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Secondary bile acids and the biliary epithelia: The good and the bad

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World Journal of Gastroenterology 2023年第2期29卷 357-366页

作者： Ilaria Lenci Martina Milana Alessandro Signorello Giuseppe Grassi leonardo baiocchi Hepatology Unit Policlinico Tor VergataRome 00133Italy

The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine.Nowadays several researches demonstrated an important role of biliary epithelia(i.***.cholangiocytes)in bile formation.The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases,such as primary biliary cholangitis or primary sclerosing cholangitis.Bile acids(BAs),produced by the liver,are the most represented organic molecules in bile.The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules.In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary(deriving by bacterial manipulation of primary molecules)ones.This class of BAs is demonstrated to have relevant biological effects,ranging from toxic to therapeutic ones.In this family ursodeoxycholic and lithocholic acid present the most interesting features.The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage.These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.

关键词： Cholangiocytes Biliary secretion Cholestasis Bile acids Secondary bile acids Ursodeoxycholic acid Lithocholic acid

Sequence of events leading to primary biliary cholangitis

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世界胃肠病学杂志:英文版 2023年第37期29卷 5305-5312页

作者： Ilaria Lenci Paola Carnì Martina Milana Agreta Bicaj Alessandro Signorello leonardo baiocchi Hepatology Unit University of Tor VergataRome 00133Italy Postgraduate School in Hepato/Gastroenterology Catholic University Our Lady of Good CounselTirana 1004Albania

Primary biliary cholangitis(PBC)is a chronic cholestatic liver disease that is observed more frequently in middle-aged women.This disorder is considered an autoimmune disease,since liver injury is sustained by the presence of selfdirected antimitochondrial antibodies targeting the bile duct cells.The prognosis may vary depending on an early diagnosis and response to therapy.However,nearly a third of patients can progress to liver cirrhosis,thus requiring a liver transplant.Traditional immunosuppressive therapies,commonly employed for other autoimmune diseases,have limited effects on PBC.In fact,dramatic functional changes that occur in the biliary epithelium in the course of inflammation play a major role in perpetuating the injury.In this minireview,after a background on the disease and possible predisposing factors,the sequential cooperation of cellular/molecular events leading to end-stage PBC is discussed in detail.The rise and maintenance of the autoimmune process,as well as the response of the biliary epithelia during inflammatory injury,are key factors in the progression of the disease.The so-called“ductular reaction(DR)”,intended as a reactive expansion of cells with biliary phenotype,is a process frequently observed in PBC and partially understood.However,recent findings suggest a strict relationship between this pathological picture and the progression to liver fibrosis,cell senescence,and loss of biliary ducts.All these issues(onset of chronic inflammation,changes in secretive and proliferative biliary functions,DR,and its relationship with other pathological events)are discussed in this manuscript in an attempt to provide a snapshot,for clinicians and researchers,of the most relevant and sequential contributors to the progression of this human cholestatic disease.We believe that interpreting this disorder as a multistep process may help identify possible therapeutic targets to prevent evolution to severe disease.

关键词： Primary biliary cholangitis Cholangiocyte Biliary secretion Biliary proliferation Ductular reaction Antimitochondrial antibody Cellular senescence Liver fibrosis

Emerging Therapeutic Strategies in The Fight Against Primary Biliary Cholangitis

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Journal of Clinical and Translational Hepatology 2023年第4期11卷 949-957页

作者： Abigail Medford Jonathan Childs Ashleigh Little Sanjukta Chakraborty leonardo baiocchi Gianfranco Alpini Shannon Glaser Department of Medical Physiology Texas A&M University School of MedicineBryanTXUSA Hepatology Unit University of Tor VergataRomeItaly Division of Gastroenterology and Hepatology Department of MedicineIndiana University School of MedicineIndianapolisINUSA

The liver has a vital role in many metabolic and regulatory processes in the body.Primary biliary cholangitis(PBC),previously known as primary biliary cirrhosis,is a chronic cholestatic autoimmune disease of the intrahepatic bile ducts associated with loss of tolerance to mitochondrial antigens.At this time there is no definitive cure for PBC;however,ursodeoxycholic acid(UDCA)has been shown to reduce injury when administered as the first line of treatment.Additional therapeutics can be given concurrently or as an alternative to UDCA to manage the symptoms and further curb disease progression.Currently,a liver transplant is the only potentially curative option when the patient has developed end-stage liver disease or intractable pruritus.This review aims to delineate the pathogenesis of primary biliary cholangitis and shed light on current therapeutic strategies in the treatment of PBC.

