Perioperative Complications and Long-Term Follow-Up of Liver Transplantation in Hemorrhagic Hereditary Telangiectasia: Report of Three Cases and Systematic Review

The aim was to describe three patients with hemorrhagic hereditary telangiectasia (HHT) requiring liver transplantation (LT) and to perform a systematic review focusing on surgical complications and long-term follow-up. Unrestricted searches of the Medline and Embase databases were performed through February 2022. Forty-five studies were selected including 80 patients plus the three new reported patients, 68 (81.9%) were female and mean age was 50 (27–72) years. Main indications for LT were high-output cardiac failure (n = 40; 48.2%), ischemic cholangitis (n = 19; 22.9%), and a combination of both conditions (n = 13;15.6%). Mean cold ischemic time and red blood cell units transfused during LT were 554 (300–941) minutes and 11.4 (0–88) units, respectively. Complications within 30 days were described in 28 (33.7%) patients, mainly bleeding complications in 13 patients, hepatic artery (HA) thrombosis in four and hepatic vein thrombosis in one. Mean follow-up was 76.4 (1–288) months, and during it, four new patients developed thrombotic complications in HA, HA aneurysm, celiac artery, and the portal–splenic–mesenteric vein. HHT relapse in the transplant allograft was detected in 13 (17.1%) patients after 1–19 years (including two fatal recurrences). Overall mortality was 12%. In conclusion, previous assessment of HA anatomy and hyperdynamic circulatory state could reduce LT complications. The risk of relapse in the hepatic graft supports a multidisciplinary follow-up for HHT patients with LT.


Introduction
Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber syndrome (OR-PHA774) is a rare autosomal dominant vascular disease characterized by telangiectases and larger systemic vascular malformations (VMs) [1]. HHT can be diagnosed either through a molecular genetic test or using the Curaçao clinical criteria (recurrent epistaxis, cutaneous/mucosal telangiectasia, visceral VMs, and a first-degree family member with

Unpublished New Patients
Consecutive HHT patients were selected from the referral HHT Unit at Hospital Universitari de Bellvitge (Barcelona, Spain). This HHT Unit caters to adult patients from all over Catalonia (Spain), which has about 7.5 million inhabitants, and all patients are included in a database. Those consecutive HHT patients who were referred to our center and who received LT were considered eligible as case reports. Three HHT patients were detected and included. None of these patients had been previously the subject of publications. LT was performed at the Hospital Universitari de Bellvitge in two of the patients and at the Hospital Clínic (Barcelona, Spain) in the third one. Personal and clinical data collection for the study were performed in line with the Spanish Data Protection Act (Ley Orgánica 3/2018 de 5 de diciembre de Protección de Datos Personales). The study was approved by the Clinical Research Ethics Committee of the Hospital Universitari de Bellvitge (Barcelona, Spain; protocol code PR023/22).

Literature Search Strategy
All stages of conception of this systematic review were conducted according to PRISMA guidelines [18]. We performed an unrestricted search of PubMed/MEDLINE and Embase electronic bibliographical databases through February 2022. The search was performed using the terms "hemorrhagic hereditary telangiectasia" or "Rendu-Osler-Weber syndrome" and "liver transplantation" in combination. All published studies describing patients with HHT and LT were selected. Eligible articles were those describing perioperative complications and/or outcomes of HHT patients undergoing LT. Prospective and retrospective cohort studies, patient series, and case reports were included and used for quantitative and qualitative synthesis of data, according to the PRISMA criteria. Reference lists of retrieved articles and review articles were manually searched to extend the original search. Disagreements on study data extraction were resolved by consensus or by discussion. The PRISMA flow diagram relative to the study selection process is provided in Figure 1.
Orgánica 3/2018 de 5 de diciembre de Protección de Datos Personales). The study was approved by the Clinical Research Ethics Committee of the Hospital Universitari de Bellvitge (Barcelona, Spain; protocol code PR023/22).

