[Opportunities and risks of advance directives : An appraisal of the practice in Germany after legal regulation in 2009]. / Chancen und Risiken der Patientenverfügung : Eine Bestandsaufnahme nach der gesetzlichen Regelung 2009.

BACKGROUND: Living wills/advance directives (AD) are an important tool for specifying patient wishes regarding medical care in the case of future inability to consent. Since 2009, German legislation defines framework conditions for the creation and validity of such directives in § 1901a BGB. METHODS: An extensive literature search in an international and a German-language database was conducted to identify, analyze, and evaluate scientific articles on opportunities, risks, and problems in the creation and implementation of living wills. RESULTS: Between 10 and 40% of patients have an AD. Among the stipulations in the AD, the demand for sufficient pain therapy is very important. However, numerous problems in the preparation and implementation of ADs reduce their value in everyday clinical practice. In particular, unclear conditions of validity, unspecific instructions for action, and lack of availability of the directives prevent practitioners from determining the patient's will. Other fundamental problems include frequent patient ambivalence and clinical ethical dissent. In addition, the framework condition of unlimited coverage set by the law carries the risk that changes of opinion in the course of life or disease are not taken into account. CONCLUSION: Preparing an AD requires a high level of information, consultation, and time, as well as regular review or adjustment of its content. These factors are often not considered, thus complicating implementation and reducing the value of living wills. Possible solutions to these problems or alternative concepts for different patient settings are discussed in this review.

Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier?

The pandemics of coronavirus disease 2019 (COVID-19) and non-alcoholic fatty liver disease (NAFLD) coexist. Elevated liver function tests are frequent in COVID-19 and may influence liver damage in NAFLD, while preexisting liver damage from NAFLD may influence the course of COVID-19. However, the prognostic relevance of this interaction, though, is unclear. Obesity is a risk factor for the presence of NAFLD as well as a severe course of COVID-19. Cohort studies reveal conflicting results regarding the influence of NAFLD presence on COVID-19 illness severity. Striking molecular similarities of cytokine pathways in both diseases, including postacute sequelae of COVID-19, suggest common pathways for chronic low-activity inflammation. This review will summarize existing data regarding the interaction of both diseases and discuss possible mechanisms of the influence of one disease on the other.

Aloe Vera-Containing Matrix in Transdermal Fentanyl Therapy Improves Adhesion, Skin Tolerance and Quality of Life: Results of a German Multicenter Study with a New Fentanyl Patch.

BACKGROUND: Chronic pain represents a significant and costly healthcare problem especially in the older patient. Transdermal opioid therapy is easy to apply and ensures constant supply of active ingredients. However, skin irritation, poor adhesion and systemic side effects complicate transdermal pain therapy. METHODS: In the Relief study, comprising 54 centers, all in Germany, 252 patients were recruited and data about the general care situation as well as the characteristics, effects and side effects of the Aloe vera fentanyl patch were collected. 92 patients had a prior treatment with fentanyl patch without Aloe vera, allowing a comparative analysis. RESULTS: Compared to patches without Aloe vera, the new fentanyl patch showed better adhesion. Systemic and local tolerance and pain reduction were also significantly better. Patients also reported improvements in side effects and central parameters of quality of life. The data regarding the care situation in Germany showed remarkably low use of coanalgetics and laxatives in pain patients. DISCUSSION: Aloe vera in transdermal pain treatment improves adhesion and local tolerance of the patch. Pain control and quality of life were also improved. Regional care data concerning cotreatment in pain therapy from this study indicate a lack of penetration of existing guidelines in general practitioners' pain therapy.

Intake of Acetylsalicylic Acid and High Age Are Risk Factors for Iron Deficiency Anemia in Patients with Large Diaphragmatic Hernias.

INTRODUCTION: In 15% of patients with iron deficiency anemia, large diaphragmatic hernias are found as the cause of chronic iron loss. Conversely, iron deficiency anemia is present in 10-40% of diaphragmatic hernia patients. However, it is unclear why some patients with large diaphragmatic hernias develop anemia and others do not. METHODS: We retrospectively analyzed 116 patients with diaphragmatic hernias larger than 5 cm for the presence of anemia and the effect of surgery on this anemia, dividing these patients into 4 groups (group A: 21 patients with anemia/surgery, group B: 27 patients without anemia but with surgery, group C: 34 patients with anemia but without surgery, and group D: 34 patients without anemia/surgery). RESULTS: Women significantly predominated in the patient population (76%). Patients with iron deficiency anemia tended to be significantly older than patients without iron deficiency anemia (74.7 ± 12.2 vs. 69.6 ± 14.8 years, p = 0.08). The proportion of patients taking ASA was significantly higher in the anemia collective (41.8% vs. 9.8%, p < 0.001). Regression analysis further confirmed that higher age and ASA intake correlated significantly with lower hemoglobin in anemic patients. Performing hernia repair significantly decreased anemia rates and PPI use in the anemia patients, while both remained almost the same in the non-operated anemia patients. CONCLUSION: ASA use and advanced age are risk factors for the presence of iron deficiency anemia in patients with large diaphragmatic hernias. Surgical hernia repair is suitable to reduce anemia.

