Recent advances in the approach to hepatopulmonary syndrome and portopulmonary hypertension.

Liver disease, cirrhosis and portal hypertension can be complicated by pulmonary vascular disease, which may affect prognosis and influence liver transplantation (LT) candidacy. Pulmonary vascular complications comprise hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). Although these two conditions develop on a same background and share a common trigger, pulmonary responses are distinct and occur at different anatomical sites of the pulmonary circulation. HPS affects 10-30% of patients referred for LT, and is characterized by gas exchange abnormalities due to pulmonary vasodilation and right-to-left shunting. POPH occurs in 5%, and is defined by pulmonary arterial hypertension due to increased pulmonary vascular resistance, which leads to hemodynamic failure. Even though HPS and POPH may have a substantial negative impact on survival, both entities are clinically underrecognized and frequently misdiagnosed. Without intervention, the 5-year survival rate is 23% in HPS and 14% in POPH. Their presence should be actively sought by organized screening in patients presenting with dyspnea and in all patients on the waitlist for LT, also because clinical symptoms are commonly non-specific or even absent. LT may lead to resolution, however, advanced stages of either HPS or POPH may jeopardize safe and successful LT. This implicates the need of proper identification of HPS and POPH cases, as well as the need to be able to successfully 'bridge' patients to LT by medical intervention. A review article on this topic has been published in this journal in 2007 (1). This updated review focuses on recent advances in the diagnosis and management of these 2 liver-induced pulmonary vascular disorders and incorporates results from our recent work.

Angiogenesis in the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and an increasing cause of liver cirrhosis and hepatocellular carcinoma. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a key pathophysiological mechanism contributing to NAFLD progression. Major triggers for angiogenesis in NAFLD include tissue hypoxia, structural and dynamic endothelial cell dysfunction, stellate cell activation and macrophage-mediated inflammation. In turn, angiogenesis drives inflammation and is closely linked to the progression of liver fibrosis and the development of liver cancer. In particular, the molecular crosstalk between pro-angiogenic endothelial cells and activated stellate cells can result in a positive feedback loop in which angiogenesis and fibrosis develop in parallel. In this review, we highlight the molecular mechanisms, drivers and consequences of angiogenesis in the progression of NAFLD to NASH, fibrosis and hepatocellular carcinoma. Evidence from animal and clinical studies suggests that mediators of angiogenesis and endothelial dysfunction are promising disease biomarkers, and that inhibiting angiogenesis may improve the course of NAFLD.

Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted.

Serum vascular cell adhesion molecule-1 predicts significant liver fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with obesity, dyslipidemia and insulin resistance. NAFLD often presents as simple steatosis (NAFL) but can progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Current non-invasive biomarkers are not tailored to identify significant (⩾F2) fibrosis, although recent guidelines recommend a stringent follow-up of this patient population. We and others have reported on the role of pathological angiogenesis in the pathogenesis of NAFLD, highlighting pro-angiogenic factors as potential diagnostic markers. OBJECTIVE: To investigate the applicability of angiogenic and endothelial dysfunction markers as non-invasive diagnostic tools for NASH or NASH-associated fibrosis in obese patients. METHODS: In a prospective cross-sectional study, male patients undergoing bariatric surgery (n=61) and control patients (n=35) were recruited. Serum protein levels and visceral adipose tissue gene expression of endothelial dysfunction and angiogenic markers were analyzed by multiplex bead-based assay and quantitative RT-PCR, respectively. For validation, we recruited a second cohort of patients undergoing bariatric surgery (n=40) and a cohort of NAFLD patients from our outpatient clinic (n=30). RESULTS: We identified serum vascular cell adhesion molecule-1 (VCAM-1) as an independent predictor for ⩾F2 fibrosis (median 14.0 vs 8.7 ng ml-1 in patients with and without significant fibrosis; P<0.0001) with an area under the receiver-operating characteristics (AUROC) curve of 0.80. The cutoff point of 13.2 ng ml-1 showed a sensitivity of 80% and specificity of 83%. In line with these results, VCAM-1 visceral adipose tissue gene expression was also elevated in patients with fibrosis (P=0.030). In the bariatric surgery and clinical validation cohorts, VCAM-1 displayed similar AUROCs of 0.89 and 0.85, respectively. CONCLUSIONS: VCAM-1 levels are able to accurately predict significant (⩾F2) fibrosis in NAFLD patients.

Longitudinal quantification of inflammation in the murine dextran sodium sulfate-induced colitis model using µPET/CT.