Literature Search Strategy
All stages of conception of this systematic review were conducted according to PRISMA guidelines [18]. We performed an unrestricted search of PubMed/MEDLINE and Embase electronic bibliographical databases through February 2022. The search was performed using the terms "hemorrhagic hereditary telangiectasia" or "Rendu-Osler-Weber syndrome" and "liver transplantation" in combination. All published studies describing patients with HHT and LT were selected. Eligible articles were those describing perioperative complications and/or outcomes of HHT patients undergoing LT. Prospective and retrospective cohort studies, patient series, and case reports were included and used for quantitative and qualitative synthesis of data, according to the PRISMA criteria. Reference lists of retrieved articles and review articles were manually searched to extend the original search. Disagreements on study data extraction were resolved by consensus or by discussion. The PRISMA flow diagram relative to the study selection process is provided in Fig

Outcome Measures
The primary objective was to describe three new HHT patients that required LT and perform a systematic review of the current relevant literature, focusing on perioperative complications within 30 days and long-term follow-up of reported patients.

Data Analysis
Data from included studies were summarized and grouped together to perform quantitative and qualitative analyses as to address the outcome measures. Categorical variables are expressed as frequencies and proportions. Continuous variables are expressed as means with standard deviations (SD) and range. Analyses were performed using IBM SPSS Statistics, version 26.0 for the PC (IBM Corp., Armonk, NY, USA).

Results
3.1. Case Reports 3.1.1. Case 1 A 28-year-old woman with no relevant medical history was diagnosed with HHT meeting all Curaçao criteria. Genetic test detected a pathogenic variant in ACVRL1. At diagnosis, an abdominal computed tomography (CT) scan revealed hepatic vascular involvement. Aside from elevated alkaline phosphatase and gamma-glutamyl transferase levels and iron-deficiency anemia related to recurrent epistaxis, the patient initially remained asymptomatic.
Ten years later, she developed right-upper abdominal pain and symptoms suggesting heart failure. Abdominal CT and magnetic resonance imaging (MRI) showed multiple liver AVMs, with hypoperfused areas. A contrast transthoracic echocardiography (TTE) demonstrated a Barzilai's grade 4 shunt and a cardiac index of 6 L/min/m 2 , with pulmonary hypertension. A thoracic CT confirmed the presence of two pulmonary AVMs. Medical therapy with diuretics and ursodeoxycholic acid was initiated, and both pulmonary AVMs were embolized, reducing shunt grade from 4 to 1. In the following weeks, the patient was readmitted for fever and was ultimately diagnosed with polymicrobial bacteremia (Streptococus anginosus and Haemophilus parainfluenza) related to underlying ischemic cholangitis. With the diagnosis of ischemic cholangitis, LT was indicated. The patient's Model for End-Stage Liver Disease (MELD) score was 19.
On November 2013, the patient underwent orthotopic liver transplantation (OLT) from a deceased 41-year old donor allograft, with caval preservation and temporary portacaval shunt. The hepatectomy was technically complex, due to multiple AVMs in the hepatic hilum. Multiple diaphragmatic arteries were also found and ligated. Cold ischemic time (CIT) was 620 min, and 16 red blood cells (RBC) units were transfused intraoperatively. The patient's native liver explants weighed 2640 g. Arterial anastomoses were performed, but immediate hepatic artery thrombosis was observed. Although different arterial revascularization maneuvers were attempted, no arterial flow was achieved. Consequently, the patient was re-listed for emergent re-transplantation, which was performed within 24 hours with a second deceased 40-year old donor allograft. Arterial revascularization was then achieved with a supraceliac aortic anastomosis. Intraoperatively, hepatic artery flow was 220 mL/min. The patient did well post-transplant and was discharged from the Intensive Care Unit (ICU) on postoperative day 3 and from the hospital on postoperative day 14. Nine years after transplantation, she remains alive and well, with normal cardiac index and liver function and a significant reduction in epistaxis severity.

