10 telangiectases or multiple: >10 telangiectases) and size (small: ≤3 mm or large: >3 mm) [13]. Patients with GI involvement were classified into two subgroups according to clinical severity: patients with either hemoglobin levels less than 8 g/dL or red blood cell (RBC) transfusion requirements and patients with none of these conditions. Endoscopic findings were compared between both subgroups.

#### *2.3. Clinical Variables, Screening Tests, and Follow-Up*

Baseline demographic characteristics, comorbidities, history of alcohol or tobacco use (previous or currently), hemoglobin levels, genetic study, blood test, and epistaxis severity score (ESS) were collected. ESS is an online tool that quantifies the epistaxis severity considering di fferent parameters during the previous three months [24].

To screen for pulmonary visceral involvement, a contrast transthoracic echocardiography (TTE) was performed [4,25]. The Barzilai scale was used to establish the degree of right-left shunt (R-L) and the need to undergo a thoracic computed tomography (CT) angiography to confirm the presence of pulmonary arteriovenous (AV) fistula [4,26]. In addition, an abdominal CT angiography was performed to study hepatic and/or abdominal VMs. A cerebral CT angiography or brain MRI angiography was carried out in cases of neurological symptoms or a family history of neurological involvement [4,25].

All patients were prospectively followed-up depending on disease severity, at the treating clinician's discretion. The lowest hemoglobin level detected and di fferent treatment strategies used during follow-up were recorded. Patients with objectively confirmed GI involvement and severe anemia despite iron therapy and/or requiring blood transfusions were assessed for treatment with octreotide or bevacizumab. The number of packed RBCs transfused before and during both treatments was recorded. Moreover, the need for visits to the emergency department (ED) and/or hospital admissions, the number of RBC transfusions required, and any mortality during follow-up were also registered. These outcomes were compared between HHT groups according to GI involvement.

#### *2.4. Statistical Analysis*

A descriptive statistical analysis was performed for all categorical and continuous variables and expressed as proportions or means with standard deviations (SD), respectively. Categorical variables were compared with the chi-square test or Fisher's exact test, whereas the t-test or the Mann–Whitney U test were used to compare continuous variables.

Logistic regression analyses were performed to identify associated risk factors for GI disease and presented as odds ratios (OR) with 95% confidence intervals (95% CI). Logistic regression was performed in patients with suggestive symptoms/signs of GI involvement. For the manual backward stepwise multivariable logistic regression model, we assessed variables that had a significant level of P less than 0.1 in univariable analyses. To analyze the predictive power of the associated risk factors, a receiver operating characteristic (ROC) curve was performed and the area under the curve (AUC) was calculated. *p* values of <0.05 were considered to be statistically significant. Analyses were performed using SPSS, version 15 for the PC (SPSS Inc., Chicago, IL, USA).
