Active clinical trials for "Cholestasis"

Newborn screening (NBS) is a global initiative of systematic testing at birth to identify babies with pre-defined severe but treatable conditions. With a simple blood test, rare genetic conditions can be easily detected, and the early start of transformative treatment will help avoid severe disabilities and increase the quality of life. Baby Detect Project is an innovative NBS program using a panel of target sequencing that aims to identify 126 treatable severe early onset genetic diseases at birth caused by 361 genes. The list of diseases has been established in close collaboration with the Paediatricians of the University Hospital in Liege. The investigators use dedicated dried blood spots collected between the first day and 28 days of life of babies, after a consent sign by parents.

Intrahepatic cholestasis of pregnancy (ICP) is a disorder characterized by itching, elevated fasting serum bile acids ≥10μmol/L (and elevated serum transaminases), with increased risks of perinatal complications, including spontaneous preterm labor, fetal distress, infant respiratory distress syndrome, meconium-stained liquor (MSL), and sudden intrauterine death (IUD). The Incidence of ICP varies from 0.1 to 15.6% of all pregnancies, with the highest cases in Chile, South Asia, America, and Scandinavia. The burden of ICP in India according to various states is as follows Punjab (3.1%), Chandigarh (4.8%), Delhi (0.79%), West Bengal (3.3%), and Lucknow (Uttar Pradesh) (2.8%).

To verify the effect of feeding milk powder rich in medium chain fatty acids on improving the nutritional status and disease status of infants with cholestatic liver disease and To evaluate the safety of feeding milk powder rich in medium chain fatty acids in infants with cholestatic liver disease.

This observational prospective study will help to determine if an immune process similar to allograft rejection is responsible for the occurrence of an intrahepatic cholestasis of pregnancy (ICP). If so, it would suggest the potential benefit of immunomodulatory therapeutics.

Biliary atresia, idiopathic neonatal hepatitis, and specific genetic cholestatic conditions are the most common causes of jaundice and hyperbilirubinemia that continue beyond the newborn period. The long term goal of the Childhood Liver Disease Research Network (ChiLDReN) is to establish a database of clinical information and plasma, serum, and tissue samples from cholestatic children to facilitate research and to perform clinical, epidemiological and therapeutic trials in these important pediatric liver diseases.

Rationale: Bile salts are potent signalling molecules influencing various metabolic and functional processes. Bile salts exert these functions by activating nuclear (e.g. FXR ) and plasma cell membrane-bound receptors (e.g. TGR5) which are expressed in several tissues (e.g. liver, small intestine, colon, kidney and gallbladder). Bile salts regulate their own biosynthesis by controlling the transcription of the hepatic bile salt synthetic enzyme CYP7A1. Two pathways are involved in the negative feedback control of bile salt synthesis: i) the hepatic FXR-SHP pathway and ii) the ileal FXR-FGF19 pathway. Studies showed that the latter is more prominent in controlling CYP7A1 transcript levels (viz. bile salt synthesis). Thus, bile salts are synthesized in the liver, excreted in bile and expelled by the gallbladder into the proximal intestine (to aid in lipid absorption and digestion) and reabsorbed in the terminal ileum to recycle back to the liver via portal blood. Bile salts reclaimed from the intestinal lumen by the ileocyte, activate FXR. This induces the expression of an enterokine, FGF19, which signals via portal blood to the liver to activate its receptor which initiates downstream signalling to repress bile salt synthesis. The FXR/FGF19 signalling pathway is the subject of the present study. Patients with obstructive cholestasis (=accumulation of bile) caused by malignancies (e.g. pancreatic cancer, cholangiocarcinoma) have a perturbed enterohepatic cycle. Obstructive cholestasis is associated with i) gut barrier dysfunction, ii) endotoxemia, iii) bacterial overgrowth and iv) liver injury. Previous study showed that FGF19 is expressed in the liver of patients with obstructive cholestasis. However, knowledge about the contribution of FGF19 protein by the gut in obstructive cholestasis has thus far been unexplored. Preliminary findings revealed that FGF19 is produced by the portal drained viscera (viz. intestine) of non-cholestatic patients undergoing liver surgery. The inter-organ signalling of FGF19 in an obstructed entero-hepatic cycle has not yet been characterized and likewise the metabolic and other functional effects of inflicted FGF19 signalling during cholestasis have not been clarified. The hypothesis is that the FXR-FGF19 pathway is disturbed in patients with obstructive cholestasis, and this is associated with organ injury and metabolic dysfunction. The investigators postulate that FGF19 is not produced by the terminal ileum under conditions of obstructive cholestatic, but production is shifted to the liver and this affects metabolic processes. The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients or post-cholestatic patients (drained patients) by calculating fluxes across the portal drained organs. Secondly, the investigators aim to investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function) of a disturbed FXR-FGF19 pathway in humans. This study will provide insights that may lead to potential therapeutic strategies for patients with a disturbed enterohepatic cycle (e.g. cholestatic liver diseases). Study population: Adult (>18 years old) cholestatic (cholestasis group), drained (restored enterohepatic cycle) and non-cholestatic patients (controls, normal enterohepatic circulation) undergoing pancreaticoduodenectomy (Whipple procedure) for hepatopancreaticobiliary malignancies (e.g. pancreatic cancer, cholangiocarcinoma) or liver resection for hepatic malignancies (e.g. cholangiocarcinoma, colorectal liver metastases) are eligible for this study. Study period: inclusion is planned from 1.12.2017 until 1.12.2024

