Abdominal Surgery in Patients With Idiopathic Noncirrhotic Portal Hypertension: A Multicenter Retrospective Study

In patients with idiopathic noncirrhotic portal hypertension (INCPH), data on morbidity and mortality of abdominal surgery are scarce. We retrospectively analyzed the charts of patients with INCPH undergoing abdominal surgery within the Vascular Liver Disease Interest Group network. Forty‐four patients with biopsy‐proven INCPH were included. Twenty‐five (57%) patients had one or more extrahepatic conditions related to INCPH, and 16 (36%) had a history of ascites. Forty‐five procedures were performed, including 30 that were minor and 15 major. Nine (20%) patients had one or more Dindo‐Clavien grade ≥ 3 complication within 1 month after surgery. Sixteen (33%) patients had one or more portal hypertension–related complication within 3 months after surgery. Extrahepatic conditions related to INCPH (P = 0.03) and history of ascites (P = 0.02) were associated with portal hypertension–related complications within 3 months after surgery. Splenectomy was associated with development of portal vein thrombosis after surgery (P = 0.01). Four (9%) patients died within 6 months after surgery. Six‐month cumulative risk of death was higher in patients with serum creatinine ≥ 100 μmol/L at surgery (33% versus 0%, P < 0.001). An unfavorable outcome (i.e., either liver or surgical complication or death) occurred in 22 (50%) patients and was associated with the presence of extrahepatic conditions related to INCPH, history of ascites, and serum creatinine ≥ 100 μmol/L: 5% of the patients with none of these features had an unfavorable outcome versus 32% and 64% when one or two or more features were present, respectively. Portal decompression procedures prior to surgery (n = 10) were not associated with postoperative outcome. Conclusion: Patients with INCPH are at high risk of major surgical and portal hypertension–related complications when they harbor extrahepatic conditions related to INCPH, history of ascites, or increased serum creatinine.


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This article is protected by copyright. All rights reserved. INCPH accounts for less than 2% of the indications for liver biopsies (1,2). Liver histological lesions found in patients with INCPH include obliterative portal venopathy, hepatoportal sclerosis, nodular regenerative hyperplasia and incomplete septal cirrhosis (3). INCPH has been associated with various conditions including thrombophilia, hematologic malignancies, human immunodeficiency virus (HIV) infection, genetic and immunological disorders (4,5).
Patients with INCPH may develop portal hypertension related complications, but usually have preserved liver function.

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Patients with chronic liver diseases may require abdominal surgery for indications related to their liver disease (e.g. splenectomy or parietal surgery), or unrelated. Most available data on the risk of surgery in patients with liver disease pertains to cirrhosis, where post-operative morbidity and mortality are influenced by liver dysfunction and degree of portal hypertension (6)(7)(8)(9), type of surgery (10,11) and comorbidities (9). Given the link between portal hypertension and post-operative outcome (11), portal decompression has been proposed to facilitate abdominal surgery and improve outcome, although reported results are contrasted (12)(13)(14)(15)(16)(17).
Experience regarding abdominal surgery in patients with INCPH is mostly limited to portosystemic shunt and/or splenectomy performed in adults or children from Eastern countries (5,(18)(19)(20). The present study thus aimed at evaluating the outcome of patients with INCPH undergoing abdominal surgery and at assessing the impact of preoperative portal decompression procedures.

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This article is protected by copyright. All rights reserved. The following data were collected at surgery: (a) clinical features before surgery, including age, gender, American Society of Anesthesiology (ASA) class (26), age-adjusted Charlson comorbidity index (the Charlson Comorbidity index is a weighted index that takes into account the number and the seriousness of comorbid diseases by assigning points for certain illnesses (27); the age-adjusted Charlson comorbidity index assigns an additional point for each decade of life after 50 years of age), clinical, laboratory, imaging and endoscopic features; (b) surgical data, including indication, type of surgery, planned or emergency procedure, laparoscopy or laparotomy. Major surgery was defined as laparotomy with operative intervention on a visceral organ (9). History of ascites was defined as a previous ascites that was controlled with diuretics at the time of surgery, or clinically

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This article is protected by copyright. All rights reserved. detectable ascites at surgery. Portal decompression intervention before surgery included TIPSS placement or surgical portosystemic shunt. Patients in whom surgical portosystemic shunt was the indication for surgery were not included.

