Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

Health-related quality of life in patients with primary sclerosing cholangitis: A longitudinal population-based cohort study.

BACKGROUND & AIMS: Data regarding health-related quality of life (HRQoL) in primary sclerosing cholangitis (PSC) are sparse and have only been studied cross-sectionally in a disease which runs a fluctuating and unpredictable course. We aim to describe HRQoL longitudinally by using repeated measurements in a population-based cohort. METHODS: Every 3 months from May 2017 up to August 2020, patients received digital questionnaires at home. These included the EQ-5D, 5-D Itch, patient-based SCCAI and patient-based HBI. The SF-36, measuring HRQoL over eight dimensions as well as a physical component summary (PCS) and mental component summary (MCS) score, was sent annually. Data were compared with Dutch reference data and a matched IBD disease control from the population-based POBASIC cohort. Mixed-effects modelling was performed to identify factors associated with HRQoL. RESULTS: Three hundred twenty-eight patients completed 2576 questionnaires. A significant reduction of small clinical relevance in several mean HRQoL scores was found compared with the Dutch reference population: 46.4 versus 48.0, p = .018 for PCS and 47.5 versus 50.5, p = .004 for MCS scores. HRQoL outcomes were significantly negatively associated with coexisting active IBD (PCS -12.2, p < .001 and MCS -12.0, p < .001), which was not the case in case of quiescent IBD. Decreasing HRQoL scores were also negatively associated with increasing age (PCS -0.1 per 10 years, p = .002), female sex (PCS -2.8, p < .001), diagnosis of AIH overlap (PCS -3.7, p = .059), end-stage liver disease (PCS -3.7, p = .015) and presence of itch (PCS -9.2, p < .001 and MCS -3.1, p = .078). The odds of reporting a clinically relevant reduction in EQ-5D scores showed seasonal variation, being lowest in summer (OR = 0.48 relative to spring, p = .037). In patients with liver transplant, HRQoL outcomes were comparable to the Dutch general population. CONCLUSIONS: PSC patients report impaired HRQoL of small clinical relevance compared with the general population. After liver transplantation, HRQoL scores are at comparable levels to the general population. HRQoL scores are associated with potentially modifiable factors such as itch and IBD activity.

Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial.

BACKGROUND: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.

Self-supervised neural network improves tri-exponential intravoxel incoherent motion model fitting compared to least-squares fitting in non-alcoholic fatty liver disease.

Recent literature suggests that tri-exponential models may provide additional information and fit liver intravoxel incoherent motion (IVIM) data more accurately than conventional bi-exponential models. However, voxel-wise fitting of IVIM results in noisy and unreliable parameter maps. For bi-exponential IVIM, neural networks (NN) were able to produce superior parameter maps than conventional least-squares (LSQ) generated images. Hence, to improve parameter map quality of tri-exponential IVIM, we developed an unsupervised physics-informed deep neural network (IVIM3-NET). We assessed its performance in simulations and in patients with non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R 2. IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with a significant increase in average parameter-map SNR from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R 2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM3-NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology similar to the bi-exponential neural network fit, while generating potentially complementary additional parameters.

Functional assessment of liver regeneration after major hepatectomy.

Background: Liver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver stiffness after major liver resection and their correlation with postoperative outcomes. Methods: Patients undergoing major liver resection (≥3 segments) between February and November 2018 underwent both functional assessment using technetium-99m mebrofenin hepatobiliary scintigraphy (HBS) and CT-volumetry of the (future) remnant liver on preoperative day 1, the 5th postoperative day, and 4-6 weeks after resection. At the same time points, patients underwent transient elastography (TE) for the assessment of liver stiffness. Severe postoperative complications (Clavien-Dindo ≥ 3A) and mortality were correlated with the functional and volumetric increases of the remnant liver. Liver failure was graded according to the International Study Group of Liver Surgery (ISGLS) criteria. Results: A total of 18 patients were included of whom 10 (56%) had severe complications and one patient (5%) developed liver failure. Function and volume of the remnant liver had increased by the 5th postoperative day from 6.9 (5.4-10.9) to 9.6 (6.7-13.8) %/min/m2, P=0.004 and from 795.5 (538.3-1,037.5) to 1,080.0 (854.0-1,283.3) mL, P<0.001, respectively. After 4-6 weeks, remnant liver volume had further increased [from 1,080.0 (854.0-1,283.3) to 1,222.0 (1,016.0-1,380.5) mL, P=0.035], however, liver function did not show any significant, further increase [from 9.6 (6.7-13.8) to 10.9 (8.8-13.6) %/min/m2, P=0.177]. Liver elasticity of the future remnant liver (FRL) increased [from 10.8 (5.7-18.7) to 17.5 (12.4-22.6) kPa, P=0.018] and gradually recovered after 4-6 weeks to a median of 10.9 (5.7-18.8) kPa (T3 vs. T4, P=0.079). Patients who had severe postoperative complications did not show a significant increase in liver function on the 5th postoperative day (P=0.203), despite increase of volume (P<0.01). Conclusions: Functional regeneration of the remnant liver predominantly occurs during the first 5 days after resection. In case of severe complications, functional regeneration is delayed, in contrast to volume increase.

