Quantifying changes in innate immune function following liver transplantation for chronic liver disease.

BACKGROUND: Liver transplantation (LT) offers patients with cirrhosis long-term survival, however many die from sepsis whilst awaiting LT. The liver's role in innate immunity may be key to improving outcomes, but the immune effects of LT have not been quantified. METHODS: Innate immune capacity was assessed by clearance of 99mTc-Albumin nanospheres in patients with chronic liver failure before and after LT. RESULTS: Twenty-eight patients with chronic liver disease on the LT waiting list entered the study during the twelve-month study period and nine patients underwent LT and completed the study protocol. One patient developed hepatic artery thrombosis in <7 days and was excluded from the study. Innate immune function was significantly impaired in patients with chronic liver disease on the LT waiting list and this was directly correlated with MELD score. LT normalised innate immune function by day 1 post LT with further improvement occurring by day 7 post LT. Donor liver weight was the only factor correlated with innate immune function at day 1 post LT but this effect was negated by day 7 post LT. CONCLUSION: Recognising the immune effects of LT may facilitate treatment of cirrhosis and inform development of extracorporeal liver support systems.

CSF1 Restores Innate Immunity After Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients With Acute Liver Failure.

BACKGROUND & AIMS: Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. METHODS: We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. RESULTS: Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. CONCLUSIONS: Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury.

Polysialic acid/neural cell adhesion molecule modulates the formation of ductular reactions in liver injury.

UNLABELLED: In severe liver injury, ductular reactions (DRs) containing bipotential hepatic progenitor cells (HPCs) branch from the portal tract. Neural cell adhesion molecule (NCAM) marks bile ducts and DRs, but not mature hepatocytes. NCAM mediates interactions between cells and surrounding matrix; however, its role in liver development and regeneration is undefined. Polysialic acid (polySia), a unique posttranslational modifier of NCAM, is produced by the enzymes, ST8SiaII and ST8SiaIV, and weakens NCAM interactions. The role of polySia with NCAM synthesizing enzymes ST8SiaII and ST8SiaIV were examined in HPCs in vivo using the choline-deficient ethionine-supplemented and 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet models of liver injury and regeneration, in vitro using models of proliferation, differentiation, and migration, and by use of mouse models with gene defects in the polysialyltransferases (St8sia 2+/-4+/-, and St8sia2-/-4-/-). We show that, during liver development, polySia is required for the correct formation of bile ducts because gene defects in both the polysialyltransferases (St8sia2+/-4+/- and St8sia2-/-4-/- mice) caused abnormal bile duct development. In normal liver, there is minimal polySia production and few ductular NCAM+ cells. Subsequent to injury, NCAM+ cells expand and polySia is produced by DRs/HPCs through ST8SiaIV. PolySia weakens cell-cell and cell-matrix interactions, facilitating HGF-induced migration. Differentiation of HPCs to hepatocytes in vitro results in both transcriptional down-regulation of polySia and cleavage of polySia-NCAM. Cleavage of polySia by endosialidase (endoN) during liver regeneration reduces migration of DRs into parenchyma. CONCLUSION: PolySia modification of NCAM+ ductules weakens cell-cell and cell-matrix interactions, allowing DRs/HPCs to migrate for normal development and regeneration. Modulation of polySia levels may provide a therapeutic option in liver regeneration.

Prospects for stem cell transplantation in the treatment of hepatic disease.

Stem cell therapy has the potential to provide a valuable adjunct to the management of hepatic disease. Preclinical studies have demonstrated a range of endogenous repair processes that can be exploited through stem cell therapy. Initial translational studies have been encouraging and have suggested improved liver function in advanced chronic liver disease and enhanced liver regeneration after portal vein embolization. This article reviews the potential for stem cell therapies to enhance hepatic regeneration in acute and chronic hepatic disease and is based on a MEDLINE and PubMed search for English language articles investigating mechanisms of hepatic regeneration and delivery of cell therapies. Two main mechanisms of potential stem cell therapy delivery have emerged: (1) a direct contribution to the functional hepatocyte population with embryonic, induced pluripotent, or adult stem cells and (2) the promotion of endogenous regenerative processes with bone marrow-derived stem cells. Bioartificial hepatic support systems may be proven to be an effective method of using ex vivo differentiated hepatocytes and be indicated as a bridging therapy to definitive surgery in acute liver failure. The administration of bone marrow-derived stem cells may enhance liver regeneration in chronic liver disease after portal vein embolization and could facilitate regeneration after partial hepatic resection. Ultimately, the most appropriate hepatic disease targets for stem cell therapies will become apparent as mechanisms of stem involvement in hepatic regeneration are further elucidated.

Pancreatic cystic lesions: risk stratification and management based on recent guidelines.

Pancreatic cystic lesions (PCLs) can present complex diagnostic and management challenges with uncertainty as to the most appropriate investigations, interventions and surveillance. Guidelines have been developed to aid decision making, including the European Study Group, American College of Gastroenterology and International Study Group guidelines. This paper presents issues relating to risk stratification and the appropriate management of patients with PCLs, reviewing these recently published guidelines. While there are similarities across these expert guidelines, there are notable differences in terms of features associated with increased risk of malignant transformation, the most appropriate imaging modality and timing of interval imaging. Where variations exist, this reflects differing interpretations of a limited evidence base, and decision making will likely evolve further as experience with these guidelines develops.

Practical barriers to delivering autologous bone marrow stem cell therapy as an adjunct to liver resection.

Liver resection has been associated with significant morbidity and mortality due to hepatic dysfunction or hepatic failure in the postoperative period. Autologous bone marrow stem cell (BMSC) therapy may offer the potential to enhance hepatic regeneration in this setting, perhaps increasing the safety of the procedure. Preclinical models and initial translational studies have suggested that autologous BMSC administration can facilitate hepatic regeneration following both acute and chronic liver disease. While translational studies have begun in chronic hepatic disease, translation to hepatic surgical indications has been limited. This review explores the practical barriers currently restricting the delivery of autologous stem cell therapies to enhance hepatic regeneration following liver resection including selection of cell type, cell isolation, therapy delivery, trial design, and assessment of efficacy.

Distal pancreatectomy: what is the standard for laparoscopic surgery?

BACKGROUND/AIMS: Distal pancreatectomy (DP) is performed for a range of benign and malignant lesions. Accurate pre-operative diagnosis can be unreliable and morbidity remains high. This study evaluates a 12-year, single-centre experience with open DP to review indications, diagnoses and associated morbidity. METHODS: Retrospective review of patients who underwent DP at a UK-based tertiary referral centre between 1994 and 2006. RESULTS: Sixty-five patients (mean age 49.9 years) had final diagnoses of chronic pancreatitis +/- pseudocyst (n= 22), benign cystadenoma (n= 15), neuroendocrine tumour (n= 8), primary pancreatic carcinoma (n= 6) and 14 other conditions. DP performed for presumed cystic neoplasm (n= 24) revealed a correct pre-operative diagnosis in 71% of patients. Histological examination confirmed that 59% of resected cystic tumours were either malignant or had malignant potential. When DP was undertaken for presumed pseudocyst (n= 12), 83% of cases were correctly diagnosed pre-operatively. Overall mortality and morbidity rates were 3% and 39%, respectively, with five patients (8%) developing a clinically significant pancreatic fistula. Ten (17%) patients developed diabetes mellitus and nine (14%) required long-term pancreatic exocrine supplementation. CONCLUSIONS: Open DP can be performed with acceptable morbidity, low mortality and preservation of pancreatic function in the majority of cases, setting the standard for laparoscopic techniques.