Alimentary Pharmacology and Therapeutics
Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy J. An*, K. W. Kim†, S. Han‡, J. Lee§ & Y.-S. Lim*
*Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. † Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ‡ Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. § School of Computer Science & Engineering, Soongsil University, Seoul, Korea.
Correspondence to: Prof. Y.-S. Lim, Department of Gastroenterology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected]
Publication data Submitted 23 November 2013 First decision 16 December 2013 Resubmitted 5 April 2014 Accepted 7 April 2014 EV Pub Online 22 April 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Spontaneous portosystemic shunt (SPSS) is a frequent cause of recurrent hepatic encephalopathy (HE) in patients with cirrhosis. Aim To assess the effectiveness and optimal candidate selection for embolisation of SPSS, for the treatment of recurrent HE in patients with cirrhosis. Methods This retrospective cohort study compared 17 patients with recurrent HE who achieved complete occlusion of SPSS by angiographic embolisation and 17 control patients. Results Most baseline characteristics were similar in the two groups. The 2-year HE recurrence rate was significantly lower in the embolisation than in the control group (39.9% vs. 79.9%, P = 0.02), whereas their 2-year overall survival rates were similar (64.7% vs. 53.4%, P = 0.98). Model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) score were significant predictors of 2year patient mortality in the embolisation group. Analysis of patients with MELD 13. Embolisation of SPSS was attempted angiographically in twenty patients, and the shunts were completely occluded in seventeen (embolisation group). In the remaining three patients, angiographic access to the SPSS was technically impossible and embolisation of the shunt was not tried. The causes of technical failure included unsuccessful catheterisation of the shunts due to acute angulation of the vessels or inability to occlude the shunt because of its extremely large maximal diameter. Together with these three patents, the fourteen patients in whom HE was primarily treated only with standard medical therapy at our center during the same period served as the control group. Two hepatologists in our institution encouraged SPSS embolisation in patients with recurrent HE, whereas others did not. Thus, the decision to perform shunt embolisation was made at the preference of the attending physician and was not based on clinical or demographical characteristics of patients. 1419
J. An et al.
Shunt embolisation procedures The angiographic access for embolisation in patients with splenorenal shunt was primarily via the femoral vein, whereas access in patients with paraumbilical shunt was percutaneous. All patients were placed under local
Table 1 | Baseline characteristics of the study population
No. 17 Age, years* 62 (56–65.5) Male gender 11 (64.7%) Aetiology HBV 9 (52.9%) HCV 2 (11.8%) Alcohol 5 (29.4%) Others 1 (5.9%) No. of HE episodes during the previous 1–2 9 (52.9%) ≥3 8 (47.1%) HE grade, maximum II 6 (35.3%) III–IV 11 (64.7%) Portosystemic shunt Splenorenal 14 (82.4%) Paraumbilical 3 (17.6%) Oesophageal varices 3 (17.6%) HCC 3 (17.6%) Albumin (mg/dL)* 2.6 (2.5–3.2) Bilirubin (mg/dL)* 1.9 (1.4–2.5) Creatinine (mg/dL)* 0.8 (0.6–0.9) INR* 1.37 (1.24–1.53) MELD* 13 (11–15) CTP score 9 (8–10)
Control group
P
17 63 (57–69) 10 (58.8%)
0.61 0.72
11 (64.7%) 4 (23.5%) 1 (5.9%) 1 (5.9%) 3 months 15 (88.2%) 2 (11.8%)
1420
(a)
100
P = 0.98
80
60
40 Embolisation (n = 17) 20
Control (n = 17)
0
0.32
0
6
12
18
24
Months of follow-up (b) 100
0.03
6 (35.3%) 11 (64.7%)
1.00
15 (88.2%) 2 (11.8%) 5 (29.4%) 0 2.7 (2.4–2.9) 2.9 (1.7–3.7) 0.8 (0.6–0.9) 1.35 (1.23–1.43) 14 (11–16) 10 (9–10)
1.00 0.43 0.23 0.57 0.16 0.74 0.46 0.38 0.10
HBV, hepatitis B virus; HCV, hepatitis C virus; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma; INR, international normalised ratio; MELD, model for end-stage liver disease; CTP, Child-Turcotte-Pugh. * Median (interquartile range, IQR).
