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.

ABO blood group does not influence Child-Pugh A cirrhosis outcome: An observational study from CIRRAL and ANRS CO12 CIRVIR cohorts.

BACKGROUND AND AIMS: Non-O blood group promotes deep vein thrombosis and liver fibrosis in both general population and hepatitis C. We aimed to evaluate the influence of Non-O group on the outcome of Child-Pugh A cirrhotic patients. METHODS: We used two prospective cohorts of Child-Pugh A cirrhosis due to either alcohol or viral hepatitis. Primary end point was the cumulated incidence of 'Decompensation' at 3 years, defined as the occurrence of ascites , hydrothorax, encephalopathy, gastrointestinal bleeding related to portal hypertension, or bilirubin >45 µmol/L. Secondary end points were the cumulated incidences of (1) 'Disease Progression' including a « decompensation¼ or « the occurrence of one or more parameters ¼ among: prothrombin time (PT) <45%, albumin <28 g/L, Child-Pugh worsening (B or C vs A or B, C vs B), hepatorenal syndrome, and hepato-pulmonary syndrome, (2) other events such as non-malignant portal vein thrombosis (nmPVT), and (3) overall survival. RESULTS: Patients (n = 1789; 59.9% Non-O group; 40.1% group O) were followed during a median of 65.4 months. At 3 years cumulated incidence of Decompensation was 8.3% in Non-O group and 7.2% in group O (P = .27). Cumulated incidence of Disease Progression was 20.7% in Non-O group and 18.9% in group O (P = .26). Cumulated incidence of nmPVT was 2.7% in Non-O group and 2.8% in group O (P = .05). At 3 years overall survival was 92.4% in Non-O group and 93.4% in group O (P = 1). CONCLUSION: Non-O group does not influence disease outcome in Child-Pugh A cirrhotic patients. Clinicals trial number NCT03342170.

Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies.

Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypic features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches, with a special focus on imaging.

Portal cavernoma or chronic non cirrhotic extrahepatic portal vein obstruction.

Chronic non cirrhotic extrahepatic portal vein obstruction (EHPVO) refers to the cavernomatous transformation of the portal vein (the so-called "portal cavernoma") which occurs following acute thrombosis of the portal vein in the absence of recanalization. In adults, EHPVO mainly occurs following thrombosis, while in children it may be related to congenital malformations and/or neonatal umbilical venous catheterization. However, 50% of the cases of EHPVO remain idiopathic [1]. Risk factors and associated diseases should be investigated (chapter 1). Indeed, the presence of a thrombophilic alteration, in particular myeloproliferative neoplasm impacts prognosis and determine a causal treatment.

Sinusoidal obstruction syndrome.

Sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, is characterized by concentric and non-thrombotic obstruction of the sinusoid and central vein lumen with no identified primitive or thrombotic hepatic vein lesions. The initial lesion is a result of endothelial denudation, corresponding to the migration of damaged sinusoidal cells to the central veins of the hepatic lobules, leading to sinusoidal and veno-occlusive congestive obstruction. SOS may be associated with other lesions such as centrilobular perisinusoidal fibrosis, peliosis, or nodular regenerative hyperplasia. The first cases of SOS were documented in 1920 in South Africa, after ingestion of food sources contaminated by pyrrolizidine alkaloids. SOS is a well-known complication of hematopoietic stem cell transplantation (HSCT). Numerous toxins and drugs have been associated with SOS, mainly chemotherapies and immunosuppressive therapies, as well as total body or liver irradiation and ABO mismatch platelet transfusion. The pathogenesis of this entity remains unknown.

Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy.

BACKGROUND & AIMS: Management of patients with cirrhosis includes endoscopic screening and surveillance to detect esophageal varices (EV) and prevent bleeding. However, the Baveno VI guidelines recommend avoiding endoscopies for patients with liver stiffness measurements below 20 kPa and platelet counts above 150,000 (favorable Baveno VI status) and endoscopic assessment of patients with higher levels of liver stiffness and platelet counts (unfavorable Baveno VI status). We aimed to validate the Baveno VI guidelines, evaluating outcomes of patients in the ANRS-CO12 CirVir cohort with compensated cirrhosis associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, with or without a sustained response to antiviral therapy. METHODS: We performed an ancillary study using data from 891 patients in the ANRS CO12 CirVir cohort, treated at 35 centers in France, with HCV or HBV infection and biopsy-proven cirrhosis, Child-Pugh A scores, no previous complications, and no hepatocellular carcinoma who underwent an endoscopic procedure and had interpretable liver stiffness measurements and platelet counts. Progression of portal hypertension (PHT) was defined as the onset of varices needing treatment (VNT) or PHT-related bleeding. An sustained response to antiviral therapy was defined as undetectable level of HCV RNA by polymerase chain reaction assay (<50 IU/mL) 12 weeks after the end of treatment (SVR) or an undetectable level of HBV DNA. The primary aims were to validate the Baveno VI guidelines for screening and surveillance of EV in patients with compensated cirrhosis and to study the effects of an SVR on the progression of PHT. RESULTS: A total of 200 patients achieved an SVR (22.4%) (94 patients with HCV infection, 98 patients with HBV infection, and 8 patients with both); 80 of these patients had favorable Baveno VI status and none had VNT. Progression of PHT was studied in 548 patients; during a follow-up period of 61.2 months (interquartile range, 39.5-80.6 months), 105 of these patients (19.1%) had progression of PHT. Lack of an SVR and grade 1 EV were independently associated with progression of PHT. At the time of PHT progression, all patients had unfavorable Baveno VI status. Achieving favorable Baveno VI status after an SVR was associated with the absence of PHT progression. Favorable Baveno VI status and SVR were independently associated with survival. CONCLUSIONS: In an analysis of data from a large cohort of patients with HBV- or HCV-associated cirrhosis in France, we validated the Baveno VI guidelines on screening and surveillance of PHT, even for patients who achieved a sustained response to antiviral therapy.

Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort).

OBJECTIVE: To assess incidence and prognostic significance of bacterial infections (BIs) occurring in compensated viral cirrhosis. DESIGN: This prospective study involved 35 French centres. Inclusion criteria were biopsy-proven HCV or HBV cirrhosis, Child-Pugh A and no previous hepatic complications. Cumulative incidence (CumI) of events was estimated in a competing risks framework. RESULTS: 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31). During a median follow-up of 43 months, 234 BIs occurred in 171 patients (5 year CumI: 12.9%), among whom 14.6% had septic shock. Main localisations included the urinary tract (27.4%), lung (25.2%) and peritoneum (10.7%) (other, 86 (36.7%)). Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%) and were community-acquired (CA, 84.2%). The risk of BI was higher in patients with HCV than in patients with HBV (5 year CumI: 15.2% vs 5.5%, p=0.0008). Digestive localisation, concomitant interferon-based treatment, isolation of resistant bacteria and non-CA BIs were associated with lowest probability of resolution. The occurrence of a first BI impaired survival in patients infected with HCV (5 year survival: 60.2% vs 90.4%, p<0.001) and patients infected with HBV (5 year survival: 69.2% vs 97.6%, p<0.001). BIs represented the third cause of death (14.1%) after liver failure and liver cancer. BI risk factors comprised older age, lower albumin, proton pump inhibitor intake and absence of virological eradication/control. CONCLUSION: BI mostly occurs as a first complication and represents a turning point in the course of compensated viral cirrhosis. Its occurrence impacts long-term prognosis and may define a subgroup of patients in whom adaptation of management is warranted.

Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).

UNLABELLED: Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). CONCLUSION: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control.

Obliterative portal venopathy: findings at CT imaging.

PURPOSE: To retrospectively analyze the computed tomographic (CT) findings in a single-center series of adult patients with biopsy-proved obliterative portal venopathy (OPV) and to compare them with those observed in patients with cirrhosis. MATERIALS AND METHODS: The requirement for informed consent was waived. This institutional review board-approved study included 42 consecutive patients with a histologically proved diagnosis of OPV who underwent CT at diagnosis. The clinical characteristics at diagnosis were recorded, and CT examination results were reviewed. Two radiologists evaluated portal vein patency and intrahepatic portal branches, the morphologic changes in the liver, the presence of hepatic nodules, and signs of portal hypertension in consensus. The control group consisted of 42 patients who had histologically proved cirrhosis. CT findings were compared between the OPV patient group and the cirrhotic group and also among the conditions associated with patients with OPV. The Fisher exact test was used. P values of .05 or less were considered to indicate significant differences. RESULTS: The following CT findings were observed significantly more frequently in OPV than in cirrhosis: extrahepatic portal vein thrombosis (18 [43%] of 42 vs five [12%] of 42); intrahepatic portal abnormalities (18 [58%] of 31 vs one [2%] of 42) such as reduced caliber, occlusive thrombosis, and lack of visibility; focal nodular hyperplasia-like nodules (six [14%] of 42 vs 0 [0%] of 42); and perfusion disorders (15 [36%] of 42 vs six [14%] of 42). Conversely, the combination of hypertrophy of the caudate lobe and atrophy of segment IV (27 [64%] of 42 vs 10 [24%] of 42) and nodular surface (37 [88%] of 42 vs seven [17%] of 42) were seen significantly more often in cirrhosis. CONCLUSION: Characteristic CT findings in patients with OPV that differ from those in patients with cirrhosis were shown, the most common being the presence of intra- or extrahepatic portal abnormalities.

Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.

UNLABELLED: Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups. CONCLUSION: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures.

Obliterative portal venopathy: portal hypertension is not always present at diagnosis.

