Splanchnic vein thrombosis associated with SARS-CoV-2 infection: A VALDIG case-control study.

Background & Aims: Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a risk factor for splanchnic vein thrombosis (SVT) is unknown. This study aims to assess the impact of SARS-CoV-2 infection on the presentation and prognosis of recent SVT and to identify specific characteristics of SARS-CoV-2-associated SVT. Methods: This is a retrospective study collecting health-related data of 27 patients presenting with recent SVT in the context of SARS-CoV-2 infection in 12 Vascular Liver Disease Group (VALDIG) centres and in comparison with 494 patients with recent SVT before the SARS-CoV-2 pandemic. Results: Twenty-one patients with SARS-CoV-2 had portal vein thrombosis with or without thrombosis of another splanchnic vein, two had superior mesenteric vein thrombosis, one had splenic vein thrombosis, and three had hepatic vein thrombosis. Diagnosis of SVT was made 10 days (95% CI 0-24 days) after the diagnosis of SARS-CoV-2 infection. Fever (52 vs. 15%; p <0.001) and respiratory symptoms (44 vs. 0%; p <0.001) were more frequent, and median lymphocyte count was lower (1.1 × 103/mm3vs. 1.6 × 103/mm3; p = 0.043) in patients with infection than in those without SARS-CoV-2 infection. A prothrombotic condition was identified in 44 and 52% of patients with and without SARS-CoV-2 infection, respectively (p = 0.5). All patients with SARS-CoV-2 received anticoagulation therapy. During a median follow-up of 250 days, three SARS-CoV-2-infected patients (11%) required intestinal resection for infarction 1 to 3 months after diagnosis of SVT compared with 13 (2.6%) controls (p = 0.044). Partial or complete recanalisation of the thrombosed splanchnic vein was performed in 33% of patients with SARS-CoV-2. Conclusions: SARS-CoV-2 infection can be associated with recent SVT. Intestinal infarction leading to intestinal resection might be more frequent in patients with SARS-CoV-2. Impact and implications: SARS-CoV-2 infection can be associated with recent SVT. SVT occurring during SARS-CoV-2 infection is characterised by a higher frequency of respiratory symptoms and a lower lymphocyte count. Intestinal infarction leading to intestinal resection appears to occur more frequently in patients with SARS-CoV-2.

Holmium-166 Transarterial Radioembolization for the Treatment of Intrahepatic Cholangiocarcinoma: A Case Series.

BACKGROUND: Transarterial radioembolization (TARE) is used to treat primary and secondary malignancies in the liver that are not amenable to curative resection. Accumulating evidence demonstrates the efficacy and safety of TARE with yttrium-90 (90Y), which is the most widely used radionuclide for TARE, and later with holmium-166 (166Ho) for various indications. However, the safety and efficacy of 166Ho TARE in patients with intrahepatic cholangiocarcinoma (ICC) remains to be studied. METHODS: This was a retrospective case series study of seven consecutive patients with ICC who were treated with 166-Ho-TARE in our center. We recorded the clinical parameters and outcomes of the TARE procedures, the tumor response according to mRECIST, subsequent treatments, and adverse events. RESULTS: Three out of the seven patients had a partial or complete response. Two patients had stable disease after the first TARE procedure, and two of the patients (one with a complete response, and one with stable disease) were alive at the time of analysis. No serious adverse events related to the procedure were recorded. CONCLUSIONS: This is the first case series reporting the safety and tumor response outcomes of 166Ho-TARE for ICC. The treatment demonstrated its versatility, allowing for reaching a high tumor dose, which is important for improving tumor response and treating patients in a palliative setting, where safety and the preservation of quality of life are paramount.

Questionnaire PLD-complaint-specific assessment identifies need for therapy in polycystic liver disease: A multi-centric prospective study.