Assessment of Imaging Modalities Against Liver Biopsy in Nonalcoholic Fatty Liver Disease: The Amsterdam NAFLD-NASH Cohort.

BACKGROUND: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD. PURPOSE: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores. STUDY TYPE: Prospective, cohort. POPULATION: Thirty-seven patients with NAFLD. FIELD STRENGTH/SEQUENCE: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence. ASSESSMENT: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFFMRS ), magnitude-based MRI (PDFFMRI-M ), and three-point Dixon (PDFFDixon ), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH). STATISTICAL TESTS: Spearman's rank test, Kruskal-Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value <0.05 was considered statistically significant. RESULTS: Histological steatosis grade correlated significantly with PDFFMRS (rs  = 0.66, P < 0.001), PDFFMRI-M (rs  = 0.68, P < 0.001), and PDFFDixon (rs  = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (rs  = 0.55, P < 0.001, rs  = -0.40, P = 0.016, rs  = -0.37, P = 0.027, respectively) and fibrosis (rs  = 0.55, P < 0.001, rs  = -0.46, P = 0.0051; rs  = -0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area-under-the-curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). DATA CONCLUSION: Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: 2.

Cholestasis-Associated Pruritus and Its Pruritogens.

Pruritus is a debilitating symptom of various cholestatic disorders, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and inherited progressive familial intrahepatic cholestasis (PFIC). The molecular mechanisms leading to cholestasis-associated pruritus are still unresolved and the involved pruritogens are indecisive. As a consequence of pruritus, patients suffer from sleep deprivation, loss of daytime concentration, auto-mutilation and sometimes even suicidal ideations. Current guideline-approved therapy of cholestasis-associated pruritus includes stepwise administration of several medications, which may alleviate complaints in some, but not all affected patients. Therefore, also experimental therapeutic approaches are required to improve patients' quality of life. This article reviews the current state of research on pruritogens and their receptors, and shortly discusses the most recent experimental therapies.

Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid.

: In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.

Donor Fecal Microbiota Transplantation Alters Gut Microbiota and Metabolites in Obese Individuals With Steatohepatitis.

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis.

Stress test of liver function using technetium-99m-mebrofenin hepatobiliary scintigraphy.

Technetium-99m (Tc) mebrofenin hepatobiliary scintigraphy (HBS) enables a quantitative assessment of liver function. This is normally performed in a fasting state and might therefore reflect the resting liver function. We evaluated the change in liver function using HBS after stimulation with an oral metabolic challenge. Healthy volunteers aged 50-60 (n=12) or older than or equal to 75 (n=12) years underwent two sequential HBS. The first scan was performed after an overnight fast and the second scan was performed after the administration of chocolate milk. Hepatic Tc-mebrofenin uptake rate (cMUR) was calculated and the difference was expressed as percentage. cMUR after fasting was 10.9±2.5%/min/m (mean±SD) and increased by 20% to 13.0±3.1%/min/m after stimulation with chocolate milk (P<0.001). cMUR increased markedly after the administration of an oral metabolic challenge in comparison with fasting. This may be a consequence of hepatocyte stimulation, reflecting the hepatic functional reserve capacity.

Enhanced liver fibrosis test predicts transplant-free survival in primary sclerosing cholangitis, a multi-centre study.

BACKGROUND & AIMS: Biomarkers reflecting disease activity and prognosis in primary sclerosing cholangitis (PSC) have not been firmly established. Enhanced liver fibrosis (ELF) test was previously reported to predict outcome in PSC. We aimed to validate the prognostic utility of ELF test in an independent, multi-centre, retrospective PSC study population. METHODS: We collected serum samples from PSC patients from seven countries. We estimated rates of transplant-free survival by the Kaplan-Meier method, used Cox proportional hazards regression to explore the association between ELF test and clinical outcome and determined prognostic performance of ELF test by computing the area under the receiver operating characteristic (AUC-ROC) curve. RESULTS: The final analysis included 534 PSC patients (61% males). Features of autoimmune hepatitis or concomitant inflammatory bowel disease affected 44 (8%) and 379 (71%) patients respectively. ELF test levels were higher in patients reaching the combined endpoint liver transplantation or death (median 10.9 [Interquartile range (IQR): 9.8-12.1]; n=24 deaths, 79 liver transplantations) compared to those censored (8.8 [IQR: 8.0-9.8]); P<.001. ELF test expressed as mild, moderate and severe fibrosis was significantly associated with the risk of reaching the endpoint (P<.001). ELF test independently predicted clinical outcome (Hazard ratio 1.31; 95% confidence interval [1.05-1.65]; P=.018), and enabled good discrimination between PSC patients with and without endpoint (AUC-ROC: 0.79). CONCLUSION: Our retrospective data validates the predictive utility of ELF test for clinical outcomes in PSC. The clinical utility of biomarkers for fibrosis in patients with PSC should be assessed in prospective patient cohorts.

PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma.

Novel systemic treatments for hepatocellular carcinoma (HCC) are strongly needed. Immunotherapy is a promising strategy that can induce specific antitumor immune responses. Understanding the mechanisms of immune resistance by HCC is crucial for development of suitable immunotherapeutics. We used immunohistochemistry on tissue-microarrays to examine the co-expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM and IDO, as well as tumor CD8+ lymphocyte infiltration in HCC, in two independent cohorts of patients. We found that at least some expression in tumor cells was seen in 97% of cases for HVEM, 83% for PD-L1, 79% for Gal-9 and 66% for IDO. In the discovery cohort (n = 94), we found that lack of, or low, tumor expression of PD-L1 (p < 0.001), Galectin-9 (p < 0.001) and HVEM (p < 0.001), and low CD8+TIL count (p = 0.016), were associated with poor HCC-specific survival. PD-L1, Galectin-9 and CD8+TIL count were predictive of HCC-specific survival independent of baseline clinicopathologic characteristics and the combination of these markers was a powerful predictor of HCC-specific survival (HR 0.29; p <0.001). These results were confirmed in the validation cohort (n = 60). We show that low expression levels of PD-L1 and Gal-9 in combination with low CD8+TIL count predict extremely poor HCC-specific survival and it requires a change in two of these parameters to significantly improve prognosis. In conclusion, intra-tumoral expression of these immune inhibiting molecules was observed in the majority of HCC patients. Low expression of PD-L1 and Galectin-9 and low CD8+TIL count are associated with poor HCC-specific survival. Combining immune biomarkers leads to superior predictors of HCC mortality.

Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion.

Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

Alkaline phosphatase at diagnosis of primary sclerosing cholangitis and 1 year later: evaluation of prognostic value.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a slowly progressive liver disease. Reliable biomarkers to predict outcome are urgently needed to serve as surrogate endpoints and/or stratifiers in clinical trials. Reduction in serum alkaline phosphatase (ALP) has been proposed as prognostic surrogate marker in PSC. The aim of this study was to asses if ALP at diagnosis (T0), 1 year later (T1), and percentage change between both time points hold prognostic value, and to determine the optimal threshold. METHODS: We retrospectively collected ALP levels at T0 and T1 for patients included in a large PSC cohort. The association of ALP at T0, T1, and percentage change with the combined endpoint (PSC-related death, liver transplantation) was analysed. Predictive value was determined using C-statistics. RESULTS: A total of 366 patients were included, of whom 66 (18%) reached an endpoint: 26 (7%) PSC-related death, 40 (11%) liver transplantation. At T0 and T1, 84% used ursodeoxycholic acid. A positive association was observed between level of ALP at T0 and T1 and the hazard of reaching an endpoint, up to values around 2.5 times upper limit of normal (xULN). A larger decrease in ALP between T0 and T1 decreased the event rate. A range of thresholds (0.5-3×ULN) with about similar C-statistics was found. In this cohort, the optimal threshold was 1.3×ULN at T1. CONCLUSION: ALP can be used to discriminate between PSC patients with a good and a poor prognosis. These findings indicate that ALP can serve as stratifier, and potentially as surrogate endpoint for clinical trials in PSC.

Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study.