Case 2
A 60-year-old woman with history of arterial hypertension was admitted for congestive heart failure. TTE revealed high a cardiac index of 5.4 L/min/m 2 , with systolic pulmonary hypertension. During admission, the patient developed hepatic encephalopathy. An abdominal CT scan showed multiple hepatic AVMs and portovenous shunts, in addition to significant hypertrophy of the hepatic artery and its branches.
An extensive evaluation for HHT was carried out. The patient had no family or personal history of epistaxis or telangiectases. A contrast TTE showed a grade 1 right-left shunt, and no pulmonary AVMs were detected on thoracic CT. Cerebral MRI angiography was negative for cerebral AVMs. Genetic test was negative for ENG, ACVRL1, and SMAD-4 pathogenic variants. Given the lack of other etiologies for chronic liver disease, a presumptive diagnosis of HHT was made despite the patient only met one Curaçao criteria.
She was admitted for repeated episodes of HOCF and hepatic encephalopathy, which were difficult to manage. Eight months after initial presentation, on November 2007, OLT was performed with a whole deceased 76-year-old donor graft, with caval preservation and temporary portacaval shunt. CIT was 300 min, and no intraoperative transfusions were required. Hepatic artery flow at the end of the procedure was 490 mL/min. The patient was discharged from the ICU on postoperative day 2 and from the hospital on postoperative day 10.
A resolution of HOCF and hepatic encephalopathy were observed during followup. However, intrahepatic and extrahepatic bile duct dilation were observed in control imaging tests. The patient had no relevant complications until the eighth post-transplant year, when she was admitted for right-upper abdominal pain and fever. Laboratory tests revealed elevated serum bilirubin, leukocytosis, and slightly prolonged prothrombin time.
Abdominal CT was performed and demonstrated intrahepatic bile duct dilation, with the formation of bile lakes suggestive of ischemic cholangitis. In blood cultures, Enterococcus faecium was isolated. An endoscopic retrograde cholangiography (ERC) was performed and was significant for intrahepatic and extrahepatic bile duct dilatation, with one common bile duct stone and sludge. Ten days after admission and 48 hours after ERC, the patient presented sudden hypotension followed by cardiac arrest. Profuse bleeding from the gastrointestinal tract was observed. Following autopsy, the diagnosis of septic shock due to ischemic cholangitis secondary to vascular recurrence of HHT on the transplanted liver was confirmed.

Case 3
The patient was a 55-year-old woman with a history of factor VII deficiency, subclinical hypothyroidism, chronic gastritis, and recurrent epistaxis. Her family medical history was unremarkable. A year prior to presentation, the patient developed mild cholestasis. After an episode of acute cholangitis, cross-sectional imaging was performed and demonstrated numerous AVMs in the liver, located predominantly in the right lobe, with moderate dilation of the intrahepatic bile ducts, though there were no signs of portal hypertension. Though having a negative genetic test for HHT, she was given a presumptive diagnosis of HHT, meeting three Curaçao criteria.
The patient was admitted because of nausea and vomiting and altered liver function in blood tests. Within hours of admission, she developed grade 4 hepatic encephalopathy and required endotracheal intubation and mechanical ventilation. An urgent CT scan was performed, demonstrating the same hepatic AVMs but new-onset hypoperfusion of hepatic segments V, VI, and VIII. A contrast TTE showed no right-left shunt and no pulmonary AVMs were detected on thoracic CT.
With the diagnosis of ischemic cholangitis secondary to HHT, she was listed for emergency LT. Her MELD score was 21. Twenty-four hours after listing, a liver from a 65-year-old deceased donor was accepted. On August 2020, OLT was performed, with caval preservation and temporary portacaval shunt. The hepatectomy of the native liver was technically complex due to diffuse bleeding from multiple telangiectases located throughout the abdominal cavity, including the parietal peritoneum. The patient s native liver explant weighed 1200 g. Transplantation of the liver graft was uneventful, and ductto-duct biliary anastomosis was performed. CIT was 219 min, and five RBC units were transfused intraoperatively.
Immediately postoperatively, the patient presented gastrointestinal bleeding with hemodynamic instability. Upper gastrointestinal endoscopy was performed emergently and demonstrated multiple gastric and duodenal ulcers with clots but no active bleeding. Once the patient stabilized, liver function improved progressively and was discharged from the ICU on postoperative day 10 and from the hospital on postoperative day 31. Currently, she is alive and well, with normal liver function after two years of follow-up.