BACKGROUND AND AIMS: Polycystic liver disease (PLD) can lead to extensive hepatomegaly. Symptom relief is the primary goal of the treatment. The role of the recently developed disease-specific questionnaires for identification of the thresholds and the assessment of therapy needs further investigation. METHODS: A five-year prospective multi-centric observational study in 21 hospitals in Belgium gathered a study population of 198 symptomatic PLD-patients of whom the disease-specific symptom questionnaire PLD-complaint-specific assessment (POLCA) scores were calculated. The thresholds of the POLCA score for the need for volume reduction therapy were analyzed. RESULTS: The study group consisted of mostly (82.8%) women with baseline mean age of 54.4 years ±11.2, median liver volume expressed as height-adjusted total liver volume(htLV) of 1994 mL (interquartile range [IQR] 1275; 3150) and median growth of the liver of +74 mL/year (IQR +3; +230). Volume reduction therapy was needed in 71 patients (35.9%). A POLCA severity score (SPI) ≥ 14 predicted the need for therapy both in the derivation (n = 63) and the validation cohort (n = 126). The thresholds to start somatostatin analogues (n = 55) or to consider liver transplantation (n = 18) were SPI scores of ≥14 and ≥ 18 and the corresponding mean htLVs were 2902 mL (IQR 1908; 3964) and 3607 mL (IQR 2901; 4337), respectively. Somatostatin analogues treatment resulted in a decrease in the SPI score -6.0 versus + 4.5 in patients without somatostatin analogues (p < 0.01). Changes in the SPI score were significantly different between the liver transplantation group and no liver transplantation group, +4.3 ± 7.1 versus -1.6 ± 4.9, respectively, (p < 0.01). CONCLUSION: A polycystic liver disease-specific questionnaire can be used as a guide on when to start a volume reduction therapy and to assess the effect of treatment.

Viral clade is associated with severity of symptomatic genotype 3 hepatitis E virus infections in Belgium, 2010-2018.

BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.

Expression of connexins and pannexins in diseased human liver.

Connexin proteins can form hexameric hemichannels and gap junctions that mediate paracrine and direct intercellular communication, respectively. Gap junction activity is crucial for the maintenance of hepatic homeostasis, while connexin hemichannels become particularly active in liver disease, such as hepatitis, fibrosis, cholestasis or even hepatocellular carcinoma. Channels consisting of connexin-like proteins named pannexins have been directly linked to liver inflammation and cell death. The goal of the present study was to characterize the expression and subcellular localization of connexins and pannexins in liver of patients suffering from various chronic and neoplastic liver diseases. Specifically, real-time quantitative reverse transcription polymerase chain reaction, immunoblotting and immunohistochemistry analyses were performed on human liver biopsies. It was found that pannexin1 and pannexin2 gene expression are correlated to a certain degree, as is pannexin1 protein expression with connexin32 and connexin43 protein expression. Furthermore, this study is the first to detect pannexin3 in human patient liver biopsies via both immunoblot and immunohistochemistry.

Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis.

BACKGROUND & AIMS: Biochemical remission, important treatment goal in autoimmune hepatitis (AIH), has been associated with better long-term survival. The aim of this study was to determine the independent prognostic value of aminotransferases and immunoglobulin G (IgG) during treatment on long-term transplant-free survival in AIH. METHODS: In a multicenter cohort alanine aminotransferase, aspartate aminotransferase (AST), and IgG were collected at diagnosis and 6, 12, 24, and 36 months after start of therapy and related to long-term outcome using Kaplan-Meier survival and Cox regression analysis with landmark analysis at these time points, excluding patients with follow-up ending before each landmark. RESULTS: A total of 301 AIH patients with a median follow-up of 99 (range, 7-438) months were included. During follow-up, 15 patients required liver transplantation and 33 patients died. Higher AST at 12 months was associated with worse survival (hazard ratio [HR], 1.86; P < .001), while IgG was not associated with survival (HR, 1.30; P = .53). In multivariate analysis AST at 12 months (HR, 2.13; P < .001) was predictive for survival independent of age, AST at diagnosis and cirrhosis. Multivariate analysis for AST yielded similar results at 6 months (HR, 2.61; P = .001), 24 months (HR, 2.93; P = .003), and 36 months (HR, 3.03; P = .010). There was a trend toward a worse survival in patients with mildly elevated aminotransferases (1-1.5× upper limit of normal) compared with patients with normal aminotransferases (P = .097). CONCLUSIONS: Low aminotransferases during treatment are associated with a better long-term survival in autoimmune hepatitis. IgG was not associated with survival in first 12 months of treatment. Normalization of aminotransferases should be the treatment goal for autoimmune hepatitis to improve long-term survival.

Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1.

BACKGROUND: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. OBJECTIVE: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. METHODS: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. RESULTS: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). CONCLUSIONS: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.

Vasomodulators and Liver Transplantation for Portopulmonary Hypertension: Evidence From a Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Untreated portopulmonary hypertension (PoPH) carries a poor prognosis. Previous reports have described vasomodulator (VM) therapy and liver transplantation (LT) as treatment options. We aimed to provide summary estimates on the endpoints of pulmonary hemodynamics and survival in patients with PoPH, treated with different modalities. APPROACH AND RESULTS: We performed a systematic review with meta-analysis of mainly observational and case-control studies describing no treatment, VM, LT, or VM + LT in patients with PoPH. Twenty-six studies (1,019 patients) were included. Both VM and VM + LT improve pulmonary hemodynamics. A substantial proportion of patients treated with VM become eligible for LT (44%; 95% confidence interval [CI], 31-58). Pooled estimates for 1-, and 3-year postdiagnosis survival in patients treated with VM were 86% (95% CI, 81-90) and 69% (95% CI, 50-84) versus 82% (95% CI, 52-95) and 67% (95% CI, 53-78) in patients treated with VM + LT. Of note, studies reporting on the effect of VM mainly included Child-Pugh A/B patients, whereas studies reporting on VM + LT mainly included Child-Pugh B/C. Seven studies (238 patients) included both patients who received VM only and patients who received VM + LT. Risk of death in VM-only-treated patients was significantly higher than in patients who could be transplanted as well (odds ratio, 3.5; 95% CI, 1.4-8.8); however, importantly, patients who proceeded to transplant had been selected very strictly. In 50% of patients, VM can be discontinued post-LT (95% CI, 38-62). CONCLUSIONS: VM and VM + LT both improve pulmonary hemodynamics and prognosis in PoPH. In a strictly selected subpopulation of cases where LT is indicated based on severe liver disease and where LT is considered safe and feasible, treatment with VM + LT confers a better prognosis. Considering successful VM, 44% can proceed to LT, with half being able to postoperatively stop medication.

Combination of sivelestat and N-acetylcysteine alleviates the inflammatory response and exceeds standard treatment for acetaminophen-induced liver injury.

Hepatocyte death during acetaminophen (APAP) intoxication elicits a reactive inflammatory response, with hepatic recruitment of neutrophils and monocytes, which further aggravates liver injury. Neutrophil elastase (NE), secreted by activated neutrophils, carries degradative and cytotoxic functions and maintains a proinflammatory state. We investigated NE as a therapeutic target in acetaminophen-induced liver injury (AILI). C57BL/6 mice were administered a toxic dose of APAP, 2 h prior to receiving the NE inhibitor sivelestat, N-acetylcysteine (NAC), or a combination therapy, and were euthanized after 24 and 48 h. Upon APAP overdose, neutrophils and monocytes infiltrate the injured liver, accompanied by increased levels of NE. Combination therapy of NAC and sivelestat significantly limits liver damage, as evidenced by lower serum transaminase levels and less hepatic necrosis compared to mice that received APAP only, and this to a greater extent than NAC monotherapy. Lower hepatic expression of proinflammatory markers was observed in the combination treatment group, and flow cytometry revealed significantly less monocyte influx in livers from mice treated with the combination therapy, compared to untreated mice and mice treated with NAC only. The potential of NE to induce leukocyte migration was confirmed in vitro. Importantly, sivelestat did not impair hepatic repair. In conclusion, combination of NE inhibition with sivelestat and NAC dampens the inflammatory response and reduces liver damage following APAP overdose. This strategy exceeds the standard of care and might represent a novel therapeutic option for AILI.

