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Primary sclerosing cholangitis is a cholestatic disease with a low prevalence in Italy. Indications for liver transplantation and the time of listing are not stated. We performed a national survey to investigate the listing criteria, comorbidities, and outcomes. In April 2022, we surveyed liver transplantation in primary sclerosing cholangitis nationwide for the last 15 years. From 2007 to 2021, 445 patients were included on waiting lists, and 411 had undergone liver transplants. The median age at transplantation was 46 years (males 63.9%); 262 patients (59%) presented an inflammatory bowel disease. Transplants increased over the years, from 1.8 % in 2007 to 3.0 % in 2021. Cholangitis (51%) and hepatic decompensation (45%) were the main indications for listing. The disease recurred in 81 patients (20%). Patient survival after the first transplant was 94 %, 86% and 84% at one, five, and ten years. Twenty-four died in the first year (50% surgical complications, 25% infections); 33 between one to five years (36% recurrence, 21% cholangiocarcinoma recurrence) and nine after five years (56% de novo cancer, 44% recurrence). Primary sclerosing cholangitis has been an increasing indication for transplantation in Italy. Cholangitis and decompensation were the main indications for listing. Recurrence and cancer were the leading causes of death. [ABSTRACT FROM AUTHOR]

Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. We recruited from the National Transplant Registry a cohort comprising 17,317 adults patients waitlisted for primary liver transplantation from January-2004 to December-2020. Patients were divided into three Eras:1(2004–2011),2(2012–2014) and 3(2015–2020). Waitlistings for cirrhosis decreased from 65.9% in Era 1 to 46.1% in Era 3, while those for HCC increased from 28.7% to 48.7%. Comparing Eras 1 and 3, waitlistings for HCV-related cirrhosis decreased from 35.9% to 12.1%, yet those for HCV-related HCC increased from 8.5% to 26.7%. Waitlistings for HBV-related cirrhosis remained almost unchanged (13.2% and 12.4%), while those for HBV-related HCC increased from 4.0% to 11.6%. ALD-related cirrhosis decreased from 16.9% to 12.9% while ALD-related HCC increased from 1.9% to 3.9%. A sharp increase in liver transplant waitlisting for HCC and a concomitant decrease of waitlisting for cirrhosis have occurred In Italy. Despite HCV infection has noticeably decreased, still remains the primary etiology of waitlisting for HCC, while ALD and HBV represent the main causes for cirrhosis. [ABSTRACT FROM AUTHOR]

Sarcopenia, defined as progressive and generalized loss of muscle mass and strength, is common in chronic liver disease. It significantly impacts the quality of life and increases the risk of liver-related complications and mortality in cirrhotic patients. Moreover, recent studies showed a negative impact of sarcopenia on patients awaiting liver transplantation (LT), on post-LT outcomes, and on response to hepatocellular carcinoma therapies. Data about the influence of sex on the incidence, prevalence, diagnosis and treatment of sarcopenia in chronic liver diseases are poor and conflicting. The aims of this review of the literature are to define sex differences in sarcopenic cirrhotic patients and to highlight the necessity of a sex stratified analysis in future studies. This analysis of the literature showed that most of the studies are retrospective, with a higher prevalence of sarcopenia in males, probably due to anatomical differences between the sexes. Moreover, diagnostic criteria for sarcopenia are different between studies, as there is not a defined cut-off and, as a consequence, no comparable results. In conclusion, sex seems to have an impact on sarcopenia, and future studies must accurately investigate its role in identifying and treating high-risk patients, reducing the negative impact of sarcopenia on the survival and quality of life of cirrhotic patients. [ABSTRACT FROM AUTHOR]

