Exacerbation of Myopathy in Glycogen Debrancher Deficiency After Liver Transplantation: Case Report and Review of the Literature.

BACKGROUND: Glycogen storage disorder (GSD) type IIIa is a rare inherited genetic disorder affecting liver and muscle tissue. Liver transplantation (LT) improves metabolic control, but muscle involvement persists. CASE: We report the case of a 31-year-old man who underwent orthotopic LT for end-stage liver disease caused by GSD type IIIa. After LT, he developed worsening clinical signs of myopathy, along with exponentially increasing levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and creatine kinase. Liver-related elevations of AST and ALT were excluded through liver biopsy and endoscopic cholangiography; consequently, AST and ALT elevations were attributed to the underlying muscle involvement. Exacerbation of muscle disease after LT could be attributed to restoration of liver glycogen metabolism after LT, leading to increased glucose accumulation in muscle cells, where the gene defect persists. A dietary intervention with a high-protein, ketogenic diet was initiated but did not lead to significant improvement of myalgia. CONCLUSION: LT exacerbated muscle disease in a patient with GSD type IIIa. Patients should be counseled about this possible side effect of LT in GSD type IIIa.

Microbiological risk factors, ICU survival, and 1-year survival in hematological patients with pneumonia requiring invasive mechanical ventilation.

PURPOSE: To identify pathogenic microorganisms and microbiological risk factors causing high morbidity and mortality in immunocompromised patients requiring invasive mechanical ventilation due to pneumonia. METHODS: A retrospective single-center study was performed at the intensive care unit (ICU) of the Department of Internal Medicine at Heidelberg University Hospital (Germany) including 246 consecutive patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia from 08/2004 to 07/2016. Microbiological and radiological data were collected and statistically analyzed for risk factors for ICU and 1-year mortality. RESULTS: ICU and 1-year mortality were 63.0% (155/246) and 81.0% (196/242), respectively. Pneumonia causing pathogens were identified in 143 (58.1%) patients, multimicrobial infections were present in 51 (20.7%) patients. Fungal, bacterial and viral pathogens were detected in 89 (36.2%), 55 (22.4%) and 41 (16.7%) patients, respectively. Human herpesviruses were concomitantly reactivated in 85 (34.6%) patients. As significant microbiological risk factors for ICU mortality probable invasive Aspergillus disease with positive serum-Galactomannan (odds ratio 3.1 (1.2-8.0), p = 0.021,) and pulmonary Cytomegalovirus reactivation at intubation (odds ratio 5.3 (1.1-26.8), p = 0.043,) were identified. 1-year mortality was not significantly associated with type of infection. Of interest, 19 patients had infections with various respiratory viruses and Aspergillus spp. superinfections and experienced high ICU and 1-year mortality of 78.9% (15/19) and 89.5% (17/19), respectively. CONCLUSIONS: Patients with hematological malignancies requiring invasive mechanical ventilation due to pneumonia showed high ICU and 1-year mortality. Pulmonary Aspergillosis and pulmonary reactivation of Cytomegalovirus at intubation were significantly associated with negative outcome.

The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population-A comparison of two German registries.

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease.

Integrative Molecular Structure Elucidation and Construction of an Extended Metabolic Pathway Associated with an Ancient Innate Immune Response in COVID-19 Patients.

We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.

Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug-drug interactions.

Changes in the pharmacokinetic and resulting pharmacodynamic properties of drugs are common in many chronic liver diseases, leading to adverse effects, drug interactions and increased risk of over- or underdosing of medications. Structural and functional hepatic impairment can have major effects on drug metabolism and transport. This review summarizes research on the functional changes in phase I and II metabolic enzymes and in transport proteins in patients with metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis and cirrhosis, providing a clinical perspective on how these changes affect drug uptake and metabolism. Generally, a decrease in expression and/or activity of many enzymes of the cytochrome P450 family (e.g. CYP2E1 and CYP3A4), and of influx and efflux transporters (e.g. organic anion-transporting polypeptide [OATP]1B1, OATP2B1, OAT2 and bile salt export pump), has been recently documented in patients with liver disease. Decreased enzyme levels often correlate with increased severity of chronic liver disease. In subjects with hepatic impairment, there is potential for strong alterations of drug pharmacokinetics due to reduced absorption, increased volume of distribution, metabolism and extraction. Due to the altered pharmacokinetics, specific drug-drug interactions are also a potential issue to consider in patients with liver disease. Given the huge burden of liver disease in western societies, there is a need to improve awareness among all healthcare professionals and patients with liver disease to ensure appropriate drug prescriptions.

