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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.

Despite being the second most frequent primary liver tumor in humans, early diagnosis and treatment of cholangiocarcinoma (CCA) are still unsatisfactory. In fact, survival after 5 years is expected in less than one fourth of patients diagnosed with this disease. Rare incidence, late appearance of symptoms and heterogeneous biology are all factors contributing to our limited knowledge of this cancer and determining its poor prognosis in the clinical setting. Several efforts have been made in the last decades in order to achieve an improved classification/understanding with regard to the diverse CCA forms. Location within the biliary tree has helped to distinguish between intrahepatic, perihilar and distal CCA types. Sequence analysis contributed to identifying several characteristic genetic aberrations in CCA that may also serve as possible targets for therapy. Novel findings are expected to significantly improve the management of this malignancy in the near future. In this changing scenario our review focuses on the current and future strategies for CCA treatment. Both systemic and surgical treatments are discussed in detail. The results of the main studies in this field are reported, together with the ongoing trials. The current findings suggest that an integrated multidisciplinary approach to this malignancy would be helpful to improve its outcome.

Background: Hepatic Ischemia Reperfusion Injury (IRI) is a serious threat that characterizes the liver but also other transplantable organs. The worst effect of long-term IRI on an impaired graft could lead to irreversible damage and organ failure. Several events characterize the cascade that ultimately leads to organ failure. Among all, multiple strategies have been attempted to identify early phenomena of IRI with divergent results, and biomarkers might represent a novel approach to early detect ischemic damage. Methods: A literature review of the current state-of-the-art on IRI was conducted in the present manuscript. Information was collected from worldwide clinical trials conducted in highly specialized institutions. Experiments conducted on IRI animal models and clinical studies were screened. The final outcomes were analyzed and reported in the present review. Results: Matrix Metalloproteinases (MMPs) represent an interesting example of the early detector of neutrophil invasion after acute and chronic hepatic IRI. Neutrophil Gelatinase-associated Lipocalin (NGAL) is another biomarker which seems more predictable of the IRI gravity phase. Mitochondrial flavin mononucleotide (FMN) was recently discovered and might become a reliable biomarker of hepatic IRI during Hypothermic Oxygenation Machine Perfusion (HOPE). Conclusion: The available strategies to avoid IRI, despite constantly improving, are still lacking a gold standard method. Further studies are still needed to explore new options in the IRI diagnosis and treatment, and to this purpose, regenerative medicine and tissue engineering surely can play a pivotal role in the transplantation field.

The coronavirus disease 2019 (COVID‐19) is a novel infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). COVID‐19 currently affected more than 108 million people worldwide with a fatality rate of 2.2%. Herein, we report the first case of liver transplantation (LT) performed with a liver procured from a SARS‐CoV‐2 positive donor. The recipient was a 35‐year‐old SARS‐CoV‐2 positive female patient affected by severe end‐stage HBV‐HDV‐related liver disease (model of end‐stage liver disease = 32) who had neutralizing SARS‐CoV‐2 antibodies (titers 1:320) at time of LT. The LT was successful, and the graft is functioning two months after surgery. The recipient cleared the SARS‐CoV‐2 infection 1 month after LT. The current case shows that the prompt use of SARS‐CoV‐2 infected liver donors offers an invaluable life‐saving opportunity for SARS‐CoV‐2 positive wait‐listed patients who developed neutralizing SARS‐CoV‐2 antibodies.

We describe the case of a 32-year-old man who developed a liver neoplasm due to previous Fontan surgery (FS) for a single ventricle anomaly and situs viscerum inversus. He was admitted to our hospital for suspected hepatocellular carcinoma during an Ultrasound (US) follow up. Computed tomography (CT) showed features of chronic liver disease and 7 cm hepatic nodule with arterial enhancement. Laboratory analyses documented preserved liver function and increased levels of alpha-fetoprotein. Trans-arterial-chemoembolization (TACE) was performed obtaining complete necrosis at 4 weeks of follow up and significant reduction of alpha-fetoprotein. The patient is currently in follow-up, being evaluated for further treatments and/or combined liver-heart transplantation. TACE is a therapeutic option for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and with severe heart disease, like those submitted to FS and with also other vascular abnormalities like those correlated to situs viscerum inversus.