Missed or inappropriate referrals of potential candidates for liver transplantation (LT) are common and traditional referral methods (t Rs) do not allow for efficient triage. We investigated the effects of a website developed for electronic outpatient referral to LT (e RW-LT) on these issues. We prospectively collected data on all consecutive outpatient referrals to 2 Italian LT centers from January 2015 to December 2019. In the second half of the study, starting from July 2017, referring physicians had the option of using e RW-LT, quickly obtaining the judgment on the appropriateness and urgency of the visit from a transplant hepatologist. In the second half of the study, there were 99 e RW-LTs and 96 traditional referrals (new t Rs), representing a 17.4% increase over the 161 traditional referrals (old t Rs) of the first half. With e RW-LT, 11.1% of referrals were judged inappropriate online without booking a visit. Appropriateness, judged at the time of the first visit, was 59.6%, 56.2%, and 94.3% with old t Rs, new t Rs, and e RW-LT, respectively. Considering the appropriate visits, the median waiting time in days between referral date and first visit appointment was significantly shorter for urgent visits referred with e RW-LT (5.0; 95% CI, 4.8–9.3) compared with nonurgent visits sent with the same system (17.0; 95% CI, 11.5–25.0; P <.0001), those referred with old t Rs (14.0; 95% CI, 8.0–23.0; P <.001) and with new t Rs (16.0; 95% CI, 10.0–23.0; P <.001). e RW-LT allows an increase in the number of referrals for LT, ensuring effective triage and better appropriateness of visits. [ABSTRACT FROM AUTHOR]

Women who have undergone liver transplantation (LT) enjoy better health, and possibility of childbearing. However, maternal and graft risks, optimal immunosuppression, and fetal outcome is still to clarify. Aim of the study was to assess outcomes of pregnancy after LT at national level. In 2019, under the auspices of the Permanent Transplant Committee of the Italian Association for the Study of the Liver, a multicenter survey including 14 Italian LT-centers was conducted aiming at evaluating the outcomes of recipients and newborns, and graft injury/function parameters during pregnancy in LT-recipients. Sixty-two pregnancies occurred in 60 LT-recipients between 1990 and 2018. Median age at the time of pregnancy was 31-years and median time from transplantation to conception was 8-years. During pregnancy, 4 recipients experienced maternal complications with hospital admission. Live-birth-rate was 100%. Prematurity occurred in 25/62 newborns, and 8/62 newborns had low-birth-weight. Cyclosporine was used in 16 and Tacrolimus in 37 pregnancies, with no different maternal or newborn outcomes. Low-birth-weight was correlated to high values of AST, ALT and GGT. Pregnancy after LT has good outcome; however, maternal complications and prematurity may occur. Compliance with the immunosuppression is fundamental to ensure the stability of graft function and prevent graft-deterioration. [ABSTRACT FROM AUTHOR]

Abstract Background Upper endoscopy is the main tool for the accurate assessment of the risk of bleeding in cirrhotic patients. Aim To evaluate the diagnostic accuracy of upper endoscopy, in cirrhotic subjects, during common clinical practice. Methods 120 endoscopic reports produced in different hospitals in our region were retrospectively and randomly selected. After a general evaluation, aimed at assessing the description of various endoscopic features, reports were evaluated by four expert endoscopists and four expert hepatologists. Experts were asked to fill in a questionnaire for each single endoscopic procedure, regarding the diagnostic accuracy of the report. Results Endoscopic reports lacked descriptions of the size of esophageal varices and red signs in 14% and 29% of cases respectively. Presence (or absence) of gastric varices or portal hypertensive gastropathy were not reported in 62% and 34% of cases respectively. According to expert endoscopists 41% of the reports were incomplete, while, according to hepatologists, reports were incomplete and inadequate for clinical purposes in 36% of cases. Conclusion Our study clearly evidenced a significant lack of information in reports on upper endoscopy in cirrhotic patients, and supports the prompt adoption of corrective strategies. [ABSTRACT FROM AUTHOR]

Background Vascular endothelial growth factor (VEGF) is one of several angiogenic factors expressed in cirrhosis and during progression to malignancy, that seem to play a major role in hepatocellular carcinoma development. Lately, another angiogenic factor, epidermal growth factor-like domain multiple 7 (EGFL7), has attracted interest due to its possible relationship with hepatocellular carcinoma metastasis. Aims To evaluate expression of VEGF and EGFL7 in human hepatocellular carcinoma, compared to corresponding cirrhotic surrounding tissue. Methods Tumoural and cirrhotic tissue was harvested from 12 consecutive patients undergoing surgical resection. VEGF and EGFL7 were assessed by immunofluorescence and quantitative reverse transcriptase-polymerase chain reaction, compared with normal controls. Results Both angiogenic factors were over-expressed in cirrhotic livers compared to normal controls. VEGF and EGFL7 expressions did not differ according to disease aetiology, nodule size or other clinical variables. While VEGF expression was constant, regardless of tumour differentiation stage and unchanged compared to surrounding cirrhotic tissue, EGFL7 expression increased in less differentiated hepatocellular carcinoma. Conclusions The preferential expression of EGFL7 in less differentiated hepatocellular carcinoma compared to VEGF, suggests a possible important role of this angiogenic factor in a later oncogenic and infiltrative/metastatic phase. [ABSTRACT FROM AUTHOR]

