ABSTRACT
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.
Subject(s)
Chemical and Drug Induced Liver Injury/drug therapy , Liver Failure/drug therapy , Liver/drug effects , Rifampin/therapeutic use , ATP Binding Cassette Transporter, Subfamily B, Member 11 , ATP-Binding Cassette Transporters/genetics , Adenosine Triphosphatases/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Bilirubin/blood , Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/physiopathology , Cholestasis/complications , Cholestasis/therapy , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inducers/pharmacology , Female , Genetic Predisposition to Disease , Glucuronosyltransferase/genetics , Glucuronosyltransferase/metabolism , HT29 Cells , Hep G2 Cells , Humans , Liver/enzymology , Liver/metabolism , Liver Failure/diagnosis , Liver Failure/etiology , Liver Failure/physiopathology , Male , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Middle Aged , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Mutation , Pregnane X Receptor , Receptors, Steroid/agonists , Receptors, Steroid/genetics , Receptors, Steroid/metabolism , Risk Factors , Severity of Illness Index , Treatment Outcome , Up-Regulation , Young AdultABSTRACT
OBJECTIVES: Asynchronous learning, using Web-based instruction, is developing a growing role in medical education. Restrictions on resident work hours continue to require restructuring of formal educational activities in many programs. The objectives of this curriculum development project was to determine whether using blended learning with case-based online modules supplemented by faculty-facilitated case discussion was effective and well received. METHODS: The pediatric gastroenterology curriculum, completed during a 4-week subspecialty rotation, consists of 8 case-based online modules and four 1-hour didactic sessions. The curriculum was pilot tested using a 1-group, pretest/posttest design as well as a survey to assess both knowledge acquisition and learner satisfaction. Resident evaluations of the rotation were examined during a 4-year pre- and postimplementation period. RESULTS: Twenty-one learners participated in pilot testing of the curriculum. After completing the curriculum, there was a significant improvement in post-test medical knowledge scores (pretest 73%, posttest 92%, P < 0.001). The satisfaction survey showed that learners were highly satisfied with the course format, and this teaching method was actually preferred to more traditional methods of teaching. Pilot learners reported increased comfort in caring for patients with gastrointestinal complaints. Evaluations of the gastroenterology rotation improved significantly across multiple domains in the years after implementation of the curriculum. CONCLUSIONS: This curriculum, which uses online teaching reinforced by faculty-facilitated case discussion, was both effective and well received by learners. The implementation of this curriculum appears to have had sustained beneficial effects on the learning environment beyond the simple acquisition of medical knowledge.