Starting from December 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has extended in the entire world giving origin to a pandemic. Although the respiratory system is the main apparatus involved by the infection, several other organs may suffer coronavirus disease 2019 (COVID-19)-related injuries. The human tissues expressing angiotensin-converting enzyme 2 (ACE2) are all possible targets of viral damage. In fact myocarditis, meningo-encephalitis, acute kidney injury and other complications have been described with regard to SARS-CoV-2 infection. The liver has a central role in the body homeostasis contributing to detoxification, catabolism and also synthesis of important factor such as plasma proteins. ACE2 is significantly expressed just by cholangiocytes within the liver, however transaminases are increased in more than one third of COVID-19 patients, at hospital admission. The reasons for liver impairment in the course of this infection are not completely clear at present and multiple factors such as: Direct viral effect, release of cytokines, ischemic damage, use of hepatotoxic drugs, sepsis, and others, may contribute to damage. While COVID-19 seems to elicit just a transient alteration of liver function tests in subjects with normal hepatic function, of concern, more severe sequelae are frequently observed in patients with a reduced hepatic reserve. In this review we report data regarding SARS-CoV-2 infection in subjects with normal or diseased liver. In addition the risks of COVID-19 in immunosuppressed patients (either transplanted or suffering for autoimmune liver diseases) are also described.

An adequate balance between electrolytes and clear water is of paramount importance to maintaining physiologic homeostasis. Natremia imbalance and, in particular, hyponatremia is the most frequent electrolyte abnormality observed in hospitalized subjects, involving approximately one-fourth of them. Pathological changes occurring during liver cirrhosis predispose patients to an increased risk of sodium imbalance, and hypervolemic hyponatremia has been reported in nearly 50% of subjects with severe liver disease and ascites. Splanchnic vasodilatation, portal-systemic collaterals’ opening and increased excretion of vasoactive modulators are all factors impairing clear water handling during liver cirrhosis. Of concern, sodium imbalance has been consistently reported to be associated with increased risk of complications and reduced survival in liver disease patients. In the last decades clinical interest in sodium levels has been also extended in the field of liver transplantation. Evidence that [Na+] in blood is an independent risk factor for in-list mortality led to the incorporation of sodium value in prognostic scores employed for transplant priority, such as model for end-stage liver disease-Na and UKELD. On the other hand, severe hyponatremic cirrhotic patients are frequently delisted by transplant centers due to the elevated risk of mortality after grafting. In this review, we describe in detail the relationship between sodium imbalance and liver cirrhosis, focusing on its impact on peritransplant phases. The possible therapeutic approaches, in order to improve transplant outcome, are also discussed.

We describe the case of a 41‐year‐old woman who developed a liver neoplasm due to previous Fontan surgery for a single ventricle anomaly and pacemaker implantation. She was admitted to our hospital for moderate ascites and she was affected by hepatocellular carcinoma treated by trans-arterial chemoembolization (TACE). Computed tomography showed features of chronic liver disease and 4 cm hepatic nodules with arterial enhancement. Laboratory analyses documented preserved liver function and increased levels of alpha-fetoprotein. TACE was performed obtaining complete necrosis at 4 weeks of follow up and significant reduction of alpha-fetoprotein after 2 months. The patient is currently in follow-up, being evaluated for further treatments and/or combined liver/heart transplantation. TACE is a therapeutic option for the treatment of patients with unresectable HCC and with severe heart disease, like those submitted to FS.