Follow-up
Duration of follow-up was calculated from the date of surgery. End-points were pre-specified before data collection (Supplementary Table 2). Postoperative complications were defined as any event occurring within one month after surgical intervention, and was categorized according Dindo-Clavien classification. (28). Portal hypertension-related complications were defined as any of decompensation ascites, hepatic encephalopathy, significant portal hypertension related bleeding (29), acute kidney injury, or spontaneous bacterial peritonitis occurring within 3 months after surgical intervention (Supplementary Table 2).
Decompensation of ascites was defined as follows: (i) in patients without ascites, onset of clinically detectable ascites, confirmed by ultrasonography; (ii) in patients with previous ascites not requiring paracentesis, ascites requiring two or more paracenteses within 3 months following surgery, or requiring a TIPSS. Post-operative death was defined as death occurring within 6 months after surgical intervention. Finally, an unfavorable outcome was defined either post-operative grade 3 complication according to Dindo-Clavien classification within one month after surgery, or portal-hypertension related complications within 3 months after surgery, or death within 6 months after surgery.
In order to evaluate the influence of portal decompression on post-operative outcome, we compared the occurrence of complications between patients who had or not a history of portal decompression procedure, i.e. TIPSS placement or surgical portosystemic shunt, performed before abdominal surgery.

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Controls
We compared 6-month post-operative cumulative risk of death in patients with INCPH with that of patients with cirrhosis who had abdominal surgery, selected from a recently published cohort (17). Two patients with cirrhosis were matched with one patient with INCPH according to the presence of ascites at surgery (i.e either clinically detectable ascites before TIPS placement or history of ascites at the time of surgery (i.e. previous ascites controlled with diuretic therapy at surgery, or clinically detectable ascites at surgery).  Table 1). Among the 101 patients meeting these criteria, 7 were excluded because they were referred to the liver hemodynamic unit for evaluation before liver transplantation, 9 because follow-up data were not available, and 3 because they were already included in the present study.

Statistical analysis
Results are presented as median (interquartile range (IQR)) or absolute number (percentage). Comparisons between quantitative variables were performed using the T test or Mann-Whitney test for normally and non-normally distributed variables, respectively. Shapiro-Wilk test was used to determine whether or not the distribution of continuous variable was normal. Comparisons between categorical variables were performed using the Chi-square or Fisher exact test, when appropriate. Univariate Cox regression analyses were performed to determine factors associated with post-operative complication grade 3 within one month after surgery, portal-hypertension related complications within 3 months after

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This article is protected by copyright. All rights reserved. previous ascites controlled with diuretic therapy at surgery, or clinically detectable ascites at surgery) (23)(24)(25)31), varices needing treatment (i.e. medium/large esophageal and/or gastric varices or history of variceal bleeding or history of endoscopic band ligation and/or glue) (11,31), portal vein thrombosis at surgery (22), serum bilirubin at surgery (8,9,31,32), serum creatinine at surgery (8,9,24,31,33), major surgery (9,10), and emergency procedures (6)(7)(8)32). Although MELD and Child-Pugh scores are known to be associated with postoperative outcome after abdominal surgery in patients with cirrhosis (9,32,33), we deliberately chose not to insert these scores, but rather serum creatinine and bilirubin, since 6 patients were treated with vitamin K antagonists and since serum albumin concentration was available in only 34/44 patients. We did not analyze HVPG because HVPG is not a good reflection of portal hypertension in patients with INCPH (25,34).
In order to assess the influence of portal decompression on postoperative outcome, we performed additional analyses including portal decompression in the Cox regression analysis. Hazard ratio (HR) for Cox logistic regression were provided with their 95% confidence interval (CI). Cumulative risk of death was assessed according to the Kaplan-Meier method and compared using the log-rank test. All tests were two-sided and p ≤0.05 was considered to be significant. Data handling and analysis were performed with SPSS 21.0 (SPSS Inc, Chicago, IL, USA).

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Patients' characteristics at surgery
Between 2002 and 2017, 45 surgical interventions were performed in 44 patients from 10 centers participating in the VALDIG network or the French network for vascular liver disease (Supplementary Table 4). Their characteristics at the time of surgery are presented in Table   1 (Table 1). Eleven (25%) patients had serum creatinine ≥100 µmol/L before surgery. HVPG was measured in 28 (64%) patients. Median (IQR) HVPG was 9 (6-15) mm Hg.

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surgical intervention in 2 patients. Thus, 5 (11%) patients were still treated with antiplatelet agents at the date of surgery.
Among the 7 patients with elevated serum creatinine concentration (i.e. serum creatinine ≥100 µmol/L) and a history of ascites at surgery, 3 had major surgery and 2 others had surgery in emergency (Supplementary Table 5). In the peri-operative period, red blood cells and platelets were transfused in 11 (24%) and 8 (18%) patients, respectively.

Post-operative complications within 1 month after surgery
According to the Dindo-Clavien classification, 61 post-operative complications occurred in 31 (70%) patients within 1 month after surgery (Table 3 Table 1.

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This article is protected by copyright. All rights reserved. Table 4, none of the pre-specified factors were significantly associated with the development of at least one grade ≥3 complications according to the Dindo-Clavien classification.