BACKGROUND & AIMS: Previous studies on obliterative portal venopathy (OPV) have been biased due to the selection of patients with non-cirrhotic portal hypertension. The aim of this study was to clarify the characteristics of OVP diagnosed by liver biopsy. METHODS: Fifty-nine consecutive patients with OPV were retrospectively selected on strict histological criteria. Clinical, laboratory, portal vein patency, and associated disorders potentially involving vascular alterations were analyzed. The occurrence of complications was recorded during follow-up. RESULTS: Mean age at diagnosis was 38.5±15 years old. Initial presentation was portal hypertension (64% of patients) and/or extrahepatic portal vein thrombosis (EHPVT) (22%) or isolated abnormal laboratory tests (20%). Associated diseases found at diagnosis were: prothrombotic disorders (30% of patients) and immune-mediated disorders (17%); 53% of patients had no causal factor (idiopathic OPV). During follow-up (median 8.6 years, range 1-23 years), features of portal hypertension worsened in 46% of patients; EHPVT and portal hypertension were finally found in 44% and 88% of patients. Anti-coagulation and beta-blockers were administered in 47% and 59% of patients, respectively. Severe complications (liver transplantation and/or death) occurred in 11 (19%) patients, 8 had idiopathic OPV. Patients with prothrombotic disorders received earlier anticoagulation therapy; all survived without transplantation. CONCLUSIONS: A confident diagnosis of OPV can be done by biopsy and is conceivable in patients under 40 years without clinically significant portal hypertension. Poor outcome was noted in 19% of patients, most of them affected with idiopathic OPV. Patients with prothrombotic disorders received early anticoagulation and appeared to have a better outcome despite a high proportion of EHPVT.

Immediate listing for liver transplantation versus standard care for Child-Pugh stage B alcoholic cirrhosis: a randomized trial.

BACKGROUND: Liver transplantation improves survival of patients with end-stage (Child-Pugh stage C) alcoholic cirrhosis, but its benefit for patients with stage B disease is uncertain. OBJECTIVE: To compare the outcomes of patients with Child-Pugh stage B alcoholic cirrhosis who are immediately listed for liver transplantation with those of patients assigned to standard treatment with delay of transplantation until progression to stage C disease. DESIGN: Randomized, controlled trial. SETTING: 13 liver transplantation programs in France. PATIENTS: 120 patients with Child-Pugh stage B alcoholic cirrhosis and no viral hepatitis, cancer, or contraindication to transplantation. INTERVENTIONS: Patients were randomly assigned to immediate listing for liver transplantation (60 patients) or standard care (60 patients). MEASUREMENTS: Overall and cancer-free survival over 5 years. RESULTS: Sixty-eight percent of patients assigned to immediate listing for liver transplantation and 25% of those assigned to standard care received a liver transplant. All-cause death and cirrhosis-related death did not statistically differ between the 2 groups: 5-year survival was 58% (95% CI, 43% to 70%) for those assigned to immediate listing versus 69% (CI, 54% to 80%) for those assigned to standard care. In multivariate analysis, independent predictors of long-term survival were absence of ongoing alcohol consumption (hazard ratio, 7.604 [CI, 2.395 to 24.154]), recovery from Child-Pugh stage C (hazard ratio, 7.633 [CI, 2.392 to 24.390]), and baseline Child-Pugh score less than 8 (hazard ratio, 2.664 [CI, 1.052 to 6.746]). Immediate listing for transplantation was associated with an increased risk for extrahepatic cancer: The 5-year cancer-free survival rate was 63% (CI, 43% to 77%) for patients who were immediately listed and 94% (CI, 81% to 98%) for those who received standard care. LIMITATION: Restriction of the study sample to alcoholic patients may limit the generalizability of results to other settings. CONCLUSION: Immediate listing for liver transplantation did not show a survival benefit compared with standard care for Child-Pugh stage B alcoholic cirrhosis. In addition, immediate listing for transplantation increased the risk for extrahepatic cancer. FUNDING: The French National Program for Clinical Research.

Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.

BACKGROUND: In patients with cirrhosis, refractory ascites is associated with a poor prognosis and is an indication for liver transplantation. However, factors that determine prognosis remain unclear. AIMS: To investigate the predictive factors of prognosis in patients with refractory ascites. METHODS: Seventy-five patients with refractory ascites were followed-up for 18+/-13 months (mean+/-SD) and survival was analyzed. RESULTS: The 1-year probability of survival was 52%. Univariate analyses showed that older patients, hepatocellular carcinoma and diabetes, all assessed at entry, were associated with significantly increased risk ratios of death. The risk ratio of death was significantly lower in abstinent alcoholics than in patients with nonalcoholic cirrhosis. The risk ratio of death did not significantly differ between patients with nonalcoholic cirrhosis and nonabstinent alcoholics. Child-Pugh score at entry had no prognostic value. Multivariate analysis showed that older age, hepatocellular carcinoma, diabetes and abstinence were independent prognostic factors. CONCLUSIONS: In patients with cirrhosis and refractory ascites, older age, hepatocellular carcinoma and diabetes, but not Child-Pugh score at entry, were independent predictive factors of poor survival while abstinence was an independent predictive factor of good survival. These findings should be taken into account when deciding on liver transplantation in patients with refractory ascites.