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Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first‐line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so‐called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug‐induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up‐to‐date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug‐induced, autoimmune‐like hepatitis (DI‐AIH). [ABSTRACT FROM AUTHOR]

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first‐line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so‐called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug‐induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up‐to‐date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug‐induced, autoimmune‐like hepatitis (DI‐AIH). [ABSTRACT FROM AUTHOR]

In the last two decades there has been significant progress in research on and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine‐tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties, and identifying still unknown aspects of HCA. We discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of β‐catenin‐mutated HCAs. The major complications of HCAs, i.e. bleeding and malignant transformation, are considered, including the dilemmas of atypical and borderline lesions. HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non‐western countries, are also discussed. The natural history of the different HCA subtypes in relation to age, sex and risk factors is a feature that is still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumour, a multicentre and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programmes with which to identify, classify and manage HCAs, focusing on several aspects, e.g. aetiology, underlying liver disease, complications, regression, and growth. Updating what we know and identifying and addressing what we do not know matters for optimal patient management. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular adenomas (HCA) are rare, hormone‐driven, benign liver tumours. HCA >50 mm are associated with haemorrhage and malignant transformation. Guidelines recommend cessation of oral contraceptive pills (OCP) for size reduction; however, it is currently unknown how HCA respond to cessation of OCP. We sought to investigate the effect of OCP cessation on HCA size. Methods: A retrospective cohort study was performed including HCA patients who stopped OCP intake within 6 months of imaging between 2005 and 2018. Biometrics and hormonal medication use were evaluated with self‐designed questionnaires. Response of the largest HCA was evaluated according to Response Evaluation Criteria in Solid Tumours (RECISTv1.1). Cox regression was performed for analysis of factors influencing HCA regression. Results: Seventy‐eight HCA patients were included, diagnosed at a median (interquartile range) age of 32 (26‐41) years. Follow‐up was 1.6 (0.4‐2.9) years. HCA size at diagnosis ranged 10‐167 mm. After a median time of 1.3 (0.6‐2.6) years after OCP cessation, 37.2% of HCA showed ≥30% regression, 5.1% complete regression, 56.4% stability and 1.3% progression. No HCA‐induced complications were observed during follow‐up. Cox regression analysis demonstrated a significant association of HCA size with rate of regression; 50 ≤ HCA < 100 mm (HR 2.4, 95% CI 1.1‐5.3; P < 0.05), HCA ≥ 100 mm (HR 8.3, 95% CI 3.3‐21.6; P < 0.001). Conclusions: Ninety‐eight per cent of HCA remained stable or regressed after OCP cessation. A longer wait‐and‐see period was associated with a larger proportion of regressing HCA, without HCA‐related complications during follow‐up. [ABSTRACT FROM AUTHOR]

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γ GT levels (each P<.02) and tended to be associated with biliary complications ( P=.06). Sinusoidal fibrosis was associated with prior rejection episodes ( P<.02) and centrilobular fibrosis with the presence of HLA mismatches ( P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions. [ABSTRACT FROM AUTHOR]

Patients with hereditary tyrosinemia type 1 have an elevated risk of developing hepatocellular carcinoma, especially if initiation of treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione is delayed. Hepatocellular carcinoma can usually be suspected when there are increased α1-fetoprotein levels and characteristic imaging features. The present case shows that a lack of a clear increase in α1-fetoprotein should still lead to consideration of liver transplantation when imaging features change. [ABSTRACT FROM AUTHOR]