Background We evaluated efficacy and safety of sofosbuvir and daclatasvir ± ribavirin in liver transplant recipients with severe recurrent hepatitis C. Methods Patients included in an international compassionate use programme for treatment with sofosbuvir and daclatasvir ± ribavirin for 24 weeks were prospectively studied. Serum hepatitis C virus RNA was measured at treatment weeks 4, 12, and 24 and during follow-up at weeks 4, 8, and 12. Results Twelve patients (3 with fibrosing cholestatic hepatitis and 9 with cirrhosis; median model for end-stage liver disease score 20) received sofosbuvir 400 mg/day + daclatasvir 60 mg/day, and 6 patients (50%) also received ribavirin 200–800 mg/day. Nine patients completed 24 weeks of treatment (75%), and all had undetectable hepatitis C virus RNA at week 24; 3 patients died (25%, liver failure, gastrointestinal bleeding and sepsis); 4 patients experienced severe liver disease-related adverse events. Post-treatment hepatitis C virus RNA was available for 5 patients (week 8, n = 2; week 4, n = 3) and was undetectable in all cases. Mean Child–Pugh score and albumin level improved significantly at week 24. No changes in immunosuppressant doses were needed. Conclusion All-oral sofosbuvir plus daclatasvir combination shows high virological efficacy in liver transplant recipients and does not interact with immunosuppressants. All adverse events were unrelated to study drugs. These data strongly suggest that this combination must be initiated before decompensation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Aim of the present study was to investigate whether 1,25(OH)(2)D(3) (Vitamin D3) modulates T lymphocyte functions in patients transplanted for hepatitis C virus-related cirrhosis. Methods: Sixteen patients and ten healthy subjects were investigated. T lymphocytes were activated in vitro in the presence or absence of Vitamin D3 and then the proliferative response and IFN-γ and TNF-α production were assessed. Results: Vitamin D3 potently reduced T-lymphocyte proliferation in a dose-related fashion. Similarly, FACS analysis and ELISA testing demonstrated that Vitamin D3 significantly decreased the response frequency and the response intensity of IFN-γ and TNF-α production in the whole CD3-positive T lymphocyte population as well as in “naive” CD4+ CD45RA+ and “memory” CD4+ CD45RO+ T lymphocyte subsets. The inhibitory effect of Vitamin D3 on T-cell proliferation and cytokine production was not different between patients and controls. No toxic effects were exerted by Vitamin D3 even at the higher concentration used (10nM). Finally, no statistically significant correlation was found between 25(OH)D serum levels and the proliferative response or cytokine production of T lymphocytes from transplanted patients. Conclusions: This study demonstrates that in patients transplanted for hepatitis C virus-related cirrhosis Vitamin D3 modulates T lymphocyte activation, and provides a rationale for the evaluation of this compound as an immunosuppressive agent in liver-transplanted patients. [Copyright &y& Elsevier]

Abstract: Background: Life-long prophylaxis against HBV recurrence is recommended in patients transplanted for HBV-related disease. The risk of HBV reactivation is due to persistence of covalently closed circular (ccc) DNA in hepatocytes. Whether cccDNA persists in livers of long-term transplant survivors who received conventional prophylaxis is unknown. Aim: To investigate the presence of intrahepatic total and cccDNA in transplanted patients with no evidence of biochemical markers of HBV recurrence. Methods: Intrahepatic total and cccDNA were assessed using sensitive nested and real-time PCR from 44 HBsAg-positive patients (75% male; mean age 55.2±8.9 years) who had undetectable serum HBV-DNA at transplant. The mean follow-up after transplant was 88.3 months (range, 18–159). Results: One patient underwent HBV recurrence after transplant and was the only who tested positive for both intrahepatic total HBV-DNA and cccDNA. Of the 43 patients negative for all serological markers of HBV infection, only 2 tested positive for intrahepatic total HBV-DNA, but none for cccDNA. Conclusions: Most patients with undetectable HBV-DNA at transplant, who received conventional HBV prophylaxis, have no evidence of intrahepatic total HBV-DNA and cccDNA. cccDNA should be considered a new additional diagnostic tool, also to identify patients at low risk of HBV recurrence after liver transplantation. [Copyright &y& Elsevier]

