Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility.

beta-Glucosidase 2 (GBA2) is a resident enzyme of the endoplasmic reticulum thought to play a role in the metabolism of bile acid-glucose conjugates. To gain insight into the biological function of this enzyme and its substrates, we generated mice deficient in GBA2 and found that these animals had normal bile acid metabolism. Knockout males exhibited impaired fertility.

Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a crucial role in the pathogenesis of hepatic fibrosis and thus may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease. We present an innovative therapy based on the assignment of inactivated enzymes acting as scavengers for TIMP-1. Hepatic fibrosis was induced in BALB/c mice by repetitive intraperitoneal CCl4 injection.

Characterization of organic anion transporter regulation, glutathione metabolism and bile formation in the obese Zucker rat.

Background/aims: Alterations in hepatobiliary transporters may render fatty livers more vulnerable against various toxic insults.

Methods: We therefore studied expression and function of key organic anion transporters and their transactivators in 8-week-old obese Zucker rats, an established model for non-alcoholic fatty liver disease.

Results: Compared to their heterozygous littermates, obese animals showed a significant reduction in canalicular bile salt secretion, which was paralleled by significantly diminished Oatp2 mRNA and protein levels together with reduced nuclear HNF3beta, while expression of bile salt export pump, organic anion transporter (Oatp) 1 and multidrug resistance-associated protein (Mrp) 4 were unchanged.

Recurrent thrombotic occlusion of a transjugular intrahepatic portosystemic stent-shunt due to activated protein C resistance.

The transjugular intrahepatic portosystemic stent-shunt (TIPS) has successfully been used in the management of refractory variceal bleeding and ascites in patients with portal hypertension. Major drawbacks are the induction of hepatic encephalopathy and shunt dysfunction. We present a 59-year-old woman with alcoholic liver cirrhosis who received a TIPS because of recurrent bleeding from esophageal varices.

The genetic background of cholesterol gallstone formation: an inventory of human lithogenic genes.

Family and twin studies as well as animal studies indicate that gallstone disease is, in part, genetically determined. Recently new single gene defects have been identified in specific patients with cholesterol and pigment gallstones. Examples include low phospholipid-associated cholelithiasis due to mutations of the gene encoding the hepatocanalicular phosphatidylcholine transporter, and pigment stones in association with mutations of the ileal bile salt transporter gene.

Interleukin-6 plays a crucial role in the hepatic expression of SOCS3 during acute inflammatory processes in vivo.

Background/aims: Interleukin-6 is mandatory for liver regeneration after injury and for the hepatic expression of acute phase proteins and cytochrome P450 enzymes during inflammation. Due to its crucial contribution to the maintenance of homeostasis IL-6 signaling is tightly controlled. Suppressor of cytokine signaling (SOCS) 3 is a potent IL-6-induced feedback inhibitor terminating IL-6 signal transduction.

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans.

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection.

Occult celiac disease prevents penetrance of hemochromatosis.

Aim: To report a patient with C282Y homozygocity, depleted body iron and intestinal atrophy caused by celiac disease (CD) who experienced resolution of the enteropathy with subsequent normalization of iron metabolism upon gluten-free diet.

Methods: To obtain information on the tissue distribution and quantitative expression of proteins involved in duodenal iron trafficking, we determined the expression of divalent-metal transporter 1 (DMT1), ferroportin 1 (FP1) and transferrin receptor (TfR1) by means of immunohistochemistry and real-time PCR in duodenal biopsies of this patient.

Results: Whereas in hereditary hemochromatosis patients without CD, DMT1 expression was up-regulated leading to excessive uptake of iron, we identified a significant reduction in protein and mRNA expression of DMT1 as a compensatory mechanism in this patient with HH and CD.

Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver.

Proinflammatory cytokines such as TNF-alpha and IL-1beta lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-alpha or IL-1beta for up to 16 h.

Enhanced migration of tissue inhibitor of metalloproteinase overexpressing hepatoma cells is attributed to gelatinases: relevance to intracellular signaling pathways.

Aim: To study the effect of gelatinases (especially MMP-9) on migration of tissue inhibitor of metalloproteinase (TIMP-1) overexpressing hepatoma cells.

Methods: Wild type HepG2 cells, cells stably transfected with TIMP-1 and TIMP-1 antagonist (MMP-9-H401A, a catalytically inactive matrix metalloproteinase (MMP) which still binds and neutralizes TIMP-1) were incubated in Boyden chambers either with or without Galardin (a synthetic inhibitor of MMP-1, -2, -3, -8, -9) or a specific inhibitor of gelatinases.

Results: Compared to wild type HepG2 cells, the cells overexpressing TIMP-1 showed 115% migration (P<0.

Cytokine-independent repression of rodent Ntcp in obstructive cholestasis.

Cholestatic liver injury is associated not only with accumulation of bile acids but also with activation of proinflammatory cytokines. Common bile duct ligation (CBDL) induces sustained downregulation of the Na(+)/taurocholate cotransporter (Ntcp) in rodent liver. Although repression of Ntcp during endotoxemia is cytokine mediated, it is unclear whether inflammatory cytokines contribute to this downregulation in obstructive cholestasis.

Characteristics of oesophageal bolus transport in patients with mild oesophagitis.

