Evolution of spontaneous portosystemic shunts over time and following aetiological intervention in patients with cirrhosis.

Background & Aims: Spontaneous portosystemic shunts (SPSS) develop frequently in cirrhosis. Changes over time and the effect of aetiological interventions on SPSS are unknown, so we aimed to explore the effect of these variables on SPSS evolution. Methods: Patients with cirrhosis from the Baveno VI-SPSS cohort were selected provided a follow-up abdominal CT or MRI scan was available. Clinical and laboratory data were collected at baseline and follow-up. Imaging tests were reviewed to evaluate changes in the presence and size of SPSS (large (L)-SPSS was ≥8 mm) over time. Regarding alcohol- or HCV-related cirrhosis, two populations were defined: cured patients (abstinent from alcohol or successful HCV therapy), and non-cured patients. Results: A total of 617 patients were included. At baseline SPSS distribution was 22% L-SPSS, 30% small (S)-SPSS, and 48% without (W)-SPSS. During follow-up (median follow-up of 63 months), SPSS distribution worsened: L-SPSS 26%, S-SPSS 32%, and W-SPSS 42% (p <0.001). Patients with worse liver function during follow-up showed a simultaneous aggravation in SPSS distribution. Non-cured patients (n = 191) experienced a significant worsening in liver function, more episodes of liver decompensation and lower transplant-free survival compared to cured patients (n = 191). However, no differences were observed regarding SPSS distribution at inclusion and at follow-up, with both groups showing a trend to worsening. Total shunt diameter increased more in non-cured (52%) than in cured patients (28%). However, total shunt area (TSA) significantly increased only in non-cured patients (74 to 122 mm2, p <0.001). Conclusions: The presence of SPSS in cirrhosis increases over time and parallels liver function deterioration. Aetiological intervention in these patients reduces liver-related complications, but SPSS persist although progression is decreased. Impact and implications: There is no information regarding the evolution of spontaneous portosystemic shunts (SPSS) during the course of cirrhosis, and especially after disease regression with aetiological interventions, such as HCV treatment with direct-acting antivirals or alcohol abstinence. These results are relevant for clinicians dealing with patients with cirrhosis and portal hypertension because they have important implications for the management of cirrhosis with SPSS after disease regression. From a practical point of view, physicians should be aware that in advanced cirrhosis with portal hypertension, after aetiological intervention, SPSS mostly persist despite liver function improvement, and complications related to SPSS may still develop.

Liver Transplantation for Porto-sinusoidal Vascular Liver Disorder: Long-term Outcome.

BACKGROUND: Porto-sinusoidal vascular liver disorder (PSVD) is a rare disease that occasionally requires liver transplantation (LT), despite usually presenting preserved liver function. There remains a paucity of data pertaining to LT in PSVD. The aim was to identify features associated with post-LT outcomes in PSVD. METHODS: Retrospective multicentre study of 79 patients who received LT for PSVD. RESULTS: Median post-LT follow-up was 37 (range 1-261) mo. Refractory ascites 24 (30%), hepatic encephalopathy 16 (20%), and hepatopulmonary syndrome 13 (16.3%) were the most frequent indications for LT. Hepatocellular carcinoma was the indication in only 2 patients. Twenty-four patients died, 7 due to liver and 17 to non-liver related causes. Post-LT survival was 82.2%, 80.7%, and 68.6% at 1, 2, and 5 y, respectively. Post-LT survival was significantly better in patients without (n = 58) than in those with a persistent severe PSVD-associated condition (n = 21). Pre-LT hyperbilirubinemia levels and creatinine >100 µmol/L were also independently associated with poor survival. Six patients (7.6%) required a second LT. Recurrence of PSVD was confirmed by liver biopsy in only 1 patient and in 3 further patients it was likely. CONCLUSIONS: LT in PSVD is associated with an acceptable outcome in the absence of associated severe conditions. However, persistence of a severe associated condition, pre-LT high bilirubin levels, or creatinine >100 µmol/L impact outcome, and these are features that should be considered when evaluating PSVD patients for LT. PSVD recurrence is possible after LT and needs to be explored, at least, in cases of posttransplant portal hypertension.

Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-AH).