Included Studies in the Systematic Review
Our search identified 208 potentially eligible studies from Medline and Embase. After exclusion for duplication (n = 66), 141 studies were screened. Among them, 78 were excluded because they were not related to LT in HHT and 20 after full text revision for different reasons. We considered three extension follow-up studies (Dumortier 2019 related to Dupuis-Girod 2010; Ullus 2019 related to Saxena 1998; and Sabba 2004 related to Bauer 1995) [16,[19][20][21][22][23]. The latter extension study provided an additional case [22]. Two studies were identified by hand-searching in the bibliography of retrieved articles [24,25]. Therefore 45 studies were finally included for analysis [10,11,13,[15][16][17]. The PRISMA flow diagram is depicted in Figure 1.

Patient-Level Main Characteristics of Included Studies
A total of 83 patients who underwent LT for HHT have been included, including the three new cases reported herein (Appendix A Table A1). Globally, 68 (81.9%) patients were female, 12 (14.5%) were male, and three (3.6%) were not described. Mean age (n = 79) was 50 (SD 12; 27-72) years. A genetic test was only described from 33 (39.7%) patients, with a disease-causing mutation being found in 30 patients (affecting ACVRL1 gene in all of them), and with an unidentified pathogenic variant in the remaining three patients. Despite the fact that not all Curaçao criteria were described in all patients, 37 (44.6%) patients met ≥ 3 Curaçao criteria, and were thus classified as having a definite diagnosis. Overall, 57 (68.7%) patients had either a positive genetic test for ACVRL1 mutations or a definite diagnosis according to Curaçao criteria.
Most patients suffered from symptomatic heart failure before LT. According to the hepatic vascular shunting classification established by Garcia-Tsao et al., the indications for LT were as follows: predominant HOCF in 40 patients (48.2%), predominant ischemic cholangitis in 19 patients (22.9%), and predominant portal hypertension in four patients (4.8%) [6]. A combination of different clinical presentations was present in 17 patients: HOCF + ischemic cholangitis in 13 patients (15.6%), HOCF + hepatic encephalopathy in three patients (3.6%), and ischemic cholangitis + hepatic encephalopathy in one patient (1.2%). Two patients had cirrhosis/liver failure and in one patient the indication for LT was not described [24]. Values of cardiac output and cardiac index were available from 35 and 30 patients, respectively. All of these patients had a HOCF component, except for four patients that had predominant ischemic cholangitis. Overall, mean cardiac output was 9.68 (SD 2.68; 5.3-18.20), and mean cardiac index was 5.43 (SD 1.29; 3.1-8.1).

Patient-Level Transplant Surgery Characteristics and Perioperative Complications of Included Studies
MELD score was infrequently described (n = 10 patients), and its mean value was 11.5 (SD 6; 6-22). Mean CIT (n = 31 patients) and mean RBC units (n = 35 patients) during LT surgery were 554 minutes (SD 130; 300-941) and 11.4 units (SD 17; 0-88), respectively. Surgical technique was described in 45 patients, and information provided was mostly related to the types of anastomoses performed. Type of graft used was poorly described: deceased whole graft in 13 patients, deceased split in one, and living donor in two patients. LT was described as elective in 10 patients and urgent in six (not described in the rest of patients). Different surgical techniques were used. Older studies mostly referred the classical technique, with caval replacement performed with or without venovenous bypass, whereas more recent studies mostly referred the caval preservation (piggyback) technique with anastomosis with two or three hepatic veins (with or without cavotomy) or a modified piggyback technique (including end-to-side or side-to-side cavocaval anastomosis).

