Characterization and treatment of persistent hepatocellular secretory failure.

BACKGROUND & AIMS: Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro. METHODS: Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 µmol/L). RESULTS: Serum bilirubin of patients with PHSF ranged from 264 to 755 µmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 µmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTß. CONCLUSION: Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTß could contribute to the anticholestatic effect of rifampicin in PHSF.

Biliary drainage of the common bile duct with an enteral metal stent.

In this case report we present an elderly patient who was referred to our hospital with recurrent episodes of cholangitis that persisted after placement of five metal stents for a distal common bile duct (CBD) stenosis. All metal stents were endoscopically removed from the CBD by forceps after balloon dilatation of the papilla. A profoundly dilated CBD with sludge and concrements was seen. To ensure adequate bile drainage an enteral metal stent was inserted in the CBD. This case shows that proximally migrated uncovered metal stents in the CBD can be safely removed endoscopically under certain circumstances. We suggest that in the case of a CBD drainage problem due to an extremely dilated CBD, placement of an enteral metal stent in the CBD could be considered, especially in patients who are unfit for surgery.

Immunoglobulin G4-associated cholangitis: one variant of immunoglobulin G4-related systemic disease.

IgG4-associated cholangitis (IAC) is a recently defined disease entity which shares a number of clinical, biochemical, and radiological features with primary sclerosing cholangitis (PSC). In contrast to PSC, IAC responds to immunosuppressive treatment, is not associated with inflammatory bowel disease, and mainly affects elderly men above the age of 60 years. Today, IAC is regarded as one variant of IgG4-related systemic disease (ISD) of which autoimmune pancreatitis (AIP) is the best studied organ manifestation. The diagnosis of IAC is based on biochemical, radiological and histologic features, among which elevated serum levels of IgG4, extra- and intrahepatic biliary strictures as visualized by cholangiography, multifocal IgG4-rich lymphoplasmacytic sclerosing infiltrations in liver and bile duct tissue, and association with AIP are of key importance. This review aims at summarizing clinical features, diagnostic criteria, therapeutic strategies and most recent insights in the pathophysiology of IAC and other organ manifestations of ISD.

Influence of corticotropin-releasing hormone on gastric sensitivity and motor function in healthy volunteers.

BACKGROUND: As stress may be involved in the generation of functional dyspeptic symptoms, we evaluated the effect of the stress hormone, corticotropin-releasing hormone, on proximal stomach function. Twelve healthy volunteers [six women; 23 years (20-26 years)] underwent a barostat study on 2 days. During the infusion of corticotropin-releasing hormone (2.3 microg/kg/h) or saline, a stepwise distension protocol was performed followed by ingestion of a liquid meal (Nutridrink, 200 ml, 300 kcal). RESULTS: Corticotropin-releasing hormone infusion induced a significant increase in cortisol levels and basal volumes compared with placebo. The threshold for discomfort, meal-induced accommodation, dyspeptic symptoms, heart rate and blood pressure were all not significantly altered by corticotropin-releasing hormone infusion. CONCLUSION: In healthy volunteers, peripheral infusion of corticotropin-releasing hormone reduces basal fundic tone, but has no effect on meal-induced accommodation or visceral sensitivity to gastric distension. Our findings suggest that in healthy volunteers, peripheral corticotropin-releasing hormone seems not to be involved in the onset of dyspeptic symptoms.

Noninvasive measurement of gastric accommodation by means of pertechnetate SPECT: limiting radiation dose without losing image quality.

UNLABELLED: The gastric accommodation response to a meal is impaired in conditions such as functional dyspepsia. At present, a barostat study is the gold standard to assess fundic relaxation in response to a meal. However, this method is invasive and possibly induces artifacts as a result of positive intraluminal balloon pressure. A noninvasive scintigraphic test has been developed to measure gastric accommodation in humans. The aim of this study was to refine this method, increasing the imaging time span and limiting the radiation dose applied without losing image quality, so that repeated measurements within 1 subject are possible without increasing radiation risk. METHODS: Thirteen healthy volunteers without gastrointestinal symptoms were recruited from a student population. Each volunteer had previously undergone a barostat study. After an overnight fast, volunteers were scanned twice on separate days after intravenous injection of 200 MBq (99m)Tc-pertechnetate. On 1 occasion, volunteers were pretreated with a proton pump inhibitor. Thirty minutes after injection, sequential, 7-min SPECT scans (72 views, 10 s/view, 128 matrix) were acquired on a dual-head gamma-camera system before and up to 2 h after ingestion of a test meal. After reconstruction (filtered backprojection, ramp-Butterworth filter; order, 10; cutoff, 0.45 Nyquist), fundus volume was calculated semiautomatically by means of a threshold voxel volume tool. RESULTS: Limiting injection dose from 370-740 MBq to 200 MBq (99m)Tc-pertechnetate resulted in good-quality images, with high target-to-background ratio up to 150 min after injection. This represents a significant dose reduction, from 4.6-9.3 to 2.5 mSv. There was no significant difference between SPECT fundic volumes or accommodation response with or without proton pump inhibitor pretreatment. Volume kinetics were similar to those with barostat studies, but gastric volumes were inferior. CONCLUSION: Refining the methodology yields an improved noninvasive test for the assessment of gastric accommodation without unnecessarily increasing radiation burden. This technique enables repeated and serial measurement of gastric accommodation to a test meal, a process that is potentially useful for characterization and follow-up of dyspeptic patients with and without drug intervention.