Abstract: Background: Fibrosis in liver transplant recipients with recurrent HCV is fast, yet, different patterns of progression are recognized. Aims: To investigate histological findings associated with maintenance ribavirin monotherapy in patients with recurrent HCV transplanted ≥4 years earlier. Methods: 14 recipients at high risk of progression (fibrosis progression rate >0.33 units/year and/or persistently elevated ALT) were assigned to receive ribavirin for 3 years. 11 patients at lower risk of progression (FPR ≤0.33 units/year and normal ALT) as controls. Biopsies were obtained yearly since transplant and 7 consecutive biopsies were evaluated. Results: Improved necroinflammation (reduction ≥2 grading) was observed in 7 treated with ribavirin and 3 untreated patients, while 1 and 3 patients worsened respectively. Fibrosis improved (reduction >1 staging) in 2 ribavirin-treated patients, unchanged in 10 and worsened (increase ≥1 staging) in 2. Fibrosis progression decreased from 0.48±0.27 observed during the 3-year pre-treatment period to 0.04±0.31 units/year (p =0.003) during the 3 years of ribavirin. Among untreated fibrosis remained unchanged in 1 and worsened in 10 (p <0.001), yearly fibrosis progression rate increasing from 0.15±0.17 units/year to 0.42±0.39 units/year (p =0.10). Conclusions: Maintenance ribavirin monotherapy delays fibrosis progression in high risk patients, offering an alternative strategy for those failing to respond to conventional treatment. [Copyright &y& Elsevier]

Abstract: Introduction: Bile leaks are a frequent complication of adult split liver transplantation. We compared surgical complications in patients who had the cut surface of the donor liver treated with a patch to those in whom the cut surface of the liver was treated with fibrin glue. Material and methods: Two consecutive cohorts of 16 patients undergoing adult right lobe split liver transplant were compared. In the first cohort, the liver surface was treated with fibrin glue and in the second the liver surface was treated with TachoSil® fibrinogen-thrombin-collagen patches. Post-operative complications were analyzed. Results: Bile leaks were significantly fewer among patients in whom the cut surface of the liver was treated with fibrin-collagen sponge compared to those where fibrin glue was used on the cut surface: 1/16 (6.25%) vs. 7/16 (43.75%), respectively; p =0.03. There were some differences in biliary anastomotic techniques used in the two groups but 7/8 leaks (87.5%) arose from the cut surface, and only one was from the anastomosis. Conclusion: Using a fibrinogen-thrombin-collagen sponge patch may reduce bile leaks from the cut surface of the liver during adult right lobe split liver transplants. [Copyright &y& Elsevier]

Background Few data are available on tolerability and quality of standard bowel cleansing for colonoscopy in patients with chronic disease. Aim We seek to evaluate the tolerability and results of lavage solution for colonoscopy in cirrhotic patients in comparison with controls. Methods Fifty-three cirrhotic and fifty-two normal subjects undergoing colonoscopy were prospectively enrolled in the study. Data regarding tolerability of lavage solution were harvested at the pre-procedure visit. Data on level of bowel cleansing and other endoscopic variables were recorded after the procedure. Results Rate of failure to complete the prescribed bowel preparation and incidence of side effects during its administration were similar between cirrhotic and normal subjects. Despite this, cirrhotic patients exhibited an insufficient level of bowel preparation with approximately half exhibiting bad colon cleansing level (49% versus 5% control, p < 0.001). Conclusion Alternative bowel cleansing protocols are needed for cirrhotic subjects to better match their colonoscopic screening needs. [ABSTRACT FROM AUTHOR]