Cholestasis is a condition in which bile is not properly transported from the liver to the small intestine. Cholestasis can be caused by an array of childhood diseases, including the genetic diseases Alagille syndrome (ALGS), alpha-1 antitrypsin (a-1AT) deficiency, bile acid synthesis and metabolism defects, and progressive familial intrahepatic cholestasis (PFIC) or benign recurrent intrahepatic cholestasis(BRIC). This study will investigate the natural history and progression of the four previously mentioned cholestatic liver diseases to provide a better understanding of the causes and effects of the diseases.

The natural course of PFIC syndromes and the effect of diversion techniques, have so far not been characterized in a rigorous manner within a larger population of patients. In fact, the clinical or biochemical parameters which most directly define and/or predict the success of reduced enterohepatic circulation (either by surgical diversion or medically) are still unclear. The present project aims to: Define the natural course of disease in genetically defined PFIC1, and PFIC2 patients, with respect to relevant biochemical and clinical parameters (and if available, histological). Included will be patients homozygous for a known, disease-causing mutation, patients compound homozygous for two disease-causing mutations or heterozygous for one disease-causing mutation in combination with the clinical phenotype of Bsep-deficiency or FIC1-deficiency. Define the change in the natural course of disease in response to biliary diversion surgery and or liver transplantation, based on short- and long(er)-term changes in biochemical (if available, histological) and clinical parameters, including outcome measures. Follow up after transplantation will be limited to max 3 months after transplant surgery, follow up after surgical biliary diversion will be as long as possible. Assessment of biochemical variables as possible surrogate endpoints for clinical hard endpoints. If possible this allows for identification of low-risk to high-risk patients early during follow-up. If patient numbers permit, to establish genotype-phenotype relationships for the most common genetic mutations causing Bsep-deficiency or FIC1-deficiency. Based on this project it is anticipated that the investigators are able: to characterize the variation in natural course of disease (whether or not genotype dependent) to allow clinicians to rationally select a target population for assessing the effect of medical intervention, rather than surgical biliary diversion); to identify and qualify one or more biomarkers that independently predict either improved or poor clinical outcomes of surgical biliary diversion; to investigate if the identified biomarker(s) can be used as surrogate end point(s) for assessing and predicting outcomes with novel interventional strategies.

The clinical success of percutaneous transhepatic biliary drainage procedures (PTBDs) is usually measured by the the decrease of the serum bilirubin value. However, the bilirubin value can be biased by other disease conditions. Furthermore, the time course of the decrease of the bilirubin value after technically successful PTBD is not well known. Serum gamma-glutamyl transferase (GGT), a liver enzyme which is typically elevated in cholestatic liver diseases, might be a good alternative to bilirubin as an indicator for the clinical success of PTBDs. The aim of this study is to analyse the bilirubin level and the GGT level in patients with technically successful PTBD.

The project will amalgamate data from several large Indian centers to describe the genotype, clinical spectrum, natural course, genotype-phenotype correlation, outcome, and response to medical therapy in Indian children with progressive familial intrahepatic cholestasis (PFIC). This will be the first such Indian registry of children with PFIC. There are currently limited single-center studies describing the genotype, natural course, and outcome of Indian children with PFIC. Data will be collected retrospectively from the participating centers across the country. Only genetically confirmed cases would be included.