Treatment of Advanced Hepatocellular Carcinoma with Somatostatin Analogues: A Review of the Literature.

Hepatocellular carcinoma, one of the most dreaded complications of cirrhosis, is a frequent cancer with high mortality. Early primary liver cancer can be treated by surgery or ablation techniques, but advanced hepatocellular carcinoma remains a challenge for clinicians. Most of these patients have underlying cirrhosis, which complicates or even precludes treatment. Therefore, efficacious treatments without major side effects are welcomed. Initial results of treatment of advanced hepatocellular carcinoma with somatostatin analogues were promising, but subsequent trials have resulted in conflicting outcomes. This might be explained by different patient populations, differences in dosage and type of treatment and differences in somatostatin receptor expression in the tumor or surrounding tissue. It has been shown that the expression of somatostatin receptors in the tumor might be of importance to select patients who could benefit from treatment with somatostatin analogues. Moreover, somatostatin receptor expression in hepatocellular carcinoma has been shown to correlate with recurrence, prognosis, and survival. In this review, we will summarize the available data on treatment of primary liver cancer with somatostatin analogues and analyze the current knowledge of somatostatin receptor expression in hepatocellular carcinoma and its possible clinical impact.

Somatostatin as Inflow Modulator in Liver-transplant Recipients With Severe Portal Hypertension: A Randomized Trial.

OBJECTIVE: To investigate the safety and efficacy of somatostatin as liver inflow modulator in patients with end-stage liver disease (ESLD) and clinically significant portal hypertension (CSPH) undergoing liver transplantation (LT) (ClinicalTrials.gov number,01290172). BACKGROUND: In LT, portal hyperperfusion can severely impair graft function and survival, mainly in cases of partial LT. METHODS: Thirty-three patients undergoing LT for ESLD and CSPH were randomized double-blindly to receive somatostatin or placebo (2:1). The study drug was administered intraoperatively as 5-mL bolus (somatostatin: 500 µg), followed by a 2.5 mL/h infusion (somatostatin: 250 µg/h) for 5 days. Hepatic and systemic hemodynamics were measured, along with liver function tests and clinical outcomes. The ischemia-reperfusion injury (IRI) was analyzed through histological and protein expression analysis. RESULTS: Twenty-nine patients (18 receiving somatostatin, 11 placebo) were included in the final analysis. Ten patients responded to somatostatin bolus, with a significant decrease in hepatic venous portal gradient (HVPG) and portal flow of -28.3% and -29.1%, respectively. At graft reperfusion, HVPG was lower in patients receiving somatostatin (-81.7% vs -58.8%; P = 0.0084), whereas no difference was observed in the portal flow (P = 0.4185). Somatostatin infusion counteracted the decrease in arterial flow (-10% vs -45%; P = 0.0431). There was no difference between the groups in the severity of IRI, incidence of adverse events, long-term complications, graft, and patient survival. CONCLUSIONS: Somatostatin infusion during LT in patients with CSPH is safe, reduces the HVPG, and preserves the arterial inflow to the graft. This study establishes the efficacy of somatostatin as a liver inflow modulator.

Unfolded protein response is an early, non-critical event during hepatic stellate cell activation.