Background: Multiple biological functions have been recognized regarding Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Stem Cell Factor (SCF). Aim: To evaluate the serum changes of GM-CSF and SCF in patients undergoing surgical resection for liver tumor, in the regenerative phase after surgery in order to identify the possible relationship with the patient, tumor or surgical variables. Methods: Thirty-two consecutive patients (50% male, median age 66), undergoing hepatic resection of liver neoplasm, were evaluated. The liver tumor was Hepatocellular Carcinoma (HCC) in 44% of cases. Other tumors were cholangiocarcinoma and metastasis. Serum levels of GM-CSF and SCF were assessed at baseline and 2 days, 7 days and 4 weeks after surgery. Personal and clinical patient data were also recorded. The statistical analysis was carried out using t-test for unpaired data or ANOVA (repeated measure) for continuous variables and Fisher test for discrete variables. Results: GM-CSF levels remained constant after surgery and were compared to baseline values. SCF levels, on the other hand, increased during the time, after surgery. The evaluation of SCF levels (fold increase) according to surgical, patient and tumor variables evidenced some differences. At day 7 and week 4, SCF levels were statistically increased: i) in patients undergoing a large resection in comparison with others (p Conclusions: During liver regeneration in humans, SCF serum levels are increased allowing to hypothesize a possible role of this chemokine during tissue growth and remodeling.

Non‐alcoholic fatty liver disease (NAFLD) and alcohol‐associated liver disease (ALD) represent a spectrum of injury, ranging from simple steatosis to steatohepatitis and cirrhosis. In humans, in fact, fatty changes in the liver, possibly leading to end‐stage disease, were observed after chronic alcohol intake or in conditions of metabolic impairment. In this article, we examined the features and the pro‐inflammatory pathways leading to non‐alcoholic and alcoholic steatohepatitis. The involvement of several events (hits) and multiple inter‐related pathways in the pathogenesis of these diseases suggest that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination treatment towards multiple pro‐inflammatory targets would eventually be required. Gut‐liver crosstalk is involved not only in the impairment of lipid and glucose homoeostasis leading to steatogenesis, but also in the initiation of inflammation and fibrogenesis in both NAFLD and ALD. Modulation of the gut‐liver axis has been suggested as a possible therapeutic approach since gut‐derived components are likely to be involved in both the onset and the progression of liver damage. This review summarizes the translational mechanisms underlying pro‐inflammatory signalling and gut‐liver axis in non‐alcoholic and alcoholic steatohepatitis. With a multitude of people being affected by liver diseases, identification of possible treatments and the elucidation of pathogenic mechanisms are elements of paramount importance.

Background 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 Aim of the study was to assess outcomes of pregnancy after LT at national level. Methods 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. Results 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. Conclusion 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.

Background: Over the last decades relevant epidemiological changes of liver diseases have occurred, together with greatly improved treatment opportunities. Aim: To investigate how the indications for elective adult liver transplantation and the underlying disease etiologies have evolved in Italy. Methods: 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). Results: 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%. Conclusions: 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.

Chronic rejection (CR) of liver allografts causes damage to intrahepatic vessels and bile ducts and may lead to graft failure after liver transplantation. Although its prevalence has declined steadily with the introduction of potent immunosuppressive therapy, CR still represents an important cause of graft injury, which might be irreversible, leading to graft loss requiring re-transplantation. To date, we still do not fully appreciate the mechanisms underlying this process. In addition to T cell-mediated CR, which was initially the only recognized type of CR, recently a new form of liver allograft CR, antibody-mediated CR, has been identified. This has indeed opened an era of thriving research and renewed interest in the field. Liver biopsy is needed for a definitive diagnosis of CR, but current research is aiming to identify new non-invasive tools for predicting patients at risk for CR after liver transplantation. Moreover, the minimization or withdrawal of immunosuppressive therapy might influence the establishment of subclinical CR-related injury, which should not be disregarded. Therapies for CR may only be effective in the “early” phases, and a tailored management of the immunosuppression regimen is essential for preventing irreversible liver damage. Herein, we provide an overview of the current knowledge and research on CR, focusing on early detection, identification of non-invasive biomarkers, immunosuppressive management, re-transplantation and future perspectives of CR.

Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes’ injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes’ proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.