Patient-Level Long-Term Follow-Up of Included Studies
Long-term data was available from 69 out of the 76 discharged patients, and mean follow-up was 76.4 (SD 72; 1-288) months (Appendix A Table A2). Thrombotic complications were described in four new patients: HA thrombosis, HA aneurysm thrombosis, celiac artery thrombosis, and portal-splenic-mesenteric venous thrombosis [10,15,47]. Regarding the four pregnant women that needed LT, one died due to intracardiac thrombus at 7.1 hours after LT, two were alive at 12 and 65 months, and no follow-up data is available for the fourth [25,45,52,54]. Interestingly, HHT relapse in the transplanted allograft was detected in 13 (17.1%) among 76 discharged patients between 1 and 19 years post-transplant, including two patients that died due to recurrence complications (Case 2, [12,[19][20][21][22][23]42]). Three patients died during follow-up due to myocardial infarction (at day 34), ischemic cholangitis due to recurrence of hepatic VM (8 years later), and portal hypertension due to recurrence of hepatic VM (6 years later) (Case 2, [32,42]). Thus, overall mortality was 12%.

Discussion
The first case of LT for HHT reported in the English literature was published by Bauer et al. in 1995 (23). Since then, 83 patients are reported herein, with an 88% of survival after a mean follow-up of more than six years. According to the classification established by Garcia-Tsao et al, the main indication for LT in our series was HOCF (isolated or in combination), as it occurred in 56 (67.5%) reported patients, followed by ischemic cholangitis in 33 (39.7%) patients [6]. These different subtypes of hepatic vascular shunting usually coexist but one of them predominates functionally and, at the same time, show fluctuation and transition from one clinical picture to another [58]. With the exception of ischemic cholangitis as an urgent indication to LT, there is no general consensus on the best timing in considering transplantation for HOCF. MELD score was designed for cirrhotic patients, and HHT patients usually need to be granted a MELD exception to be included and prioritized in the LT waitlist [59,60].
Invasive treatments performed prior to LT, such as ligation, banding, or embolization of the HA, are not recommended because of high associated morbidity and mortality [61]. In a previous revision by Whiting et al., 10 (41.7%) out of 24 patients who underwent HA embolization experienced significant morbidity (two required emergency LT and four experienced serious complications) and mortality (four patients) [62]. It is important to note that these techniques were used in the oldest reports of our systematic review, so complications and survival reported herein might be disproportionately influenced by the use of these treatments before LT [9,63,64]. Moreover, transjugular intrahepatic portosystemic shunt (TIPS) in HHT has been described in an attempt to treat ascites and variceal hemorrhage, though its application in this context is largely unsuccessful [42,65].
As such, LT is currently the recommended surgical option for HHT patients with severe hepatic vascular involvement [61]. Bevacizumab has shown to improve cardiac index in HHT patients with HOCF and may potentially alleviate the need for LT in HHT patients with HOCF in some case reports [12,61,66]. However, its use as a bridge therapy for LT, as it was used in nine of herein reported patients, is questionable, because of unpredictable efficacy (considering the strength of the response, time to improvement, and duration of the benefit), toxicity (such as gastrointestinal perforation, thromboembolic events, hypertensive crisis, or nephrotic syndrome) and surgical complications with respect to angiogenesis-dependent phenomena such as wound repair or healing of anastomoses [10,11,[27][28][29][30]35,37,57,67].
Reported cases reflect the complexity of LT for HHT, with high blood transfusion requirements and prolonged graft CIT. Although reports are heterogeneous and surgical complications are not always described, perioperative complications are high compared to other indications [68]. The HA in HHT patients may be dilated and/or tortuous and should be handled with care. At the start of hilar dissection during recipient hepatectomy, it may be advantageous to place a bulldog or other vascular clamp proximally on the common hepatic artery before dissecting and dividing branches distally, in order to avoid propagation and potentially catastrophic consequences of any intimal dissection. Moreover, this maneuver also contributes to reducing the hyperdynamic state and potential risk for bleeding. Arterial anastomosis