The hepatic sinusoids comprise a complex of vascular conduits to transport blood from the porta hepatis to the inferior vena cava through the liver. Under normal conditions, portal venous and hepatic artery pressures are equalized within the sinusoids, oxygen and nutrients from the systemic circulation are delivered to the parenchymal cells and differentially distributed throughout the liver acini, and proteins of liver derivation are carried into the cardiac/systemic circulation. Liver sinusoid structures are lined by endothelial cells unique to their location, and Kupffer cells. Multifunctional hepatic stellate cells and various immune active cells are localized within the space of Disse between the sinusoid and the adjacent hepatocytes. Flow within the sinusoids can be compromised by physical or pressure blockage in their lumina as well as obstructive processes within the space of Disse. The intimate relationship of the liver sinusoids to neighbouring hepatocytes is a significant factor affecting the health of hepatocytes, or transmission of the effects of injury within the sinusoidal space. Pathologists should recognize several patterns of injury involving the sinusoids and surrounding hepatocytes. In this review, injury, alterations and accumulations within the liver sinusoids are illustrated and discussed. [ABSTRACT FROM AUTHOR]

Objectives: Sonic hedgehog hepatocellular adenoma (shHCA) is a new hepatocellular adenoma (HCA) subgroup characterized by high risk of hemorrhage. ShHCA account for below 10% of all HCA cases and are often associated with female gender, obesity, and non-alcoholic steatohepatitis. No specific MRI characteristics have been described to date. The objective of this study was to assess the value of using MRI to identify shHCA, and correlate MRI findings with histology. Methods: We retrospectively collected MRI scans of 29 patients with shHCA from our center and from different liver referral centers to include 35 lesions. Diagnosis of shHCA was assessed by immunohistochemical overexpression of argininosuccinate synthase 1 or prostaglandin D2 synthase, then confirmed by molecular analysis of sonic hedgehog pathway activation and/or by proteomic analysis. Results: In 46% (n = 16/35) of shHCA cases, we detected intralesional fluid-filled cavities defined on MR images as fluid-like foci markedly hyperintense on T2-weighted sequences, and hypointense on T1-weighted sequences, with or without delayed enhancement. Pathologically, these cavities were observed in 54% of cases as vacuoles filled with blood at different stages of degradation. Hemorrhage and/or necrosis were detected among 71% of cases by MRI analysis (n = 25/35) versus 82% pathologically. Seventeen percent of shHCA cases (n = 6/35) were completely homogeneous via MRI and pathological analysis. No MRI criteria was found in favor of focal nodular hyperplasia, HNF1A-mutated HCA, or typical inflammatory HCA. Conclusion: We reveal the presence of intralesional fluid-filled cavities among 46% of our shHCA cases that represent a new MRI finding possibly helpful for shHCA diagnosis. Clinical relevance statement: This multicenter study is the first clinical study about the radiological aspect of this new hepatocellular adenoma subgroup. This highlights a strong correlation between MRI and histological analysis, with a specific pattern emerging for diagnosis. Key Points: • Sonic hedgehog hepatocellular adenoma is a new hepatocellular adenoma subgroup associated with high risk of hemorrhage, but imaging features of this subgroup remain unknown. • Analysis of MR images and correlation with pathology revealed intralesional fluid-filled cavities and necrotic-hemorrhagic changes. • Intralesional fluid-filled cavities have not yet been described in other adenoma subtypes and represent a new MRI finding for sonic hedgehog hepatocellular adenoma. [ABSTRACT FROM AUTHOR]

Background & Aims: Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Methods: Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. Results: The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal‐based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. Conclusions: The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH. [ABSTRACT FROM AUTHOR]

