ABCB4 deficiency: A family saga of early onset cholelithiasis, sclerosing cholangitis and cirrhosis and a novel mutation in the ABCB4 gene.

Gallstones are very common. However, there is a small group of patients with low phospholipid-associated cholelithiasis (LPAC) that is characterized by symptomatic cholelithiasis at a young age (<40 years), recurrence of biliary symptoms despite cholecystectomy and concrements or sludge in the intra- and extrahepatic biliary system. The LPAC syndrome is associated with mutations of the adenosine triphosphate-binding cassette, subfamily B, member 4 (ABCB4) gene encoding the hepatobiliary phospholipid translocator multidrug resistance protein 3 (MDR3).

Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis.

Background: TGR5, the G protein-coupled bile acid receptor 1 (GPBAR1), has been linked to inflammatory pathways as well as bile homeostasis, and could therefore be involved in primary sclerosing cholangitis (PSC) a chronic inflammatory bile duct disease. We aimed to extensively investigate TGR5 sequence variation in PSC, as well as functionally characterize detected variants.

Methodology/principal Findings: Complete resequencing of TGR5 was performed in 267 PSC patients and 274 healthy controls.

Phosphatidylinositol-3-kinase p110γ contributes to bile salt-induced apoptosis in primary rat hepatocytes and human hepatoma cells.

Background & Aims: Glycochenodeoxycholate (GCDC) and taurolithocholate (TLC) are hepatotoxic and cholestatic bile salts, whereas tauroursodeoxycholate (TUDC) is cytoprotective and anticholestatic. Yet they all act, in part, through phosphatidylinositol-3-kinase(PI3K)-dependent mechanisms ("PI3K-paradox"). Hepatocytes express three catalytic PI3K Class I isoforms (p110α/β/γ), specific functions of which, in liver, are unclear.

Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis.

Background & Aims: Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine.

Lysophosphatidic acid is a potential mediator of cholestatic pruritus.

Background & Aims: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.

Late reuse of liver allografts from brain-dead graft recipients: the Munich experience and a review of the literature.

The increasing donor organ shortage requires the consideration of any possible organ donor in order to meet the current demand. However, the growing number of long-term survivors of liver transplantation may create a situation in which former organ recipients may experience brain death with a functioning graft and therefore become organ donors themselves. Previous reports concerning this rare situation predominantly refer to the reuse of donor organs within the first 8 days after primary liver transplantation.

Genome-wide association analysis in primary sclerosing cholangitis.

Background & Aims: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers.

Methods: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls.

Immune-mediated liver diseases: programmed cell death ligands and circulating apoptotic markers.

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are the three major immune-mediated liver diseases. The etiologies of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis are largely unknown, but seem to be influenced by genetic and environmental factors. Autoantibodies can be found in nearly all patients with primary sclerosing cholangitis and autoimmune hepatitis, and in the vast majority of patients with primary sclerosing cholangitis.

Bile acid-induced apoptosis in hepatocytes is caspase-6-dependent.

Apoptosis induced by hydrophobic bile acids is thought to contribute to liver injury during cholestasis. Caspase-6 is an executioner caspase that also appears to have regulatory functions in hematopoetic cell lines. We aimed to elucidate the role of caspase-6 in bile acid-induced apoptosis.

PR3-ANCA-positive necrotizing multi-organ vasculitis following cocaine abuse.

A 22-year-old man with a history of cocaine abuse from 2003 to 2005 developed recurrent bleeding of the nasal septum and a progressive cough and dyspnoea. He was admitted to the intensive care unit because of fulminant pneumonia, impaired renal function and progressive general deterioration. While hospitalized, he developed cutaneous vasculitis, thrombosis of the right subclavian and right jugular veins, testicular pain and, eventually, expanding red papules and plaques on the limbs.

Medical treatment of primary sclerosing cholangitis: a role for novel bile acids and other (post-)transcriptional modulators?

Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease of the liver and bile ducts that is associated with inflammatory bowel disease, generally leads to end-stage liver disease, and is complicated by malignancies of the biliary tree and the large intestine. The pathogenesis of PSC remains enigmatic, making the development of targeted therapeutic strategies difficult. Immunosuppressive and antifibrotic therapeutic agents were ineffective or accompanied by major side effects.

Primary biliary cirrhosis following Lactobacillus vaccination for recurrent vaginitis.

Background/aims: Antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex, PDC-E2, and other mitochondrial 2-oxoacid dehydrogenases (AMA-M2) are the hallmark for diagnosis of primary biliary cirrhosis (PBC). AMA-M2 formation as an early step in the pathogenesis of PBC has recently been assumed to be triggered by bacterial mimics of the E2 subunit and certain reactant xenobiotics. We report a case of symptomatic PBC diagnosed after sequential immunization with a lactobacillus vaccine for recurrent vaginitis over years.

Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKC alpha-/PKA-dependent mechanism in rat liver.

