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ObjectiveBile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD.DesignSerum bile acid levels and fibroblast growth factor 19 (FGF19), liver gene expression profiles and gut microbiome compositions were determined in patients with NAFLD, high-fat diet-fed rats and their controls.ResultsSerum concentrations of primary and secondary bile acids were increased in patients with NAFLD. In per cent, the farnesoid X receptor (FXR) antagonistic DCA was increased, while the agonistic CDCA was decreased in NAFLD. Increased mRNA expression for cytochrome P450 7A1, Na+-taurocholate cotransporting polypeptide and paraoxonase 1, no change in mRNA expression for small heterodimer partner and bile salt export pump, and reduced serum FGF19 were evidence of impaired FXR and fibroblast growth factor receptor 4 (FGFR4)-mediated signalling in NAFLD. Taurine and glycine metabolising bacteria were increased in the gut of patients with NAFLD, reflecting increased secondary bile acid production. Similar changes in liver gene expression and the gut microbiome were observed in high-fat diet-fed rats.ConclusionsThe serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

Neonatal cholestasis (NC) is defined as conjugated hyperbilirubinemia during the first months of life secondary to decreased formation and/or excretion of bile. Prompt recognition and investigation is of utmost importance since delay in diagnosis can be associated with decreased native liver survival. Infection, metabolic and transport defects are among the differential diagnosis. A full term infant was born via urgent caesarean section due to late decelerations. Baby was vigorous with APGAR of 8 and 9 at 1 and 5 minutes of life. At 18 hours of life the infant appeared jaundiced prompting early evaluation. Total bilirubin was 9.9 mg/dL, direct bilirubin: 6.9 mg/dL, AST: 230 U/L, ALT: 81 U/L, PT 24.7 sec and INR 2.25 which corrected with vitamin K. Blood and urine cultures as well as TORCH panel were negative. Liver ultrasound showed small gallbladder and hepatobiliary scintigraphy showed no excretion into the small bowel. Intraoperative cholangiography showed normal filling of both intra and extra hepatic ducts with contrast entering the duodenum, ruling out biliary atresia. Marked cholestasis with balloon degeneration of hepatocytes and minimal inflammation without fibrosis was seen on liver biopsy. Urine bile acid profile by FAB-MS was negative for bile acid synthesis defects. A genetic cholestasis panel was sent and reported as normal. Hereditary conjugated hyperbilirubinemia was suspected. Testing revealed elevation of total porphyrins (976.1mcg/g) as well as coproporphyrin isomer I (509.2mcg/g) and III (423.3mcg/g). A homozygous mutation on SLCO1B1 (GLY488AIa) gene was identified. Total and direct bilirubin peaked (15.4 and 11.5) on day 25 and normalized by 3 months of age. Syndromes associated with hereditary conjugated hyperbilirubinemia are Dubin-Johnson and Rotor Syndrome. Persistent cholestasis with normal liver function should raise suspicion about these conditions. Rotor syndrome is an autosomal recessive disease caused by absence of both SLCO1B1 and SLCO1B3 genes that encodes transport proteins OATP1B1 and OATP1B3. This mutation has never been described as pathologic, and there are no reports of a symptomatic single gene mutation. Our patient's phenotype resembled Rotor Syndrome, and this single gene mutation might be a cause of NC. Theoretical clinical implication of this gene mutation exceeds the newborn period since OATP1B1 is involved in uptake and clearance of drugs.

