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Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH., (© 2024. The Author(s).)

Background and Aims: The diagnosis of alcoholic steatohepatitis (ASH) is based on liver biopsy, which is costly and invasive with non-negligible morbidity. The aim of this study was to evaluate the accuracy of circulating cytokeratin 18 M65 fragment (K18-M65) alone or in association with other markers for the non-invasive diagnosis of ASH in patients ongoing alcohol withdrawal., Methods: This study examined the serum level of K18-M65 in a test cohort of 196 patients. All patients underwent liver biopsy, transient elastography (TE) and serum collection. The diagnostic accuracy of K18-M65 alone or combined with clinico-biological data was assessed and the best defined cut-offs were validated in an independent validation cohort of 58 patients., Results: K18-M65 had an area under the curve (AUC) of 0.82 (test cohort) and 0.90 (validation cohort). Using two cut-off decision points, K18-M65 was able to classify 46.9% (test cohort) and 34.5% (validation cohort) of patients with 95% sensitivity or specificity. Combining K18-M65, alpha-2-macroglobulin, TE, body mass index, and age, we created a score allowing accurate diagnosis of ASH with an AUC of 0.93 (test cohort) and 0.94 (validation cohort). This new score was able to rule out or rule in the diagnosis of steatohepatitis for probability ≤0.135 or ≥0.667 respectively in more than two-thirds of patients., Conclusions: We propose a new validated non-invasive score for the diagnosis of ASH in patients ongoing alcohol withdrawal. This score can help to identify patients that may benefit from potential therapeutics or motivate them to reduce alcohol consumption., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Variations in graft arterial anatomy can increase the risk of postoperative hepatic arterial thrombosis (HAT), especially in presence of a replaced or accessory right hepatic artery (RHA). We retrospectively analyzed 223 cases of liver transplantations with the presence of an RHA on the graft. Patient outcomes were compared according to the four different reconstruction methods used: (i) the re-implantation of the RHA into the splenic or gastroduodenal artery (n = 106); (ii) the interposition of the superior mesenteric artery (SMA) (n = 83); (iii) dual anastomosis (n = 24); (iv) use of an aortic patch including the origins of both the SMA and the coeliac trunk (n = 10). A competing risk analysis and Inverse Probability Weighting (IPW) were used. We found that the interposition of the SMA method was associated with a significantly lower incidence of HAT, at 4.8% compared to the re-implantation method at 17.9%, dual anastomosis at 12.5%, and aortic patch at 20%, p = .03. In the competing risk analysis with IPW, the only risk factor for RHA thrombosis was the type of reconstruction. Taking the SMA interposition group as the reference, the sub-hazard ratio (sHR) was 5.05 (CI 95 [1.72; 14.78], p < .01) for the re-implantation group, sHR = 2.37 (CI 95 [0.51; 11.09], p = .27) for the dual anastomosis group and sHR = 2.24 (CI 95 [0.35; 14.33], p = .40) for the aortic patch group. There were no differences for intraoperative transfusion, hospitalization duration (p = .37) or incidence of severe complications (p = .1). The long-term graft (p = .69) and patient (p = .52) survival was not different. In conclusion, the SMA interposition method was associated with a lower incidence of RHA thrombosis., (© 2022 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Artificial Intelligence (AI)-based Deep Neural Networks (DNNs) can handle a wide range of applications in image analysis, ranging from automated segmentation to diagnostic and prediction. As such, they have revolutionized healthcare, including in the liver pathology field., Objective: The present study aims to provide a systematic review of applications and performances provided by DNN algorithms in liver pathology throughout the Pubmed and Embase databases up to December 2022, for tumoral, metabolic and inflammatory fields., Results: 42 articles were selected and fully reviewed. Each article was evaluated through the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, highlighting their risks of bias., Conclusions: DNN-based models are well represented in the field of liver pathology, and their applications are diverse. Most studies, however, presented at least one domain with a high risk of bias according to the QUADAS-2 tool. Hence, DNN models in liver pathology present future opportunities and persistent limitations. To our knowledge, this review is the first one solely focused on DNN-based applications in liver pathology, and to evaluate their bias through the lens of the QUADAS2 tool.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes., (© 2023. Springer Nature Limited.)

