Histopathological assessment of the viability of hepatic alveolar echinococcosis.

AIMS: Infections by the larval stage of the tape worms Echinococcus multilocularis and Echinococcus granulosus s.l. are potentially fatal zoonoses affecting humans as dead-end hosts. Histopathological evaluation of hepatic echinococcosis is an integral part of patient management, including the distinction between alveolar (AE) and cystic echinococcosis (CE), which are associated with different disease courses and treatments. To improve histopathological assessment of Echinococcus lesions, we aimed to develop robust criteria to evaluate their viability and decay. METHODS AND RESULTS: Histomorphological criteria for determining parasitic viability based on the morphology of parasite structures and different stages of their decay were defined based on a clinically and molecularly defined cohort comprising 138 specimens from 112 patients (59 AE and 53 CE); 618 AE lesions were assessed for histopathological viability comparing haematoxylin and eosin (H&E) staining with mAbEm18 and mAbEm2G11 immunostaining. Moreover, parasite viability was systematically mapped in cross-sections of five additional AE lesions. Protoscoleces in CE and AE displayed variable states of degeneration. Albendazole had no significant effect on the morphology of parasite structures. Viability assessment revealed high agreement between H&E and mAbEm18, but not mAbEm2G11 staining, suggesting mAbEm18 staining as reliable for parasite viability assessment. H&E and mAbEm18 staining displayed a central-peripheral gradient of parasite viability and decay across parasitic lesions, with decayed cystic lesions located more towards the lesion centre while the most viable cystic lesions were located more peripherally. CONCLUSIONS: Histopathological criteria corroborated by mAbEm18 staining provide a simple and reliable tool to assess the viability of AE lesions, knowledge of which is a valuable decision-making tool for further treatment.

Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis.

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. METHODS: This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. RESULTS: A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. CONCLUSIONS: SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.

Rare HCV subtypes and retreatment outcomes in a cohort of European DAA-experienced patients.

Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.

A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

Cardio-Hepatic Interaction in Cardiac Amyloidosis.

Background: Congestion is associated with poor prognosis in cardiac amyloidosis (CA). The cardio-hepatic interaction and the prognostic impact of secondary liver affection by cardiac congestion in CA are poorly understood and require further characterisation. Methods: Participants of the amyloidosis cohort study AmyKoS at the Interdisciplinary Amyloidosis Centre of Northern Bavaria with proven transthyretin (ATTR-CA) and light chain CA (AL-CA) underwent serial work-up including laboratory tests, echocardiography, and in-depth hepatic assessment by vibration-controlled transient elastography (VCTE) and 13C-methacetin breath test. Results: In total, 74 patients with AL-CA (n = 17), ATTR-CA (n = 26) and the controls (n = 31) were analysed. ATTR-CA patients showed decreased microsomal liver function expressed by maximal percentage of dose rate (PDRpeak) related to hepatic congestion. Reduced PDRpeak in AL-CA could result from altered pharmacokinetics due to changed hepatic blood flow. Liver stiffness as a combined surrogate of chronic liver damage and congestion was identified as a predictor of all-cause mortality. Statistical modelling of the cardio-hepatic interaction revealed septum thickness, NT-proBNP and PDRpeak as predictors of liver stiffness in both CA subtypes; dilatation of liver veins and the fibrosis score FIB-4 were only significant for ATTR-CA. Conclusions: Non-invasive methods allow us to characterise CA-associated hepatic pathophysiology. Liver stiffness might be promising for risk stratification in CA.

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.

AIMS OF THE STUDY: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. METHODS: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. RESULTS: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). CONCLUSION: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.

Evaluation of soluble suppression of tumorigenicity 2 (sST2) as serum marker for liver fibrosis.

BACKGROUND & AIMS: With the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C. METHODS: 424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman's correlation and AUROC analyses. RESULTS: Data of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman's rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65-0.83), and 0.67(95%CI 0.56-0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests. CONCLUSIONS: sST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

How best to combine liver transplantation and bariatric surgery?-Results from a global, web-based survey.