Portal hypertension related complications within 3 months after surgery
Twenty-seven portal hypertension related complications occurred in 16 (36%) patients within 3 months after surgery. Median time between surgery and occurrence of such complications was 6 (1-17) days. Decompensation of ascites, occurring in 12 (26%) patients, was the most frequent of such complications. In two patients, a TIPSS was placed for refractory ascites,  Table 5). Length of hospital stay was significantly longer in patients who developed portal hypertension related complications than in those who did not (30 (6-45) days vs. 6 (3-16) days, p=0.002).
Factors associated with the occurrence of at least one portal hypertension related complication included a history of ascites and extra-hepatic conditions associated with INCPH. Serum creatinine at surgery was not associated with the occurrence of at least one portal hypertension related complication (Table 4).

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This article is protected by copyright. All rights reserved. out of the 3 patients received anticoagulation, and complete recanalization was observed after 4 and 5.5 months, respectively. The third patient did not receive anticoagulation, since a TIPSS was inserted; complete recanalization was observed after 8 months.

Death after surgery
Thirteen (29%) patients were admitted in intensive care unit after surgery, with a median (IQR) length of stay in intensive care unit of 4 (2-7) days. Median (IQR) overall length of hospital stay was 10 (4-28) days. Four patients died within 6 months after surgery. Their characteristics are presented in Table 5. None of the patients underwent liver transplantation within the observation period.
As shown in Table 4, age-adjusted Charlson comorbidity index and serum creatinine level were associated with death within 6 months after surgery. Patients with age-adjusted Charlson comorbidity index 6 before surgery had a 6-month cumulative risk of death of 27% vs. 0% for patients with an index below this threshold (p=0.002). We have previously reported that serum creatinine level higher than 100 µmol/L is associated with a poor outcome after TIPSS in patients with INCPH (25). Using this threshold here, we observed that patients with serum creatinine 100 mol/L had a 6-month cumulative risk of death of 33% vs. 0% for patients with serum creatinine below this threshold ( Figure 1 Figure 1B

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This article is protected by copyright. All rights reserved. from the present study) with that of patients with INCPH but without abdominal surgery (n= 82). As shown in Figure 1C, 3-year transplant-free survival was similar between the two groups.

Overall post-operative unfavorable outcome
Overall post-operative outcome was unfavorable in 22 (50%) patients. History of ascites was associated with an unfavorable outcome ( Table 4). As extra-hepatic conditions related with INCPH and serum creatinine levels fell short of statistical significance and as we have previously reported that these features are associated with a poor outcome after TIPSS in patients with INCPH (25), we classified patients according to these items and to history of ascites at surgery. As shown in Figure 2, 5% of the patients with neither extra-hepatic condition associated with INCPH nor history of ascites at surgery nor serum creatinine ≥100 µmol/L had an unfavorable outcome. Only one patient without these criteria had an unfavorable outcome; this patient had post-operative bleeding after cholecystectomy, requiring reintervention under local anesthesia. By contrast, 64% of the patients with ≥2 features had an unfavorable outcome.

Influence of portal decompression on post-operative outcome
As shown in Figure 3, 11 patients had portal decompression prior to, or at the time of, surgery. In 1 of these patients, portosystemic shunt was the indication for surgery, with concomitant splenectomy (Table 2 and Figure 3). In the 10 remaining patients, median time between portal decompression and surgical intervention was 4.0 (0.3-44.6) months.
In order to assess the effect of portal decompression on the outcome after surgery, we compared the outcome of the 10 patients who had either TIPSS or portosystemic shunt before surgery, to the 33 patients who did not (Supplementary Table 8). Except for betablockers, baseline characteristics did not differ between the two groups. Post-operative outcomes did not differ between patients with previous TIPSS or portosystemic shunt and those without. In patients who had a previous TIPSS or surgical portosystemic shunt, one

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Discussion
This study focusing on the outcome of patients with INCPH undergoing abdominal surgery shows that 6-month mortality after surgery was 9%, affecting patients with comorbidities and/or serum creatinine level  100 µmol/L. Patients without extra-hepatic conditions related with INCPH, without increased serum creatinine and without a history of ascites at surgery had a favorable post-operative outcome. Although this study gathered the largest number of patients with INCPH undergoing abdominal surgery reported at present, interpretation of the results should take into account that number of patients included remained limited, that the study was retrospective, and that various surgical interventions were performed. Given the rarity of the disease, conducting a prospective study seems however not realistic.
The main information derived from this study is that mortality of patients with INCPH undergoing abdominal surgery is higher than that reported in the general population. We observed a 6-month mortality rate of 9% (95% CI 1-17%) in patients with INCPH, while in the general population, in-hospital or 1-month mortality after abdominal surgery ranges from 3 % (95% CI 0.4-7%) to 12% (95% CI 7-18 %) (35)(36)(37). We observed that 6-month mortality rate of patients with INCPH did not differ from that of patients with cirrhosis, matched for ascites, who underwent abdominal surgery between 2005 and 2016 (17). It should however