Hepatic stellate cells activate upon liver injury and help at restoring damaged tissue by producing extracellular matrix proteins. A drastic increase in matrix proteins results in liver fibrosis and we hypothesize that this sudden increase leads to accumulation of proteins in the endoplasmic reticulum and its compensatory mechanism, the unfolded protein response. We indeed observe a very early, but transient induction of unfolded protein response genes during activation of primary mouse hepatic stellate cells in vitro and in vivo, prior to induction of classical stellate cell activation genes. This unfolded protein response does not seem sufficient to drive stellate cell activation on its own, as chemical induction of endoplasmic reticulum stress with tunicamycin in 3D cultured, quiescent stellate cells is not able to induce stellate cell activation. Inhibition of Jnk is important for the transduction of the unfolded protein response. Stellate cells isolated from Jnk knockout mice do not activate as much as their wild-type counterparts and do not have an induced expression of unfolded protein response genes. A timely termination of the unfolded protein response is essential to prevent endoplasmic reticulum stress-related apoptosis. A pathway known to be involved in this termination is the non-sense-mediated decay pathway. Non-sense-mediated decay inhibitors influence the unfolded protein response at early time points during stellate cell activation. Our data suggest that UPR in HSCs is differentially regulated between acute and chronic stages of the activation process. In conclusion, our data demonstrates that the unfolded protein response is a JNK1-dependent early event during hepatic stellate cell activation, which is counteracted by non-sense-mediated decay and is not sufficient to drive the stellate cell activation process. Therapeutic strategies based on UPR or NMD modulation might interfere with fibrosis, but will remain challenging because of the feedback mechanisms between the stress pathways.

Connexin and Pannexin (Hemi)Channels: Emerging Targets in the Treatment of Liver Disease.

Connexin proteins are the building blocks of hemichannels, which dock further between adjacent cells to form gap junctions. Gap junctions control the intercellular exchange of critical homeostasis regulators. By doing so, gap junctions control virtually all aspects of the hepatic life cycle. In the last decade, it has become clear that connexin hemichannels also provide a pathway for cellular communication on their own independent of their role as structural precursors of gap junctions, namely between the cytosol of an individual cell and its extracellular environment. In contrast to gap junctions, connexin hemichannels become particularly active in liver disease by facilitating inflammation and cell death. This equally holds true for cellular channels composed of pannexins, being connexin-like proteins recently identified in the liver that gather in structures reminiscent of hemichannels. This paper gives an overview of the involvement of connexin-based and pannexin-based channels in noncancerous liver disease.

Clinical burden of hepatitis E virus infection in a tertiary care center in Flanders, Belgium.

BACKGROUND: Hepatitis E virus (HEV) infection is increasingly recognized as a cause of hepatitis in developed countries. A high HEV IgG seroprevalence in humans and pigs is reported as well as sporadic clinical cases of autochtonous HEV but there are currently no data available on the clinical burden of HEV in Belgium. OBJECTIVES: The objective of the current study was to evaluate the actual clinical burden of HEV infections in our tertiary care center in Flanders, Belgium. STUDY DESIGN: In the setting of Ghent University Hospital, patients were assessed for the presence of HEV IgG and IgM as well as HEV RNA if no other cause was found for one of the following clinical presentations: a) elevation of liver enzymes in post-liver transplant; b) suspicion of acute or toxic hepatitis; c) unexplainable elevation of liver enzymes; d) cirrhosis with acute-on-chronic exacerbation. RESULTS: In a period of 39 months (January 2011-April 2014) 71 patients were enrolled. HEV IgG was found positive in 13 (18,3%) patients; HEV IgM in 6 patients (8,5%) and HEV RNA in 4 (5,6%) patients. All HEV IgM/RNA positive patients were male, aged 41-63, and classified in the clinical groups a), b) or d). HEV IgG seroprevalence was slightly higher but not significantly different from the seroprevalence in the general population in this region in Belgium previously reported to be 14% (p-value 0.41) by our group. CONCLUSIONS: HEV should be considered as a cause of liver pathology especially in middle-aged men with elevation of liver enzymes.

Hepatorenal syndrome: the clinical impact of vasoactive therapy.