Objective: Patients with gastroesophageal reflux disease (GORD) frequently have oesophageal motility disturbance. However, detailed data about bolus transport characteristics in these patients are still lacking. In the present study the new technology of concurrent impedance manometry was applied for characterization of oesophageal motor function in patients with mild GORD.

Patients with acute on chronic liver failure display "sepsis-like" immune paralysis.

Background/aims: Cellular immune depression is linked to high mortality in sepsis, but has yet to be systematically analysed in liver cirrhosis. The aim of the present study was to directly compare functional immune parameters in patients with acute on chronic liver failure (ACLF), severe sepsis, and non-decompensated cirrhosis.

Methods: Patients with ACLF (n=27) were investigated at admission to a medical ICU.

Enlarged cervical lymph nodes and elevated liver chemistry tests: a therapeutic dilemma.

We describe the case of a 36-years-old male patient, originating from India, who presented with enlarged cervical lymph nodes and elevated liver chemistry tests. Histologically necrosing granulomas were observed in the lymph nodes, and PCR revealed DNA from mycobacterium tuberculosis. However, in the liver biopsy granulomatous hepatitis without central necrosis was seen.

Prevalence of pituitary deficiency in patients after aneurysmal subarachnoid hemorrhage.

After aneurysmal subarachnoid hemorrhage (SAH), patients frequently present with persistent bodily, psychosocial, and cognitive impairments that resemble those of patients with untreated partial or complete pituitary insufficiency. Because of these similarities, the authors hypothesized that aneurysmal SAH may cause pituitary dysfunction. Pituitary function testing was performed in 40 aneurysmal SAH patients between 12 and 72 months after the SAH.

Haplotype-tagging RANTES gene variants influence response to antiviral therapy in chronic hepatitis C.

The response to antiviral therapy for chronic hepatitis C virus (HCV) is complex and is determined by both environmental and genetic factors. Recently, interacting gene polymorphisms of the chemokine RANTES have been shown to affect HIV disease progression. Our aim was to assess if these RANTES variants are associated with response to anti-HCV therapy.

Interleukin-6 regulates hepatic transporters during acute-phase response.

Cholestasis develops during inflammatory conditions characterized by the release of cytokines like interleukin-6 (IL-6), which is the major player in the hepatic acute-phase response. However, the exact contribution of IL-6 to transporter down-regulation is unclear. Therefore, we compared wild-type and IL-6-deficient mice after IL-6-injection and induction of an aseptic (turpentine-injection) or septic (LPS-injection) acute-phase response.

Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C.

Background: Chronic hepatitis C is frequently associated with increased hepatic iron stores. It remains controversial whether heterozygous mutations of hemochromatosis genes affect fibrosis progression. Therefore our aim was to assess associations between HFE mutations and hepatic inflammation and stage of fibrosis in German hepatitis C patients.

[Evidence-based prevention of cholecystolithiasis].

Evidence based prevention of cholecystolithiasis. Cholesterol cholelithiasis is one of the most common and expensive gastroenterological diseases. Beside common exogenous risk factors, recent molecular genetic studies have identified genetic risk factors for both cholesterol and pigment stone formation.

Hyperglycemia at admission to the intensive care unit is associated with elevated serum concentrations of interleukin-6 and reduced ex vivo secretion of tumor necrosis factor-alpha.

Objectives: The aim of the study was to investigate the association between admission blood glucose concentrations and immune function variables and its correlation to mortality rate in patients of a medical intensive care unit.

Design: Prospective, observational study.

Setting: Medical intensive care unit of a university hospital.

Simultaneous determination of matrix metalloproteinase (MMP)-7, MMP-1, -3, and -13 gene expression by multiplex PCR in colorectal carcinomas.

Background And Aims: MMP-7, a member of the matrix metalloproteinase family, is believed to play a significant role in the growth and proliferation of colon cancer cells. The aim of this study was to evaluate MMP-7 gene expression in comparison with MMP-1, MMP-3, and MMP-13 in patients with resectable rectal and colon cancer by a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR).

Materials And Methods: Biopsy samples of tumor ( n=30) and distant normal mucosa ( n=30) from 30 patients were obtained intraoperation.

Consequences of bile duct obstruction on intestinal expression and function of multidrug resistance-associated protein 2.

Background & Aims: Multidrug resistance-associated protein 2 (MRP2), a transporter of organic anions in hepatocytes, renal epithelial cells, and enterocytes, is differentially regulated in liver and kidney during cholestasis, but little is known about its regulation in the intestine.

Methods: We investigated duodenal protein expression of MRP2 in male Sprague-Dawley rats with bile duct ligation (BDL) or biliary diversion as well as in 20 cholestatic patients with biliary obstruction.

Results: In biliary obstruction, but not biliary depletion, intestinal Mrp2 protein mass was reduced to 9.

The presence of non-organ-specific autoantibodies is associated with a negative response to combination therapy with interferon and ribavirin for chronic hepatitis C.

Background: Non-organ-specific autoantibodies are found in a considerable number of anti-HCV positive patients. Previous studies investigated the clinical relevance of these antibodies in patients treated with interferon monotherapy, but not combination therapies.

Methods: Anti-nuclear, anti-smooth muscle, anti-mitochondrial, anti-neutrophil-cytoplasmatic and anti-liver/kidney microsomal antibodies were determined in 78 consecutive anti-HCV positive patients by indirect immunofluorescence.