Background & Aim Experimental studies in animals have suggested that liver regeneration is impaired in steatotic livers. However, few studies have focused on the impact of steatosis in patients undergoing partial hepatectomy ( PH). This study aims to determine the role of steatosis on liver regeneration in humans following PH. Methods Eighty-eight patients undergoing PH were included in this study. All patients underwent CT-scanning of the liver preoperatively and 7 days after surgery. Additional CT-scans were performed 6 months post-operatively. Preoperative and post-operative volumes of the total liver ( TLV), future liver remnant ( FLR) and liver remnant ( LR) were measured on CT-scans. Regeneration indices ( RI) were calculated at 7 days and 6 months using the formula: (Volume LR−Volume FLR)/Volume FLR × 100%. Based on histological examination of the resected part of the liver, patients were classified into three groups: (1) no steatosis, (2) mild steatosis (1-29%) and (3) moderate-to-severe steatosis (≥30%). Results The early RI (at day 7) was 40%, 24% and 20% for patients in group 1, 2 and 3 respectively. Late RI (at 6 months) was 81% for group 1, 44% for group 2 and 22% for group 3 ( P = 0.019). At 7 days, the LR represented 79%, 80% and 79% of the TLV for groups 1-3. At 6 months, this was 93%, 92% and 79% respectively. Conclusion Although early RI after PH did not differ in patients with or without steatosis, the late RI in patients with moderate-to-severe steatosis was lower, suggesting that late liver regeneration is impaired in these patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with a choledochal malformation, formerly described as cysts, are at increased risk of developing a cholangiocarcinoma and resection is recommended. Given the low incidence of choledochal malformation (CM) in Western countries, the incidence in these countries is unclear. Our aim was to assess the incidence of malignancy in CM patients and to assess postoperative outcome. Methods: In a nationwide, retrospective study, all adult patients who underwent surgery for CM between 1990 and 2016 were included. Patients were identified through the Dutch Pathology Registry and local patient records and were analysed to determine the incidence of malignancy, as well as postoperative mortality and morbidity. Results: A total of 123 patients with a CM were included in the study (Todani Type I, n = 71; Type II, n = 10; Type III, n = 3; Type IV, n = 27; unknown, n = 12). Median age was 40 years (range 18‐70) and 81% were female. The majority of patients (99/123) underwent extrahepatic bile duct resection, with additional liver parenchyma resections in eight patients, only exploration in two, and a local cyst resection in eight patients. Postoperative 30‐day mortality was 2% (2/123) and limited to patients who underwent liver resection. Severe morbidity occurred in 24%. In 14 of the 123 patients (11%), a malignancy was found in the resected specimen. One patient developed a periampullary malignancy 7 years later. Conclusions: In a large Western series of CM patients, 11% were found to have a malignancy. This justifies resection in these patients, despite the risk of morbidity (24%) and mortality (2%). [ABSTRACT FROM AUTHOR]

Background: Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP.Methods: The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry.Results: One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio.Conclusion: The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival. [ABSTRACT FROM AUTHOR]

Background & Aims: Bu Gu Zhi (BGZ) is a Chinese herb consumed mainly for osteoporosis treatment. Only small case series of BGZ‐induced liver injury (BGZILI) have been reported. We describe the clinicopathological features and clinical course of BGZILI. Methods: Patients diagnosed with drug‐induced liver injury (DILI) at Beijing Friendship Hospital from 2005 to 2017 were reviewed. Clinical and follow‐up data were analysed. Results: Of the 547 DILI patients, 40 cases (7.3%) were attributed to BGZILI. About 34/40 (85.0%) patients were females with a median age of 63 (range, 54‐70) years. The median latency period was 45 (range, 29‐90) days. Patients commonly presented with loss of appetite (57.5%), dark urine (57.5%) and fatigue (55.0%). The median level of alanine aminotransferase and aspartate aminotransferase at BGZILI onset was 673.5 and 423.0 U/L respectively. Total bilirubin (TB) and direct bilirubin (DB) were 59.0 and 39.4 µmol/L respectively. The biochemical liver injury pattern was hepatocellular (92.5%), cholestatic (5.0%) and mixed (2.5%). They were categorized into 'mild' (N = 23, 57.5%), 'moderate' (6, 15.0%) or 'severe' (11, 27.5%) according to severity assessment by DILI network. The main histological injury pattern in 9/40 patients with liver biopsy was acute hepatitis with/without cholestasis. Median duration of follow‐up was 26.3 months with recovery in 37 patients within 6 months. No patients died or required transplantation. Conclusions: BGZ‐induced liver injury manifested more often as a hepatocellular injury pattern with mild to moderate hepatocellular damage. Most patients recovered after cessation of BGZ within 6 months, and none developed end‐stage liver disease or died. [ABSTRACT FROM AUTHOR]