BACKGROUND Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients. AIM To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients. METHODS A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy. RESULTS Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences. CONCLUSION The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

Background: The 20th century represents a breakthrough in the transplantation era, since the first kidney transplantation between identical twins was performed. This was the first case of tolerance, since the recipient did not need immunosuppression. However, as transplantation became possible, an immunosuppression-free status became the ultimate goal, since the first tolerance case was a clear exception from the hard reality nowadays represented by rejection. Methods: A plethora of studies was described over the past decades to understand the molecular mechanisms responsible for rejection. This review focuses on the most relevant studies found in the literature where renal tolerance cases are claimed. Contrasting, and at the same time, encouraging outcomes are herein discussed and a glimpse on the main renal biomarkers analyzed in this field is provided. Results: The activation of the immune system has been shown to play a central role in organ failure, but also it seems to induce a tolerance status when an allograft is performed, despite tolerance is still rare to register. Although there are still overwhelming challenges to overcome and various immune pathways remain arcane; the immunosuppression minimization might be more attainable than previously believed. Conclusion: Multiple biomarkers and tolerance mechanisms suspected to be involved in renal transplantation have been investigated to understand their real role, with still no clear answers on the topic. Thus, the actual knowledge provided necessarily leads to more in-depth investigations, although many questions in the past have been answered, there are still many issues on renal tolerance that need to be addressed.

Background:Domino transplant occurs when a recipient explanted graft is used for a second recipient.Introduction:The first experience came from thoracic surgery by the observation that many patients during heart-lung transplantation actually showed a functional heart that could be employed in other subjects with a good result.Results:This concept was then extended to the field of liver transplantation. At present, some patients transplanted for an inborn metabolic disease may be considered as excellent domino liver donors.Conclusion:The results, limitations, clinical challenges and the donor and recipient features of domino liver transplantation are discussed in this manuscript.

Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.

Background: Hepatic encephalopathy (HE) is a complication of transjugular intrahepatic portosystemic shunt (TIPS). Aims: Extend the knowledge about the early detection of multiple brain metabolic abnormalities following TIPS; these abnormalities can be detected and managed prior to the clinical manifestation of HE with use of Multiparametric Magnetic Resonance with Spectroscopy. Methods: 12 cirrhotic Patients underwent TIPS; each Patient underwent a 3 T MRI evaluation before and after TIPS. The spectroscopic images were processed measuring the values of the metabolites N-acetylaspartate (NAA) - Glutamine / Glutamate (Glx) - Colina (Cho) - Myinositol (mI) at the level of the nuclei of the base. Results: Spectroscopic examination performed before the TIPS procedure showed low values of Cho and Mi, instead following the procedure: an increase in the Glx value, a mean reduction in the values of Cho and mI, a statistically significant reduction in the Cho / Creatine ratio, in the mI / Creatine ratio and an increase of the Glx / Creatine ratio. Conclusions: Our study demonstrated the efficacy of spectroscopy in Patient subjected to TIPS. MR 3 T with spectroscopy can become a valid tool for monitor the dynamics of changes in brain metabolism after TIPS and to provide an early diagnosis of HE allowing an early treatment. Keywords: Hepatic encephalopathy (HE), Transjugular intrahepatic portosystemic shunt (TIPS), Multiparametric magnetic resonance, Spectroscopy

Patients with liver cirrhosis are fragile and present specific clinical hallmarks. When undergoing to gastrointestinal (GI) endoscopy, these subjects require an individual pre evaluation, taking into account: Level of haemostasis impairment, the individual risk of infection, the impact of sedation on hepatic encephalopathy and other factors. The overall assessment of liver function, employing common scoring systems, should be also assessed in the preprocedural phase. Beside some common general problems, regarding GI endoscopy in cirrhotic subjects, also specific issues are present for some frequent indications or procedures. For instance, despite an increased incidence of adenomas in cirrhosis, colon cancer screening remains suboptimal in subjects with this disease. Several studies in fact demonstrated liver cirrhosis as a negative factor for an adequate colon cleansing before colonoscopy. On the other hand, also the routine assessment of gastroesophageal varices during upper GI endoscopy presents some concern, since important inter-observer variability or incomplete description of endoscopic findings has been reported in some studies. In this review we discussed in details the most relevant issues that may be considered while performing general GI endoscopic practice, in patient with cirrhosis. For most of these issues there are no guidelines or clear indications. Moreover until now, few studies focused on these aspects. We believe that targeting these issues with corrective measures may be helpful to develop a tailored endoscopic approach for cirrhosis, in the future.