BACKGROUND AND AIMS: Obesity is a growing healthcare challenge worldwide and a significant risk factor for liver failure as seen with non-alcoholic steatohepatitis (NASH). Combining metabolic-bariatric surgery (MBS) with liver transplantation (LT) appears as attractive strategy to treat both, the underlying liver disease and obesity. However, there is an ongoing debate on best timing and patient selection. This survey was designed to explore the current treatment practice for patients with NASH and obesity worldwide. METHODS: A web-based survey was conducted in 2022 among bariatric and LT surgeons, and hepatologists from Europe, North and South America and Asia. RESULTS: The survey completion rate was 74% (145/196). The average respondents were 41-50 years (38%), male (82.1%) and had >20 years of clinical experience (42.1%). Centres with a high LT-caseload for NASH were mainly located in the USA and United Kingdom. Almost 30% have already performed a combination of LT with MBS and 49% plan to do it. A majority of bariatric surgeons prefer MBS before LT (77.2%), whereas most of LT surgeons (52%) would perform MBS during LT. Most respondents (n = 114; 80%) favour sleeve gastrectomy over other bariatric techniques. One third (n = 42; 29.4%) has an established protocol regarding MBS for LT candidates. CONCLUSION: The most experienced centres doing LT for NASH are in the USA and United Kingdom with growing awareness worldwide. Overall, a combination of MBS and LT has already been performed by a third of respondents. Sleeve gastrectomy is the bariatric technique of choice-preferably performed either before or during LT.

Management of biliary obstruction in patients with newly diagnosed alveolar echinococcosis: a Swiss retrospective cohort study.

BACKGROUND AND STUDY AIMS: Alveolar echinococcosis, an orphan zoonosis affecting the liver, is of increasing concern worldwide. Most symptomatic cases present at an advanced and inoperable stage, sometimes with biliary obstruction prompting biliary tract interventions. These are, however, associated with a high risk of infectious complications. The aim of this retrospective study was to compare the effectiveness and safety of conservative and interventional treatment approaches in patients with newly diagnosed alveolar echinococcosis and biliary obstruction. PATIENTS AND METHODS: Alveolar echinococcosis patients treated at two referral centres in Switzerland, presenting with hyperbilirubinaemia (total bilirubin >1.5 Upper Limit of Normal) at diagnosis were included, unless another underlying aetiology, i.e. common bile duct stones or decompensated cirrhosis, was identified. Patients were divided into two groups, according to whether they initially received a biliary tract intervention. The primary endpoint was normalisation of bilirubin levels within a 6-month period. Secondary endpoints included, among others, the occurrence of early and late biliary complications, the need for biliary tract interventions during follow-up and overall duration of hospital stays for treatment initiation and for biliary complications. RESULTS: 28 patients were included in this study, of whom 17 received benzimidazole therapy alone and 11 additionally received a biliary tract intervention. Baseline characteristics did not differ between groups. All but one patient in each group achieved the primary endpoint (p=0.747). Biliary tract intervention was associated with faster laboratory improvement (t1/2 1.3 vs 3.0 weeks), but also with more frequent early biliary complications (7/11 vs 1/17, p=0.002) and longer initial hospital stay (18 days vs 7 days, p=0.007). CONCLUSION: Biliary obstruction in patients with newly diagnosed alveolar echinococcosis can be treated effectively with benzimidazole therapy alone. Biliary tract intervention, on the other hand, is associated with a high complication rate and should probably be reserved for patients with insufficient response to benzimidazole therapy.

The current and future burden of hepatitis B in Switzerland: a modelling study.