Objective: Ursodeoxycholic acid (UDCA) exerts anticholestatic effects in part by protein kinase C (PKC)-dependent mechanisms. Its taurine conjugate, TUDCA, is a cPKC alpha agonist. We tested whether protein kinase A (PKA) might contribute to the anticholestatic action of TUDCA via cooperative cPKC alpha-/PKA-dependent mechanisms in taurolithocholic acid (TLCA)-induced cholestasis.

Overlap syndromes among autoimmune liver diseases.

The three major immune disorders of the liver are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Variant forms of these diseases are generally called overlap syndromes, although there has been no standardised definition. Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.

[A 47-year-old dog breeder with chronic polyarthritis, weight loss and high fever].

A 47-year-old dog breeder had suffered from unclassified polyarthritis for four years. During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and Adalimumab he developed severe systemic inflammatory disease with high fever, weight loss, and severe arthralgia. Fever and arthralgias temporarily improved under antibiotic therapy, although a causative organism had not been found.

Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis.

Delivery of free fatty acids to the liver in nonalcoholic fatty liver disease (NAFLD) may render hepatocytes more vulnerable to glycochenodeoxycholic acid (GCDCA)-induced apoptosis. Fat overloading was induced in HepG2-Ntcp cells and primary rat hepatocytes by incubation with palmitic or oleic acid. Apoptosis was quantified by measuring caspase 3/7 activity and transcription of interleukin (IL) 8 and IL-22 by quantitative real-time PCR.

Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer.

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m(-2) bid on days 1-14 and oxaliplatin 130 mg m(-2) on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m(-2) bid on days 22-35 and 43-56, and oxaliplatin 50 mg m(-2) on days 22, 29, 43 and 50).

Role of mitogen-activated protein kinases in tauroursodeoxycholic acid-induced bile formation in cholestatic rat liver.

Aim: Ursodeoxycholic acid exerts anticholestatic effects in various cholestatic disorders and experimental models of cholestasis. Its taurine conjugate (TUDCA) stimulates bile salt secretion in isolated perfused rat livers (IPRL) under physiological, non-cholestatic conditions, in part by mitogen-activated protein kinase (MAPK)-dependent mechanisms. The role of MAPK in the anticholestatic effect of TUDCA, however, is unclear.

High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective.

Background/aims: Ursodeoxycholic acid (UDCA) has been shown to improve serum liver tests in primary sclerosing cholangitis (PSC), but controlled trials have shown inconsistent effects on liver histology, and did not reveal a survival benefit. This pilot, randomised dose-ranging trial attempted to determine whether further enrichment of the bile acid pool with UDCA would lead to an improvement in outcome for PSC patients.

Methods: Thirty-one patients with PSC were randomised to treatment with either 10 mg/kg (low dose), 20 mg/kg (standard dose) or 30 mg/kg (high dose) daily of UDCA for 2 years.

Tauroursodeoxycholic acid reduces bile acid-induced apoptosis by modulation of AP-1.

Ursodeoxycholic acid (UDCA) is used in the therapy of cholestatic liver diseases. Apoptosis induced by toxic bile acids plays an important role in the pathogenesis of liver injury during cholestasis and appears to be mediated by the human transcription factor AP-1. We aimed to study if TUDCA can decrease taurolitholic acid (TLCA)-induced apoptosis by modulating AP-1.

Innovative dietary sources of n-3 fatty acids.

It is now established that dietary n-3 polyunsaturated fatty acids (PUFAs) are involved in health promotion and disease prevention, particularly those traditionally derived from marine sources (e.g., eicosapentaenoic acid and docosahexaenoic acid).

[A 67-year-old patient with somnolence and severe hyponatraemia].

A 67-year-old female patient with known depression was admitted to the intensive care unit with severe hyponatraemia (105 mmol/l) and somnolence caused by inadequate antidiuretic hormone secretion (SIADH) syndrome after starting therapy with the selective serotonin reuptake inhibitor (SSRI) Citalopram. This medication was stopped, and the hyponatraemia was carefully treated with fluid restriction and diuretics. Seven days later, the patient was discharged to a psychiatric ward with normal sodium levels and markedly improved vigilance.

Phenotypic traits of the hypothalamic PVN cells innervating airway-related vagal preganglionic neurons.

The paraventricular nucleus of the hypothalamus (PVN) integrates multiple inputs via projections from arginine vasopressin (AVP)- and oxytocin (OXT)-containing neurons to the brain stem and spinal cord as well as regulates respiratory and cardiovascular stress-related responses, which also affect airway function. In the present study, we used immunocytochemistry and the retrograde transneuronal tracer, Bartha strain of pseudorabies virus expressing green fluorescent protein (PRV-GFP), to localize AVP- and OXT-producing neurons that project to airway-related vagal preganglionic neurons (AVPNs) innervating intrapulmonary airways. PRV-GFP was microinjected into the upper right lung lobe, and after 4 days survival, hypothalamic tissue sections were processed for co-expression of PRV-GFP and AVP or PRV-GFP and OXT.