Background: Single-operator peroral cholangioscopy (sPOCS) is considered a valuable diagnostic modality for indeterminate biliary strictures. Nevertheless, studies show large variation in its characteristics and measures of diagnostic accuracy. Our aim was to estimate the diagnostic accuracy of sPOCS visual assessment and targeted biopsies for indeterminate biliary strictures. Additional aims were: estimation of the clinical impact of sPOCS and comparison of diagnostic accuracy with brush cytology.Methods: A retrospective single-center study of adult patients who underwent sPOCS for indeterminate biliary strictures was performed. Diagnostic accuracy was defined as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The clinical impact of sPOCS was assessed by review of medical records, and classified according to its influence on patient management.Results: 80 patients were included, with 40 % having primary sclerosing cholangitis (PSC). Prior ERCP was performed in 88 %, with removal of a biliary stent prior to sPOCS in 55 %. The sensitivity, specificity, PPV, and NPV for sPOCS visual impression and targeted biopsies were 64 %, 62 %, 41 %, and 84 %, and 15 %, 65 %, 75 %, and 69 %, respectively. The clinical impact of sPOCS was limited; outcome changed management in 17 % of patients. Sequential brush cytology sensitivity, specificity, PPV, and NPV were 47 %, 95 %, 80 %, and 83 %.Conclusions: The diagnostic accuracy of sPOCS for indeterminate biliary strictures was found to be inferior to brush cytology, with a low impact on patient management. These findings are obtained from a select patient population with a high prevalence of PSC and plastic stents in situ prior to sPOCS. [ABSTRACT FROM AUTHOR]

Hepatocyte nuclear factor 1A (HNF1A) maturity‐onset diabetes of the young (MODY) is a monogenetic, autosomal dominantly inherited form of diabetes. HNF1A‐MODY is associated with HNF1A‐inactivated hepatocellular adenoma (H‐HCA) formation. Hepatocellular adenoma (HCA) are benign liver tumours and related complications are rare but serious: hepatic haemorrhage and malignant transformation. Guidelines recommend resection of all HCA in men and do not take any co‐occurring metabolic disorders into account. We report a family with HCA preceding diabetes mellitus. Male index patient presented with numerous, irresectable HCA. After initial diagnostic and aetiologic uncertainty HNF1A germline mutation c.815G>A (p.Arg272His) was confirmed 8 years later. No HCA‐related complications occurred. His diabetic mother was diagnosed with HCA after severe hepatic haemorrhage years before. HNF1A‐MODY should be considered in (non‐)diabetic (male) patients with H‐HCA. We advocate liver biopsy and, if necessary, genetic analysis to precede any intervention for HCA in males and screening for HCA in HNF1A‐MODY patients. [ABSTRACT FROM AUTHOR]

Background & Aims The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. Methods Cases of newly diagnosed, untreated autoimmune hepatitis without overlap syndrome were selected. Pretreatment and follow up biopsies were scored for inflammation, fibrosis, bile ductal injury and ductular reaction. Results Thirty-five cases were studied of whom 14 cases had follow up biopsies. Bile duct injury was present in 29 cases (83%), mostly in a PBC-like pattern and was not correlated with demographical or laboratory findings. Ductular reaction, observed in 25 of 35 cases (71%) using conventional histology and in 30 of 32 cases (94%) using immunohistochemistry, was correlated with portal and lobular inflammation, interface hepatitis and centrilobular necrosis as well as bile duct injury and fibrosis. In 11 of 14 cases (79%) ductular reaction remained present on post-treatment biopsy whereas bile duct injury persisted in six of 14 (43%) of cases. Conclusions Bile duct injury and ductular reaction are very common in newly diagnosed autoimmune hepatitis and cannot be predicted biochemically. Bile duct injury may subside in the majority of treated AIH cases while DR tends to persist during follow up. These findings show that the two phenomena are part of the spectrum of AIH with dissimilar responses to treatment and do not necessarily point towards an overlap syndrome. Persistence of ductular reaction after treatment supports the notion that it represents a regenerative response. [ABSTRACT FROM AUTHOR]