BACKGROUND AND AIMS: Chronic hepatitis B infection (defined as sustained detection of hepatitis B virus [HBV] surface antigen [HBsAg] protein in serum) is a leading cause of cirrhosis, hepatocellular carcinoma and liver-related deaths. A situation analysis carried out by the Swiss Federal Office of Public Health estimated the HBsAg prevalence in Switzerland to be 0.53% (95% CI: 0.32-0.89%) in 2015 (~44,000 cases). A lower prevalence of chronic HBV in the younger generation and the adoption of universal coverage in the first year of life are expected to decrease the burden of HBV; however, a number of people in key populations (including migrants) remain undiagnosed and untreated, and infected individuals remain at risk of progressing to cirrhosis, hepatocellular carcinoma and death. Our primary objective was to examine the current and estimate the future disease burden of HBV in Switzerland and the impact of migration. The secondary objective was to estimate the impact of changing future treatment numbers. METHODS: A modelling study was performed using an existing, validated model (PRoGReSs Model) applied to the Swiss context. Model inputs were selected through a literature search and expert consensus. Population data from the Federal Statistical Office were used alongside prevalence data from the Polaris Observatory to estimate the number of HBV infections among people born abroad. The PRoGReSs Model was populated with and calibrated to the available data and what-if scenarios were developed to explore the impact of intervention on the future burden of disease. A Monte Carlo simulation was used to estimate 95% uncertainty intervals (95% UIs). RESULTS: In 2020, there were an estimated 50,100 (95% UI: 47,500-55,000) HBsAg+ cases among people born abroad. Among people born in Switzerland, there were approximately 62,700 (UI: 58,900-68,400) total HBV infections (0.72% [UI: 0.68-0.79%] prevalence). Prevalence among infants and children under the age of 5 were both <0.1%. By 2030, prevalence of HBV is expected to decrease, although morbidity and mortality will increase. Increasing diagnosis (90%) and treatment (80% of those eligible) to meet the global health sector strategy on viral hepatitis programme targets could prevent 120 cases of hepatocellular carcinoma and 120 liver-related deaths. CONCLUSIONS: Thanks to the historical vaccination programmes and the continued rollout of universal 3-dose coverage in the first year of life, Switzerland is expected to exceed the global health sector strategy targets for the reduction of incidence. While overall prevalence is decreasing, the current diagnosis and treatment levels remain below global health sector strategy targets.

Mortality and morbidity related to hepatitis C virus infection in hospitalized adults-A propensity score matched analysis.

The World Health Organization (WHO) aims to reduce HCV mortality, but estimates are difficult to obtain. We aimed to identify electronic health records of individuals with HCV infection, and assess mortality and morbidity. We applied electronic phenotyping strategies on routinely collected data from patients hospitalized at a tertiary referral hospital in Switzerland between 2009 and 2017. Individuals with HCV infection were identified using International Classification of Disease (ICD)-10 codes, prescribed medications and laboratory results (antibody, PCR, antigen or genotype test). Controls were selected using propensity score methods (matching by age, sex, intravenous drug use, alcohol abuse and HIV co-infection). Main outcomes were in-hospital mortality and attributable mortality (in HCV cases and study population). The non-matched dataset included records from 165,972 individuals (287,255 hospital stays). Electronic phenotyping identified 2285 stays with evidence of HCV infection (1677 individuals). Propensity score matching yielded 6855 stays (2285 with HCV, 4570 controls). In-hospital mortality was higher in HCV cases (RR 2.10, 95%CI 1.64 to 2.70). Among those infected, 52.5% of the deaths were attributable to HCV (95%CI 38.9 to 63.1). When cases were matched, the fraction of deaths attributable to HCV was 26.9% (HCV prevalence: 33%), whilst in the non-matched dataset, it was 0.92% (HCV prevalence: 0.8%). In this study, HCV infection was strongly associated with increased mortality. Our methodology may be used to monitor the efforts towards meeting the WHO elimination targets and underline the importance of electronic cohorts as a basis for national longitudinal surveillance.

Donor-derived fulminant herpes simplex virus hepatitis after liver transplantation: Two cases and review of literature.