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort. METHODS: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days. RESULTS: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment. CONCLUSIONS: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients.

Spontaneous portosystemic shunt embolization in liver transplant recipients with recurrent hepatic encephalopathy.

INTRODUCTION AND OBJECTIVES: Spontaneous portosystemic shunts (SPSS) are a common cause of recurrent hepatic encephalopathy (HE). Shunt occlusion is an effective and safe procedure when performed in patients with cirrhosis and preserved liver function. We aimed to describe our experience with SPSS embolization after liver transplantation (LT). PATIENTS: We identified five patients who underwent SPSS embolization after LT. Clinical, biochemical and technical procedure data were collected. RESULTS: At presentation, all patients had developed graft cirrhosis and HE after LT. Median Model for End-stage Liver Disease (MELD) at embolization was 9 (range 7-12), median Child-Pugh was 8 (range 7-9). Splenorenal and mesocaval shunt were the most frequent types of SPSS found. Three patients have been completely free of HE. Of the two patients who had HE recurrence after embolization, one patient had two episodes of HE which was controlled well with medications. The other patient required three embolizations because of recurrent HE. Median follow-up was 4.4 years (range 1.0-5.0) and MELD score at last follow up was 13 (range 10-18) and median Child-Pugh score B, 7 points (range 5-12). CONCLUSIONS: SPSS can be considered as a cause of HE after LT. SPSS embolization is feasible and safe in LT recipients.

Effects of Albumin on Survival after a Hepatic Encephalopathy Episode: Randomized Double-Blind Trial and Meta-Analysis.

No therapies have been proven to increase survival after a hepatic encephalopathy (HE) episode. We hypothesize that two doses of albumin could improve 90-day survival rates after a HE episode. METHODS: (1) A randomized double-blind, placebo-controlled trial (BETA) was conducted in 12 hospitals. The effect of albumin (1.5 g/kg at baseline and 1 g/kg on day 3) on 90-day survival rates after a HE episode grade II or higher was evaluated. (2) A meta-analysis of individual patient's data for survival including two clinical trials (BETA and ALFAE) was performed. RESULTS: In total, 82 patients were included. Albumin failed to increase the 90-day transplant-free survival (91.9% vs. 80.5%, p = 0.3). A competing risk analysis was performed, observing a 90-day cumulative incidence of death of 9% in the albumin group vs. 20% in the placebo (p = 0.1). The meta-analysis showed a benefit in the albumin group, with a lower rate of clinical events (death or liver transplant) than patients in the placebo (HR, 0.44; 95% CI, 0.21-0.82), when analyzed by a competing risk analysis (90-days mortality rate of 11% in the albumin group vs. 30% in the placebo, p = 0.02). CONCLUSIONS: Repeated doses of albumin might be beneficial for patient's survival as an add-on therapy after an HE episode, but an adequately powered trial is needed.

The role of liver steatosis as measured with transient elastography and transaminases on hard clinical outcomes in patients with COVID-19.

Liver injury has been widely described in patients with Coronavirus disease 2019 (COVID-19). We aimed to study the effect of liver biochemistry alterations, previous liver disease, and the value of liver elastography on hard clinical outcomes in COVID-19 patients. We conducted a single-center prospective observational study in 370 consecutive patients admitted for polymerase chain reaction (PCR)-confirmed COVID-19 pneumonia. Clinical and laboratory data were collected at baseline and liver parameters and clinical events recorded during follow-up. Transient elastography [with Controlled Attenuation Parameter (CAP) measurements] was performed at admission in 98 patients. All patients were followed up until day 28 or death. The two main outcomes of the study were 28-day mortality and the occurrence of the composite endpoint intensive care unit (ICU) admission and/or death. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at admission in 130 patients (35%) and 167 (45%) patients, respectively. Overall, 14.6% of patients presented the composite endpoint ICU and/or death. Neither ALT elevations, prior liver disease, liver stiffness nor liver steatosis (assessed with CAP) had any effect on outcomes. However, patients with abnormal baseline AST had a higher occurrence of the composite ICU/death (21% versus 9.5%, p = 0.002). Patients ⩾65 years and with an AST level > 50 U/ml at admission had a significantly higher risk of ICU and/or death than those with AST ⩽ 50 U/ml (50% versus 13.3%, p < 0.001). In conclusion, mild liver damage is prevalent in COVID-19 patients, but neither ALT elevation nor liver steatosis influenced hard clinical outcomes. Elevated baseline AST is a strong predictor of hard outcomes, especially in patients ⩾65 years.