Outcomes The primary outcome was the recurrence of overt HE during 2 years of follow-up. HE of grade 2 or higher was considered as recurrence regardless of the presence of identifiable precipitant. Secondary outcomes included overall survival, changes in liver function and liver volume, and safety. Changes in liver function were evaluated by measuring albumin and total bilirubin concentrations, international normalised ratio (INR), model
Recurrence of encephalopathy (%)
Embolisation group
anaesthesia. Embolisation was performed using vascular plugs (Amplatzer Vascular Plug; AGA Medical, Golden Valley, MN, USA) or coils combined with gelatin sponges (Gelfoam; Upjohn, Kalamazoo, MI, USA).
Patient survival (%)
The baseline time point was defined as the date of the first shunt embolisation in the embolisation group and the date of the second hospitalisation in our institution for the treatment of HE in the control group. Patients were followed up for survival, HE recurrence, liver function parameters and liver volume. Recurrence of HE was defined as a hospitalisation or emergency room visit for the management of HE. The occurrence or worsening of ascites or oesophago-gastric varices was also evaluated. All the clinical and laboratory data that were necessary for the analyses were acquired at every visit to the out-patient clinic or emergency room of patients.
P = 0.02 Embolisation (n = 17) Control (n = 17)
80
60
40
20
0 0
6
12
18
24
Months of follow-up
Figure 1 | Kaplan–Meier analyses of patient overall survival (a) and recurrence of hepatic encephalopathy (b) in the embolisation and control groups. Aliment Pharmacol Ther 2014; 39: 1418-1426 ª 2014 John Wiley & Sons Ltd
Portosystemic shunt embolisation and survival for end-stage liver disease (MELD) and CTP score before and 1 year after shunt embolisation. Liver volume was measured by computer-aided liver volumetry on venous phase CT images, as described.23
Statistical analysis Categorical variables were compared by Fisher’s exact test, and continuous variables were compared by Mann– Whitney U-test for unpaired data, and Wilcoxon signed rank test for paired data. Overall survival and cumulative rates of HE recurrence were estimated by the Kaplan–Meier method, and differences between groups were compared using log-rank test. Factors predictive of patient mortality and HE recurrence were evaluated by Cox proportional hazards model. The ability of prognostic variables to predict patient mortality and recurrence of HE was analysed using the area under a receiver operating characteristic (ROC) curve, with the Youden index (sensitivity + specificity-1) used to determine the optimal cut-off point. A P-value 0.99). Patients with alcoholic cirrhosis in either group were abstinent for at least 6 months before inclusion in this study.
Overall patient survival and HE recurrence Complete follow-up was defined when a patient was followed until the time of death, transplantation or the last follow-up date (April 12, 2013). These data were available for the entire study patients, and there was no drop-out. The median follow-up periods were 19 months [interquartile range (IQR), 8–36 months]; 17 months (IQR, 6– 37 months) and 19 months (IQR, 7–36 months) for the embolisation and control groups, respectively (P = 0.66). During 2 years of follow-up period, a total of 12 patients (35.3%) died. Causes of death were progression of HCC (n = 2), sepsis (n = 1), and hepatorenal syndrome (n = 3) in the embolisation group, and HCC (n = 1), sepsis (n = 2), variceal bleeding (n = 1) and hepatorenal syndrome (n = 2) in the control group. One patient in the control group received a liver transplantation. Kaplan–Meier analysis showed that the 2-year overall survival rates were comparable in the embolisation and control groups (64.7% vs. 53.4%, P = 0.98; Figure 1a), whereas the 2-year HE recurrence rate was significantly
Table 2 | Factors predictive of patient mortality and HE recurrence in the embolisation group Mortality Predictive factors Age Male gender Aetiology* No. of HE episodes during the previous 3 months HE grade, maximum HCC Albumin Bilirubin Creatinine INR† MELD CTP score
HE recurrence
HR
95% CI
P
HR
95% CI
P
1.06 0.49 0.61 0.16 3.43 9.45 0.16 3.55 0.34 2.46 1.86 2.34
0.97–1.16 0.01–2.46 0.11–3.35 0.02–1.42 0.40–29.47 1.54–58.22 0.03–0.92 1.21–10.42 0.01–23.24 1.33–4.58 1.22–2.85 1.27–4.33
0.21 0.39 0.57 0.10 0.26 0.02 0.04 0.02 0.62
Improvement in survival associated with embolisation of spontaneous portosystemic shunt in patients with recurrent hepatic encephalopathy J. An*, K. W. Kim†, S. Han‡, J. Lee§ & Y.-S. Lim*
*Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. † Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ‡ Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. § School of Computer Science & Engineering, Soongsil University, Seoul, Korea.