Background: Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms., Objective: The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD., Methods: Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up., Results: Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis., Conclusions: In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objective: To evaluate the short- and long-term outcomes of RPA in a large multicentric series., Summary Background: The current knowledge on RPA for portal reconstruction during LT in patients with diffuse PVT and a large splenorenal shunt is poor and limited to case reports and small case series., Methods: All consecutive LTs with RPA performed in 5 centers between 1998 and 2020 were included. RPA was physiological provided it drained the splanchnic venous return through a large splenorenal shunt (≥ 1 cm diameter). Complications of PHT, long-term RPA patency, and patient and graft survival were assessed. RPA success was achieved provided the 3 following criteria were all fulfilled: patients were alive with patent RPA and without clinical PHT., Results: RPA was attempted and feasible in 57 consecutive patients and was physiological in 51 patients (89.5%). Ninety-day mortality occurred in 5 (8.5%) patients, and PHT-related complications occurred in 42.9% of patients. With a median follow-up of 63 months, the 1-, 3- and 5-year patient and graft survival rates were 87%, 83%, and 76% and 82%, 80%, and 73%, respectively. The primary and primary-assisted patency rates at 5 years were 84.5% and 94.3%, respectively. Success was achieved in 90% (27/30) of patients with a follow-up ≥5 years., Conclusions: Despite a high rate of PHT-related complications, excellent long-term patient and graft survival could be achieved. RPA could be considered successful in the vast majority of patients. The expanded use of RPA is warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Because of a narrow therapeutic index and a wide inter- and intra-patient variability, therapeutic drug monitoring of the immunosuppressant drug tacrolimus (TAC) based on whole-blood concentrations (C blood ) is mandatory in solid organ transplant recipients. Using peripheral blood mononuclear cells concentrations (C PBMC ) could improve patient outcomes. The poor correlation between C blood and C PBMC makes hypothesize that drug transporters are implicated in the intracellular accumulation of TAC. The aim of this work was therefore to clinically study: i) the role of genetic variants and ii) the effect of mRNA and protein expression of 4 drug transporters on the TAC C PBMC/blood ratio. In addition, functional in vitro experiments were performed to mechanistically validate the clinical observations. Genetic variants of ABCB1/P-gp and SLC28A3/CNT3 did not influence TAC C PBMC in liver transplant recipients (LTR). ABCC2/MRP2 at the mRNA level; ABCB1/P-gp, SLC28A3/CNT3 and SLC29A1/ENT1 at the protein level; correlated with the C PBMC/blood in kidney and LTR. In vitro results suing transporter-expressing cells confirmed that TAC is substrate of P-gp but not MRP2, whereas experiments remained inconclusive for CNT3 and ENT1. In conclusion, the genetic-transcription-protein-functional approach presented in this work provides new insights in the understanding of TAC transport at the T lymphocyte plasma membrane., Competing Interests: Declaration of competing interest Gwendal Coste's Ph.D. has been partly funded by Astellas Pharma. Florian Lemaitre has been invited to participation in congresses by Chiesi and Sandoz., (Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: The standard of care for haemochromatosis is regular phlebotomy in order to maintain low ferritin levels. Many patients report fatigue or joint pain despite serum ferritin within the therapeutic targets. We evaluated Patient-Reported Outcomes, and their relation with iron parameters, in C282Y homozygous patients undergoing maintenance phlebotomy., Methods: Patients were prospectively enrolled in a French referral care centre. At each phlebotomy, patients completed a numeric fatigue scale, a joint pain questionnaire and SF-36 Mental Component Score (MCS) and Physical Component Score (PCS). Haemoglobin, iron, TS and ferritin were collected concomitantly., Results: About 701 visits were performed in 259 patients. The median fatigue score was 3/10; 171 (66%) patients reported joint pain. Age and worsening of joint pain were associated with fatigue (p < .0001 for both). Female gender (p < .037), age (p < .003), and a decrease of TS (p = .050) were associated with joint pain. Main features associated with PCS <50 were worsening of joint pain and age (p < .001 for both) and TS <20% (p < .02)., Conclusions: Fatigue was independent from iron parameters. The main factor impacting quality of life was joint pain, which was more severe in patients with low TS values. Then, a more precise monitoring of TS should be proposed during haemochromatosis maintenance therapy; while less stringent monitoring of serum ferritin levels could be tested., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Liver stiffness measurement by transient elastography (TE) is a promising method for staging fibrosis in alcohol-related liver disease, but uncertainties remain regarding the influence of alcohol consumption and thus the ideal timing for TE performance. We evaluated the performance of TE compared with liver biopsy to exclude compensated advanced chronic liver disease (cACLD) in patients hospitalized for alcohol detoxification., Methods: Patients were recruited prospectively at 6 in-patient addiction centers in France. Eligible patients had increased aspartate aminotransferase levels, and no history or signs of overt cirrhosis. TE, histology, and biochemistry measurements were obtained within a median of 6 days after alcohol withdrawal. TE and biochemistry were repeated 1 and 2 months later., Results: The study included 259 patients for per-protocol analysis, of whom 45 (17%) had cACLD. TE identified patients with high accuracy at inclusion and at the 1- and 2-month follow-up evaluation, with area under the curve values of 0.96 (95% CIs, 0.94-0.99), 0.96 (95% CIs, 0.92-0.99), and 0.93 (95% CIs, 0.85-1.00), respectively. In 84% of patients, cACLD was ruled out when liver stiffness was less than 10 kPa (negative predictive value, 99% (95% CIs, 98%-100%)) or ruled in when greater than 25 kPa (positive predictive value, 93% (95% CI, 83%-102%)). Algorithms based on aminotransferase levels and/or bilirubin did not add to the diagnostic performance of TE in this period. Among patients with initial liver stiffness of 10 to 25 kPa, more than half of those with no cACLD showed liver stiffness of less than 10 at 1- and 2-month follow-up testing., Conclusions: TE performed during the first 2 months after alcohol cessation is an excellent method for excluding alcohol-related cACLD., Clinical Trial Number: NCT01789008., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

Background: Venesection is the key therapy in haemochromatosis, but it remains controversial in hyperferritinaemia with moderate iron accumulation. There is substantial evidence that the results of HFE genotyping are routinely misinterpreted, while elevated serum ferritin has become more frequent in recent years in white adult populations following the increase of obesity and metabolic traits., Aims: To examine the reasons for prescribing venesection in 1,059 French patients during the period 2012-2015, determine the true prevalence of HFE-related haemochromatosis, and compare iron overload profiles between haemochromatosis and non-haemochromatosis patients., Results: Only 258 of the 488 patients referred for haemochromatosis had the p.[Cys282Tyr];[Cys282Tyr] disease causative genotype (adjusted prevalence: 24.4%). Of the 801 remaining patients, 112 (14.0%) had the debated p.[Cys282Tyr];[His63Asp] compound heterozygote genotype, 643 (80.3%) had central obesity, 475 (59.3%) had metabolic syndrome (MetS) and 93 (11.6%) were heavy drinkers. The non-haemochromatosis patients started therapeutic venesection 9 years later than haemochromatosis patients (P < 0.001). Despite similar serum ferritin values, they had lower transferrin saturation (41.1% vs 74.3%; P < 0.001), lower amounts of iron removed by venesection (1.7 vs 3.2 g; P < 0.001) and lower hepatic iron concentrations (107 vs 237 µmol/g; P < 0.001)., Conclusions: Haemochromatosis is over-diagnosed and is no longer the main reason for therapeutic venesection in France. Obesity and other metabolic abnormalities are frequently associated with mild elevation of serum ferritin, the MetS is confirmed in ~50% of treated patients. There is a minimal relationship between serum ferritin and iron overload in non-p.Cys282Tyr homozygotes. Our observations raise questions about venesection indications in non-haemochromatosis patients., (© 2022 John Wiley & Sons Ltd.)