Frozen section analysis ( FS) during cancer surgery is widely used to assess resection margins. However, in hilar cholangiocarcinoma ( HCCA), FS may be less reliable because of the specific growth characteristics of the tumor. The aim of this study was to determine the accuracy and consequences of intraoperative FS of the proximal bile duct margins in HCCA. Between 1990 and 2014, 67 patients underwent combined extrahepatic bile duct resection and partial liver resection for HCCA with the use of FS. Sensitivity and specificity of FS was 68% and 97%, respectively. Seventeen of 67 patients (25%) displayed a positive bile duct margin at FS. The false-negative rate was 16% (eight patients). Ten patients (15%) with a positive bile duct margin underwent an additional resection in an attempt to achieve negative margins, which succeeded in three patients (4%). However, only one of these three patients did not have concomitant lymph node metastases, which are associated with a poor prognosis by itself. The use of FS of the proximal bile duct is of limited clinical value because of the relatively low sensitivity, high risk of false-negative results, and the low rate of secondary obtained tumor-free resection margins. Supported by the literature, a new approach to the use of FS in HCCA should be adopted, reserving the technique only for cases in which a substantial additional resection is possible. [ABSTRACT FROM AUTHOR]

Background: Livers with moderate (30-60%) macrovesicular steatosis have been associated with poor outcome after transplantation. Aim of this study was to examine the outcome after transplantation of livers with moderate macrovesicular steatosis when the cold ischemia time (CIT) is kept very short. Methods: Postoperative outcome of 19 recipients of a moderate steatotic liver were compared with a matched control group of 95 recipients of a nonsteatotic liver graft (1:5 ratio). We studied graft/patient survival rates, incidences of primary nonfunction, postoperative complications (classified according to the Clavien- Dindo classification), first-week postoperative hepatic injury serum markers (AST/ALT), and liver function tests (PT time/bilirubin/lactate). In addition, we studied reversal of graft steatosis in follow-up biopsies. Results: Median CIT in livers with moderate steatosis and in controls was below 8 h in both groups. Although short- and long-term patient/graft survival rates and results of liver function tests were similar, serum markers of hepatic injury and postoperative complications (especially grade IVa) were significantly higher in recipients of a moderate steatotic liver. Reversal of steatosis was seen in 9 of the 11 (82%) recipients with follow-up liver biopsies. Conclusion: Despite the association with severe postoperative complications, moderate macrovesicular steatotic livers can be used successfully for transplantation if the CIT is kept very short. [ABSTRACT FROM AUTHOR]

The cause of Cystic fibrosis liver disease (CFLD), is unknown. It is well recognized that hepatic exposure to hydrophobic bile salts is associated with the development of liver disease. For this reason, we hypothesize that, CFTR dependent variations, in the hepatic handling of hydrophobic bile salts, are related to the development CFLD. To test our hypothesis we studied, in Cftr-/- and control mice, bile production, bile composition and liver pathology, in normal feeding condition and during cholate exposure, either acute (intravenous) or chronic (three weeks via the diet). In Cftr-/- and control mice the basal bile production was comparable. Intravenous taurocholate increased bile production to the same extent in Cftr-/- and control mice. However, chronic cholate exposure increased the bile flow significantly less in Cftr-/- mice than in controls, together with significantly higher biliary bile salt concentration in Cftr-/- mice. Prolonged cholate exposure, however, did not induce CFLD like pathology in Cftr-/- mice. Chronic cholate exposure did induce a significant increase in liver mass in controls that was absent in Cftr-/- mice. Chronic cholate administration induces a cystic fibrosis-specific hepatobiliary phenotype, including changes in bile composition. These changes could not be associated with CFLD like pathological changes in CF mouse livers. However, chronic cholate administration induces liver growth in controls that is absent in Cftr-/- mice. Our findings point to an impaired adaptive homeotrophic liver response to prolonged hydrophobic bile salt exposure in CF conditions. [ABSTRACT FROM AUTHOR]

Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37°C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a classical example of inflammation-linked cancer and is characterized by hypervascularity suggesting rich angiogenesis. Cycloxygenase-2 (COX-2) is a potent mediator of inflammation and is considered to upregulate angiogenesis. The aims of the study are (1) to analyze expression of Cox-2 mRNA, Cox-2 protein, miR-16, miR-21 and miR-101 in HCC and adjacent liver parenchyma in cirrhotic and noncirrhotic liver, (2) to investigate the relation between COX-2 expression, miR-21 expression and angiogenic factors in these tissues and (3) to investigate the association between miR-16 and miR-101 and COX-2 expression. Methods: Tissue samples of HCC and adjacent liver parenchyma of 21 noncirrhotic livers and 20 cirrhotic livers were analyzed for COX-2 expression at the mRNA level (qRT-PCR) and at the protein level by Western blot and immunohistochemistry. Gene expression of VEGFA, VEGFR1, VEGFR2, Ang-1, Ang-2 and Tie-2 were correlated with COX-2 levels. miR-16, miR-21 and miR-101 gene expression levels were quantified in HCC tumor tissue. Results: COX-2 mRNA and protein levels were lower in HCC as compared to adjacent liver parenchyma both in cirrhotic and noncirrhotic liver. COX-2 protein localized mainly in vascular and sinusoidal endothelial cells and in Kupffer cells. At the mRNA level but not at the protein level, COX-2 correlated with mRNA levels of angiogenic factors VEGFR1, Ang-1, and Tie2. miR-21 expression was higher in cirrhotic tissues versus noncirrhotic tissues. MiR-101 expression was lower in cirrhotic versus noncirrhotic adjacent liver parenchyma. None of the miRNAs correlelated with COX-2 expression. miR-21 correlated negatively with Tie-2 receptor in adjacent liver parenchyma. Conclusions: In human HCC, COX-2 mRNA but not COX-2 protein levels are associated with expression levels of angiogenic factors. MiR-21 levels are not associated with angiogenic molecules. MiR-16 and miR-101 levels do not correlate with COX-2 mRNA and protein levels. [ABSTRACT FROM AUTHOR]

Background: Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model. Methods: After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system. Results: After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024). Conclusions: Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts. [ABSTRACT FROM AUTHOR]

The inflammatory type hepatocellular adenoma (IHCA) is a subtype of HCA which is a benign liver tumor, predominantly occurring in young women in an otherwise normal liver. IHCA contains either a mutation of gp130 or STAT3. Both mutations lead to a similar morphologic phenotype and to increased expression of C-reactive protein (CRP) and/or serum amyloid-A (SAA). IHCA comprised about 40% of all HCAs and is associated with obesity. We investigated the histomorphological and immunophenotypical changes of the nontumorous liver of 32 resected IHCA specimens. Similar types of changes are present in samples taken adjacent to tumor and distant ones. The lobular architecture is well preserved. Mild/moderate steatosis is found in a high frequency which is in accordance with the median BMI of 32 in our cases. Of note are the regular findings of sinusoidal dilatation, single arteries, and minute CRP foci which are all features of HCA. These distinct CRP foci are mostly found in cases of multiple IHCA which indicates that the remnant liver may also contain IHCA foci. These findings show that the nonlesional liver in IHCA does contain abnormalities, and this may have consequences for the followup, especially since it is known that obesity may stimulate malignant growth. [ABSTRACT FROM AUTHOR]