Correspondence to: Prof. Y.-S. Lim, Department of Gastroenterology, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected]
Publication data Submitted 23 November 2013 First decision 16 December 2013 Resubmitted 5 April 2014 Accepted 7 April 2014 EV Pub Online 22 April 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Spontaneous portosystemic shunt (SPSS) is a frequent cause of recurrent hepatic encephalopathy (HE) in patients with cirrhosis. Aim To assess the effectiveness and optimal candidate selection for embolisation of SPSS, for the treatment of recurrent HE in patients with cirrhosis. Methods This retrospective cohort study compared 17 patients with recurrent HE who achieved complete occlusion of SPSS by angiographic embolisation and 17 control patients. Results Most baseline characteristics were similar in the two groups. The 2-year HE recurrence rate was significantly lower in the embolisation than in the control group (39.9% vs. 79.9%, P = 0.02), whereas their 2-year overall survival rates were similar (64.7% vs. 53.4%, P = 0.98). Model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) score were significant predictors of 2year patient mortality in the embolisation group. Analysis of patients with MELD 13. Embolisation of SPSS was attempted angiographically in twenty patients, and the shunts were completely occluded in seventeen (embolisation group). In the remaining three patients, angiographic access to the SPSS was technically impossible and embolisation of the shunt was not tried. The causes of technical failure included unsuccessful catheterisation of the shunts due to acute angulation of the vessels or inability to occlude the shunt because of its extremely large maximal diameter. Together with these three patents, the fourteen patients in whom HE was primarily treated only with standard medical therapy at our center during the same period served as the control group. Two hepatologists in our institution encouraged SPSS embolisation in patients with recurrent HE, whereas others did not. Thus, the decision to perform shunt embolisation was made at the preference of the attending physician and was not based on clinical or demographical characteristics of patients. 1419
J. An et al.
Shunt embolisation procedures The angiographic access for embolisation in patients with splenorenal shunt was primarily via the femoral vein, whereas access in patients with paraumbilical shunt was percutaneous. All patients were placed under local
Table 1 | Baseline characteristics of the study population
No. 17 Age, years* 62 (56–65.5) Male gender 11 (64.7%) Aetiology HBV 9 (52.9%) HCV 2 (11.8%) Alcohol 5 (29.4%) Others 1 (5.9%) No. of HE episodes during the previous 1–2 9 (52.9%) ≥3 8 (47.1%) HE grade, maximum II 6 (35.3%) III–IV 11 (64.7%) Portosystemic shunt Splenorenal 14 (82.4%) Paraumbilical 3 (17.6%) Oesophageal varices 3 (17.6%) HCC 3 (17.6%) Albumin (mg/dL)* 2.6 (2.5–3.2) Bilirubin (mg/dL)* 1.9 (1.4–2.5) Creatinine (mg/dL)* 0.8 (0.6–0.9) INR* 1.37 (1.24–1.53) MELD* 13 (11–15) CTP score 9 (8–10)
Control group
P
17 63 (57–69) 10 (58.8%)
0.61 0.72
11 (64.7%) 4 (23.5%) 1 (5.9%) 1 (5.9%) 3 months 15 (88.2%) 2 (11.8%)
1420
(a)
100
P = 0.98
80
60
40 Embolisation (n = 17) 20
Control (n = 17)
0
0.32
0
6
12
18
24
Months of follow-up (b) 100
0.03
6 (35.3%) 11 (64.7%)
1.00
15 (88.2%) 2 (11.8%) 5 (29.4%) 0 2.7 (2.4–2.9) 2.9 (1.7–3.7) 0.8 (0.6–0.9) 1.35 (1.23–1.43) 14 (11–16) 10 (9–10)
1.00 0.43 0.23 0.57 0.16 0.74 0.46 0.38 0.10
HBV, hepatitis B virus; HCV, hepatitis C virus; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma; INR, international normalised ratio; MELD, model for end-stage liver disease; CTP, Child-Turcotte-Pugh. * Median (interquartile range, IQR).