The Fontan procedure was first performed in the seventies as a palliation for patients with single ventricle physiology. A feared complication after a Fontan procedure is the development of protein losing enteropathy (PLE). Systemic inflammation has a negative effect on the intestinal barrier integrity, which has supported the use of steroids in this setting. To the best of our knowledge there are no studies linking intestinal inflammation in patients with PLE after Fontan. The objective of this study was to identify the presence of intestinal inflammation measured by FC in patients with PLE after a Fontan procedure. A cross-sectional analysis was performed examining 23 stool samples from 23 Fontan patients for both Fecal alpha-1-antitrypsin (FA1AT) and FC with and without PLE. The median FC was 21 mcg/gm of stool (IQR: 15.7–241 mcg/gm of stool), and the median FA1AT was 40 mg/dL (IQR: 30–220 mg/dL). The median FC and FA1AT were significantly higher in the PLE group than in the Non-PLE group ( p  = 0.002 and p  < 0.0001, respectively). Significantly elevated levels of FC were demonstrated in Fontan patients with PLE, which correlated with the elevated levels of FA1AT. Inversely, levels of FC in Fontan patients without suspected PLE were within the normal range. To our knowledge, this is the first study to demonstrate intestinal inflammation using FC in the setting of PLE within this cohort, and may prove to be useful as a diagnostic tool in its treatment.

As a chronic inflammatory disease with eosinophilic infiltrate of the esophagus, eosinophilic esophagitis (EoE) causes a variety of gastrointestinal (GI) clinical manifestations. None of the symptoms, endoscopic features, or biopsy findings is pathognomonic of the disease, even with high degrees of esophageal eosinophilia. The pathogenesis has been explored by several studies, yet it still far from being completely understood. Evidence supports a role of allergen-driven Th2 lymphocyte mechanism, though not in every patient. This article addresses the disease’s clinical manifestations, endoscopic findings, diagnosis, and differential diagnoses. In addition to the current diagnostic criteria, we summarize some recently emerging procedures that promise of enhancing more precise diagnosis and institution of early appropriate management, with consequent better quality of life and reduction of complications.

The signaling lymphocytic activation molecule 1 (SLAMF1) exerts a role in regulating the immune response to some viruses and parasite infections. In the present study, we identified SLAMF1 as a potential therapeutic target and biomarker for Non-Alcoholic Fatty Liver Disease (NASH) in humans. We found that SLAMF1 is highly expressed in liver samples from mice and humans with NASH. Our data also show SLAMF1 is detected in plasma, and its levels correlate with the severity of the disease. To uncover a molecular role for SLAMF1 in hepatocytes, we treated two hepatocyte cell lines (HepG2 and HuH-7) and primary mouse hepatocyte with palmitic acid (PA) to induce lipotoxicity, characteristic of NASH. We found that PA treatment leads to a significant increase in SLAMF1 protein levels in the cell lines and primary hepatocytes. We found an increase in HepG2 cell apoptosis in response to PA treatment, and downregulation of SLAMF1 in hepatocytes with siRNA improved cell viability and reduced cytotoxicity, apoptosis, and the expression of inflammatory mediators. Moreover, we found that PA-treated HepG2 cells secrete SLAMF1 in the culture medium, which may be mediating part of these effects through paracrine action. Our findings suggest a role for SLAMF1 in NASH's pathogenesis and highlight SLAMF1 as a reliable clinical biomarker of the disease. Presentation: Saturday, June 11, 2022 12:00 p.m. - 12:15 p.m.

Aplastic anemia (AA) is most frequently due to autoimmune attack on its own stem cells. Alemtuzumab is a monoclonal antibody which recognizes the CD52 antigen on the surface of T and B cells. It has proved useful in autoimmune diseases, lymphoproliferative conditions, and graft versus host disease. Based on its immunosuppressive properties, we treated 14 AA patients with alemtuzumab. Median age was 23 years. Ten milligrams of alemtuzumab were injected subcutaneously each day for five consecutive days. Cyclosporine A was also administered orally at a dose of 2 mg/kg every 12 h for 3 months, and then gradually tapered. Response to alemtuzumab was followed for a median of 20 months. There were eight responses (57.1%), two complete and six partial. Whereas six (42.8%) patients were non-responders. Median complete blood count values on alemtuzumab responders were Hb 13.1 mg/dL, absolute neutrophil count 2.4 × 10⁹/L, and platelets 97.5 × 10⁹/L. A good response was produced in 57% of AA patients with the administration of alemtuzumab, who lacked a stem cell donor.