BACKGROUND & AIMS Missed or inappropriate referrals of potential candidates for liver transplantation (LT) are common and traditional referral methods (tRs) do not allow for efficient triage. We investigated the effects of a website developed for electronic outpatient referral to LT (eRW-LT) on these issues. METHODS 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 eRW-LT, quickly obtaining the judgment on the appropriateness and urgency of the visit from a transplant hepatologist. RESULTS In the second half of the study, there were 99 eRW-LTs and 96 traditional referrals (new tRs), representing a 17.4% increase over the 161 traditional referrals (old tRs) of the first half. With eRW-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 tRs, new tRs, and eRW-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 eRW-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 tRs (14.0; 95% CI, 8.0-23.0; P < .001) and with new tRs (16.0; 95% CI, 10.0-23.0; P < .001). CONCLUSIONS eRW-LT allows an increase in the number of referrals for LT, ensuring effective triage and better appropriateness of visits.

Purpose. To assess the ability of Cone-Beam CT (CBCT), performed during the Transcatheter Arterial Chemoembolization (TACE), in predicting the response to treatment of hepatocellular carcinoma (HCC). Materials and Methods. We evaluated fifty patients (M/F = 40/10, mean age: 66.7 years ± 8.22) with hepatocellular carcinoma (HCC), for a total of 82 nodules evaluated (mean diameter: 21.4 ± 11 mm). All patients performed a CT scan one month before and one month after TACE. After TACE is completed, a CBCT was performed to assess the degree of drug retention in the lesions. For each lesion, the major diameter, volume, and density of the vital portion were evaluated. The response to TACE was assessed using the mRECIST criteria on the CT scan carried out one month after the procedure. The receiver operating characteristic (ROC) curves were performed to assess the accuracy of the CBCT in predicting the response to treatment and to identify the cut-off points for each parameter under examination. Results. A complete response (CR) was observed in 24/50 patients (48%), a partial response (PR) in 16/50 (32%), stable disease (SD) in 8/50 (16%), and progressive disease (PD) in 2/50 (4%). Evaluation of the area under the ROC curve showed that the diameter, volume, and density of the lesion, measured with CBTC, had an accuracy of 94%, 96%, and 98%, respectively, in discriminating a complete response from a not complete response. Conclusion. CBCT is effective in predicting short-term response at 1-month follow-up of HCC treated by chemoembolization.

Liver and kidney are strictly connected in a reciprocal manner, in both the physiological and pathological condition. The Italian Association for the Study of Liver, in collaboration with the Italian Society of Nephrology, with this position paper aims to provide an up-to-date overview on the principal relationships between these two important organs. A panel of well-recognized international expert hepatologists and nephrologists identified five relevant topics: 1) The diagnosis of kidney damage in patients with chronic liver disease; 2) Acute kidney injury in liver cirrhosis; 3) Association between chronic liver disease and chronic kidney disease; 4) Kidney damage according to different etiology of liver disease; 5) Polycystic kidney and liver disease. The discussion process started with a review of the literature relating to each of the five major topics and clinical questions and related statements were subsequently formulated. The quality of evidence and strength of recommendations were graded according to the GRADE system. The statements presented here highlight the importance of strong collaboration between hepatologists and nephrologists for the management of critically ill patients, such as those with combined liver and kidney impairment.

The poor prognosis of cholangiocarcinoma in humans is related to several factors, such as (i) the heterogeneity of the disease, (ii) the late onset of symptoms and (iii) the limited comprehension of the carcinogenic pathways determining neoplastic changes, which all limit the pursuit of appropriate treatment. Several risk factors have been recognized, including different infective, immune-mediated, and dysmorphogenic disorders of the biliary tree. In this review, we report the details of possible mechanisms that lead a specific premalignant pathological condition to become cholangiocarcinoma. For instance, during liver fluke infection, factors secreted from the worms may play a major role in pathogenesis. In primary sclerosing cholangitis, deregulation of histamine and bile-acid signaling may determine important changes in cellular pathways. The study of these molecular events may also shed some light on the pathogenesis of sporadic (unrelated to risk factors) forms of cholangiocarcinoma, which represent the majority (nearly 75%) of cases.