BACKGROUND: Fulminant herpetic hepatitis due to herpes simplex virus (HSV), serotype 1 or 2, is a rare but often fatal complication after solid organ transplantation (SOT). HSV hepatitis in SOT recipients can occur either due to primary infection acquired post transplantation, viral reactivation in a seropositive patient, or as donor-derived infection. Cases of fatal hepatitis have been reported in the liver as well as in other SOT recipients. The fatal outcome is mostly due to delayed diagnosis and treatment, which is explained by the lack of clinical specificity of HSV hepatitis. METHODS: We report two cases of fatal donor-derived HSV hepatitis in liver-transplanted recipients. We reviewed all published cases of donor-derived HSV infections after SOT with an evaluation of the presence of prophylaxis and outcome. RESULTS: In both liver recipients, the retrospective determination of HSV serostatus was negative, and both cases occurred in the absence of cytomegalovirus or HSV prophylaxis. A review of the literature showed a significant series of cases of severe hepatitis, mostly fatal, as well as the absence of specific preventive therapy guidelines in cases of HSV serology mismatch. CONCLUSIONS: The occurrence of two fatal donor-derived hepatitis made the Swiss Transplant Infectious Diseases working group modify its national recommendations regarding pretransplant serostatus determination and HSV prophylaxis after liver transplantation. Further studies are needed to assess this approach.

Determinants of Advanced Liver Fibrosis in Adult Patients After Fontan Palliation: Usefulness of Ultrasound Transient Elastography.

BACKGROUND: Fontan-associated liver disease is an increasing concern. Our aim was to assess prevalence and predictors of advanced liver fibrosis with a specific focus on utility of liver stiffness measurement by ultrasound transient elastography. METHODS: A total of 97 adult Fontan patients (55% male, median age: 23.1 years, interquartile range [IQR]: 18.7-30.6); 92 (95%) were evaluated with transient elastography, and 50 (52%) underwent transjugular liver biopsy. Advanced liver fibrosis was defined as congestive hepatic fibrosis score 3 or 4. RESULTS: Only 4 patients (4%) had liver stiffness values < 10 kilopascal (kPa). Liver-stiffness measurements correlated weakly with peak oxygen uptake on exercise testing and Fontan pressure but not with Model for End-Stage Liver Disease excluding INR (MELD-XI) score or spleen size. Serial follow-up liver stiffness measurements in 73 clinically stable patients showed large variability among individual patients. Advanced liver fibrosis was present in 35 of 50 (70%) patients on liver biopsy and was associated to MELD-XI-Score ≥ 11 and splenomegaly but not to liver-stiffness measurements. Advanced liver fibrosis was not associated with patient age or time since Fontan operation but with younger age at completion of Fontan (3.7 years, IQR: 2.3-6.3 vs 6.8 years; IQR: 3.5-12.1; P = 0.037). CONCLUSIONS: In our cohort, advanced liver fibrosis was present in the majority of adult Fontan patients. Liver stiffness as measured by transient elastography was not associated with the degree of liver fibrosis. Because of its high variability on serial measurements, it seems not to be useful for clinical decision making. The unexpected finding that younger age at completion of Fontan was associated with advanced liver fibrosis merits further evaluation.

Monoclonal antibody-based localization of major diagnostic antigens in metacestode tissue, excretory/secretory products, and extracellular vesicles of Echinococcus species.