Background & Aims: Ferroportin disease is a rare genetic iron overload disorder which may be underdiagnosed, with recent data suggesting it occurs at a higher prevalence than suspected. Costs and the lack of defined criteria to prompt genetic testing preclude large-scale molecular screening. Hence, we aimed to develop a readily available scoring system to promote and enhance ferroportin disease screening., Methods: Our derivation cohort included probands tested for ferroportin disease from 2008 to 2016 in our rare disease network. Data were prospectively recorded. Univariate and multivariate logistic regression were used to determine significant criteria, and odds ratios were used to build a weighted score. A cut-off value was defined using a ROC curve with a predefined aim of 90% sensitivity. An independent cohort was used for cross validation., Results: Our derivation cohort included 1,306 patients. Mean age was 55±14 years, ferritin 1,351±1,357 μg/L, and liver iron concentration (LIC) 166±77 μmol/g. Pathogenic variants (n = 32) were identified in 71 patients. In multivariate analysis: female sex, younger age, higher ferritin, higher LIC and the absence of hypertension or diabetes were significantly associated with the diagnosis of ferroportin disease (AUROC in whole derivation cohort 0.83 [0.78-0.88]). The weighted score was based on sex, age, the presence of hypertension or diabetes, ferritin level and LIC. An AUROC of 0.83 (0.77-0.88) was obtained in the derivation cohort without missing values. Using 9.5 as a cut-off, sensitivity was 93.6 (91.7-98.3) %, specificity 49.5 (45.5-53.6) %, positive likelihood ratio 1.8 (1.6-2.0) and negative likelihood ratio 0.17 (0.04-0.37)., Conclusion: We describe a readily available score with simple criteria and good diagnostic performance that could be used to screen patients for ferroportin disease in routine clinical practice., Lay Summary: Increased iron burden associated with metabolic syndrome is a very common condition. Ferroportin disease is a dominant genetic iron overload disorder whose prevalence is higher than initially thought. They can be difficult to distinguish from each other, but the limited availability of genetic testing and the lack of definitive guidelines prevent adequate screening. We herein describe a simple and definitive clinical score to help clinicians decide whether to perform genetic testing., Competing Interests: Conflict of interest Dr. LOUSTAUD-RATTI reports personal fees from Abbvie, personal fees from Gilead, personal fees from IPSEN, outside the submitted work. Dr. Causse reports personal fees from Abbvie, personal fees from Gilead Sciences, personal fees from MSD, outside the submitted work. Dr. SI AHMED reports grants and non-financial support from Abbvie, grants and non-financial support from Gilead, grants from MSD, outside the submitted work. Dr. Ganne-Carrié reports personal fees and non-financial support from GILEAD, personal fees and non-financial support from BAYER, personal fees from IPSEN, outside the submitted work. Dr. Loréal reports personal fees and other from Diafir, outside the submitted work. Other authors have no conflict of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Few studies have analyzed outcomes of liver transplantation (LT) when the recipient hepatic artery (HA) was not usable., Methods: We retrospectively evaluated the outcomes of LT performed using the different alternative sites to HA., Results: Between 2002 and 2017, 1,677 LT were performed in our institution among which 141 (8.4%) with unusable recipient HA were analyzed. Four groups were defined according to the site of anastomosis: the splenic artery (SA group, n=26), coeliac trunk (CT group, n=12), aorta using or not the donor's vessel (Ao group, n=91) and aorta using a vascular prosthesis (Ao-P group, n=12) as conduit. The median number of intraoperative red blood cell transfusions was significantly increased in the Ao and Ao-P groups (5, 5, 8.5 and 16 for SA, CT, Ao and Ao-P group respectively, P=0.002), as well as fresh frozen plasma (4.5, 2.5, 10, 17 for the SA, CT, Ao and Ao-P groups respectively, P=0.001). Hospitalization duration was also significantly increased in the Ao and Ao-P groups (15, 16, 24, 26.5 days for the SA, CT, Ao and Ao-P groups respectively, P<0.001). The occurrence of early allograft dysfunction (EAD) (P=0.07) or arterial complications (P=0.26) was not statistically different. Level of factor V, INR, bilirubin and creatinine during the 7 th postoperative days (POD) was significantly improved in the SA group. No difference was observed regarding graft (P=0.18) and patient (P=0.16) survival., Conclusions: In case of unusable HA, intraoperative and postoperative outcomes are improved when using the SA or CT compared to aorta., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-20-10/coif). GBLS serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2022 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Increased serum ferritin is a very frequent cause of referral for which thorough evaluation is required to avoid unnecessary exploration and inaccurate diagnosis. Clinicians must thus know factors and tools that are relevant in this setting. Several biochemical and radiological tools drastically improved the diagnosis work-up of increased serum ferritin. Because serum ferritin value can be altered by many cofounding factors, scrutiny in the initial clinical evaluation is crucial. Alcohol consumption, and the metabolic syndrome are the most frequent causes of secondary increased ferritin. Serum transferrin saturation level is a pivotal test, and if increased prompt testing for HFE C282Y patients in Caucasian population. In most cases further tests are require to establish whether increased ferritin is associated or not to iron overload. Magnetic resonance imaging is the reference method allowing to accurately establish liver iron content which indirectly reflect body iron load. Second line genetic testing for rare forms of iron overload or increased serum ferritin are available in reference center and should be discussed if diagnosis is equivocal or remain uncertain after careful evaluation. Definite genetic diagnosis is worthwhile as it allows family screening and refining long term management of the patient. Liver biopsy remains seldom useful to assess liver fibrosis, mostly in patients with severe iron overload., Competing Interests: Declarations of Competing Interest BARDOU-JACQUET Edouard: Gilead, Intercept, La Jolla, Novartis, Synageva BOURLIÈRE Marc: Abbott, BMS, Boehringer Ingelheim, Gilead, GSK, Idenix, Intercept, Janssen, Merck, Novartis, Roche, Vertex BUREAU Christophe: AbbVie, Gilead, Gore DE LÉDINGHEN Victor: AbbVie, Alfasigma, BMS, Diafir, Echosens, Gilead, Indivior, Intercept, Medac, Myr Pharma, Pfizer, Promethera, Spimaco, Supersonic Imagine DECRAECKER Marie: No conflict of interest GANNE-CARRIÉ Nathalie: Bayer, Gilead, Ipsen, Roche, Shionogi HAMDI-ROZE Houda: No conflict of interest PAISANT Anita: Declared no conflicts of interest, (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Portal vein thrombosis (PVT) is no longer a contraindication for liver transplantation (LT). While therapeutic anticoagulation (tAC) is recommended during the waiting period, there is no evidence for its usefulness in the prevention of PVT recurrence after LT., Objectives: The aim of our study was to evaluate the role of tAC post-LT in the prevention of PVT recurrence., Patients/methods: All adult LTs performed in two high-volume centers between 2003 and 2018 were retrospectively analysed. Only patients with PVT classified as Yerdel grade I or II and with standard portal reconstruction were included. PVT recurrence and tAC-associated morbidity within 1 year were compared between patients receiving tAC or not., Results: During the study period, of 2612 LTs performed, 235 (9%) patients with PVT were included; 113 patients (48.1%) received post-LT tAC (tAC group) while 122 (51.9%) did not (non-tAC group). The incidence of bleeding events was significantly higher in the tAC group (26 [23%] vs. 5 [4.1%], P < .01) and the initial hospitalization duration was longer (21 vs. 17.5 days, P < .01). Within the first year, PVT recurrence was observed for 9 (3.8%) patients without any difference between the tAC and non-tAC groups (6 [5.1%] vs. 3 [2.5%], P = .39). The only identified risk factor for PVT recurrence was the recipients' age (odds ratio= 0.94, P = .03). Graft (P = .11) and patient (P = .44) survival were similar between the two groups., Conclusion: Therapeutic anticoagulation is not necessary in the prevention of grade I/II PVT recurrence and is associated with higher morbidity and longer hospital stay., (© 2021 International Society on Thrombosis and Haemostasis.)