Screening for nonalcoholic fatty liver disease-when, who and how?

Nonalcoholic fatty liver disease (NAFLD) is becoming a frequent liver disease, especially in patients with metabolic syndrome and especially in Western countries. Complications of NAFLD comprise progressive fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD also represents an independent risk factor for cardiovascular disease, extrahepatic neoplasia and other organ damage, such as renal insufficiency. Given the epidemiological importance of the disease, new developments in specific treatment of the disease and the wide availability of noninvasive techniques in estimating steatosis and fibrosis, NAFLD should be subject to screening programs, at least in countries with a high prevalence of the disease. The review discusses prerequisites for screening, cost-effectiveness, current guideline recommendations, suitability of techniques for screening and propositions for the following questions: Who should be screened? Who should perform screening? How should screening be performed? It is time for a screening program in patients at risk for NAFLD.

Paraesophageal hernia and iron deficiency anemia: Mechanisms, diagnostics and therapy.

There is ample clinical evidence suggesting that the presence of large axial or paraesophageal hernias may lead to iron deficiency anemia. So-called Cameron lesions, as well as other small mucosa erosions, in the sliding area of these diaphragmatic hernias lead to invisible chronic blood loss and consequently to iron depletion. While the spectrum of symptoms in these patients is large, anemia is often not the only indication and typically not the primary indication for surgical correction of diaphragmatic hernias. Drug treatment with proton pump inhibitors and iron substitution can alleviate anemia, but this is not always successful. To exclude other possible bleeding sources in the gastrointestinal tract, a comprehensive diagnostic program is necessary and reviewed in this manuscript. Additionally, we discuss controversies in the surgical management of paraesophageal hernias.

Primary presentation of COVID-19 solely with gastrointestinal symptoms: a problem for the containment of the disease.

An oligosymptomatic patient with initially exclusively gastrointestinal symptoms (massive nausea and mild pancreatitis) turned out to suffer from COVID-19 during the hospital stay. The patient did not exhibit the typical COVID-symptoms cough or fever despite lung involvement. The gastroenterological diagnostic investigations comprised abdominal ultrasound, gastroscopy and endoscopic ultrasound and first revealed no clear cause of these symptoms. In an abdominal computed tomography (CT) scan, patchy ground-glass opacities in both lungs were discovered and the following chest CT scan and a virus PCR test revealed the right and surprising diagnosis. This case report depicts the clinical course of this atypical case and discusses gastrointestinal COVID-manifestations and clinical consequences as well as consequences of this atypical presentation for disease control.

Percutaneous endoscopic gastrostomy - Too often? Too late? Who are the right patients for gastrostomy?

Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories. Here, we review the methods, indications and complications of this procedure. While gastrostomy can be safely and easily performed during gastroscopy, the right patients and timing for this intervention are not always chosen. Especially in patients with dementia, the indication for and timing of gastrostomies are often improper. In this patient group, clear data for enteral nutrition are lacking; however, some evidence suggests that patients with advanced dementia do not benefit, whereas patients with mild to moderate dementia might benefit from early enteral nutrition. Additionally, other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength. We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.

The "Aachen sings" study ("Aachen choir engagement study into GERD symptoms"): moderate singing and breathing exercises in a choir reduce reflux symptoms - a cohort study in non-specialist choristers.

BACKGROUND: The influence of singing activities and breathing exercises on the presence of gastroesophageal reflux disease (GERD) symptoms is not clear. While an Austrian study found symptom reduction, an Italian study showed more symptoms in professional opera choristers. These contradictory results may be due to differential intensity of the singing exercises. We therefore developed a questionnaire to investigate the presence of GERD typical symptoms and defined GERD in nonprofessional choristers with moderate singing activity and breathing exercises and compared the results to those from related non-singing control persons. METHODS: 434 actively engaged lay-choir persons and 310 non-singing friends or relatives answered questions in a questionnaire regarding basic data, singing habits, GERD symptoms, and past or present diagnostic events and medications. RESULTS: Non-singing control persons experienced more frequently heartburn (1.1 ±â€Š4.1 vs. 0.5 ±â€Š1.2 episodes/week, p = 0.001) and acid regurgitation (0.9 ±â€Š4.1 vs. 0.5 ±â€Š1.3 episodes/week, p < 0.001) and had more often already received the diagnosis of GERD (16.8 % vs. 10.4 %, p = 0.011). From the persons without known GERD, members of the control cohort more often fulfilled the simplified diagnostic criteria of GERD (14.3 % vs. 5.1 %, p < 0.001). A multivariate analysis identified non-singing, high body mass index, and smoking as significant risk factors for the presence of GERD symptoms. CONCLUSION: The frequency of reflux symptoms and GERD is probably still increasing. Moderate singing activities and breathing exercises seem to be helpful in avoiding reflux symptoms such as heartburn and acid regurgitation.