Alveolar (AE) and cystic echinococcosis (CE) are severe parasitic zoonoses caused by the larval stages of Echinococcus multilocularis and E. granulosus sensu lato, respectively. A panel of 7 monoclonal antibodies (mAbs) was selected against major diagnostic epitopes of both species. The binding capacity of the mAbs to Echinococcus spp. excretory/secretory products (ESP) was analyzed by sandwich-ELISA, where mAb Em2G11 and mAb EmG3 detected in vitro extravesicular ESP of both E. multilocularis and E. granulosus s.s. These findings were subsequently confirmed by the detection of circulating ESP in a subset of serum samples from infected hosts including humans. Extracellular vesicles (EVs) were purified, and the binding to mAbs was analyzed by sandwich-ELISA. Transmission electron microscopy (TEM) was used to confirm the binding of mAb EmG3 to EVs from intravesicular fluid of Echinococcus spp. vesicles. The specificity of the mAbs in ELISA corresponded to the immunohistochemical staining (IHC-S) patterns performed on human AE and CE liver sections. Antigenic small particles designated as ''spems'' for E. multilocularis and ''spegs'' for E. granulosus s.l. were stained by the mAb EmG3IgM, mAb EmG3IgG1, mAb AgB, and mAb 2B2, while mAb Em2G11 reacted with spems and mAb Eg2 with spegs only. The laminated layer (LL) of both species was strongly visualized by using mAb EmG3IgM, mAb EmG3IgG1, mAb AgB, and mAb 2B2. The LL was specifically stained by mAb Em2G11 in E. multilocularis and by mAb Eg2 in E. granulosus s.l. In the germinal layer (GL), including the protoscoleces, a wide staining pattern with all structures of both species was observed with mAb EmG3IgG1, mAb EmG3IgM, mAb AgB, mAb 2B2, and mAb Em18. In the GL and protoscoleces, the mAb Eg2 displayed a strong E. granulosus s.l. specific binding, while mAb Em2G11 exhibited a weak granular E. multilocularis specific reaction. The most notable staining pattern in IHC-S was found with mAb Em18, which solely bound to the GL and protoscoleces of Echinococcus species and potentially to primary cells. To conclude, mAbs represent valuable tools for the visualization of major antigens in the most important Echinococcus species, as well as providing insights into parasite-host interactions and pathogenesis.

AXL Expression on Homeostatic Resident Liver Macrophages Is Reduced in Cirrhosis Following GAS6 Production by Hepatic Stellate Cells.

BACKGROUND & AIMS: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced tumor necrosis factor-α/interleukin-6 production and T-cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment, but not interstitial lung- and tissue-resident synovial lining macrophages. Here, we assessed AXL expression on tissue macrophages in patients with cirrhosis. METHODS: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n = 22), chronic liver disease (n = 8), non-cirrhotic portal hypertension (n = 4), and healthy controls (n = 4). Phenotype and function of isolated primary human liver macrophages were characterized by flow cytometry (cirrhosis, n = 11; control, n = 14) ex vivo. Also, AXL expression was assessed on peritoneal (n = 29) and gut macrophages (n = 16) from cirrhotic patients. Regulation of AXL expression was analyzed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells, and GAS6 in co-culture experiments. RESULTS: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (healthy, 90.2%; Child-Pugh A, 76.1%; Child-Pugh B, 64.5%; and Child-Pugh C, 18.7%; all P < .05) and negatively correlated with Model for End-Stage Liver Disease and C-reactive protein (all P < .05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. CONCLUSIONS: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSC-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

Performance of two-dimensional shear wave elastography and transient elastography compared to liver biopsy for staging of liver fibrosis.

BACKGROUND: Staging of liver fibrosis traditionally relied on liver histology; however, transient elastography (TE) and more recently two-dimensional shear wave elastography (2D-SWE) evolved to noninvasive alternatives. Hence, we evaluated the diagnostic accuracy of 2D-SWE assessed by the Canon Aplio i800 ultrasound system using liver biopsy as reference and compared the performance to TE. METHODS: In total, 108 adult patients with chronic liver disease undergoing liver biopsy, 2D-SWE and TE were enrolled prospectively at the University Hospital Zurich. Diagnostic accuracies were evaluated using the area under the receiver operating characteristic (AUROC) analysis, and optimal cut-off values by Youden's index. RESULTS: Diagnostic accuracy of 2D-SWE was good for significant (≥F2; AUROC 85.2%, 95% confidence interval (95%CI):76.2-91.2%) as well as severe fibrosis (≥F3; AUROC 86.8%, 95%CI: 78.1-92.4%) and excellent for cirrhosis (AUROC 95.6%, 95%CI: 89.9-98.1%), compared to histology. TE performed equally well (significant fibrosis: 87.5%, 95%CI: 77.7-93.3%; severe fibrosis: 89.7%, 95%CI: 82.0-94.3%; cirrhosis: 96%, 95%CI: 90.4-98.4%), and accuracy was not statistically different to 2D-SWE. 2D-SWE optimal cut-off values were 6.5, 9.8 and 13.1 kPa for significant fibrosis, severe fibrosis and cirrhosis, respectively. CONCLUSIONS: Performance of 2D-SWE was good to excellent and well comparable with TE, supporting the application of this 2D-SWE system in the diagnostic workup of chronic liver disease.