Association of perioperative use of statins, metformin, and aspirin with recurrence after curative liver resection in patients with hepatocellular carcinoma: A propensity score matching analysis.

BACKGROUND: Statins, metformin, and aspirin have been reported to reduce the incidence of hepatocellular carcinoma (HCC). However, the effect of their perioperative use on survival outcomes of HCC patients following curative liver resection still remains unclear. METHOD: Three hundred and fifty three patients with a first diagnosis of HCC who underwent curative liver resection were included. Propensity score matching analysis with a users: nonusers ratio of 1:2 were performed for each of the medications (statins, metformin, and aspirin). Overall survival (OS) and recurrence-free survival (RFS) were evaluated and multivariable Cox proportional hazard analysis was performed. RESULTS: Sixty two patients received statins, 48 patients used metformin, and 53 patients received aspirin for ≥90 days before surgery. None of the medications improved OS. RFS of statin users was significantly longer than that of nonusers (p = 0.021) in the matched cohort. Users of hydrophilic statins, but not lipophilic ones had a significantly longer RFS than nonusers. Multivariable analysis showed that statin use significantly improved RFS (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.17-0.97, p = 0.044). No difference was seen in RFS between metformin users and nonusers. Among patients with diabetes, RFS was nonsignificantly longer in metformin users than in non-metformin users (84.1% vs. 60.85%, p = 0.069) in the matched cohort. No difference in postoperative RFS was seen between aspirin users and nonusers. CONCLUSION: Preoperative use of statins in patients with HCC can increase RFS after curative liver resection, but metformin and aspirin were not associated with improved survival. Randomized controlled trials are needed to confirm the findings of the present study.

Vascular pathology in patients with alveolar echinococcosis: framework for assessment and clinical management - a retrospective case series.

OBJECTIVE: Alveolar echinococcosis (AE) is a parasitic liver disease with infiltrative growth similar to solid organ malignancies. Major vascular damage is frequent and often remains untreated until catastrophic events precipitate. Detailed clinical and radiological assessment is required to guide individualised treatment decisions. Standardised radiological reporting templates of malignancies with profiles resembling AE are candidates for adaptation. Our objectives are to describe vascular pathology in AE and establish a framework for structured evaluation as the basis for treatment decisions and monitoring. DESIGN: Retrospective case series. RESULTS: 69 patients (37.1%) had vascular involvement: portal vein (PV) 24.7%, hepatic vein (HV) 22.6% inferior vena cava (IVC) 13.4%. Significant stenosis/occlusion of vessels was present in 15.1% of PV, in 13.4% of HV and in 7.5% of IVC involvement. Vascular pathology needing specific treatment or monitoring was present in 8.6% of patients. The most frequent clinical presentation was high grade IVC stenosis or occlusion which was seen in 11 patients of the cohort. CONCLUSION: Advanced AE requires early multidisciplinary assessment to prevent progressive impairment of liver function due to vascular damage. The focus at first presentation is on complete evaluation of vascular (and biliary) involvement. The focus in non-resectable AE is on prevention of vascular (and biliary) complications while suppressing growth of AE lesions by benzimidazole treatment to improve the quality of life of patients. We developed a framework for standardised vascular assessment and follow-up of patients with AE to recognise and treat complications early.

Five-year follow-up of a phase I trial of donor-derived modified immune cell infusion in kidney transplantation.

Background: The administration of modified immune cells (MIC) before kidney transplantation led to specific immunosuppression against the allogeneic donor and a significant increase in regulatory B lymphocytes. We wondered how this approach affected the continued clinical course of these patients. Methods: Ten patients from a phase I clinical trial who had received MIC infusions prior to kidney transplantation were retrospectively compared to 15 matched standard-risk recipients. Follow-up was until year five after surgery. Results: The 10 MIC patients had an excellent clinical course with stable kidney graft function, no donor-specific human leukocyte antigen antibodies (DSA) or acute rejections, and no opportunistic infections. In comparison, a retrospectively matched control group receiving standard immunosuppressive therapy had a higher frequency of DSA (log rank P = 0.046) and more opportunistic infections (log rank P = 0.033). Importantly, MIC patients, and in particular the four patients who had received the highest cell number 7 days before surgery and received low immunosuppression during follow-up, continued to show a lack of anti-donor T lymphocyte reactivity in vitro and high CD19+CD24hiCD38hi transitional and CD19+CD24hiCD27+ memory B lymphocytes until year five after surgery. Conclusions: MIC infusions together with reduced conventional immunosuppression were associated with good graft function during five years of follow-up, no de novo DSA development and no opportunistic infections. In the future, MIC infusions might contribute to graft protection while reducing the side effects of immunosuppressive therapy. However, this approach needs further validation in direct comparison with prospective controls. Trial registration: https://clinicaltrials.gov/, identifier NCT02560220 (for the TOL-1 Study). EudraCT Number: 2014-002086-30.