Outcomes The primary outcome was the recurrence of overt HE during 2 years of follow-up. HE of grade 2 or higher was considered as recurrence regardless of the presence of identifiable precipitant. Secondary outcomes included overall survival, changes in liver function and liver volume, and safety. Changes in liver function were evaluated by measuring albumin and total bilirubin concentrations, international normalised ratio (INR), model
Recurrence of encephalopathy (%)
Embolisation group
anaesthesia. Embolisation was performed using vascular plugs (Amplatzer Vascular Plug; AGA Medical, Golden Valley, MN, USA) or coils combined with gelatin sponges (Gelfoam; Upjohn, Kalamazoo, MI, USA).
Patient survival (%)
The baseline time point was defined as the date of the first shunt embolisation in the embolisation group and the date of the second hospitalisation in our institution for the treatment of HE in the control group. Patients were followed up for survival, HE recurrence, liver function parameters and liver volume. Recurrence of HE was defined as a hospitalisation or emergency room visit for the management of HE. The occurrence or worsening of ascites or oesophago-gastric varices was also evaluated. All the clinical and laboratory data that were necessary for the analyses were acquired at every visit to the out-patient clinic or emergency room of patients.
P = 0.02 Embolisation (n = 17) Control (n = 17)
80
60
40
20
0 0
6
12
18
24
Months of follow-up
Figure 1 | Kaplan–Meier analyses of patient overall survival (a) and recurrence of hepatic encephalopathy (b) in the embolisation and control groups. Aliment Pharmacol Ther 2014; 39: 1418-1426 ª 2014 John Wiley & Sons Ltd
Portosystemic shunt embolisation and survival for end-stage liver disease (MELD) and CTP score before and 1 year after shunt embolisation. Liver volume was measured by computer-aided liver volumetry on venous phase CT images, as described.23
Statistical analysis Categorical variables were compared by Fisher’s exact test, and continuous variables were compared by Mann– Whitney U-test for unpaired data, and Wilcoxon signed rank test for paired data. Overall survival and cumulative rates of HE recurrence were estimated by the Kaplan–Meier method, and differences between groups were compared using log-rank test. Factors predictive of patient mortality and HE recurrence were evaluated by Cox proportional hazards model. The ability of prognostic variables to predict patient mortality and recurrence of HE was analysed using the area under a receiver operating characteristic (ROC) curve, with the Youden index (sensitivity + specificity-1) used to determine the optimal cut-off point. A P-value 0.99). Patients with alcoholic cirrhosis in either group were abstinent for at least 6 months before inclusion in this study.
Overall patient survival and HE recurrence Complete follow-up was defined when a patient was followed until the time of death, transplantation or the last follow-up date (April 12, 2013). These data were available for the entire study patients, and there was no drop-out. The median follow-up periods were 19 months [interquartile range (IQR), 8–36 months]; 17 months (IQR, 6– 37 months) and 19 months (IQR, 7–36 months) for the embolisation and control groups, respectively (P = 0.66). During 2 years of follow-up period, a total of 12 patients (35.3%) died. Causes of death were progression of HCC (n = 2), sepsis (n = 1), and hepatorenal syndrome (n = 3) in the embolisation group, and HCC (n = 1), sepsis (n = 2), variceal bleeding (n = 1) and hepatorenal syndrome (n = 2) in the control group. One patient in the control group received a liver transplantation. Kaplan–Meier analysis showed that the 2-year overall survival rates were comparable in the embolisation and control groups (64.7% vs. 53.4%, P = 0.98; Figure 1a), whereas the 2-year HE recurrence rate was significantly
Table 2 | Factors predictive of patient mortality and HE recurrence in the embolisation group Mortality Predictive factors Age Male gender Aetiology* No. of HE episodes during the previous 3 months HE grade, maximum HCC Albumin Bilirubin Creatinine INR† MELD CTP score
HE recurrence
HR
95% CI
P
HR
95% CI
P
1.06 0.49 0.61 0.16 3.43 9.45 0.16 3.55 0.34 2.46 1.86 2.34
0.97–1.16 0.01–2.46 0.11–3.35 0.02–1.42 0.40–29.47 1.54–58.22 0.03–0.92 1.21–10.42 0.01–23.24 1.33–4.58 1.22–2.85 1.27–4.33
0.21 0.39 0.57 0.10 0.26 0.02 0.04 0.02 0.62