should be performed using a recipient artery of adequate caliber and wall consistency; in fact, severely dilated or aneurysmatic recipient artery should be avoided. Adequate flow through the anastomosis should be ideally confirmed intraoperatively using ultrasound flow measurement confirming flow rate and triphasic waveform. Additionally, arterial telangiectases may play a role in arterial steal, which may help explain the high incidence of HA thrombosis after LT in HHT patients. HA thrombosis was described in six out of the 83 reported patients (four in the in-hospital setting after LT and two during follow-up) and resulted in re-transplantation in two (Case 1, [15]). Moreover, it is important to note that fatal pulmonary bleeding was described in two patients, so, HHT patients should also be screened for pulmonary AVM and, if present, embolization should be considered previously to LT [24,49].
Intrahepatic relapse of the hallmark lesions of HHT (hepatic telangiectasia or large AVMs) has been described in 13 patients after LT (Case 2, [19,20,22,23,42]). In a recent study by Dumortier et al., which included long-term follow-up of 14 patients (this series include one new female patient from the series published by Dupuis-Girod), HHT recurrence was diagnosed by abnormal radiological features in 8 (seven female) and confirmed in three out of the five patients with liver biopsy. The median interval between LT and recurrence diagnosis was 127 months (range: 74-184), increasing the risk of recurrence over time with an estimated cumulative risk of 0% at 5 years, 16.7% at 10 years, 47.9% at 15 years, and 87% at 20 years [16,19]. Four previous cases of HHT recurrence were reported and diagnosis of HHT recurrence was made at 5, 8, 10, and 19 years after LT [20,22,23,42]. In our case 2, allograft recurrence was detected in the context of symptomatic ischemic cholangitis eight years after LT. This patient, together with one described by Cura et al., who developed portal hypertension five years after LT, are together the only two reported symptomatic relapses after LT (both patients died, one and 11 months after the diagnosis of HHT recurrence) (Case 2, [42]). All these findings suggest that HHT recurrence is a very late event after LT, and even may be underdiagnosed. Thus, these patients require life-long follow-up in the setting of a multidisciplinary HHT Unit.
The pathophysiology of LT recurrence is still unclear. However, Dumortier et al. found the coexistence of an angiogenic process combined with endothelial microchimerism, as shown by the presence of vascular lining cells of recipient origin in three female recipients of male liver grafts [19]. Microchimerism is a well-known feature after LT, but it may develop into an aberrant angiogenic process due to abnormal endothelial cells repopulating the liver graft [69,70]. The use of an mTOR inhibitor-based immunosuppression regimen may be useful for these patients, as sirolimus block the overactivated PI3K signaling pathway in HHT reducing vascular growth and may reduce allograft recurrence [4,5,13,14,71].
In conclusion, the management of LT in HHT patients is complex. An optimal screening and management of VMs prior to LT is needed. Surgical challenges should include the assessment of HA anatomy and the hyperdynamic circulatory state to reduce surgical complications. The risk of relapse in the hepatic graft supports the need for a multidisciplinary follow-up of these patients.  Informed Consent Statement: Patient consent was waived due to no personal data is used and patients cannot be identified.

Data Availability Statement: Not applicable.
Acknowledgments: We thank the CERCA Programme/Generalitat de Catalunya for their institutional support.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.           P1: a complete vascular exclusion of the liver was performed before hepatic mobilization to avoid a septic embolisms. Therefore, extracorporeal VVB was necessary. Because of the enlarged liver, the upper vascular hepatic exclusion was achieved by clamping the IVC in its intrapericardial region. P2 and P3: extracorporeal circulation was not used; nevertheless, in P3 a piggyback procedure was performed because of the discrepancy between the donor and the recipient IVC. In all patients, the HA was tied and cut before liver dissection to minimize the risk of hemorrhage caused by telangiectases and to obtain an early reduction in central venous pressure and cardiac output during surgery. Because of the enlarged caliber of the patient's HA, the arterial anastomosis was made between the recipient's HA and the celiac patch of the donor artery.