Surgical management of primary liver cancers during the COVID-19 pandemic: overcoming the dilemma with standardization.

BACKGROUND: The present study evaluates the impact of the pandemic on outcomes after surgical treatment for primary liver cancer in a high-volume hepatopancreatobiliary surgery center. METHODS: Patients, who underwent liver resection for primary liver resection between January 2019 and February 2020, comprised pre-pandemic control group. The pandemic period was divided into two timeframes: early pandemic (March 2020-January 2021) and late pandemic (February 2021-December 2021). Liver resections during 2022 were considered as the post-pandemic period. Peri-, and postoperative patient data were gathered from a prospectively maintained database. RESULTS: Two-hundred-eighty-one patients underwent liver resection for primary liver cancer. The number of procedures decreased by 37.1% during early phase of pandemic, but then increased by 66.7% during late phase, which was comparable to post-pandemic phase. Postoperative outcomes were similar between four phases. The duration of hospital stay was longer during the late phase, but not significantly different compared to other groups. CONCLUSION: Despite an initial reduction in number of surgeries, COVID-19 pandemic had no negative effect on outcomes of surgical treatment for primary liver cancer. The structured standard operating protocol in a high-volume and highly specialized surgical center can withstand negative effects, a pandemic may have on treatment of patients.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Comparison of HAV and HCV infections in vivo and in vitro reveals distinct patterns of innate immune evasion and activation.

BACKGROUND & AIMS: Hepatitis A virus (HAV) infections are considered not to trigger innate immunity in vivo, in contrast to hepatitis C virus (HCV). This lack of induction has been imputed to strong interference by HAV proteases 3CD and 3ABC. We aimed to elucidate the mechanisms of immune activation and counteraction by HAV and HCV in vivo and in vitro. METHODS: Albumin-urokinase-type plasminogen activator/severe combined immunodeficiency (Alb/uPA-SCID) mice with humanised livers were infected with HAV and HCV. Hepatic cell culture models were used to assess HAV and HCV sensing by Toll-like receptor 3 and retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 (RIG-I/MDA5), respectively. Cleavage of the adaptor proteins TIR-domain-containing adapter-inducing interferon-ß (TRIF) and mitochondrial antiviral-signalling protein (MAVS) was analysed by transient and stable expression of HAV and HCV proteases and virus infection. RESULTS: We detected similar levels of interferon-stimulated gene induction in hepatocytes of HAV- and HCV-infected mice with humanised liver. In cell culture, HAV induced interferon-stimulated genes exclusively upon MDA5 sensing and depended on LGP2 (laboratory of genetics and physiology 2). TRIF and MAVS were only partially cleaved by HAV 3ABC and 3CD, not sufficiently to abrogate signalling. In contrast, HCV NS3-4A efficiently degraded MAVS, as previously reported, whereas TRIF cleavage was not detected. CONCLUSIONS: HAV induces an innate immune response in hepatocytes via MDA5/LGP2, with limited control of both pathways by proteolytic cleavage. HCV activates Toll-like receptor 3 and lacks TRIF cleavage, suggesting that this pathway mainly contributes to HCV-induced antiviral responses in hepatocytes. Our results shed new light on the induction of innate immunity and counteraction by HAV and HCV. IMPACT AND IMPLICATIONS: Understanding the mechanisms that determine the differential outcomes of HAV and HCV infections is crucial for the development of effective therapies. Our study provides insights into the interplay between these viruses and the host innate immune response in vitro and in vivo, shedding light on previously controversial or only partially investigated aspects. This knowledge could tailor the development of new strategies to combat HCV persistence, as well as improve our understanding of the factors underlying successful HAV clearance.

Discovery and systematic assessment of early biomarkers that predict progression to severe COVID-19 disease.