Endpoints and design of clinical trials in patients with decompensated cirrhosis: Position paper of the LiverHope Consortium.

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.

Spontaneous portosystemic shunts in liver cirrhosis: new approaches to an old problem.

Portal hypertension is the main consequence of liver cirrhosis, leading to severe complications such as variceal hemorrhage, ascites or hepatic encephalopathy. As an attempt to decompress the portal venous system, portal flow is derived into the systemic venous system through spontaneous portosystemic shunts (SPSSs), bypassing the liver. In this review, we aim to provide an overview of the published reports in relation to the prevalence and physiopathology behind the appearance of SPSS in liver cirrhosis, as well as the complications derived from its formation and its management. The role of SPSS embolization is specifically discussed, as SPSSs have been assessed as a therapeutic target, mainly for patients with recurrent/persistent hepatic encephalopathy and preserved liver function. Furthermore, different aspects of the role of SPSS in liver transplantation, as well as in candidates for transjugular intrahepatic portosystemic shunt are reviewed. In these settings, SPSS occlusion has been proposed to minimize possible deleterious effects, but results are so far inconclusive.

Covert hepatic encephalopathy and spontaneous portosystemic shunts increase the risk of developing overt hepatic encephalopathy.

AIM: The aim of the study was to evaluate the presence of covert hepatic encephalopathy (cHE) and its characteristics according to the presence of spontaneous portosystemic shunts (SPSS) and their influence on the development of overt hepatic encephalopathy. METHODS: Secondary analysis of a multicentre study, which evaluated the association between SPSS and complications of cirrhosis. The present study population includes those patients who also underwent cHE diagnostic evaluation. Presence of SPSS was evaluated by cross-sectional imaging and quantified by total SPSS-area. Logistic and Cox-regression competing risk analyses were performed. RESULTS: About 65 patients were included of age 58 (IQR 50-66), MELD 15 (IQR 10-20), with alcoholic liver disease 63%. Thirty-two patients (49%) had cHE, had higher MELD [16 (IQR 12-24) vs 13 (IQR 9-17), P = .027], a greater proportion of SPSS [n = 18 (56%) vs n = 8 (24%); P = .008] and a higher total cross-sectional SPSS-area [28.3 (0-94.2) vs 0 (0-14.1); P = .005]. On multivariate analysis MELD [OR 1.11 (95% CI 1.01-1.21)] and presence of SPSS [OR 3.95 (95% CI 1.22-12.80)] were independently associated to cHE at baseline. During follow-up cHE was an independent predictor of oHE [cHE: HR 6.93 (95% CI 2.64-18.20). The effect of cHE on the development of oHE was greater in patients with SPSS [only cHE: HR 5.66 (95% CI 1.82-17.62), cHE and SPSS: HR 8.63 (95% CI 3.15-23.65)]. CONCLUSIONS: cHE is independently associated to the presence of SPSS (and total cross-sectional SPSS-area) and MELD. Furthermore, the presence of SPSS seems to increase the risk of cHE of developing of overt hepatic encephalopathy.

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis.