The gastrointestinal peptide, secretin (Sct) is an important homeostatic regulator of pancreatic and liver secretory function. With regard to the liver, discoveries have been made, in the last decades, indicating a key role for the secretin/secretin receptor axis during normal or cholestatic conditions. Since large cholangiocytes are the only cells to express secretin receptor in the liver, research on secretin also expanded our knowledge on biliary epithelia. In this review we examined in detail the role of the secretin/secretin receptor axis, not only on biliary secretion, but also on cholangiocyte proliferation and senescence, as well as in prompting fibrotic processes involving biliary epithelia. Relevant data on human chronic cholestatic liver diseases, such as primary biliary cholangitis or primary sclerosing cholangitis, and obtained in animal models mimicking the diseases or in correlative studies on human are also reported. The aim of this review is to provide an update on the progress regarding the interactions between secretin and the biliary epithelia in normal and pathological conditions, underlining the aspects that suggests modulation of secretin pathway as a possible therapeutic approach for chronic cholestatic human liver disease.

Hepatitis B virus (HBV) recurrence after liver transplantation (LT) has been described more than 50 years ago. Similarly, to other clinical conditions, in which impairment of host immune defense favors viral replication, early reports described in details recurrence and reactivation of HBV in liver transplant recipients. The evidence of a possible, severe, clinical evolution of HBV reappearance in a significant percentage of these patients, allowed to consider, for some years, HBV positivity a contraindication for LT. Moving from the old to the new millennium this picture has changed dramatically. Several studies contributed to establish efficient prophylactic protocols for HBV recurrence and with the advent of more potent anti-viral drugs an increased control of infection was achieved in transplanted patients as well as in the general immune-competent HBV population. Success obtained in the last decade led some authors to the conclusion that HBV is now to consider just as a “mere nuisance”. However, with regard to HBV and LT, outstanding issues are still on the table: (1) A standard HBV prophylaxis protocol after transplant has not yet been clearly defined; (2) The evidence of HBV resistant strains to the most potent antiviral agents is claiming for a new generation of drugs; and (3) The possibility of prophylaxis withdrawal in some patients has been demonstrated, but reliable methods for their selection are still lacking. The evolution of LT for HBV is examined in detail in this review together with the description of the strategies adopted to prevent HBV recurrence and their pros and cons.

INTRODUCTION: Cholangiocarcinoma (CCA) is a devastating liver tumor with a poor prognosis. While less than 50% of patients with CCA may benefit from surgical resection, the rest undergoes chemotherapy with disappointing results (mean survival

Background Recent innovations in the field of liver transplantation have led to a wealth of new treatment regimes, with potential impact on the onset of de novo malignancies (DNM). The aim of this multicenter cohort study was to provide contemporary figures for the cumulative incidences of solid and hematological DNM after liver transplantation. Methods We designed a retrospective cohort study including patients undergoing LT between 2000 and 2015 in three Italian transplant centers. Cumulative incidence was calculated by Kaplan–Meyer analysis. Results The study included 789 LT patients with a median follow-up of 81 months (IQR: 38–124). The cumulative incidence of non-cutaneous DNM was 6.2% at 5-years, 11.6% at 10-years and 16.3% at 15-years. Post-Transplant Lymphoproliferative Disorders (PTLD) were demonstrated to have a cumulative incidence of 1.0% at 5-years, 1.6% at 10-years and 2.2% at 15-years. Solid Organ Tumors (SOT) demonstrated higher cumulative incidences – 5.3% at 5-years, 10.3% at 10-years and 14.4% at 15-years. The most frequently observed classifications of SOT were lung (rate 1.0% at 5-years, 2.5% at 10-years) and head & neck tumors (rate 1.3% at 5-years, 1.9% at 10-years). Conclusions Lung tumors and head & neck tumors are the most frequently observed SOT after LT.

