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The incidence of hepatocellular carcinomas (HCCs) has increased worldwide in line with an improved screening by high-resolution imaging of cirrhotic livers. Besides abdominal ultrasonography and computerised tomography, magnetic resonance imaging (MRI) is an important tool to detect HCCs. With commercialisation of MR hepatobiliary contrast agents that cross membrane transporters in hepatocytes or tumour cells, MRI adds new information to detect and characterise HCCs. When tumour cells lose organic anion transporting polypeptides (OATP1B1/B3) in cell membranes facing sinusoidal blood, tumours appear hypointense (decreased contrast agent concentrations) in comparison to surrounding normal or cirrhotic liver that retains OATP1B1/B3 expression. However, expression, regulation, and prognostic significance of transporter evolution along carcinogenesis are not completely known. Moreover, understanding signal intensities in focal lesions also relies on transport functions of cellular efflux transporters. This manuscript reviews all the publications that associate liver imaging with hepatobiliary contrast agents and expression of transporters. The regulation of transporters along carcinogenesis to anticipate the prognosis of focal lesions is also included., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Acute pancreatitis is an inflammatory disease of the pancreas, which varies greatly in course and severity. Severe forms are associated with serious local and/or systemic complications, and eventually death. The pathobiology of acute pancreatitis is complex. Animal models have been developed to investigate pathobiological processes and identify factors determining disease course. We performed a time-course proteomic analysis using a rat model of severe necrotizing acute pancreatitis induced by taurocholate perfusion in the pancreatic ducts. Results showed that levels of proteins associated to a given biological process changed in a coordinated fashion after disease onset. It was possible to follow the response of a particular pathobiological process to pancreatitis induction and to compare the course of protein pathways. Proteins involved in acinar cell secretion were found to follow a different kinetics than other cellular processes. After an initial decrease, secretory pathway-associated proteins raised again at 18 h post-induction. This phenomenon coincided with a burst in the expression of pancreatitis-associated protein (REG3A), an acute phase protein produced by the exocrine pancreas, and with the decrease of classical markers of pancreatic injury, suggesting that the expression of proteins associated to the secretory pathway may be a modulating factor of pancreas injury., Biological Significance: Acute pancreatitis (AP) is a complex inflammatory disease, the pathobiology of which is not yet fully understood. Various animal models, relying on different mechanisms of disease induction, have been developed in order to investigate pathobiological processes of AP. In this study, we performed a time-course proteomic analysis to investigate changes of the pancreas proteome occurring in an experimental model of AP induced by perfusion of taurocholate, a bile acid, into the pancreatic duct. This experimental model is characterized by a severe disease with pancreatic necrosis and systemic inflammation. The objectives of this study were to determine the kinetics of functionally related proteins in the early steps of the experimental disease in order to identify protein pathways playing key roles in AP pathobiology and to correlate these data with parameters classically used to assess disease severity. The present work provides for the first time an overview of protein expression in the pancreas during the course of taurocholate-induced necrotizing AP. We believe that correlation of these results with data obtained using proteomic or biochemical approaches in various experimental models of AP will help in highlighting new features, generating hypotheses and constitute therefore a strong and reliable basis for further targeted investigations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Gadolinium ethoxybenzyl dimeglumine (Gd-EOB-DTPA, Primovist in Europe and Eovist in the USA) is a liver-specific magnetic resonance imaging contrast agent that has up to 50% hepatobiliary excretion in the normal liver. After intravenous injection, Gd-EOB-DTPA distributes into the vascular and extravascular spaces during the arterial, portal venous and late dynamic phases, and progressively into the hepatocytes and bile ducts during the hepatobiliary phase. The hepatocyte uptake of Gd-EOB-DTPA mainly occurs via the organic anion transporter polypeptides OATP1B1 and B3 located at the sinusoidal membrane and biliary excretion via the multidrug resistance-associated proteins MRP2 at the canalicular membrane. Because of these characteristics, Gd-EOB-DTPA behaves similarly to non-specific gadolinium chelates during the dynamic phases, and adds substantial information during the hepatobiliary phase, improving the detection and characterization of focal liver lesions and diffuse liver disease. This information is particularly relevant for the detection of metastases, and for the detection and characterization of nodular lesions in liver cirrhosis, including early hepatocellular carcinomas. Finally, GD-EOB-DTPA-enhanced magnetic resonance imaging may provide quantitative assessment regarding liver perfusion and hepatocyte function in diffuse liver diseases. The full potential of GD-EOB-DTPA-enhanced magnetic resonance imaging has to be established further. It is already clear that GD-EOB-DTPA-enhanced magnetic resonance imaging provides anatomic and functional information in the setting of focal and diffuse liver disease that is unattainable with magnetic resonance imaging enhanced with non-specific contrast agents., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Acute pancreatitis is an inflammatory disease of the pancreas. Acute abdominal pain is the most common symptom, and increased concentrations of serum amylase and lipase confirm the diagnosis. Pancreatic injury is mild in 80% of patients, who recover without complications. The remaining patients have a severe disease with local and systemic complications. Gallstone migration into the common bile duct and alcohol abuse are the most frequent causes of pancreatitis in adults. About 15-25% of pancreatitis episodes are of unknown origin. Treatment of mild disease is supportive, but severe episodes need management by a multidisciplinary team including gastroenterologists, interventional radiologists, intensivists, and surgeons. Improved understanding of pathophysiology and better assessments of disease severity should ameliorate the management and outcome of this complex disease.

Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of patients with end-stage liver diseases. HPS is diagnosed by hypoxemia and pulmonary vascular dilatation and is an independent risk factor of mortality. Orthotopic liver transplantation (OLT) is the only factor that modifies the natural course of HPS. Once patients with HPS have been transplanted, their long-term survival rate is similar to transplanted patients without HPS. Consequently, HPS is an indication of OLT whatever the severity of hypoxemia. However, besides the favorable long-term survival of HPS patients with OLT, a high postoperative mortality (mostly within 6 months) has been suggested. The aim of our study was to analyze the incidence of HPS and postoperative outcome after OLT in 90 consecutive patients. All patients were prospectively included and had blood gas analysis to detect HPS. Patients with hypoxemia had contrast echocardiography to confirm HPS. Nine patients had HPS with a 50 50 mmHg in all HPS patients transplanted.

In rat portal veins (RPV) isolated from septic rats, we previously showed that the contractile response to angiotensin II (AT(II)) was significantly decreased and that the vascular failure was correlated with the severity of the disease. We hypothesized that hyperthermia might be one of the factors responsible for the vascular failure. Moreover, hyperthermia should concomitantly increase heat shock proteins (Hsps) expression. We then compared the vascular contractility and the heat shock protein 70 (Hsp70) expression in RPV incubated at 37 degrees C and 39.5 degrees C and sought for a relationship between both events. In our experimental model, hyperthermia increased the Hsp70 expression and decreased the contractile response to AT(II). Incorporation of the Hsp70 antisense oligonucleotide in RPV blocked the increase in Hsp70 expression but had no consequence on the contractile response to AT(II). In conclusion, hyperthermia increases Hsp70 expression but does not mediate the decreased response to AT(II). Hsp70 overexpression has no effect on the actin-myosin interaction in vascular smooth muscle.

Background/aims: Little information is available regarding the effect of cold storage and hyperthermic preconditioning on the contractile responses of hepatic vessels. We then studied, after cold preservation, the in vitro contractile responses of rat portal veins (RPV) isolated from normal rats or from rats previously subjected to hyperthermia., Methods: Rats were or were not subjected to hyperthermia 24 h before the RPV isolation. Then, RPV were stored at 4 degrees C in Krebs-Henseleit bicarbonate (KHB) or University of Wisconsin solution or conserved at 20 degrees C in KHB solution. Control RPV were tested after rat sacrifice., Results: The contractile responses were importantly decreased in RPV conserved at room temperature. The morphology of the vessels was altered and the heat shock protein 70 (Hsp70) protein expression disappeared. These abnormalities were prevented by cold preservation. The type of preservation solution did not interfere with the beneficial effect. Hyperthermic preconditioning increased the expression of Hsp70 protein in freshly isolated and cold preserved RPV but decreased the contractile responses. In RPV conserved at room temperature, hyperthermic preconditioning further worsened the decreased contractile response., Conclusions: Thus, hyperthermic preconditioning, which is beneficial in protecting hepatic injury following cold preservation, alters the contractile responses of RPV., (Copyright 2002 European Association for the Study of the Liver)

Background: Few data exist concerning the consequences of acidosis on intrahepatic vascular resistances and hepatic functions., Methods: The consequences of pH and PCO2 changes on the intrahepatic vascular reactivity to norepinephrine (NE, 10(-9) to 3 x 10(-5) M) have been investigated in isolated rat livers perfused with solutions bubbled with 5, 10, or 15% CO2 and in solutions in which pH was decreased by replacing HCO3- with NaCl while maintaining a normal PCO2. Hepatic O2 consumption (VO2) and urea release were also measured during these experiments., Results: The NE-induced increase of portal pressure did not change during hypercarbic and normocarbic acidosis. In contrast, the NE-induced increase of urea release was higher when the solution of perfusion was bubbled with 10 and 15% CO2, while during normocarbic acidosis the NE-induced increase of urea release did not change with pH. In the absence of NE, acidosis decreased hepatic VO2 and urea release but portal pressure was not modified by changing % CO2 or pH in the Krebs-Henseleit-bicarbonate solution., Conclusions: This study clearly shows that, in the liver, the consequences of acidosis are far more important on the metabolism (VO2 and urea release) than on the intrahepatic vascular resistance.

Background/aims: The portal vein has spontaneous and agonist-induced contractile activities and whether sepsis alters these two types of contractile activities is unknown., Methods: To study the effect of sepsis on the spontaneous contractile activity and the contractile responses to norepinephrine (NE), angiotensin II (AT(II)), and neurokinin B (NKB) in the rat portal vein (RPV), we performed a cecal ligature and puncture (CLP) 24 h before RPV isolation., Results: CLP decreased the spontaneous activity and induced hyporesponsiveness to AT(II) and NKB. The vascular failure was correlated to the severity of sepsis. In contrast, the reactivity to NE was not altered. Although inducible NO synthase was detected in RPV isolated from CLP rats, NO synthase inhibitors did not restore either the responsiveness to AT(II) and NKB or the spontaneous activity. Additionally, hyporesponsiveness to AT(II) and NKB was not modified by indomethacin., Conclusions: CLP decreases the spontaneous activity of the RPV as well as the contractile responses to AT(II) and NKB. The vascular failure is correlated to the severity of sepsis. The reactivity to NE is not altered in this model. Neither NO nor prostaglandins are responsible for the vascular abnormalities observed during CLP.