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 impact of elevation of total bilirubin level and etiology of the liver disease on serum N-glycosylation patterns in mice and men

The GlycoFibroTest and GlycoCirrhoTest are noninvasive alternatives for liver biopsy that can be used as a follow-up tool for fibrosis patients and to diagnose cirrhotic patients, respectively. These tests are based on the altered N-glycosylation of total serum protein. Our aim was to investigate the impact of etiology on the alteration of N-glycosylation and whether other characteristics of liver patients could have an influence on N-glycosylation. In human liver patients, no specific alteration could be found to make a distinction according to etiological factor, although alcoholic patients had a significant higher mean value for the GlycoCirrhoTest. Undergalactosylation did not show a significantly different quantitative alteration in the cirrhotic and non-cirrhotic population of all etiologies. Importantly, patients with an elevation of total bilirubin level (>2 mg/dl) had a strong increase of glycans modified with alpha 1-6 fucose. The fucosylation index was therefore significantly higher in fibrosis/cirrhosis and hepatocellular carcinoma patients with elevated total bilirubin levels irrespective of etiology. Furthermore, in a multiple linear regression analysis, only markers for cholestasis significantly correlated with the fucosylation index. In mouse models of chronic liver disease, the fucosylation index was uniquely significantly increased in mice that were induced with a common bile duct ligation. Mice that were chronically injected with CCl4 did not show this increase. Apart from this difference, common changes characteristic to fibrosis development in mice were observed. Finally, mice induced with a partial portal vein ligation did not show biological relevant changes indicating that portal hypertension does not contribute to the alteration of N-glycosylation

The roles of transforming growth factor-β, Wnt, Notch and hypoxia on liver progenitor cells in primary liver tumours

Primary liver tumours have a high incidence and mortality. The most important forms are hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both can occur together in the mixed phenotype hepatocellular-cholangiocarcinoma. Liver progenitor cells (LPCs) are bipotential stem cells activated in case of severe liver damage and are capable of forming both cholangiocytes and hepatocytes. Possibly, alterations in Wnt, transforming growth factor-, Notch and hypoxia pathways in these LPCs can cause them to give rise to cancer stem cells, capable of driving tumourigenesis. In this review, we summarize and discuss current knowledge on the role of these pathways in LPC activation and differentiation during hepatocarcinogenesis

Treatment of a mixed acinar-endocrine carcinoma with uptake on 68Gallium-DOTATOC positron emission tomography-computed tomography : a case report

The case of a 35-year old female patient with a diagnosis of metastatic mixed acinar-endocrine carcinoma (MAEC) is investigated in the present study. The patient was believed to have a well-differentiated neuroendocrine tumor (NET) with a high Ki-67 index and uptake on (68)Gallium-DOTATOC positron emission tomography-computed tomography for 9 years, and was treated accordingly. The patient had long lasting disease control by treatment with sunitinib, and a response was observed in numerous lesions with peptide receptor radionuclide therapy (PRRT). Following treatment for metastatic disease for >4 years, liver transplantation was performed, as an exception to normal recommendations, at the time of progression of a centrally located liver lesion inducing obstructive jaundice. Following transplantation, the diagnosis of a Grade 3 NET, as defined by the WHO 2010 classification, was challenged and changed to MAEC. MAEC is a rare type of tumor of the pancreas, exhibiting endocrine and acinar differentiation. It is difficult to diagnose, often being misidentified as acinar cell carcinoma or predominantly as neuroendocrine neoplasms. Immunohistochemical labelling provides the only evidence for the dual differentiation of neuroendocrine (synaptophysin and chromogranin) and acinar (lipase, trypsin and chymotrypsin) cell markers. Studies investigating MAECs with a clear histopathological diagnosis are scarce, in addition to evidence of disease behaviour and treatment options. It is generally agreed that surgery is the primary treatment in patients with resectable tumors. The responses to sunitinib and PRRT suggested that treatments considered or developed for NETs may be beneficial in MAEC cases

The angiopoietin/tie2 pathway in hepatocellular carcinoma

Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today's systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy

Cu isotopic signature in blood serum of liver transplant patients: a follow-up study

End-stage liver disease (ESLD) is life-threatening and liver transplantation (LTx) is the definitive treatment with good outcomes. Given the essential role of hepatocytes in Cu homeostasis, the potential of the serum Cu isotopic composition for monitoring a patient's condition post-LTx was evaluated. For this purpose, high-precision Cu isotopic analysis of blood serum of ESLD patients pre- and post-LTx was accomplished via multi-collector ICP-mass spectrometry (MC-ICP-MS). The Cu isotopic composition of the ESLD patients was fractionated in favour of the lighter isotope (by about -0.50 parts per thousand). Post-LTx, a generalized normalization of the Cu isotopic composition was observed for the patients with normal liver function, while it remained light when this condition was not reached. A strong decrease in the delta Cu-65 value a longer term post-LTx seems to indicate the recurrence of liver failure or cancer. The observed trend in favour of the heavier Cu isotopic composition post-LTx seems to be related with the restored biosynthetic capacity of the liver, the restored hepatic metabolism and/or the restored biliary secretion pathways. Thus, Cu isotopic analysis could be a valuable tool for the follow-up of liver transplant patients and for establishing the potential recurrence of liver failure