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This article is protected by copyright. All rights reserved. be noted that mortality of patients with cirrhosis in this cohort was lower than previously reported (7,10,(31)(32)(33). Indeed, in patients with cirrhosis, reported mortality after surgery ranges from 7 % (95% CI 2-12%) to 30 % (95% CI 15-44%) (7,8,31,33)  Interestingly, transplant-free survival after INCPH diagnosis was similar in patients who did and did not undergo abdominal surgery during follow-up, suggesting that, in selected patients managed in expert centers, surgery does not have a deleterious impact on the natural history of INCPH. We did not find any association between the type of intervention and post-operative outcomes, but cannot rule out a lack of power due to the limited sample size.
The second major finding of the present study was that portal hypertension related complications, especially ascites, were the most frequent, occurring within 3 months after surgery in 36% and 26% of the patients, respectively. Portal hypertension related complications increased the length of hospital stay, and 3/16 (19%) required a TIPSS after surgery for refractory ascites or variceal bleeding. However, they were transient in most

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This article is protected by copyright. All rights reserved. De novo PVT occurred in 5 (11%) patients after surgery. Interestingly, PVT following splenectomy was 10-fold more frequent than following other surgeries. Reported rates of PVT following splenectomy range between 17% (95% CI 13-21%) and 36% (95% CI 17-55%) in patients with cirrhosis (38,39), and are of 54% (95% CI 46-61%) in patients with benign hematologic disorders (40). In the present study, the incidence of PVT was similar to that of non-cirrhotic patients, since PVT was observed in 50% (95% CI 9-90%) of the patients with INCPH and splenectomy. Four cases of PVT were diagnosed within one month after surgery. Recanalization occurred in 60% of the patients. These findings suggest that routine ultrasound examination at 1 week, 1 month and 3 months after surgery would allow an early detection of PVT, especially after splenectomy.
Infections within 1 month after surgery were common, being observed in 34% of the patients. This figure is in the same range as estimates of post-operative infections after abdominal surgery in patients with cirrhosis and higher than in the general population [29% (95% CI 21-36%) and 13% (95% CI 12-14%), respectively, p<0.001] (41). In cirrhosis, the risk of infection is likely related to altered innate and adaptive immunity and to increased bacterial translocation (42). In patients with INCPH, susceptibility to infection may be related to portal hypertension but also to extrahepatic conditions associated with INCPH, namely immunological disorders and HIV infection. Bleeding occurred within 1 month in 10 (22%) patients and was associated with administration of anticoagulant or antiplatelet agents. This high incidence is reminiscent of the frequent bleeding episodes reported in patients with Budd-Chiari syndrome undergoing invasive procedures while receiving anticoagulation therapy (43).
In the present study, we identified a group of patients having an unfavorable outcome, namely those with extra-hepatic condition associated with INCPH, elevated serum creatinine and/or significant ascites before surgery. By contrast, only 5% of the patients with neither extra-hepatic condition associated with INCPH nor elevated serum creatinine nor significant

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This article is protected by copyright. All rights reserved. ascites before surgery had an unfavorable outcome. These simple features could be helpful in making a decision for abdominal surgery with due information of the patient on the risks of the intervention. Due to the retrospective and uncontrolled design of the study, we could not evaluate the survival benefit of surgery (vs. no intervention), taking into account the indication of surgery, the severity of INCPH and extrahepatic comorbidities.
In patients with cirrhosis, the experience of pre-emptive TIPSS placement before surgery is limited to small, retrospective studies (12)(13)(14)(15)(16)(17). A limited number of studies compared patients with cirrhosis with preserved or moderately impaired liver function who had preoperative TIPSS, to patients who underwent elective surgery without preoperative TIPSS.
Outcome after surgery was similar between patients who had or not a preoperative TIPSS (15,17). In the present study, portal decompression was not associated with post-operative outcome after surgery. However, present findings are insufficient to draw any firm conclusion for or against preemptive portal decompression before surgery in patients with INCPH.
Indeed, TIPSS was placed as a preparation for surgery in only 4 patients; in the 5 remaining patients, TIPSS had been previously inserted for other reasons, with sometimes a broad interval of time between TIPSS insertion and surgery. Larger dedicated studies are thus needed to address this important question.
In conclusion, in this study, we observed that patients with INCPH were at high risk of major surgical and portal hypertension related complications when they harbored extrahepatic conditions related to INCPH, and/or increased serum creatinine and/or a history of ascites.
Comorbidities and higher serum creatinine were significantly associated with 6-month mortality. Further studies are needed to evaluate the impact of each type of surgery on the natural history of INCPH and the influence of TIPSS on post-operative outcome.

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