Bile acids are a family of amphipathic compounds predominantly known for their role in solubilizing and absorbing hydrophobic compounds (including liposoluble vitamins) in the intestine. Bile acids also are key signaling molecules and inflammatory agents that activate transcriptional factors and cell signaling pathways that regulate lipid, glucose, and energy metabolism in various human disorders, including chronic liver diseases. However, in the last decade increased awareness has been founded on the physiological and chemical heterogeneity of this category of compounds and their possible beneficial or injurious effects on the biliary tree. In this review, we provide an update on the current understanding of the molecular mechanism involving bile acid and biliary epithelium. The last achievements of the research in this field are summarized, focusing on the molecular aspects and the elements with relevance regarding human liver diseases.

Background & aims We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. Methods Eighteen HCV-infected patients undergoing LT/HR, 94.0% naive to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. Results At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naive patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. Conclusions Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.

A 39-year-old female, liver transplanted for Autosomic Dominant Polycystic Kidney Disease (ADPKD) developed refractory ascites early after surgery, with frequent need of large-volume paracentesis. This was associated with severe sarcopenia and kidney impairment. Liver biopsy showed a sinusoidal congestion with a significant enlargement of hepatic portal veins. This picture suggested the diagnosis of vascular obstructions. Due to an unfavorable passage through the piggy-back surgical anastomosis and the angle between the hepatic veins and the portal branches, a conventional placement of a transjugular portosystemic shunt (TIPS) was not feasible. An alternative approach was pursued with success, using a combined percutaneous-transjugular approach and achieving a complete recovery of ascites, sarcopenia and renal function.

The study was undertaken in order to provide a snapshot from real clinical practice of virological presentation and outcome of patients developing immunosuppression-driven HBV reactivation. Seventy patients with HBV reactivation were included (66.2% treated with rituximab, 10% with corticosteroids and 23.8% with other immunosuppressive drugs). Following HBV reactivation, patients received anti-HBV treatment for a median (IQR) follow-up of 31(13-47) months. At baseline-screening, 72.9% of patients were HBsAg-negative and 27.1% HBsAg-positive. About 71.4% had a diagnosis of biochemical reactivation [median (IQR) HBV DNA and ALT: 6.9 (5.4-7.8) log IU/mL and 359 (102-775) U/L]. Moreover, 10% of patients died from hepatic failure. Antiviral prophylaxis was documented in 57.9% and 15.7% of HBsAg-positive and HBsAg-negative patients at baseline-screening (median [IQR] prophylaxis duration: 24[15-33] and 25[17-36] months, respectively). Notably, HBV reactivation occurred 2-24 months after completing the recommended course of anti-HBV prophylaxis in 35.3% of patients. By analysing treatment outcome, the cumulative probability of ALT normalization and of virological suppression was 97% and 69%, respectively. Nevertheless, in patients negative to HBsAg at baseline-screening, only 27% returned to HBsAg-negative status during prolonged follow-up, suggesting the establishment of chronic infection. In conclusion, most patients received a diagnosis of HBV reactivation accompanied by high ALT and 10% died for hepatic failure, supporting the importance of strict monitoring for an early HBV reactivation diagnosis. Furthermore, HBV reactivation correlates with high risk of HBV chronicity in patients negative for HBsAg at baseline-screening, converting a silent into a chronic infection, requiring long-term antiviral treatment. Finally, a relevant proportion of patients experienced HBV reactivation after completing the recommended course of anti-HBV prophylaxis, suggesting the need to reconsider proper duration of prophylaxis particularly in profound immunosuppression.

Introduction and aim Cirrhotic patients with hepatitis C virus genotype 3 infection show unsatisfactory outcomes after 12 weeks’ treatment with direct antiviral agents. The National Italian Drug Agency allows 24 weeks of therapy in difficult-to-treat patients, including genotype 3 cirrhotics. Aim of this study was to evaluate efficacy and safety of a 24-week course of sofosbuvir plus daclatasvir ± ribavirin in this population. Materials and methods 106 consecutive cirrhotics (70.8% males, mean age 55.3 ± 7.6 years) in 8 tertiary hepatology centers received sofosbuvir plus daclatasvir for 24 weeks. Ribavirin was administered in 85 (80.2%) based expected tolerability, at a mean dose of 964 ± 202 mg/day. Baseline Child-Pugh class was A 91.5%, B 6.6%, C 1.9%; mean baseline MELD was 8.5 ± 2.7. Results All patients completed 12-week follow-up post-treatment, and 104 (98.1%) obtained sustained virological response (100% in ribavirin -treated patients vs. 90.4% without ribavirin; p = 0.04). No worsening in renal and liver function was observed, no serious adverse events occurred. Two virological failures showed resistance associated variants (Y93H and S282T). Conclusion An extended 24-week treatment with sofosbuvir plus daclatasvir + ribavirin obtained 100% efficacy in genotype 3 hepatitis C cirrhosis, with very limited side effects. The role of ribavirin seems crucial in this setting and should be administered if clinically feasible.