BACKGROUND: The clinical course of COVID-19 patients ranges from asymptomatic infection, via mild and moderate illness, to severe disease and even fatal outcome. Biomarkers which enable an early prediction of the severity of COVID-19 progression, would be enormously beneficial to guide patient care and early intervention prior to hospitalization. METHODS: Here we describe the identification of plasma protein biomarkers using an antibody microarray-based approach in order to predict a severe cause of a COVID-19 disease already in an early phase of SARS-CoV-2 infection. To this end, plasma samples from two independent cohorts were analyzed by antibody microarrays targeting up to 998 different proteins. RESULTS: In total, we identified 11 promising protein biomarker candidates to predict disease severity during an early phase of COVID-19 infection coherently in both analyzed cohorts. A set of four (S100A8/A9, TSP1, FINC, IFNL1), and two sets of three proteins (S100A8/A9, TSP1, ERBB2 and S100A8/A9, TSP1, IFNL1) were selected using machine learning as multimarker panels with sufficient accuracy for the implementation in a prognostic test. CONCLUSIONS: Using these biomarkers, patients at high risk of developing a severe or critical disease may be selected for treatment with specialized therapeutic options such as neutralizing antibodies or antivirals. Early therapy through early stratification may not only have a positive impact on the outcome of individual COVID-19 patients but could additionally prevent hospitals from being overwhelmed in potential future pandemic situations.

We aimed to identify components of the blood present during the early phase of SARS-CoV-2 infection that distinguish people who are likely to develop severe symptoms of COVID-19. Blood from people who later developed a mild or moderate course of disease were compared to blood from people who later had a severe or critical course of disease. Here, we identified a combination of three proteins that were present in the blood of patients with COVID-19 who later developed a severe or critical disease. Identifying the presence of these proteins in patients at an early stage of infection could enable physicians to treat these patients early on to avoid progression of the disease.

Declined Organs for Liver Transplantation: A Right Decision or a Missed Opportunity for Patients with Hepatocellular Carcinoma?

BACKGROUND: Liver transplantation is the only promising treatment for end-stage liver disease and patients with hepatocellular carcinoma. However, too many organs are rejected for transplantation. METHODS: We analyzed the factors involved in organ allocation in our transplant center and reviewed all livers that were declined for transplantation. Reasons for declining organs for transplantation were categorized as major extended donor criteria (maEDC), size mismatch and vascular problems, medical reasons and risk of disease transmission, and other reasons. The fate of the declined organs was analyzed. RESULTS: 1086 declined organs were offered 1200 times. A total of 31% of the livers were declined because of maEDC, 35.5% because of size mismatch and vascular problems, 15.8% because of medical reasons and risk of disease transmission, and 20.7% because of other reasons. A total of 40% of the declined organs were allocated and transplanted. A total of 50% of the organs were completely discarded, and significantly more of these grafts had maEDC than grafts that were eventually allocated (37.5% vs. 17.7%, p < 0.001). CONCLUSION: Most organs were declined because of poor organ quality. Donor-recipient matching at time of allocation and organ preservation must be improved by allocating maEDC grafts using individualized algorithms that avoid high-risk donor-recipient combinations and unnecessary organ declination.

Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial.

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 (n = 134) within four risk groups ((1) cancer (n = 56); (2) immunosuppression (n = 16); (3) laboratory-based risk factors (n = 36); and (4) advanced age (n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer (P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.

Induction of Long-Lasting Regulatory B Lymphocytes by Modified Immune Cells in Kidney Transplant Recipients.

BACKGROUND: We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. METHODS: Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. RESULTS: Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. CONCLUSIONS: These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: MIC Cell Therapy for Individualized Immunosuppression in Living Donor Kidney Transplant Recipients (TOL-1), NCT02560220.

Myeloid- and hepatocyte-specific deletion of group VIA calcium-independent phospholipase A2 leads to dichotomous opposing phenotypes during MCD diet-induced NASH.

Polymorphisms of phospholipase A2VIA (iPLA2ß or PLA2G6) are associated with body weights and blood C-reactive protein. The role of iPLA2ß/PLA2G6 in non-alcoholic steatohepatitis (NASH) is still elusive because female iPla2ß-null mice showed attenuated hepatic steatosis but exacerbated hepatic fibrosis after feeding with methionine- and choline-deficient diet (MCDD). Herein, female mice with myeloid- (MPla2g6-/-) and hepatocyte- (LPla2g6-/-) specific PLA2G6 deletion were generated and phenotyped after MCDD feeding. Without any effects on hepatic steatosis, MCDD-fed MPla2g6-/- mice showed further exaggeration of liver inflammation and fibrosis as well as elevation of plasma TNFα, CCL2, and circulating monocytes. Bone-marrow-derived macrophages (BMDMs) from MPla2g6-/- mice displayed upregulation of PPARγ and CEBPα proteins, and elevated release of IL6 and CXCL1 under LPS stimulation. LPS-stimulated BMDMs from MCDD-fed MPla2g6-/- mice showed suppressed expression of M1 Tnfa and Il6, but marked upregulation of M2 Arg1, Chil3, IL10, and IL13 as well as chemokine receptors Ccr2 and Ccr5. This in vitro shift was associated with exaggeration of hepatic M1/M2 cytokines, chemokines/chemokine receptors, and fibrosis genes. Contrarily, MCDD-fed LPla2g6-/- mice showed a complete protection which was associated with upregulation of Ppara/PPARα and attenuated expression of Pparg/PPARγ, fatty-acid uptake, triglyceride synthesis, and de novo lipogenesis genes. Interestingly, LPla2g6-/- mice fed with chow or MCDD displayed an attenuation of blood monocytes and elevation of anti-inflammatory lipoxin A4 in plasma and liver. Thus, PLA2G6 inactivation specifically in myeloid cells and hepatocytes led to opposing phenotypes in female mice undergoing NASH. Hepatocyte-specific PLA2G6 inhibitors may be further developed for treatment of this disease.