INTRODUCTION: Hepatorenal syndrome (HRS) is a unique form of acute kidney injury seen in cirrhotic patients and associated with significant mortality and morbidity. Despite its impact, diagnosis and treatment of HRS remains challenging and this review aims to assess and compare the available vasoconstrictors used as first-line treatment for HRS. Areas covered: A literature review was undertaken on the use of vasoconstrictors in HRS, using PubMed/Medline database searches of: 'hepatorenal syndrome', 'HRS' and 'vasoconstrictor'. Expert commentary: Current diagnosis criteria are based on an exclusion-based approach using serum creatinine as a biomarker. However, this method relies on the measurement over a sustained period of time resulting in delayed treatment. Using urine biomarkers, the revised acute kidney injury guidelines and novel plasma expanders may improve diagnosis and the implementation of time-sensitive management of HRS. Vasoconstrictors are the first-line treatment for HRS, in which terlipressin is the vasoconstrictor of choice supported by current guidelines and a substantial clinical evidence base over other vasoconstrictors, such as noradrenaline or midodrine plus octreotide. Future developments in dosage and administrative techniques for terlipressin may have an important role to play in maintaining clinical efficacy whilst improving tolerability in the management of HRS.

Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice.

Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis with increased risk of mortality. Pulmonary microvascular alterations are key features of HPS; but underlying mechanisms are incompletely understood, and studies on HPS are limited to rats. Placental growth factor (PlGF), a proangiogenic molecule that is selectively involved in pathological angiogenesis, may play an important role in HPS development; however, its role has never been investigated. In this study, we validated an HPS model by common bile duct ligation (CBDL) in mice, investigated the kinetic changes in pulmonary angiogenesis and inflammation during HPS development, and provide evidence for a novel therapeutic strategy by targeting pathological angiogenesis. Mice with CBDL developed hypoxemia and intrapulmonary shunting on a background of liver fibrosis. Pulmonary alterations included increased levels of proangiogenic and inflammatory markers, which was confirmed in serum of human HPS patients. Increased PlGF production in HPS mice originated from alveolar type II cells and lung macrophages, as demonstrated by immunofluorescent staining. Dysfunctional vessel formation in CBDL mice was visualized by microscopy on vascular corrosion casts. Both prophylactic and therapeutic anti-PlGF (αPlGF) antibody treatment impeded HPS development, as demonstrated by significantly less intrapulmonary shunting and improved gas exchange. αPlGF treatment decreased endothelial cell dysfunction in vivo and in vitro and was accompanied by reduced pulmonary inflammation. Importantly, αPlGF therapy did not affect liver alterations, supporting αPlGF's ability to directly target the pulmonary compartment. CONCLUSION: CBDL in mice induces HPS, which is mediated by PlGF production; αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. (Hepatology 2017).

Characteristics of patients with hepatitis B virus and hepatitis C virus dual infection in a Western European country: Comparison with monoinfected patients.

The epidemiology of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is continuously evolving. Updated data on dual HBV and HCV infection are still needed. AIMS: To assess the main characteristics of patients with HBV and HCV dual infection, to compare these with those of patients infected with either HBV or HCV and, among patients with dual infection, to assess fibrosis according to HCV replication. METHODS: Data of 23 patients with dual infection were compared to data from 92 age and sex-matched HBV or HCV monoinfected patients. RESULTS: Patients with dual infection were more often immigrants from Africa or Asia than HCV or HBV patients (52% vs. 20% and 22%, respectively, P=0.01). Intravenous drug use was the route of transmission in 22% of patients with dual infection, which was less frequent than in HCV patients (41%) but more frequent than in HBV patients (0%). Extensive fibrosis or cirrhosis was as frequent among dual-infected patients as among those with HCV or chronic hepatitis B infection (19% vs. 29% vs. 14%, respectively, P=0.4), even when fibrosis stage was reported considering the duration of infection. In dual-infected patients, the prevalence of extensive fibrosis or cirrhosis was similar in patients with and without detectable HCV RNA (18% vs. 20%). CONCLUSIONS: Patients with HBV and HCV dual infection were more often immigrants from Africa or Asia and had similar fibrosis stages than HCV or HBV monoinfected patients. In patients with dual infection, extensive fibrosis or cirrhosis was not associated with HCV replication.