Changes in drug transport and metabolism and their clinical implications in non-alcoholic fatty liver disease.

INTRODUCTION: The incidence of non-alcoholic fatty liver disease (NAFLD) is rising, especially in Western countries. Drug treatment in patients with NAFLD is common since it is linked to other conditions like diabetes, obesity, and cardiovascular disease. Consequently, changes in drug metabolism may have serious clinical implications. Areas covered: A literature search for studies in animal models or patients with obesity, fatty liver, non-alcoholic steatohepatitis (NASH) or NASH cirrhosis published before November 2016 was performed. After discussing epidemiology and animal models for NAFLD, we summarized both basic as well as clinical studies investigating changes in drug transport and metabolism in NAFLD. Important drug groups were assessed separately with emphasis on clinical implications for drug treatment in patients with NAFLD. Expert opinion: Given the frequency of NAFLD even today, a high degree of drug treatment in NAFLD patients appears safe and well-tolerated despite considerable changes in hepatic uptake, distribution, metabolism and transport of drugs in these patients. NASH causes changes in biliary excretion, systemic concentrations, and renal handling of drugs leading to alterations in drug efficacy or toxicity under specific circumstances. Future clinical drug studies should focus on this special patient population in order to avoid serious adverse events in NAFLD patients.

Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance.

Liver cirrhosis is the common endpoint of many hepatic diseases and represents a relevant risk for liver failure and hepatocellular carcinoma. The progress of liver fibrosis and cirrhosis is accompanied by deteriorating liver function. This review summarizes the regulatory and functional changes in phase I and phase II metabolic enzymes as well as transport proteins and provides an overview regarding lipid and glucose metabolism in cirrhotic patients. Interestingly, phase I enzymes are generally downregulated transcriptionally, while phase II enzymes are mostly preserved transcriptionally but are reduced in their function. Transport proteins are regulated in a specific way that resembles the molecular changes observed in obstructive cholestasis. Lipid and glucose metabolism are characterized by insulin resistance and catabolism, leading to the disturbance of energy expenditure and wasting. Possible non-invasive tests, especially breath tests, for components of liver metabolism are discussed. The heterogeneity and complexity of changes in hepatic metabolism complicate the assessment of liver function in individual patients. Additionally, studies in humans are rare, and species differences preclude the transferability of data from rodents to humans. In clinical practice, some established global scores or criteria form the basis for the functional evaluation of patients with liver cirrhosis, but difficult treatment decisions such as selection for transplantation or resection require further research regarding the application of existing non-invasive tests and the development of more specific tests.

Commercially available probiotic drinks containing Lactobacillus casei DN-114001 reduce antibiotic-associated diarrhea.

AIM: To investigate the effect of Lactobacillus-containing commercially available probiotic formulations in Germany during antibiotic treatment with an analysis of cost-efficiency. METHODS: In an observational study, we analyzed the frequency of bowel movements from 258 patients with infections in a primary care hospital in western Germany; 107 of the patients were offered a probiotic drink containing at least 10 billion cultures of Lactobacillus casei DN 114001 b.i.d. The economic analysis was based on the costs of patient isolation vs preventive intake of probiotics. In a second pilot study, two commercially available probiotic drinks with different Lactobacillus casei strains were directly compared in 60 patients in a randomized controlled fashion. RESULTS: In the first study, the incidence of antibiotic-associated diarrhea (AAD) was significantly reduced in the intervention group (6.5% vs 28.4%), and the duration of AAD in days was significantly shorter (1.7 ± 1.1 vs 3.1 ± 2.1). Higher age and creatinine and lower albumin were identified as risk factors for AAD. Ampicillin was the antibiotic with the highest rate of AAD (50%) and with the greatest AAD reduction in the probiotic group (4.2%, relative risk reduction 92%). The economic analysis showed a cost advantage of nearly 60000 €/year in a department of this size. The second study confirmed the preventive effect of the drink with Lactobacillus casei DN114001; however, there were no advantages found for the other tested probiotic drink containing Lactobacillus casei Shirota. CONCLUSION: In contrast to a drink containing Lactobacillus casei Shirota, a commercially available probiotic drink containing Lactobacillus casei DN 114001 cost-efficiently reduces the prevalence of AAD during antibiotic treatment.