BACKGROUND & AIMS: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that the presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, the presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcomes in patients with liver cirrhosis. METHODS: In this retrospective international multicentric study, CT scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. One-year survival was the primary endpoint and acute decompensation (oHE, variceal bleeding, ascites) was the secondary endpoint. RESULTS: A total of 301 patients (169 male) were included in the training cohort. Thirty percent of all patients presented with >1 SPSS. A TSA cut-off of 83 mm2 was used to classify patients with small or large TSA (S-/L-TSA). Patients with L-TSA presented with higher model for end-stage liver disease score (11 vs. 14) and more commonly had a history of oHE (12% vs. 21%, p <0.05). During follow-up, patients with L-TSA experienced more oHE episodes (33% vs. 47%, p <0.05) and had lower 1-year survival than those with S-TSA (84% vs. 69%, p <0.001). Multivariate analysis identified L-TSA (hazard ratio 1.66; 95% CI 1.02-2.70, p <0.05) as an independent predictor of mortality. An independent multicentric validation cohort of 607 patients confirmed that patients with L-TSA had lower 1-year survival (77% vs. 64%, p <0.001) and more oHE development (35% vs. 49%, p <0.001) than those with S-TSA. CONCLUSION: This study suggests that TSA >83 mm2 increases the risk for oHE and mortality in patients with cirrhosis. Our results support the clinical use of TSA/SPSS for risk stratification and decision-making in the management of patients with cirrhosis. LAY SUMMARY: The prevalence of spontaneous portosystemic shunts (SPSS) is higher in patients with more advanced chronic liver disease. The presence of more than 1 SPSS is common in advanced chronic liver disease and is associated with the development of hepatic encephalopathy. This study shows that total cross-sectional SPSS area (rather than diameter of the single largest SPSS) predicts survival in patients with advanced chronic liver disease. Our results support the clinical use of total cross-sectional SPSS area for risk stratification and decision-making in the management of SPSS.

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.

Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.

BACKGROUND & AIMS: Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS: There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS: In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY: Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) and albumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.

Patients with refractory ascites treated with alfapump® system have better health-related quality of life as compared to those treated with large volume paracentesis: the results of a multicenter randomized controlled study.

BACKGROUND: Refractory ascites (RA) is a complication of cirrhosis which is treated with large volume paracentesis (LVP) as the standard of care. Alfapump® system is a fully implantable pump system which reduces the need for LVP. The aim was to assess health-related quality of life (HRQL) in patients treated with alfapump® versus LVP. METHODS: The data were collected in a multicenter open-label randomized controlled trial (clinicaltrials.gov #NCT01528410). Subjects with cirrhosis Child-Pugh class B or C accompanied by RA were randomized to receive alfapump® or LVP. The SF-36v2 and CLDQ scores were compared between the two treatment arms at screening and monthly during treatment. RESULTS: Of 60 subjects randomized, HRQL data were available for 58 (N = 27 received alfapump® and N = 31 received LVP only). At baseline, no differences were seen between the treatment arms (all p > 0.05): age 61.9 ± 8.4, 79.3% male, MELD scores 11.7 ± 3.3, 85.2% Child-Pugh class B, 70.7% had alcoholic cirrhosis. The mean number of LVP events/subject was lower in alfapump® than LVP (1.1 vs. 8.6, p < 0.001). The HRQL scores showed a moderate improvement from the baseline levels in subjects treated with alfapump® (p < 0.05 for abdominal and activity scores of CLDQ) but not with LVP (all one-sided p > 0.05) in the first 3 months. Multivariate analysis showed that treatment with alfapump® was independently associated with better HRQL at 3 months (total CLDQ score: beta = 0.67 ± 0.33, p = 0.05). CONCLUSION: As compared to LVP, the use of alfapump® system is associated with both a reduction in the number of LVP events and improvement of health-related quality of life.

Duration of the acute hepatic encephalopathy episode determines survival in cirrhotic patients.

BACKGROUND: Episodes of hepatic encephalopathy (HE) have been related to low survival rate. However, the relation between its clinical evolution and mortality has not been assessed. METHODS: A retrospective analysis of 245 cirrhotic patients admitted for an acute episode of HE (⩾grade 2) or who developed an HE episode after an upper gastrointestinal bleeding (UGIB) event was performed to assess the relation between time in HE and transplant-free survival. RESULTS: Median (IQR25-75) time in HE was 48 h (24-96 h) in the whole cohort. Patients who presented a longer time in HE (>48 h; n = 89) exhibited a lower transplant-free survival at 28 days (67.2% versus 88.9%, p < 0.001), 90 days (48.7% versus 73.8%, p < 0.001) and 365 days (30.3% versus 53.2%, p < 0.001), as compared to those with less time in HE (⩽48 h; n = 156). Survival rates remained significantly different, with lower percentages in the group with time in HE >48 h, when comparing patients according to baseline HE grade (2 versus ⩾3) or model for end-stage liver disease (MELD) function (⩽15 versus >15). Time in HE was also an independent risk factor for mortality at each time point, hazard ratio (HR) (95 CI%) 28 days 2.59 (1.39-4.84); 90 days 1.98 (1.28-3.1) and 365 days 1.5 (1.08-2.19). CONCLUSIONS: The duration of the acute HE episode determines survival in cirrhotic patients independently of liver function and baseline HE grade.

