The potential of glycomics as prognostic biomarkers in liver disease and liver transplantation

The study of glycomics is a novel and fascinating approach for the development of biomarkers. It has become clear that in the field of liver disease specific glycomic patters are present in specific disease states, which has led to the development of diagnostic biomarkers. In this manuscript, we will describe two new applications of this technology for the development of prognostic biomarkers. The first biomarker is associated with the risk of hepatocellular carcinoma development in patients with compensated cirrhosis. The second biomarker is present in perfusate and is related to the risk of primary non function occurrence after liver transplantation. The technology used for these biomarkers could easily be implemented on routine capillary electrophoresis equipment

Effect of PlGF-inhibition on survival in mice with hepatocellular carcinoma

Background: Inhibition of angiogenesis is currently hot topic in the search for an effective treatment for hepatocellular carcinoma (HCC). Up till recently, the focus was mainly on VEGF, an important regulator in the pathologic and physiologic angiogenesis. Although promising results are seen by inhibiting the VEGF-pathway, patients often suffer from major side effects. Placental growth factor (PlGF) is a VEGF analogue only involved in pathologic angiogenesis and its inhibition has the potential to restrain tumour growth, without affecting healthy organs. Therefore, we assessed whether administration of PlGF-antibodies could serve as a potential therapy for HCC in mice. Methods: 5-week-old male mice (sv129) received intraperitoneal (ip) injections once per week with N-nitrosodiethylamine (35 mg/kg bodyweight) or saline , which gives rise to HCC after 25W in WT. PlGF-knock-out mice (PlGF-/-) received weekly ip DEN-injections and were compared with their WT counterparts. At 26W, WT mice were treated with twice a week with murine monoclonal PlGF-antibodies (20 mg/kg anti-PlGF) or IgG for 5W and 10W. Results: By 25 weeks of DEN treatment, 29% of the WT mice but none of the PlGF-/- mice had succumbed to the disease (p = 0,056). Also, treatment of DEN-injected HCC mice from 25 weeks for 5 weeks with 5D11D4 (ThromboGenics N.V.) or IgG showed a significant difference in mortality. While 45% died in the control IgG group, only 23% mortality was observed in the anti-PlGF group (N=48; P < 0.05). Also, the liver/body weight ratio was 0.057 ± 0.003 in the control group versus 0.042 ± 0.004 in the 5D11D4 group (N=19; P < 0,05). After 10W treatment 90% died in the control IgG group, while only 41 % mortality was observed in the anti-PlGF group (N = 11, P < 0,05). No mortality was observed in mice injected with saline instead of DEN, followed by 5 wks of treatment with anti-PlGF or IgG. The liver/body weight ratio was 0.038 ± 0.001 in the saline and IgG group versus 0.041 ± 0.002 in the anti-PlGF group (N=12, P = 0,27). Figure 1: left: Mean survival of IgG and aPlGF treated mice ; right: mean survival of PlGF knock out mice and WT’s during DEN-induction Conclusion: Our study showed that administration of 20 mg/kg anti-PlGF twice a week, has a positive effect on survival in mice with HCC. The liver/bodyweight ratio of anti-PlGF treated mice was significantly lower than in the control IgG group, showing a specific effect on liver tumours. Treatment of anti-PlGF in healthy mice did not induce negative side effects. Therefore, treatment with PlGF antibodies might serve as a promising systemic treatment in hepatocellular carcinoma patients

Severe hepatic and pulmonary involvement in Rendu-Osler-Weber syndrome

We report the case of a young woman with hereditary hemorrhagic telangiectasia (HHT) with severe liver involvement and pulmonary shunting. The medical imaging in this patient illustrates the severe shunting that can occur in these patients who often are asymptomatic. By showing this case, we want to highlight the role of liver transplantation in HHT with hepatic involvement

