Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis.

Background & Aims: Although worsening liver-related symptoms during pregnancy can occur in primary sclerosing cholangitis (PSC), there are insufficient data to effectively counsel patients on their pre-conception risk and no clear recommendations on monitoring and management during pregnancy. We aimed to describe maternal liver-related symptoms in pregnancy, both before and after PSC diagnosis, and explore factors associated with worsening symptoms and liver-related outcomes. Methods: We conducted a multicentre retrospective observational study of females with PSC and known pregnancy with live birth, via the International PSC Study Group. We included 450 patients from 12 European centres. Data included clinical variables, liver-related symptoms (pruritus and/or cholangitis) during pregnancy, and liver biochemistry. A composite primary endpoint of transplant-free survival from time of PSC diagnosis was used. Results: There were 266 pregnancies in 178 patients following PSC diagnosis. Worsening liver-related symptoms were reported in 66/228 (28.9%) pregnancies; they had a reduced transplant-free survival (p = 0.03), which retained significance on multivariate analysis (hazard ratio 3.02, 95% CI 1.24-7.35; p = 0.02).Abnormal biochemistry and/or liver-related symptoms (pruritus and/or cholangitis) were noted during pregnancy before PSC diagnosis in 21/167 (12.6%) patients. They had a reduced transplant-free survival from pregnancy (p = 0.01), which did not retain significance in a multivariable model (hazard ratio 1.10, 95% CI 0.43-2.85; p = 0.84). Conclusions: Liver-related symptoms are frequently encountered during pregnancies before the diagnosis of PSC, and pregnancy may expose the pre-clinical phase of PSC in some patients. Worsening liver-related symptoms were seen in a third of our cohort with known PSC during pregnancy; and this subgroup had a poorer prognosis, which may be related to more advanced liver disease at time of pregnancy and/or a more severe disease phenotype. Impact and implications: Patients with PSC can develop worsening of their liver-related symptoms during pregnancy; however, risk factors for this and the long-term implications are not known. We identified that there is a significant risk of these symptoms in pregnancy, both before and after PSC has been diagnosed, particularly in patients with elevated alkaline phosphatase. Furthermore, our findings suggest that worsening symptoms during pregnancy may be associated with adverse long-term clinical outcomes of liver transplantation and death in patients with known PSC. This may be related to the presence of more advanced liver disease at time of pregnancy. This information can be used to counsel patients with PSC before conception and identify patients who need close follow-up after delivery.

Outcome of pregnancy in patients with primary sclerosing cholangitis.

BACKGROUND: Data on the clinical course of primary sclerosing cholangitis (PSC) during pregnancy remain scarce. Herein, we assessed the maternal and fetal outcomes of pregnancy in this condition. METHODS: We reviewed 104 consecutive female outpatients with PSC using a structured questionnaire. The outcomes were assessed both before and after the diagnosis of PSC. RESULTS: In total, 62 patients (60%) reported 126 pregnancies. Of these, 25 patients reported 44 pregnancies occurring after the diagnosis of PSC. There were two (5%) pregnancies in progress, and among the completed pregnancies there were 34 (80%) live births, six (14%) miscarriages, one (2%) stillbirth, and one (2%) termination. The median neonatal APGAR score was 10, the median body weight was 3375 g and the median body length was 55 cm. In three pregnancies, there was a flare-up of inflammatory bowel disease. In 45 patients, 82 pregnancies occurred before PSC was diagnosed with comparable maternal and fetal outcomes. Out of 42 pregnancies following PSC diagnosis, in 29 UDCA was continued. There was no difference in the fetal outcomes between the UDCA and non-UDCA groups. CONCLUSIONS: Pregnancy in patients with PSC seems to be well tolerated, but should be closely monitored by an obstetrician and an experienced hepatologist.

Relevance of Preoperative Hyperbilirubinemia in Patients Undergoing Hepatobiliary Resection for Hilar Cholangiocarcinoma.

