Background Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant... more Background Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant portal hypertension (CSPH). This study assesses different features of CSPH and their distinct prognostic impact regarding decompensation and survival in patients with PBC. Methods Patients with PBC were identified during a database query of our digital patient reporting system. Results A total of 333 PBC patients (mean age 54.3 years, 86.8% females, median follow-up 5.8 years) were retrospectively assessed and 127 (38.1%) showed features of CSPH: 63 (18.9%) developed varices, 98 (29.4%) splenomegaly, 62 (18.6%) ascites and 20 (15.7%) experienced acute variceal bleeding. Splenomegaly, portosystemic collaterals and esophageal varices were associated with an increased 5-year (5Y) risk of decompensation (15.0%, 17.8% and 20.9%, respectively). Patients without advanced chronic liver disease (ACLD) had a similar 5Y-transplant free survival (TFS) (96.6%) compared to patients with compensated A...
Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate ... more Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. 8 weeks old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4 weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1 week of ASBT inhibitor feeding....
Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary scler... more Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g., obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable intere...
To demonstrate the overlap of the hepatic and bile phosphorus ((31)P) magnetic resonance (MR) spe... more To demonstrate the overlap of the hepatic and bile phosphorus ((31)P) magnetic resonance (MR) spectra and provide evidence of phosphatidylcholine (PtdC) contribution to the in vivo hepatic (31)P MRS phosphodiester (PDE) signal, suggested in previous reports to be phosphoenolpyruvate (PEP). Phantom measurements to assess the chemical shifts of PEP and PtdC signals were performed at 7 T. A retrospective analysis of hepatic 3D (31)P MR spectroscopic imaging (MRSI) data from 18 and five volunteers at 3 T and 7 T, respectively, was performed. Axial images were inspected for the presence of gallbladder, and PDE signals in representative spectra were quantified. Phantom experiments demonstrated the strong pH-dependence of the PEP chemical shift and proved the overlap of PtdC and PEP (~2 ppm relative to phosphocreatine) at hepatic pH. Gallbladder was covered in seven of 23 in vivo 3D-MRSI datasets. The PDE gall/γ-ATPliver ratio was 4.8-fold higher (p = 0.001) in the gallbladder (PDEgall/γ-ATPliver = 3.61 ± 0.79) than in the liver (PDEliver/γ-ATPliver = 0.75 ± 0.15). In vivo 7 T (31)P MRSI allowed good separation of PDE components. The gallbladder is a strong source of contamination in adjacent (31)P MR hepatic spectra due to biliary phosphatidylcholine. In vivo (31)P MR hepatic signal at 2.06 ppm may represent both phosphatidylcholine and phosphoenolpyruvate, with a higher phosphatidylcholine contribution due to its higher concentration. • In vivo (31) P MRS from the gallbladder shows a dominant biliary phosphatidylcholine signal at 2.06 ppm. • Intrahepatic (31) P MRS signal at 2.06 ppm may represent both intrahepatic phosphatidylcholine and phosphoenolpyruvate. • In vivo (31) P MRS has the potential to monitor hepatic phosphatidylcholine.
Many of the concepts describing molecular mechanisms of sepsis-induced liver failure are derived ... more Many of the concepts describing molecular mechanisms of sepsis-induced liver failure are derived from endotoxin models. However, the biological significance of such models is questionable as the complexity of clinical sepsis and associated organ failure is only partially replicated. Comparison of cytokine response, leucocyte recruitment, oxidative stress and markers of hepatic organ dysfunction in rat models of endotoxaemia or peritoneal contamination and infection (PCI). Endotoxemia and polymicrobial sepsis were induced in rats by intraperitoneal injection of lipopolysaccharide (LPS) or stool suspension, respectively. Both insults produced clinical and laboratory signs of multiple organ dysfunction, including hepatic excretory dysfunction. However, TNF alpha, oxidative stress responses and the degree of cell death were significantly higher in endotoxaemia compared to PCI (e.g. serum TNF levels (pg/ml) at 1.5 h post-insult: sham 5 ± 1.4, LPS 1 mg/kg bw 2176.92 ± 373.78, sepsis below detection limit; P P < 0.05). Cholestasis was significantly more pronounced in polymicrobial sepsis whereas serum bilirubin in endotoxaemic animals did not differ from sham-operated controls (plasma levels of bilirubin (μmol/L) at 15 h after the insult: sham 7.1 ± 0.6, LPS 30 mg/kg 9.1 ± 0.6, sepsis 15.2 ± 1.3). Polymicrobial sepsis produces profound hepatocellular dysfunction in the absence of traditional cytokine-mediated mechanisms of cellular injury. This questions the central role of cytokines and the ensuing oxidative stress as key molecular events in mediating liver dysfunction.