The impact of donor age on the recurrence of hepatocellular carcinoma (HCC) after liver transplantation is still debated. Between 2002 and 2014, all patients transplanted for HCC in 2 European liver transplantation tertiary centres were retrospectively reviewed. Risk factors for HCC recurrence were assessed using competing risk analysis, and the impact of donor age < or ≥65 years and < or ≥80 years was specifically evaluated after propensity score matching. 728 patients transplanted with a median follow-up of 86 months were analysed. The 1-, 3- and 5-year recurrence rates were 4.9%, 10.7% and 13.9%, respectively. In multivariable analysis, recipient age (sHR: 0.96 [0.93; 0.98], P < 0.01), number of lesions (sHR: 1.05 [1.04; 1.06], P < 0.001), maximum size of the lesions (sHR: 1.37 [1.27; 1.48], P < 0.01), presence of a hepatocholangiocarcinoma (sHR: 6.47 [2.91; 14.38], P < 0.01) and microvascular invasion (sHR: 3.48 [2.42; 5.02], P < 0.01) were significantly associated with HCC recurrence. After propensity score matching, neither donor age ≥65 (P = 0.29) nor donor age ≥80 (P = 0.84) years increased the risk of HCC recurrence. In conclusion, donor age was not found to be a risk factor for HCC recurrence. Patients listed for HCC can receive a graft from an elderly donor without compromising the outcome., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD)., Methods: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots., Results: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel., Conclusion: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Iron overload disorders represent an important class of human diseases. Of the primary iron overload conditions, by far the most common and best studied is HFE-related hemochromatosis, which results from homozygosity for a mutation leading to the C282Y substitution in the HFE protein. This disease is characterized by reduced expression of the iron-regulatory hormone hepcidin, leading to increased dietary iron absorption and iron deposition in multiple tissues including the liver, pancreas, joints, heart and pituitary. The phenotype of HFE-related hemochromatosis is quite variable, with some individuals showing little or no evidence of increased body iron, yet others showing severe iron loading, tissue damage and clinical sequelae. The majority of genetically predisposed individuals show at least some evidence of iron loading (increased transferrin saturation and serum ferritin), but a minority show clinical symptoms and severe consequences are rare. Thus, the disorder has a high biochemical penetrance, but a low clinical prevalence. Nevertheless, it is such a common condition in Caucasian populations (1:100-200) that it remains an important clinical entity. The phenotypic variability can largely be explained by a range of environmental, genetic and physiological factors. Men are far more likely to manifest significant disease than women, with the latter losing iron through menstrual blood loss and childbirth. Other forms of blood loss, immune system influences, the amount of bioavailable iron in the diet and lifestyle factors such as high alcohol intake can also contribute to iron loading and disease expression. Polymorphisms in a range of genes have been linked to variations in body iron levels, both in the general population and in hemochromatosis. Some of the genes identified play well known roles in iron homeostasis, yet others are novel. Other factors, including both co-morbidities and genetic polymorphisms, do not affect iron levels per se , but determine the propensity for tissue pathology., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5512). The series “Unresolved Basic Issues in Hepatology” was commissioned by the editorial office without any funding or sponsorship. Dr. GJA reports personal fees from Protagonist Therapeutics, other from PharmaNutra, outside the submitted work. EBJ has no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Few studies have evaluated the efficacy or the cost of hypothermic oxygenated perfusion (HOPE) in the conservation of extended criteria donor (ECD) grafts from donation after brain death (DBD) donors during liver transplantation (LT). We