Preoperative hyperbilirubinemia is known to increase the risk of mortality and morbidity in patients undergoing resection for hilar cholangiocarcinoma. The aim of this study was to characterize the associations between the preoperative bilirubin concentration and the risk of postoperative mortality and severe complications to guide decision-making regarding preoperative biliary drainage. Eighty-one patients undergoing liver and bile duct resection for hilar cholangiocarcinoma between 2005 and 2015 were analyzed retrospectively. Postoperative mortality and severe complications, defined as a Clavien⁻Dindo grade of ≥III, were the primary and secondary outcome measures, respectively. The severe postoperative complications and mortality rates were 28.4% (23/81) and 11.1% (9/81), respectively. Patients with preoperative biliary drainage had significantly lower bilirubin concentrations (p = 0.028) than did those without. The preoperative bilirubin concentration was a risk factor of postoperative mortality (p = 0.003), with an optimal cut-off of 6.20 mg/dL (c-statistic = 0.829). The preoperative bilirubin concentration was a risk factor of severe morbidity (p = 0.018), with an optimal cut-off of 2.48 mg/dL (c-statistic = 0.662). These results indicate that preoperative hyperbilirubinemia is a major risk factor of negative early postoperative outcomes of patients who undergo surgical treatment for hilar cholangiocarcinoma and may aid in decision-making with respect to preoperative biliary drainage.

Challenging the principle of utility as a barrier for wider use of liver transplantation for hepatocellular cancer.

BACKGROUND: Although transplant benefit appears superior for patients with advanced hepatocellular cancer (HCC), liver transplantation remains limited to selected low-risk HCC patients to keep their outcomes similar to heterogeneous group of non-HCC patients. The purpose of this study was to assess the rationale for current policy of restricting access to liver transplantation to minority of HCC patients based on utility principle. METHODS: This retrospective cohort study comprised 1246 liver transplant recipients, including 206 HCC and 1040 non-HCC patients. Patient survival was the primary outcome measure. Patients with HCC and benign diseases were divided into low-, moderate-, and high-risk subgroups basing on independent risk factors for disease-free survival and model for end-stage liver disease (MELD) score (<30, 30-40, >40), respectively. RESULTS: MELD (p < 0.001) and presence of HCC (p = 0.008) were independent risk factors for early and late mortality, respectively. Total tumor volume (p = 0.008) and alpha-fetoprotein (p = 0.013) were independent predictors of recurrence and mortality used for division of HCC patients into low-, moderate-, and high-risk subgroups, with disease-free survival rates of 74.9% (5 years), 51.7% (5 years), and 8.0% (3 years), respectively (p < 0.001). There were no differences in 5-year overall survival between low-risk HCC (74.9%) and non-HCC (81.9%) patients (p = 0.210), moderate-risk HCC (63.3%) and non-HCC (68.0%) patients (p = 0.372), and high-risk HCC (55.0%) and non-HCC (56.0%) patients (p = 0.559). CONCLUSIONS: The principle of utility is unequally applied for restriction of access to liver transplantation for HCC patients. The results provide rationale for discussion on reinitiation of liver transplantation for advanced HCCs.

Effects of continuous use of probiotics before liver transplantation: A randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Although there is increasing evidence for the benefits of probiotics in patients with liver diseases, data on the benefits of pre-LT administration of probiotics are lacking. The aim of this study was to evaluate the effects of continuous administration of probiotics before liver transplantation (LT) on pre- and post-transplant patient outcomes. METHODS: In this randomized, double-blind, and placebo-controlled trial adult cirrhotic patients listed for LT received a 4-strain probiotic preparation or placebo daily from enrollment until LT. The primary outcome measures were postoperative mortality and infection rates. The secondary outcome measures were 5-day post-transplant aspartate and alanine aminotransferase activities, bilirubin concentration, and international normalized ratio; waiting-list mortality; pre-transplant Model for End-stage Liver Disease score and Child-Turcotte-Pugh class changes; and pre-transplant infections. RESULTS: A total of 55 patients were randomized. The 90-day postoperative mortality rates were 0% and 4.3% in the probiotic and placebo groups, respectively (p > 0.99). Patients receiving probiotics had significantly reduced 30-day (4.8% versus 34.8%, p = 0.02) and 90-day (4.8% versus 47.8%, p = 0.002) infection rates, lower post-LT bilirubin concentration (p = 0.02), and more rapid decrease of aspartate (p = 0.03) and alanine (p = 0.03) aminotransferase activities. Probiotics did not have significant effects on other secondary outcome measures. CONCLUSIONS: Although continuous administration of probiotics before LT does not appear to affect postoperative mortality, it effectively prevents postoperative infections and improves early biochemical parameters of allograft function. CLINICALTRIALS. GOV IDENTIFIER: NCT01735591.

Liver Transplantation Outcomes in Recipients with High Model for End-Stage Liver Disease (MELD) Scores: The Relevance of MELD Scores.