关键词： Cholestatic liver disease Therapeutic approaches Biliary epithelia ursodeoxycholic acid

COVID-19 in normal,diseased and transplanted liver

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World Journal of Gastroenterology 2021年第20期27卷 2576-2585页

作者： Alessandro Signorello Ilaria Lenci Martina Milana Giuseppe Grassi leonardo baiocchi Hepatology Unit Department of MedicineUniversity of Tor VergataRome 00133Italy

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.

关键词： COVID-19 Liver Non-alcoholic fatty-liver-disease Cirrhosis Liver transplant Angiotensin-converting enzyme 2

Liver transplantation for hepatocellular carcinoma: Where do we stand?

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World Journal of Gastroenterology 2019年第21期25卷 2591-2602页

作者： Francesco Santopaolo Ilaria Lenci Martina Milana Tommaso Maria Manzia leonardo baiocchi Hepatology Unit Department of MedicinePoliclinico Universitario Tor VergataRome 00133Italy Transplant Surgery Unit Department of SurgeryPoliclinico Universitario Tor VergataRome 00133Italy

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.

关键词： Hepatocellular carcinoma Liver transplantation Bridging Down-staging Milan Criteria

Natremia and liver transplantation:The right amount of salt for a good recipe

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World Journal of Hepatology 2020年第11期12卷 919-930页

作者： Ilaria Lenci Martina Milana Giuseppe Grassi Alessandro Signorello Andrea Aglitti leonardo baiocchi Department of Internal Medicine Hepatology UnitTor Vergata UniversityRome 00133Italy

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.

关键词： Sodium imbalance Liver transplant Cirrhosis Vaptan Transplant list Hypervolemic hyponatremia

Hepatitis B virus recurrence after liver transplantation: An old tale or a clear and present danger?

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World Journal of Gastroenterology 2020年第18期26卷 2166-2176页

作者： Ilaria Lenci Martina Milana Giuseppe Grassi Tommaso M Manzia Carlo Gazia Giuseppe Tisone Roberta Angelico leonardo baiocchi Hepatology and Liver Transplant Unit University of Tor VergataRome 00133Italy Hepato-Pancreato-Biliary and Transplant Department of SurgeryUniversity of Rome Tor VergataRome 00133Italy

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 immunecompetent 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.

关键词： Liver transplant Hepatitis B virus Viral recurrence Prophylaxis Minimization Antiviral drug

Chronic rejection after liver transplantation:Opening the Pandora’s box

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World Journal of Gastroenterology 2021年第45期27卷 7771-7783页

作者： Roberta Angelico Bruno Sensi Tommaso M Manzia Giuseppe Tisone Giuseppe Grassi Alessandro Signorello Martina Milana Ilaria Lenci leonardo baiocchi Department of Surgery Sciences HPB and Transplant UnitUniversity of Tor VergataRome 00100Italy Hepatology Unit University of Tor VergataRome 00100Italy

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.

关键词： Liver transplantation Chronic rejection Immunosuppression T cell-mediated rejection Antibody-mediated rejection Donor-specific antibody Re-transplantation Graft loss Complications Outcomes

Prevention of hepatitis C recurrence after liver transplantation:An update

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2012年第4期3卷 36-48页

作者： Marco Carbone Ilaria Lenci leonardo baiocchi Liver Unit Queen Elizabeth HospitalBirminghamB15 2THUnited Kingdom Hepatology Unit Department of Internal MedicineUniversity of "Tor Vergata"00133 RomeItaly

Hepatitis C related liver failure and hepatocarcinoma are the most common indications for liver transplantation in Western countries.Recurrent hepatitis C infection of the allograft is universal and immediate following liver transplantation,being associated with accelerated progression to cirrhosis,graft loss and death.Graft and patient survival is reduced in liver transplant recipients with recurrent Hepatitis C virus(HCV) infection compared to HCV-negative recipients.Many variables may impact on recurrent HCV liver disease.Overall,excess immunosuppression is believed to be a key factor;however,no immunosuppressive regimen has been identified to be more beneficial or less harmful.Donor age limitations,exclusion of moderately to severely steatotic livers and minimization of ischemic times could be a potential strategy to minimize the severity of HCV disease in transplanted subjects.After transplantation,antiviral therapy based on pegylated IFN alpha with or without ribavirin is associated with far less results than that reported for immunocompetent HCV-infected patients.New findings in the field of immunotherapy and genomic medicine applied to this context are promising.

关键词： Hepatitis C Liver transplantation Recurrence Immunosuppression Treatment