Background Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant... more Background Primary biliary cholangitis (PBC) may progress to cirrhosis and clinically significant portal hypertension (CSPH). This study assesses different features of CSPH and their distinct prognostic impact regarding decompensation and survival in patients with PBC. Methods Patients with PBC were identified during a database query of our digital patient reporting system. Results A total of 333 PBC patients (mean age 54.3 years, 86.8% females, median follow-up 5.8 years) were retrospectively assessed and 127 (38.1%) showed features of CSPH: 63 (18.9%) developed varices, 98 (29.4%) splenomegaly, 62 (18.6%) ascites and 20 (15.7%) experienced acute variceal bleeding. Splenomegaly, portosystemic collaterals and esophageal varices were associated with an increased 5-year (5Y) risk of decompensation (15.0%, 17.8% and 20.9%, respectively). Patients without advanced chronic liver disease (ACLD) had a similar 5Y-transplant free survival (TFS) (96.6%) compared to patients with compensated A...
Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate ... more Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. 8 weeks old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4 weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1 week of ASBT inhibitor feeding....
Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary scler... more Chronic inflammatory bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) result in progressive fibrosis of the biliary tract and ultimately cirrhosis of the liver. Since the etiology and pathogenesis of these fibrosing cholangiopathies are still poorly understood, therapeutic options are rather limited at present. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and established standard treatment for PBC, but its role for medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid, a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g., obeticholic acid) which currently undergo clinical development for fibrosing cholangiopathies such as PBC and PSC. Other nuclear receptors such as vitamin D receptor and fatty acid-activated peroxisome proliferator-activated receptors are also of considerable intere...
To demonstrate the overlap of the hepatic and bile phosphorus ((31)P) magnetic resonance (MR) spe... more To demonstrate the overlap of the hepatic and bile phosphorus ((31)P) magnetic resonance (MR) spectra and provide evidence of phosphatidylcholine (PtdC) contribution to the in vivo hepatic (31)P MRS phosphodiester (PDE) signal, suggested in previous reports to be phosphoenolpyruvate (PEP). Phantom measurements to assess the chemical shifts of PEP and PtdC signals were performed at 7 T. A retrospective analysis of hepatic 3D (31)P MR spectroscopic imaging (MRSI) data from 18 and five volunteers at 3 T and 7 T, respectively, was performed. Axial images were inspected for the presence of gallbladder, and PDE signals in representative spectra were quantified. Phantom experiments demonstrated the strong pH-dependence of the PEP chemical shift and proved the overlap of PtdC and PEP (~2 ppm relative to phosphocreatine) at hepatic pH. Gallbladder was covered in seven of 23 in vivo 3D-MRSI datasets. The PDE gall/γ-ATPliver ratio was 4.8-fold higher (p = 0.001) in the gallbladder (PDEgall/γ-ATPliver = 3.61 ± 0.79) than in the liver (PDEliver/γ-ATPliver = 0.75 ± 0.15). In vivo 7 T (31)P MRSI allowed good separation of PDE components. The gallbladder is a strong source of contamination in adjacent (31)P MR hepatic spectra due to biliary phosphatidylcholine. In vivo (31)P MR hepatic signal at 2.06 ppm may represent both phosphatidylcholine and phosphoenolpyruvate, with a higher phosphatidylcholine contribution due to its higher concentration. • In vivo (31) P MRS from the gallbladder shows a dominant biliary phosphatidylcholine signal at 2.06 ppm. • Intrahepatic (31) P MRS signal at 2.06 ppm may represent both intrahepatic phosphatidylcholine and phosphoenolpyruvate. • In vivo (31) P MRS has the potential to monitor hepatic phosphatidylcholine.
Many of the concepts describing molecular mechanisms of sepsis-induced liver failure are derived ... more Many of the concepts describing molecular mechanisms of sepsis-induced liver failure are derived from endotoxin models. However, the biological significance of such models is questionable as the complexity of clinical sepsis and associated organ failure is only partially replicated. Comparison of cytokine response, leucocyte recruitment, oxidative stress and markers of hepatic organ dysfunction in rat models of endotoxaemia or peritoneal contamination and infection (PCI). Endotoxemia and polymicrobial sepsis were induced in rats by intraperitoneal injection of lipopolysaccharide (LPS) or stool suspension, respectively. Both insults produced clinical and laboratory signs of multiple organ dysfunction, including hepatic excretory dysfunction. However, TNF alpha, oxidative stress responses and the degree of cell death were significantly higher in endotoxaemia compared to PCI (e.g. serum TNF levels (pg/ml) at 1.5 h post-insult: sham 5 ± 1.4, LPS 1 mg/kg bw 2176.92 ± 373.78, sepsis below detection limit; P P < 0.05). Cholestasis was significantly more pronounced in polymicrobial sepsis whereas serum bilirubin in endotoxaemic animals did not differ from sham-operated controls (plasma levels of bilirubin (μmol/L) at 15 h after the insult: sham 7.1 ± 0.6, LPS 30 mg/kg 9.1 ± 0.6, sepsis 15.2 ± 1.3). Polymicrobial sepsis produces profound hepatocellular dysfunction in the absence of traditional cytokine-mediated mechanisms of cellular injury. This questions the central role of cytokines and the ensuing oxidative stress as key molecular events in mediating liver dysfunction.
Uploads
Papers by Emina Halilbasic