*3.4. Outcomes*

Overall, mean follow-up was 34.2 ± 22.8 (1–124) months, with no differences between groups according to GI involvement. Patients with GI involvement required significantly more often RBC transfusions, ED attention, and hospital admissions than patients without GI disease or than those with unsuspected GI involvement. Overall, five patients (2.1%) died, with no differences in mortality between groups (Table 4).


**Table 4.** Clinical outcomes during follow-up according to gastrointestinal involvement.

GI: gastrointestinal; SD: standard deviation; RBC: red blood cells; ED: Emergency Department; *\** Comparison between GI involvement and unsuspected GI involvement groups.

Nine patients received treatment with octreotide: four with 100 mcg bid and five with long-acting release (LAR) octreotide at doses between 10 and 30 mcg monthly. In five of these nine patients, a marked decrease in the number of packed RBC units transfused was observed in the first weeks of treatment. Only one patient presented diarrhea as a side effect with the 100 mcg bid dose, which disappeared after switching to a monthly LAR formulation. Two patients without improvement after octreotide daily doses received bevazicumab at doses of 5 mg/kg every two weeks with tapering frequency to a final maintenance dose every 6–8 weeks. One of these patients needed hypertension therapy adjustment because of bevacizumab-induced hypertension with severe epistaxis and an increase of RBC transfusion requirements during the first six months of treatment. After blood pressure control, both patients experienced a rather marked reduction in the number of packed RBC units transfused under bevacizumab therapy (Table 5).



bevacizumab treatments. \* All during the first six months of bevacizumab treatment because of bevacizumab-induced hypertension and resulting severe epistaxis.

## **4. Discussion**

In our study, age, *ENG* mutation, tobacco use, and hemoglobin levels were associated with GI involvement in HHT patients. We found a 7% increased risk of GI involvement per year of age. These results are consistent with the mean age of GI bleeding onset observed in previous studies [4,13]. However, we have not detected previously described female predominance [4,17,21]. Smoking history has been related to a 7-fold increase risk of GI involvement in our series. Tobacco use has already been associated with an increased risk of upper GI bleeding and gastroduodenal ulcers in non-HHT patients, but no relationship between tobacco and GI telangiectasia has been published [27]. Though this finding strengthens the importance of avoiding tobacco in HHT patients, it also needs to be confirmed in further studies. Canzonieri et al. and van Tuyl et al. systemically studied the extent of GI involvement with EGD, VCE, and CS in 22 and 35 HHT patients, respectively, and found a higher prevalence of telangiectasia in patients with *ENG* mutation [13,19]. However, Berg et al., Sabbà et al., and Letteboer et al. assessing genotype–phenotype relationships in HHT patients, reported similar incidence of GI telangiectasia between HHT1 and HHT2 patients [28–30]. Differently, and according to current guidelines, we studied patients with clinical suspicion of GI bleeding, but not indiscriminately screened [4]. Thus, *ENG* mutation was associated with 5-fold increase risk of GI involvement compared to those with negative endoscopic study. In addition, in our cohort, hemoglobin levels were also associated with GI involvement. These four variables could help physicians experiencing the difficult managemen<sup>t</sup> of GI involvement in HHT patients.

Many cases of anemia are misattributed to overt epistaxis instead of attributing them to GI bleeding among patients with HHT [16,31]. In fact, we have not found significant differences in epistaxis severity measured by the ESS between patients with and without GI involvement. This finding supports that lower hemoglobin levels found in patients with GI involvement were disproportionate. Moreover, among patients with GI involvement, the ESS was higher in those with hemoglobin levels < 8 g/dL or with transfusion requirements. This relationship could be explained by a microvessel predominant pattern, as telangiectasis is a pathological feature in both nasal and digestive mucosae. Because both types of bleeding can coexist, a high clinical suspicion of GI bleeding in patients with severe anemia, despite a high ESS, is necessary.

In our series, telangiectasia is more frequently found in the stomach or duodenum. This location is highly related to small bowels and colon telangiectasia in VCE. These results are in line with international guidelines, which recommend EGD as the initial screening procedure when GI involvement is suspected [4,13]. However, if the EGD is negative, VCE should be considered in patients with high suspicion of GI involvement and severe anemia to detect telangiectasia within the small intestine, as it occurred in 18.5% of our patients [13,19]. Longrace et al., in 43 consecutive HHT patients with GI bleeding, reported that patients with >20 telangiectases had significantly lower hemoglobin levels and higher transfusion requirements [21]. We found that patients with hemoglobin levels <8 g/dL or RBC transfusion requirements had larger telangiectases. These endoscopic findings strengthen the usefulness and benefits of VCE and should be taken into account in the follow-up and treatment assessment of HHT patients with GI involvement.

Chronic GI bleeding treatment is largely endoscopic and supported by frequent blood transfusions. In our study, patients with GI involvement needed RBC transfusions and medical attention more often than those with no or unsuspected GI involvement. However, no difference in mortality was found between groups. Although severe anemia secondary to GI bleeding can lead to multiple complications, GI bleeding has not been described as a cause of the lower life expectancy of HHT patients [29,32]. HHT patients with GI bleeding usually have telangiectases that are not fit for APC treatment, and require pharmacological treatment, with different and controversial options [4,13,16,21]. Our series included nine patients on octreotide treatment from daily clinical practice. This agen<sup>t</sup> has shown a reduction in digestive bleeding and an anemia improvement in non-HHT patients with intestinal angiodysplasia by reducing splanchnic blood flow, but evidence of its use in HHT patients is scarce [33–36]. A non-randomized prospective clinical trial to assess the efficacy of monthly injection of 20 mg of octreotide LAR has been recently published [36]. Although this study was underpowered (beta of 0.5), RBC transfusion requirements were lower during the six months treatment period than they were prior to treatment, in all 11 patients included. We have observed similar results in five out of nine patients treated with octreotide. Further studies are needed to confirm the e fficacy and safety of long-term octreotide therapy. Similarly, the benefit of bevacizumab in patients with GI involvement needs has been poorly described [37,38]. Bevacizumab-induced hypertension is a well-known adverse effect; high blood pressure can make epistaxis worse and provoke RBC transfusion requirements, as it occurred in one of our patients [39]. Other treatments such as talidomide or estrogen/progesterone preparations have also shown improvement in hemoglobin levels or transfusion requirements in case reports or short series [21,22,40,41]. The hypothetical benefit in this scenario of future agents that block or activate pathways involved in HHT pathogenesis, such as sirolimus, tacrolimus, nintedanib, or a combination of them, needs further investigation [42–44].

There are some limitations and strengths of our study that should be mentioned. VCE was not performed in all patients and GI involvement could be underestimated in patients with negative EGD. Additionally, VCE could have influenced the number and size of small bowel telangiectases. Another limitation is that endoscopic study was not performed on all patients. However, this is in agreemen<sup>t</sup> with recommendations of current guidelines [4]. Di fficulties in attributing low hemoglobin levels to epistaxis or GI bleeding could be another inherent limitation. However, our study represents the largest series of HHT patients with objectively confirmed GI involvement, and is the only one comparing these patients with those with a negative endoscopic study or with unsuspected GI involvement. On top of that, the prospective nature of our study and the broad long-term follow-up reinforce the robustness of the results and allow for a better assessment of outcomes.