performed a prospective, monocentric study (NCT03376074) designed to evaluate the interest of HOPE for ECD-DBD grafts. For comparison, a control group was selected after propensity score matching among patients who received transplants between 2010 and 2017. Between February and November 2018, the HOPE procedure was used in 25 LTs. Immediately after LT, the median aspartate aminotransferase (AST) level was significantly lower in the HOPE group (724UI versus 1284UI; P = 0.046) as were the alanine aminotransferase (ALT; 392UI versus 720UI; P = 0.01), lactate (2.2 versus 2.7; P = 0.01) There was a significant reduction in intensive care unit stay (3 versus 5 days; P = 0.01) and hospitalization (15 versus 20 days; P = 0.01). The incidence of early allograft dysfunction (EAD; 28% versus 42%; P = 0.22) was similar . A level of AST or ALT in perfusate >800UI was found to be highly predictive of EAD occurrence (areas under the curve, 0.92 and 0.91, respectively). The 12-month graft (88% versus 89.5%; P = 1.00) and patient survival rates (91% versus 91.3%; P = 1.00) were similar. The additional cost of HOPE was estimated at € 5298 per patient. The difference between costs and revenues, from the hospital's perspective, was not different between the HOPE and control groups (respectively, € 3023 versus € 4059]; IC, -€ 5470 and € 8652). HOPE may improve ECD graft function and reduce hospitalization stay without extra cost. These results must be confirmed in a randomized trial., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT., Methods: Of 1677 LTs performed between 2002 and 2017, 904 LT cases were analyzed. The cases were categorized into the following 3 groups and compared: low- (n = 247, 27.3%), intermediate- (n = 344, 37.9%), and high-exposure groups (n = 313, 34.5%) with TAC Cmin of 4-7 ng/mL, 7-10 ng/mL, and >10 ng/mL, respectively. In addition, propensity score matching was performed to reduce heterogeneity and population bias., Results: At months 1 and 3, when compared with the 2 other groups, the low-exposure group had similar grafts (P = 0.75) and patient (P = 0.77) survival, but lower alanine aminotransferase (P < 0.001), bilirubin (P < 0.001), international normalized ratio (P = 0.046), and creatinine (P < 0.001) levels. After propensity score matching, the bilirubin (P < 0.001) and creatinine (P = 0.001) levels in the low-exposure group still improved at months 3, but the graft (P = 0.86) and patient (P = 0.99) survival were still similar., Conclusions: A TAC Cmin of 4-7 ng/mL seems safe and capable of improving graft and kidney function. This finding should be confirmed in a prospective randomized trial.

Background & Aims: Fibrosis stage can decrease following treatment in patients with hemochromatosis caused by mutations in the homeostatic iron regulator gene (HFE), but the effects on cirrhosis are not clear. We assessed regression of severe fibrosis and the ensuing risk of liver cancer after treatment., Methods: We performed a retrospective analysis of data from 106 patients in France or Australia who were homozygous for the C282Y mutation in HFE with F3 fibrosis (n = 40) or F4 fibrosis (n = 66) at diagnosis and from whom at least 1 liver biopsy was collected during follow up. We collected data from the time of first biopsy and during follow-up period on patient demographics, treatment, smoking habits, alcohol consumption, infection with hepatitis B or C viruses, and other diseases. The median time between first and last liver biopsy was 9.5 years (range, 3.5-15.6 years). We collected results of tests for liver function, markers of iron stores, and platelet levels. Patients were followed for a median 17.6 years (range, 9.8-24.1 years) for development of liver cancer occurrence., Results: At last liver biopsy, 41 patients (38.6%) had fibrosis scores of F2 or less. Liver cancer occurred in 34 patients (52.3%) with F3 or F4 fibrosis at last liver biopsy vs 2 patients (4.8%) with fibrosis scores of F2 or less at last liver biopsy (P < .001). Liver cancer incidences were 32.8 per 1000 person-years (95% CI, 22.7-45.9 per 1000 person-years) in patients with F3 or F4 fibrosis and 2.3 per 1000 person-years (95% CI, 0.2-8.6 per 1000 person-years) in