Effect of drug transporter pharmacogenetics on cholestasis.

INTRODUCTION: The liver is the central place for the metabolism of drugs and other xenobiotics. In the liver cell, oxidation and conjugation of compounds take place, and at the same time, bile formation helps in extrusion of these compounds via the biliary route. A large number of transporters are responsible for drug uptake into the liver cell and excretion into bile or efflux to the sinusoidal blood. AREAS COVERED: Genetic variants of these transporters and their transactivators contribute to changes in drug handling and are also responsible for cholestatic syndromes of different severity. This review summarizes the current knowledge regarding the influence of these genetic changes. The review covers progressive hereditary cholestatic syndromes as well as recurrent or transient cholestatic syndromes such as drug-induced liver injury, intrahepatic cholestasis of pregnancy, and benign recurrent intrahepatic cholestasis. EXPERT OPINION: Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.

Sedation-associated complications in endoscopy are not reduced significantly by implementation of the German S-3-guideline and occur in a severe manner only in patients with ASA class III and higher.

INTRODUCTION: The German guideline for sedation in gastrointestinal endoscopy was published in 2008. Several recommendations in this guideline, especially concerning staffing and structural requirements for sedation, have low evidence and therefore are subject to discussion in the field. AIM: Comparison of endoscopic complications in a department specialized for gastrointestinal and pulmological diseases before and after implementation of the German guideline grouped in sedation-associated and non-sedation-associated complications. METHODS: Prospective documentation of complications with retrospective analysis of two patient groups (before guideline: 1.5.2008-30.4.2010; after guideline: 1.5.2010-30.4.2012) at which the sedation technique remained the same (balanced propofol sedation, BPS). RESULTS: Both investigation periods covered almost 7000 procedures. Interventional and general complications were nonsignificantly elevated in the latter group (1.27% before vs. 1.55% after guideline, p = 0.08). Saturation decline (in both groups 0.26%) was unchanged, and circulation-associated complications (0.27% vs. 0.13%, p = 0.07) were reduced nonsignificantly. Necessity for the administration of flumazenil and for intensive care monitoring was reduced in a nonsignificant manner after the implementation of the guideline. Severe complications (reanimation, apnea, and death) were unchanged, and no patient with ASA I-II suffered from a severe complication. Propofol consumption was higher after guideline implementation. CONCLUSIONS: The recommendations of the new German sedation guideline do not significantly reduce complications in endoscopic procedures. Especially, procedures involving patients with ASA classes I and II do not require an additional staff member solely for sedation. Prospective randomized studies might be necessary to optimize the utilization of resources.

Efficacy of submucosal injection of different solutions inclusive blood components on mucosa elevation for endoscopic resection.

BACKGROUND: Endoscopic resection has become the standard treatment for noninvasive gastrointestinal malignancies. In flat mucosal tumors, normal saline is frequently used for submucosal fluid injection in order to reduce the risk of complications during endoscopic resection. Recent studies have demonstrated longer-lasting mucosa elevation by injection of agents such as hyaluronic acid or glyceol, rather than normal saline. We investigated the efficacy of different blood components in comparison with other solutions for use as a submucosal fluid cushion. METHODS: Normal saline, sodium hyaluronate, glyceol, hydroxyethyl starch, serum, plasma, and whole blood were evaluated for their effectiveness in creating a submucosal cushion. One milliliter of each solution was injected into the submucosa of 5 × 5 cm specimens of resected porcine stomach. Mucosa elevation was measured before and up to 60 minutes after injection. RESULTS: The shortest duration of mucosa elevation was observed after injection of normal saline, glyceol, and 0.125% hyaluronic acid. A significantly longer duration was obtained after injection of hydroxyethyl starch, 0.25% and 0.5% hyaluronic acid, serum, and plasma. However, whole blood generated a longer-lasting mucosa elevation than all other agents. CONCLUSION: The results of the current study suggest that whole blood is more effective in generating long-lasting mucosa elevation than any other commonly used solution. Because autologous blood is readily available at almost no cost, this seems to be an optimal agent for creating the mucosa elevation needed for endoscopic resection. Further in vivo studies in humans are needed to clarify the potential role of autologous blood for long-lasting endoscopic mucosa resection or endoscopic submucosal dissection.