Perioperative prothrombin complex concentrate and fibrinogen administration are associated with thrombotic complications after liver transplant.

Background: Use of intraoperative prothrombin complex concentrates (PCC) and fibrinogen concentrate administration has been linked to thrombotic events. However, it is unknown if its use is associated with thrombotic events after liver transplant. Methods and analysis: We conducted a post hoc analysis of a prospectively conducted registry database study on patients who underwent liver transplant between 2004 and 2017 at Heidelberg University Hospital, Heidelberg, Germany. Univariate and multivariate analyses were used to determine the association between PCC and fibrinogen concentrate administration and thrombotic complications. Results: Data from 939 transplantations were included in the analysis. Perioperative PCC or fibrinogen administration was independently associated with the primary composite endpoint Hepatic artery thrombosis (HAT), Portal vein thrombosis (PVT), and inferior vena cava thrombosis [adjusted HR: 2.018 (1.174; 3.468), p = 0.011]. PCC or fibrinogen administration was associated with the secondary endpoints 30-day mortality (OR 4.225, p < 0.001), graft failure (OR 3.093, p < 0.001), intraoperative blood loss, red blood cell concentrate, fresh frozen plasma and platelet transfusion, longer hospitalization, and longer length of stay in intensive care units (ICUs) (all p < 0.001). PCC or fibrinogen administration were not associated with pulmonary embolism, myocardial infarction, stroke, or deep vein thrombosis within 30 days after surgery. Conclusion: A critical review of established strategies in coagulation management during liver transplantation is warranted. Perioperative caregivers should exercise caution when administering coagulation factor concentrate during liver transplant surgery. Prospective randomized controlled trials are needed to establish causality for the relationship between coagulation factors and thrombotic events in liver transplantation. Further studies should be tailored to identify patient subgroups that will likely benefit from PCC or fibrinogen administration.

iPLA2ß-Null Mice Show HCC Protection by an Induction of Cell-Cycle Arrest after Diethylnitrosamine Treatment.

Group VIA phospholipase A2 (iPLA2ß) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2ß-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3-5 weeks of age (12-13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1ß, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2ß deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2ß inhibition in HCC treatment.

COVID-19 pneumonia: Prediction of patient outcome by CT-based quantitative lung parenchyma analysis combined with laboratory parameters.

OBJECTIVES: To evaluate the prognostic value of fully automatic lung quantification based on spectral computed tomography (CT) and laboratory parameters for combined outcome prediction in COVID-19 pneumonia. METHODS: CT images of 53 hospitalized COVID-19 patients including virtual monochromatic reconstructions at 40-140keV were analyzed using a fully automated software system. Quantitative CT (QCT) parameters including mean and percentiles of lung density, fibrosis index (FIBI-700, defined as the percentage of segmented lung voxels ≥-700 HU), quantification of ground-glass opacities and well-aerated lung areas were analyzed. QCT parameters were correlated to laboratory and patient outcome parameters (hospitalization, days on intensive care unit, invasive and non-invasive ventilation). RESULTS: Best correlations were found for laboratory parameters LDH (r = 0.54), CRP (r = 0.49), Procalcitonin (r = 0.37) and partial pressure of oxygen (r = 0.35) with the QCT parameter 75th percentile of lung density. LDH, Procalcitonin, 75th percentile of lung density and FIBI-700 were the strongest independent predictors of patients' outcome in terms of days of invasive ventilation. The combination of LDH and Procalcitonin with either 75th percentile of lung density or FIBI-700 achieved a r2 of 0.84 and 1.0 as well as an area under the receiver operating characteristic curve (AUC) of 0.99 and 1.0 for the prediction of the need of invasive ventilation. CONCLUSIONS: QCT parameters in combination with laboratory parameters could deliver a feasible prognostic tool for the prediction of invasive ventilation in patients with COVID-19 pneumonia.