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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., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

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%)., (© 2020 The Authors. Liver International published by John Wiley & Sons Ltd.)

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., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.)

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., (© 2019 The Authors. Liver International Published by John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2012 John Wiley & Sons A/S.)

Background & Aims: Although regeneration of intrahepatic bile ducts has been extensively studied and intrahepatic progenitor cells have been identified, few studies have focussed on the extrahepatic bile duct (EHBD). We hypothesized that local progenitor cells are present within the EHBD of humans. Human EHBD specimens (n = 17) were included in this study., Methods: Specimens of normal EHBD tissue were obtained from healthy donor livers (n = 6), mildly injured EHBD from patients with cholangitis (n = 6) and severely injured EHBD from patients with ischaemic type biliary lesions (n = 5). Double immunostaining for K19 and the proliferation marker Ki-67 was performed to identify and localize proliferating cells. In addition, immunofluorescent doublestaining using antibodies against K19 and c-Kit was performed to identify and localize cholangiocytes co-expressing putative progenitor cell markers., Results: In normal EHBD, few Ki-67(+) cells were detected, whereas large numbers of Ki-67(+) were found in the diseased EHBD. In EHBD affected by cholangitis, Ki-67(+) cells were mainly located in the basal layer of the lumen. EHBD specimens from patients with ischaemic type biliary lesions displayed histological signs of epithelial cell loss and large numbers of Ki-67(+) cells were observed in the peribiliary glands. C-Kit expression was localized throughout the EHBD wall and immunofluorescent doublestaining identified a few K19(+) /c-Kit(+) cells in the luminal epithelium of the EHBD as well as in the peribiliary glands., Conclusions: These findings support the hypothesis that progenitor cells exist in the EHBD and that the peribiliary glands can be considered a local progenitor cell niche in the human EHBD., (© 2011 John Wiley & Sons A/S.)