PURPOSE: To (a) study the optimal timing and dosing for ultrasmall superparamagnetic iron oxide particle (USPIO)-enhanced magnetic resonance (MR) imaging of the liver in nonalcoholic fatty liver disease, (b) evaluate whether hepatic USPIO uptake is decreased in nonalcoholic steatohepatitis (NASH), and (c) study the diagnostic accuracy of USPIO-enhanced MR imaging to distinguish between NASH and simple steatosis. MATERIALS AND METHODS: This prospective study was approved by the local institutional review board, and informed consent was obtained from all patients. Quantitative R2* MR imaging of the liver was performed at baseline and 72 hours after USPIO administration in patients with biopsy-proven NASH (n = 13), hepatic steatosis without NASH (n = 11), and healthy control subjects (n = 9). The hepatic USPIO uptake in the liver was quantified by the difference in R2* (ΔR2*) between the contrast material-enhanced images and baseline images. Between-group differences in mean ΔR2* were tested with the Student t test, and diagnostic accuracy was tested by calculating the area under the receiver operating characteristic curve. RESULTS: Patients with NASH had a significantly lower ΔR2* 72 hours after USPIO administration when compared with patients who had simple steatosis and healthy control subjects (mean ± standard deviation for patients with NASH, 37.0 sec(-1) ± 16.1; patients with simple steatosis, 61.0 sec(-1) ± 17.3; and healthy control subjects, 72.2 sec(-1) ± 22.0; P = .006 for NASH vs simple steatosis; P < .001 for NASH vs healthy control subjects). The area under the receiver operating characteristic curve to distinguish NASH from simple steatosis was 0.87 (95% confidence interval: 0.72, 1.00). CONCLUSION: This proof-of-concept study provides clues that hepatic USPIO uptake in patients with NASH is decreased and that USPIO MR imaging can be used to differentiate NASH from simple steatosis.

The Long-Term Impact of Autoimmune Pancreatitis on Pancreatic Function, Quality of Life, and Life Expectancy.

OBJECTIVE: To evaluate the long-term outcome of autoimmune pancreatitis. METHODS: Patients with at least 2 years of follow-up were included. Information was collected regarding disease characteristics, treatment outcome, diagnosed malignancies, and mortality. In addition, pancreatic function and quality of life were assessed prospectively. RESULTS: 107 patients were included (87% men, 90% with type 1), with a median follow-up of 74 (interquartile range, 49-108) months. One third was operated for suspected pancreatic cancer (32%). Most patients were (successfully) treated with steroids (83%), but relapses were common (52%), for which no risk factors could be identified. Pancreatic carcinoma was not observed.Prospective data were obtained from 64%, as 17% had died, 7% were lost to follow-up, and 13% refused to participate. After a median of 75 (interquartile range, 50-106) months, 46% still used active treatment. Exocrine and endocrine insufficiencies were highly prevalent (82% and 57%, respectively). Quality of life and survival were not impaired, as compared with a reference population. CONCLUSIONS: Despite an excellent initial treatment response, relapses are common, even in type 2, and almost half of the patients require maintenance therapy. Pancreatic insufficiency is highly prevalent, which calls for active screening. Pancreatic cancer was not observed, and quality of life and survival are not impaired.

[A child with primary sclerosing cholangitis]. / Een kind met primaire scleroserende cholangitis.

BACKGROUND: Primary sclerosing cholangitis is a rare liver disease which is mainly diagnosed in adults. This chronic progressive disease, characterised by inflammation, fibrosis and strictures of the intra- and extrahepatic bile ducts, leads to cirrhosis. There is a strong association between primary sclerosing cholangitis and inflammatory bowel disease (IBD). CASE DESCRIPTION: A 10-year-old boy presented at the accident and emergency department with fever, episodes of abdominal pain, nausea, vomiting, fatigue and hepatomegaly. Blood tests, pathology investigations, liver biopsy and magnetic resonance cholangiopancreatography (MRCP) led to the diagnosis of primary sclerosing cholangitis. The patient was treated with ursodeoxycholic acid and later, because of unbearable itching, sequentially with lidocaine 3% ointment, rifampicin, an endoprosthesis in the common bile duct and glucocorticoids. One year later he returned to the paediatrician with abdominal pain and bloody diarrhoea. Endoscopy revealed features of indeterminate colitis. Remission of the disease was achieved quickly after treatment with mesalazine. CONCLUSION: Primary sclerosing cholangitis can develop in childhood and is often associated with IBD.

Lysophosphatidic acid and signaling in sensory neurons.

Lysophosphatidic acid is a potent signaling lipid molecule that has initially been characterized as a growth factor. However, later studies have revealed many more functions such as modulation of cell shape, cell migration, prevention of apoptosis, platelet aggregation, wound healing, osteoclast differentiation, vasopressor activity, embryo implantation, angiogenesis, lung fibrosis, hair growth and more. The molecule mainly acts through the activation of a set of at least 6 G-protein-coupled receptors (LPA1-6), but intracellular LPA was also shown to signal through the activation of the nuclear receptor PPARγ. In this short review we discuss the recent observations which suggest that in pathological conditions LPA also modulates signaling in sensory neurons. Thus, LPA has been shown to play a role in the initiation of neuropathic pain and, more recently, a relation was observed between increased LPA levels in the circulation and cholestatic itch. The mechanism by which this occurs remains to be elucidated. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.

Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands.

BACKGROUND AND AIMS: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS: The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.