BACKGROUND: This study investigates whether deoxy-2-[18F]fluoro-d-glucose (FDG) micro-positron emission tomography (µPET)/computed tomography (CT) can serve as a tool for monitoring of the commonly used dextran sodium sulfate (DSS)-induced murine model of inflammatory bowel disease (IBD). METHODS: DSS-colitis was induced in Sv129 mice. In a first experiment, four animals were serially scanned with CT and FDG-µPET on days 0, 3, 7, 11, and 14. The ratio of the mean voxel count of the PET images in the colon and the brain was compared with the histological inflammation score and the colonic myeloperoxidase levels. A second experiment was performed to investigate whether FDG-µPET was able to detect differences in inflammation between two DSS-treated groups, one receiving placebo (n = 4) and one receiving dimethyloxalylglycine (DMOG) (n = 4), a compound that protects against DSS-induced colitis. RESULTS: The progression of the colonic/brain FDG-signal ratio (over days 0-14) agreed with the predicted histological inflammation score, obtained from a parallel DSS-experiment. Moreover, the quantification of normalized colonic FDG-activity at the final timepoint (day 14) showed an excellent correlation with both the MPO levels (Spearman's rho = 1) and the histological inflammation score (Spearman's rho = 0.949) of the scanned mice. The protective action of DMOG in DSS colitis was clearly demonstrated with FDG-µPET/CT (normalized colonic FDG-activity DMOG versus placebo: P < 0.05). CONCLUSIONS: FDG-µPET-CT is a feasible and reliable noninvasive method to monitor murine DSS-induced colitis. The implementation of this technique in this widely used IBD model opens a new window for pathophysiological research and high-throughput screening of potential therapeutic compounds in preclinical IBD research.

Risk factors for equine postoperative ileus and effectiveness of prophylactic lidocaine.

BACKGROUND: Postoperative ileus (POI) is a frequent and often fatal complication of colic surgery. Reliably effective treatments are not available. OBJECTIVES: To determine risk factors and protective factors associated with POI, and to assess the effect of lidocaine IV on short-term survival. ANIMALS: One hundred and twenty-six horses that underwent small intestinal colic surgery and that survived for at least 24 hours postoperatively. METHODS: Retrospective cross-sectional study. The association of 31 pre-, intra-, and postoperative variables with POI and the association of lidocaine treatment with short-term survival were investigated. Associations were evaluated with univariable logistic regression models, followed by multivariable analysis. RESULTS: Significant associations of high heart rate (odds ratio [OR] = 1.05, 95% confidence interval [CI] 1.03-1.08), the presence of more than 8 L of reflux at admission (OR = 3.02, 95% CI 1.13-8.02) and the performance of a small intestinal resection (OR = 2.46, 95% CI 1.15-5.27) with an increased probability of POI were demonstrated. Prophylactic lidocaine treatment was significantly associated with a reduced incidence of POI (OR = 0.25, 95% CI 0.11-0.56). Lidocaine treatment was also significantly associated with enhanced short-term survival (OR = 0.30, 95% CI 0.09-0.98). CONCLUSIONS AND CLINICAL IMPORTANCE: The variables associated with an increased risk of POI can be useful in identifying horses at risk of POI and in providing a more accurate prognosis. The results are supportive for lidocaine IV as an effective prokinetic treatment after small intestinal colic surgery.

Distal limb cast sores in horses: risk factors and early detection using thermography.

REASONS FOR PERFORMING STUDY: There is a lack of evidence-based data on the prevalence, outcome and risk factors of distal limb cast sores, and no objective tool has been described for the early detection of cast sores. OBJECTIVES: To investigate the prevalence, location, outcome and risk factors of cast sores after application of a distal limb cast and to determine whether static thermography of the cast is a valuable tool for the assessment of sores. METHODS: A prospective study was conducted on horses treated with a distal limb cast. At each cast removal, cast sores were graded as superficial sores (SS), deep dermal sores (DS) or full thickness skin ulcerations (FS). In several cases, a thermographic evaluation of the cast was performed immediately prior to removal and differences in temperature (AT) between the coolest point of the cast and 2 cast regions predisposed for sore development (dorsoproximal mc/mtIII and palmar/plantar fetlock) were calculated. RESULTS: Mean +/- s.d. total casting time of 70 horses was 31 +/- 18 days. Overall, 57 legs (81%) developed at least SS. Twenty-four legs (34%) ultimately developed DS and one horse had an FS. Multivariable analysis showed that the severity of sores was positively associated with increasing age (OR: 1.111, P = 0.028), a normal (vs. swollen) limb (OR: 3387, P = 0.023) and an increase in total casting time (OR per week: 1.363, P = 0.002). The thermographic evaluation (35 casts) revealed that the severity of sores was positively associated with increasing deltaT (OR: 2.100, P = 0.0005). The optimal cut-off values for the presence of SS and DS were set at, respectively, deltaT = 23 and 43 degrees C. CONCLUSION AND POTENTIAL RELEVANCE: Distal limb cast is a safe coaptation technique with increasing risk of developing sores with time. Thermography is a valuable and rapid clinical tool to monitor the development of cast sores.