Downregulation of breast cancer resistance protein in colon adenomas reduces cellular xenobiotic resistance and leads to accumulation of a food-derived carcinogen.

Several molecular changes in colorectal adenomas provide the basis of the adenoma-carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 ± 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 ± 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 ± 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1-methyl-6-phenylimidazo[4,5-ß] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 ± 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma.

Origin of and therapeutic approach to cardiac syndrome X: results of the proton pump inhibitor therapy for angina-like lingering pain trial (PITFALL trial).

AIM: To investigate the frequency of gastroenterological diseases in the etiology and the efficacy of proton pump inhibitors (PPIs) in the treatment of cardiac syndrome X (CSX) as a subform of non-cardiac chest pain (NCCP). METHODS: We investigated 114 patients with CSX using symptom questionnaires. A subgroup of these patients were investigated regarding upper gastrointestinal disorders (GIs) and treated with PPI. Patients not willing to participate in investigation and treatment served as control group. RESULTS: Thirty-six patients denied any residual symptoms and were not further evaluated. After informed consent in 27 of the remaining 78 patients, we determined the prevalence of disorders of the upper GI tract and quantified the effect of treatment with pantoprazole. We found a high prevalence of gastroenterological pathologies (26/27 patients, 97%) with gastritis, gastroesophageal reflux disease (GERD) and acid reflux as the most common associated disorders. If treated according to the study protocol, these patients showed a significant improvement in the symptom score. Patients treated by primary care physicians, not according to the study protocol had a minor response to treatment (n = 19, -43%), while patients not treated at all (n = 26) had no improvement of symptoms (-0%). CONCLUSION: Disorders of the upper GI tract are a frequent origin of CSX in a German population and can be treated with pantoprazole if given for a longer period.

Hepatocyte nuclear factor-4alpha is a central transactivator of the mouse Ntcp gene.

Sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake system for conjugated bile acids. Deletions of hepatocyte nuclear factor (HNF)-1alpha and retinoid X receptor-alpha:retinoic acid receptor-alpha binding sites in the mouse 5'-flanking region corresponding to putatively central regulatory elements of rat Ntcp do not significantly reduce promoter activity. We hypothesized that HNF-4alpha, which is increasingly recognized as a central regulator of hepatocyte function, may directly transactivate mouse (mNtcp). A 1.1-kb 5'-upstream region including the mouse Ntcp promoter was cloned and compared with the rat promoter. In contrast to a moderate 3.5-fold activation of mNtcp by HNF-1alpha, HNF-4alpha cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4alpha consensus site at -345/-326 and -335/-316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1alpha but shows a 50-fold enhanced activity upon cotransfection with HNF-4alpha. Gel mobility shift assays demonstrated a complex of the HNF-4alpha-element formed with liver nuclear extracts that was blocked by an HNF-4alpha specific antibody. HNF-4alpha binding was confirmed by chromatin immunoprecipitation. Using Hepa 1-6 cells, HNF-4alpha-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4alpha via a conserved distal cis-element independently of HNF-1alpha.

Extrahepatic cholestasis downregulates Oatp1 by TNF-alpha signalling without affecting Oatp2 and Oatp4 expression and sodium-independent bile salt uptake in rat liver.

Hepatic uptake of bile salts is mediated by sodium-dependent and sodium-independent transport systems. During extrahepatic cholestasis, both the function and the expression of the Na(+)/taurocholate cotransporting polypeptide (Ntcp) are downregulated. To test whether sodium-independent organic anion-transporting polypeptides are also affected by extrahepatic cholestasis, the function and expression of all three Oatps have been determined in common bile duct-ligated (CBDL) rats. Oatp1/Oatp1a1 protein mass remained unchanged after CBDL for 1 day, but then declined by 75+/-7% and 90+/-17%, respectively, after 3 and 7 days. In contrast, Oatp2/Oatp1a4 and Oatp4/Oatp1b2 protein expression was not affected by CBDL as compared with controls. After CBDL, Oatp1 mRNA was rapidly downregulated by 68+/-21% of untreated controls (P<0.05) within 24 h, and remained at similar levels at 3 and 7 days. Cytokine-inactivation studies with etanercept pretreatment demonstrated that TNF-alpha-dependent signals mediated the down-regulation of this transporter gene at both protein and mRNA levels during obstructive cholestasis. Sodium-independent uptake of taurocholate and cholate into freshly isolated hepatocyte suspensions showed neither significant differences in K(m) nor V(max) values. These results indicate that sodium-independent transport of bile salts may be mediated by Oatp2 and 4 during biliary obstruction, because its expression remains unaffected and may compensate for loss of Oatp1 expression and function in cholestatic hepatocytes.