Association Between Portosystemic Shunts and Increased Complications and Mortality in Patients With Cirrhosis.

BACKGROUND & AIMS: Spontaneous portosystemic shunts (SPSS) have been associated with hepatic encephalopathy (HE). Little is known about their prevalence among patients with cirrhosis or clinical effects. We investigated the prevalence and characteristics of SPSS in patients with cirrhosis and their outcomes. METHODS: We performed a retrospective study of 1729 patients with cirrhosis who underwent abdominal computed tomography or magnetic resonance imaging analysis from 2010 through 2015 at 14 centers in Canada and Europe. We collected data on demographic features, etiology of liver disease, comorbidities, complications, treatments, laboratory and clinical parameters, Model for End-Stage Liver Disease (MELD) score, and endoscopy findings. Abdominal images were reviewed by a radiologist (or a hepatologist trained by a radiologist) and searched for the presence of SPSS, defined as spontaneous communications between the portal venous system or splanchnic veins and the systemic venous system, excluding gastroesophageal varices. Patients were assigned to groups with large SPSS (L-SPSS, ≥8 mm), small SPSS (S-SPSS, <8 mm), or without SPSS (W-SPSS). The main outcomes were the incidence of complications of cirrhosis and mortality according to the presence of SPSS. Secondary measurements were the prevalence of SPSS in patients with cirrhosis and their radiologic features. RESULTS: L-SPSS were identified in 488 (28%) patients, S-SPSS in 548 (32%) patients, and no shunt (W-SPSS) in 693 (40%) patients. The most common L-SPSS was splenorenal (46% of L-SPSS). The presence and size of SPSS increased with liver dysfunction: among patients with MELD scores of 6-9, 14% had L-SPSS and 28% had S-SPSS; among patients with MELD scores of 10-13, 30% had L-SPSS and 34% had S-SPSS; among patients with MELD scores of 14 or higher, 40% had L-SPSS and 32% had S-SPSS (P < .001 for multiple comparison among MELD groups). HE was reported in 48% of patients with L-SPSS, 34% of patients with S-SPSS, and 20% of patients W-SPSS (P < .001 for multiple comparison among SPSS groups). Recurrent or persistent HE was reported in 52% of patients with L-SPSS, 44% of patients with S-SPSS, and 37% of patients W-SPSS (P = .007 for multiple comparison among SPSS groups). Patients with SPSS also had a larger number of portal hypertension-related complications (bleeding or ascites) than those W-SPSS. Quality of life and transplantation-free survival were lower in patients with SPSS vs without. SPSS were an independent factor associated with death or liver transplantation (hazard ratio, 1.26; 95% confidence interval, 1.06-1.49) (P = .008) in multivariate analysis. When patients were stratified by MELD score, SPSS were associated with HE independently of liver function: among patients with MELD scores of 6-9, HE was reported in 23% with L-SPSS, 12% with S-SPSS, and 5% with W-SPSS (P < .001 for multiple comparison among SPSS groups); among those with MELD scores of 10-13, HE was reported in 48% with L-SPSS, 33% with S-SPSS, and 23% with W-SPSS (P < .001 for multiple comparison among SPSS groups); among patients with MELD scores of 14 or more, HE was reported in 59% with L-SPSS, 57% with S-SPSS, and 48% with W-SPSS (P = .043 for multiple comparison among SPSS groups). Patients with SPSS and MELD scores of 6-9 were at higher risk for ascites (40.5% vs 23%; P < .001) and bleeding (15% vs 9%; P = .038) than patients W-SPSS and had lower odds of transplant-free survival (hazard ratio 1.71; 95% confidence interval, 1.16-2.51) (P = .006). CONCLUSIONS: In a retrospective analysis of almost 2000 patients, we found 60% to have SPSS; prevalence increases with deterioration of liver function. SPSS increase risk for HE and with a chronic course. In patients with preserved liver function, SPSS increase risk for complications and death. ClinicalTrials.gov ID NCT02692430.