Tailored approaches have been attempted to prevent hepatitis B virus (HBV) reinfection in antibodies against hepatitis B surface antigen (HBsAg)-positive liver transplantation (LT) recipients in order to minimize the use of hepatitis B immune globulin (HBIG) and nucleoside analogues (NAs). We report the results of complete HBV prophylaxis withdrawal after a follow-up of at least 6 years in LT recipients with undetectable serum HBV DNA and intrahepatic total HBV DNA and covalently closed circular DNA at LT. We included 30 HBsAg positive, hepatitis B e antigen-negative recipients, 6 with hepatitis C virus and 7 with hepatitis D virus coinfection, who had received HBIG plus NA for at least 5 years after LT. Stepwise HBIG and NA withdrawal was performed in two 6-month periods under strict monitoring of HBV virology. All patients underwent a clinical, biochemical, and virological follow-up at 3-6 month intervals. HBV recurrence (HBsAg seroreversion ± detectable HBV DNA) occurred in 6 patients: in 1 patient after HBIG interruption and in 5 after both HBIG and NA cessation. Only 3 patients required reinstitution of HBV prophylaxis because of persistent HBV replication, and all achieved optimal control of HBV infection and did not experience clinical events. The other who recurred showed only short-lasting HBsAg positivity, with undetectable HBV DNA, followed by spontaneous anti-HBs seroconversion. An additional 15 patients mounted an anti-HBs titer, without previous serum HBsAg detectability. At the end of follow-up, 90% of patients were still prophylaxis-free, 93.3% were HBsAg negative, and 100% were HBV DNA negative; 60% had anti-HBs titers >10 IU/L (median, 143; range, 13-1000). This small series shows that complete prophylaxis withdrawal is safe in patients transplanted for HBV-related disease at low risk of recurrence and is often followed by spontaneous anti-HBs seroconversion. Further studies are needed to confirm this finding. Liver Transplantation 22 1205-1213 2016 AASLD.

Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients&rsquo, age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV-fitness. Conversely, HDAg was characterized by a lower percentage of conserved-residues than HBsAg (p &lt, 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg-domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection.

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.

Background: In 2012, an Italian Named Patient Program began for hepatitis C virus (HCV)-infected liver transplant (LT) recipients with advanced fibrosis, before approval of direct antiviral agents (DAA), to benefit severely ill patients. The aim of this “real-life” study was to assess treatment efficacy and safety with an extended course of daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV). Methods: All HCV LT recipients with severe fibrosis in 15 Italian transplant centers were treated with DCV+SOF±RBV for 24weeks; sustained virological response was assessed at 12weeks post-treatment (SVR12). Results: Eighty-seven patients were enrolled (75.9% males, mean age 58.4±7.2years, 83.9% genotype 1, 81.6% cirrhosis); 52 (59.8%) received RBV. Overall, 79 obtained SVR12 (90.8%): 100% in F3 and 88.7% in cirrhotics (91.5% in Child-Pugh A, 83.3% in Child-Pugh B and C). According to the treatment group, SVR was 80% in DCV+SOF group and 98.1% in SOF+DCV+RBV. Two virological relapses occurred during follow-up in cirrhotic patients who received DCV+SOF. Four cirrhotic patients in DCV+SOF group and 1 in DCV+SOF+RBV group died on treatment. Conclusion: An extended course of SOF plus DCV for 24weeks, with or without RBV, is effective and well tolerated for the treatment of post-LT HCV recurrence with severe fibrosis.