BACKGROUND The aim of this study was to assess risk factors for postoperative mortality after liver transplantation among patients with Model for End-Stage Liver Disease (MELD) scores ≥35, with special focus on the MELD scores. MATERIAL AND METHODS Data from 68 primary liver transplantations in patients with MELD scores ≥35 among 1376 liver transplantations performed in the Department of General, Transplant, and Liver Surgery (Medical University of Warsaw) between January 2002 and October 2014 were analyzed retrospectively. Postoperative (90-day) mortality was set as the primary outcome measure. RESULTS Postoperative mortality was 29.4% (20 of 68). The overall survival rates after 1, 5, and 10 years were 61.9%, 59.7%, and 59.7%, respectively. According to univariate analyses, MELD (p=0.014), conventional technique of liver transplantation (p=0.049), intraoperative fresh frozen plasma (p=0.040), and red blood cells (p=0.026) transfusions were risk factors for postoperative mortality. MELD score was the only independent risk factor for postoperative mortality (p=0.023) in multivariate analysis. According to receiver operating characteristics analysis, the optimal cut-off for MELD score in prediction of postoperative mortality was ≥43 (Area Under Curve=0.703, 95% Confidence Interval 0.575-0.831). Postoperative mortality was 21.4% and 42.3% among patients with MELD score <43 and ≥43, respectively (p=0.066). CONCLUSIONS MELD score is an important predictor of early mortality after liver transplantation, even among recipients with high MELD scores. In particular, patients with MELD score ≥43 should be considered as very high-risk candidates for liver transplantation.

Limitations of predicting microvascular invasion in patients with hepatocellular cancer prior to liver transplantation.

Microvascular invasion (MVI) is well known to negatively influence outcomes following surgical treatment of hepatocellular cancer (HCC) patients. The aim of this study was to evaluate the rationale for prediction of MVI before liver transplantation (LT). Data of 200 HCC patients after LT were subject to retrospective analysis. MVI was present in 57 patients (28.5%). Tumor number (p = 0.001) and size (p = 0.009), and alpha-fetoprotein (p = 0.049) were independent predictors of MVI used to create a prediction model, defined as: 0.293x(tumor number) + 0.283x(tumor size in cm) + 0.164xloge(alpha-fetoprotein in ng/ml) (c statistic = 0.743). The established cut-off (≥2.24) was associated with sensitivity and specificity of 72%. MVI was not an independent risk factor for recurrence (p = 0.307), in contrast to tumor number (p = 0.047) and size (p < 0.001), alpha-fetoprotein (p < 0.001) and poor differentiation (p = 0.039). Recurrence-free survival at 5 years for patients without MVI was 85.9% as compared to 83.3% (p = 0.546) and 55.3% (p = 0.001) for patients with false negative and true positive prediction of MVI, respectively. The use of both morphological and biological tumor features enables effective pre-transplant prediction of high-risk MVI. Provided that these parameters are combined in selection of HCC patients for LT, pre-transplant identification of all patients with MVI does not appear necessary.

The Warsaw Proposal for the Use of Extended Selection Criteria in Liver Transplantation for Hepatocellular Cancer.

BACKGROUND: Combination of the University of California, San Francisco (UCSF) and the up-to-7 criteria with alpha-fetoprotein (AFP) cutoff of 100 ng/ml was proposed as the Warsaw expansion of the Milan criteria in selection of hepatocellular cancer (HCC) patients for liver transplantation. The purpose of this retrospective study was to validate this proposal. METHODS: A total of 240 HCC patients after liver transplantation were included. Recurrence-free survival and overall survival at 5 years were set as the primary and secondary outcome measures, respectively. RESULTS: The Warsaw expansion increased transplant eligibility rate by 20.3 %. AFP >100 ng/ml significantly increased the recurrence risk in patients within the Milan criteria (p = 0.025) and in those beyond, yet within either the UCSF or the up-to-7 criteria (p < 0.001). Recurrence-free survival at 5 years was 90.8 % for patients within the Milan criteria, 100.0 % in patients within the Warsaw expansion, 54.9 % in patients beyond the Warsaw expansion but within either the UCSF or the up-to-7 criteria, and 45.1 % in patients beyond both the UCSF and the up-to-7 criteria (p < 0.001). The corresponding overall survival rates were 71.6, 82.4, 64.3, and 55.3 %, respectively (p = 0.027). CONCLUSIONS: The Warsaw expansion of the Milan criteria substantially increases the recipient pool without compromising outcomes.