A multicenter randomized-controlled trial of hypothermic oxygenated perfusion (HOPE) for human liver grafts before transplantation.

BACKGROUND & AIMS: Machine perfusion is a novel method intended to optimize livers before transplantation. However, its effect on morbidity within a 1-year period after transplantation has remained unclear. METHODS: In this multicenter controlled trial, we randomly assigned livers donated after brain death (DBD) for liver transplantation (LT). Livers were either conventionally cold stored (control group), or cold stored and subsequently treated by 1-2 h hypothermic oxygenated perfusion (HOPE) before implantation (HOPE group). The primary endpoint was the occurrence of at least one post-transplant complication per patient, graded by the Clavien score of ≥III, within 1-year after LT. The comprehensive complication index (CCI), laboratory parameters, as well as duration of hospital and intensive care unit stay, graft survival, patient survival, and biliary complications served as secondary endpoints. RESULTS: Between April 2015 and August 2019, we randomized 177 livers, resulting in 170 liver transplantations (85 in the HOPE group and 85 in the control group). The number of patients with at least one Clavien ≥III complication was 46/85 (54.1%) in the control group and 44/85 (51.8%) in the HOPE group (odds ratio 0.91; 95% CI 0.50-1.66; p = 0.76). Secondary endpoints were also not significantly different between groups. A post hoc analysis revealed that liver-related Clavien ≥IIIb complications occurred less frequently in the HOPE group compared to the control group (risk ratio 0.26; 95% CI 0.07-0.77; p = 0.027). Likewise, graft failure due to liver-related complications did not occur in the HOPE group, but occurred in 7% (6 of 85) of the control group (log-rank test, p = 0.004, Gray test, p = 0.015). CONCLUSIONS: HOPE after cold storage of DBD livers resulted in similar proportions of patients with at least one Clavien ≥III complication compared to controls. Exploratory findings suggest that HOPE decreases the risk of severe liver graft-related events. IMPACT AND IMPLICATIONS: This randomized controlled phase III trial is the first to investigate the impact of hypothermic oxygenated perfusion (HOPE) on cumulative complications within a 12-month period after liver transplantation. Compared to conventional cold storage, HOPE did not have a significant effect on the number of patients with at least one Clavien ≥III complication. However, we believe that HOPE may have a beneficial effect on the quantity of complications per patient, based on its application leading to fewer severe liver graft-related complications, and to a lower risk of liver-related graft loss. The HOPE approach can be applied easily after organ transport during recipient hepatectomy. This appears fundamental for wide acceptance since concurring perfusion technologies need either perfusion at donor sites or continuous perfusion during organ transport, which are much costlier and more laborious. We conclude therefore that the post hoc findings of this trial should be further validated in future studies.

Unveiling the incidences and trends of the neglected zoonosis cystic echinococcosis in Europe: a systematic review from the MEmE project.

The neglected zoonosis cystic echinococcosis affects mainly pastoral and rural communities in both low-income and upper-middle-income countries. In Europe, it should be regarded as an orphan and rare disease. Although human cystic echinococcosis is a notifiable parasitic infectious disease in most European countries, in practice it is largely under-reported by national health systems. To fill this gap, we extracted data on the number, incidence, and trend of human cases in Europe through a systematic review approach, using both the scientific and grey literature and accounting for the period of publication from 1997 to 2021. The highest number of possible human cases at the national level was calculated from various data sources to generate a descriptive model of human cystic echinococcosis in Europe. We identified 64 745 human cystic echinococcosis cases from 40 European countries. The mean annual incidence from 1997 to 2020 throughout Europe was 0·64 cases per 100 000 people and in EU member states was 0·50 cases per 100 000 people. Based on incidence rates and trends detected in this study, the current epicentre of cystic echinococcosis in Europe is in the southeastern European countries, whereas historical endemic European Mediterranean countries have recorded a decrease in the number of cases over the time.