The Role of Bariatric Surgery in Fatty Liver

Non-alcoholic fatty liver disease (NAFLD) is a crucial health problem with a prevalence that is increasing concurrently with the obesity epidemic on a global scale. Steatosis, nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), cirrhosis, and advanced fibrosis constitute the disease spectrum covered by NAFLD. NASH-related cirrhosis and HCC is currently the second most common indication for liver transplantation. Although lifestyle modifications, especially weight loss, effectively reduces the liver injury in NASH, adherence in the clinical setting is low. Potential treatments for NASH are still under investigation in phase 2–3 studies. Bariatric surgery can improve metabolic components and cause great weight loss. Therefore, bariatric surgery may reverse the pathological liver changes in NAFLD and NASH patients. However, complications such as liver failure after bariatric surgery can occur. This chapter will give an overview of the benefits and pitfalls of bariatric surgery in patients with NAFLD, liver transplant candidates and post-liver transplant patients

Insulin resistance associates with hepatic lobular inflammation in subjects with obesity

Purpose: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. Objective: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. Methods: This cross-sectional study included 78 obese subjects (mean age 46 +/- 11 years; BMI 42.2 +/- 4.7 kg/m(2)). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. Results: A positive association between overall NAFLD Activity Score and HOMA-IR was found (r(s) = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. Conclusion: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances

Portal vein thrombosis in patients on the waiting list for liver transplantation : a single center cohort study

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Modulation of the unfolded protein response by tauroursodeoxycholic acid counteracts apoptotic cell death and fibrosis in a mouse model for secondary biliary liver fibrosis

The role of endoplasmic reticulum stress and the unfolded protein response (UPR) in cholestatic liver disease and fibrosis is not fully unraveled. Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, has been shown to reduce endoplasmic reticulum (ER) stress and counteract apoptosis in different pathologies. We aimed to investigate the therapeutic potential of TUDCA in experimental secondary biliary liver fibrosis in mice, induced by common bile duct ligation. The kinetics of the hepatic UPR and apoptosis during the development of biliary fibrosis was studied by measuring markers at six different timepoints post-surgery by qPCR and Western blot. Next, we investigated the therapeutic potential of TUDCA, 10 mg/kg/day in drinking water, on liver damage (AST/ALT levels) and fibrosis (Sirius red-staining), in both a preventive and therapeutic setting. Common bile duct ligation resulted in the increased protein expression of CCAAT/enhancer-binding protein homologous protein (CHOP) at all timepoints, along with upregulation of pro-apoptotic caspase 3 and 12, tumor necrosis factor receptor superfamily, member 1A (TNFRsf1a) and Fas-Associated protein with Death Domain (FADD) expression. Treatment with TUDCA led to a significant reduction of liver fibrosis, accompanied by a slight reduction of liver damage, decreased hepatic protein expression of CHOP and reduced gene and protein expression of pro-apoptotic markers. These data indicate that TUDCA exerts a beneficial effect on liver fibrosis in a model of cholestatic liver disease, and suggest that this effect might, at least in part, be attributed to decreased hepatic UPR signaling and apoptotic cell death

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

Liver transplantation for alcoholic liver disease: a retrospective analysis of recidivism, survival and risk factors predisposing to alcohol relapse

Background and study aims : Alcoholic liver disease (ALD) is the second most common indication for liver transplantation. The aim of this study was to evaluate the alcohol relapse rate and long-term survival after liver transplantation for ALD and to identify risk factors predisposing to alcohol relapse. Patients and methods : Between 2000 and 2007, 108 patients transplanted for ALD in the Ghent University Hospital were included in this retrospective analysis. Relapse was defined as any drinking after transplantation, problem drinking as more than 2 units/day for women and 3 units/day for men. A wide range of variables was obtained from a questionnaire and medical records. Results : The mean follow-up was 55 months. Relapse was observed in 29%, 16% in problem drinking. The one-and five-year survival was 87% and 74% respectively. No significant difference in survival was found between non-relapsers, occasional drinkers and problem drinkers. The following risk factors were found to be significantly associated with relapse into problem drinking in an univariate analysis : a shorter pre-transplant abstinence period, the presence of a first degree relative with alcohol abuse and a higher number of prior attempts to quit. In multivariable analysis, the presence of a first degree relative with alcohol abuse was found associated with relapse into problem drinking. Conclusions : The presence of a first degree relative with alcohol abuse is a valuable pre-transplant variable evaluating an ALD patient's eligibility for liver transplantation. Other variables are also helpful to outline the broader context of the drinking behavior of the patient