patients with fibrosis scores of F2 or less (P < .001). In multivariate analysis, male sex (hazard ratio [HR], 6.09; 95% CI, 1.21-30.4), age at diagnosis (HR, 1.16; 95% CI, 1.09-1.25), presence of diabetes (HR, 3.07; 95% CI, 1.35-6.97), excess alcohol consumption (HR, 3.1; 95% CI, 1.47-6.35), serum level of ferritin at diagnosis (P < .01), and regression to fibrosis scores of F2 or less (HR, 0.08; 95% CI, 0.01-0.62) were significantly associated with risk of liver cancer., Conclusions: In a retrospective analysis of patients with hemochromatosis caused by the C282Y mutation in HFE, we found that severe liver fibrosis can regress with treatment. In patients with fibrosis regression to a stage F2 or less, the long-term risk for liver cancer is significantly reduced., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Liver transplantation (LT) is the best treatment for patients with liver cancer or end stage cirrhosis, but it is still associated with a significant mortality. Therefore identifying factors associated with mortality could help improve patient management. The impact of iron metabolism, which could be a relevant therapeutic target, yield discrepant results in this setting. Previous studies suggest that increased serum ferritin is associated with higher mortality. Surprisingly iron deficiency which is a well described risk factor in critically ill patients has not been considered., Aim: To assess the impact of pre-transplant iron metabolism parameters on post-transplant survival., Methods: From 2001 to 2011, 553 patients who underwent LT with iron metabolism parameters available at LT evaluation were included. Data were prospectively recorded at the time of evaluation and at the time of LT regarding donor and recipient. Serum ferritin (SF) and transferrin saturation (TS) were studied as continuous and categorical variable. Cox regression analysis was used to determine mortality risks factors. Follow-up data were obtained from the local and national database regarding causes of death., Results: At the end of a 95-mo median follow-up, 196 patients were dead, 38 of them because of infections. In multivariate analysis, overall mortality was significantly associated with TS > 75% [HR: 1.73 (1.14; 2.63)], SF < 100 µg/L [HR: 1.62 (1.12; 2.35)], hepatocellular carcinoma [HR: 1.58 (1.15; 2.26)], estimated glomerular filtration rate (CKD EPI Cystatin C) [HR: 0.99 (0.98; 0.99)], and packed red blood cell transfusion [HR: 1.05 (1.03; 1.08)]. Kaplan Meier curves show that patients with low SF (< 100 µg/L) or high SF (> 400 µg/L) have lower survival rates at 36 mo than patients with normal SF ( P = 0.008 and P = 0.016 respectively). Patients with TS higher than 75% had higher mortality at 12 mo (91.4% ± 1.4% vs 84.6% ± 3.1%, P = 0.039). TS > 75% was significantly associated with infection related death [HR: 3.06 (1.13; 8.23)]., Conclusion: Our results show that iron metabolism imbalance (either deficiency or overload) is associated with post-transplant overall and infectious mortality. Impact of iron supplementation or depletion should be assessed in prospective study., Competing Interests: Conflict-of-interest statement: Authors have no conflict of interest to declare., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Inborn errors of metabolism (IEM) are rare diseases caused by mutations in genes encoding enzymes or carriers. Qualitative or quantitative protein deficiency induces both an accumulation of precursor metabolites and a lack of products downstream of the blockade. Pregnancy in patients with IEM is a condition likely to promote metabolic decompensation. In this review, we presented liver symptoms described during pregnancy in a context of hepatic IEM. In particular, we detailed clinical and biological abnormalities specifically occurring in tyrosinemia type I, Wilson disease, and main urea cycle defects. In the case of hepatic IEM, depending on the deficit, pregnant women have an increased risk of pre-eclampsia and HELLP syndrome, as well as hyperammonemia. Wilson disease, and principal urea cycle defects. Multidisciplinary consultation is essential for the optimal management of pregnant women with IEM as well as newborns.