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Hepatology (Baltimore, Md.) Dec 2023Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated...
BACKGROUND AND AIMS
Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.
APPROACH AND RESULTS
We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival.
CONCLUSIONS
Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.
Topics: Humans; Alagille Syndrome; Progression-Free Survival; Retrospective Studies; Bilirubin; Pruritus; Bile Acids and Salts
PubMed: 37278241
DOI: 10.1097/HEP.0000000000000502 -
The Journal of Maternal-fetal &... Dec 2023Congenital segmental dilatation of the intestine (CSDI) is a rare gastrointestinal condition. We conducted a scoping review through MEDLINE and Google Scholar,... (Review)
Review
OBJECTIVE
Congenital segmental dilatation of the intestine (CSDI) is a rare gastrointestinal condition. We conducted a scoping review through MEDLINE and Google Scholar, collecting data from 1959 through August 2020 to better understand this peculiar disease.
METHODS
The clinical and pathological features of 150 patients were reviewed.
RESULTS
The mean age was 25.9 days, and 61.3% of patients were male. An antenatal diagnosis was made in 15.3% of patients. Predominant symptoms included abdominal distension (83.9%) and vomiting (61.3%). Pallor and anemia were associated with ileal CSDI. The most common sites of the lesion were the ileum (56%) and colon (27.3%). Associated anomalies occurred in 57.3% of the patients, of which the most common included other abnormalities of the digestive system (69.8%), abdominal wall (19.8%), and cardiovascular system (11.6%). Resection and anastomosis was performed in 83.3% of patients. Postoperative complications occurred in 10%. Normal ganglion cells were commonly found (97.3%), while muscle layer hypertrophy and atrophy were found in 14.7% and 13.3% of the patients, respectively. Abnormal interstitial cells of Cajal were identified in four patients. Death occurred in 12.7% of patients. Demise was significantly associated with the duodenal location of CSDI (Mantel-Cox test, = 0.002).
CONCLUSION
CSDI remains poorly understood, and mortality is associated chiefly with its duodenal location. Further research is needed, and biorepositories should be promptly set up to study this disease in the future better.
Topics: Pregnancy; Humans; Female; Male; Adult; Dilatation; Intestinal Diseases; Colon
PubMed: 37726217
DOI: 10.1080/14767058.2023.2259047 -
Microbiome Nov 2023Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is...
BACKGROUND
Intestinal epithelial cell (IEC) mitochondrial dysfunction involvement in inflammatory bowel diseases (IBD), including Crohn's disease affecting the small intestine, is emerging in recent studies. As the interface between the self and the gut microbiota, IECs serve as hubs of bidirectional cross-talk between host and luminal microbiota. However, the role of mitochondrial-microbiota interaction in the ileum is largely unexplored. Prohibitin 1 (PHB1), a chaperone protein of the inner mitochondrial membrane required for optimal electron transport chain function, is decreased during IBD. We previously demonstrated that mice deficient in PHB1 specifically in IECs (Phb1) exhibited mitochondrial impairment, Paneth cell defects, gut microbiota dysbiosis, and spontaneous inflammation in the ileum (ileitis). Mice deficient in PHB1 in Paneth cells (epithelial secretory cells of the small intestine; Phb1) also exhibited mitochondrial impairment, Paneth cell defects, and spontaneous ileitis. Here, we determined whether this phenotype is driven by Phb1 deficiency-associated ileal microbiota alterations or direct effects of loss of PHB1 in host IECs.
RESULTS
Depletion of gut microbiota by broad-spectrum antibiotic treatment in Phb1 or Phb1 mice revealed a necessary role of microbiota to cause ileitis. Using germ-free mice colonized with ileal microbiota from Phb1-deficient mice, we show that this microbiota could not independently induce ileitis without host mitochondrial dysfunction. The luminal microbiota phenotype of Phb1 mice included a loss of the short-chain fatty acid butyrate. Supplementation of butyrate in Phb1-deficient mice ameliorated Paneth cell abnormalities and ileitis. Phb1-deficient ileal enteroid models suggest deleterious epithelial-intrinsic responses to ileal microbiota that were protected by butyrate.
CONCLUSIONS
These results suggest a mutual and essential reinforcing interplay of gut microbiota and host IEC, including Paneth cell, mitochondrial health in influencing ileitis. Restoration of butyrate is a potential therapeutic option in Crohn's disease patients harboring epithelial cell mitochondrial dysfunction. Video Abstract.
Topics: Humans; Animals; Mice; Crohn Disease; Gastrointestinal Microbiome; Ileitis; Inflammation; Inflammatory Bowel Diseases; Paneth Cells; Butyrates; Mitochondria; Intestinal Mucosa
PubMed: 37978573
DOI: 10.1186/s40168-023-01686-9 -
Revista Espanola de Enfermedades... Apr 2024Case of a 24-year-old woman presenting due to edema in lower extremities. The patient had had infectious mononucleosis three weeks prior and had medical history of...
Case of a 24-year-old woman presenting due to edema in lower extremities. The patient had had infectious mononucleosis three weeks prior and had medical history of suspicion of Crohn's disease (CD) (due to a non-specific ileocolitis in a colonoscopy/EnteroRM). No ongoing medication. Laboratory evaluation unveiled hypoproteinemia with severe hypoalbuminemia, no renal abnormalities. A PLE was assumed, with post-infectious or CD being the most likely culprits. Alternative causes were extensively excluded. A videocapsule revealed white-tipped or granular villi, some white nodular villi and diffuse edema of the mucosa, and multiple extensive erosions and superficial ulcers in the jejunum and proximal ileum, not suggestive of CD. A push enteroscopy revealed unspecific histopathology. After incomplete response to enteral nutrition, corticotherapy was initiated resulting in sustained improvement. A follow-up Ileocolonoscopy and double balloon enteroscopy revealed no abnormalities. Six months post-treatment, the patient remains asymptomatic, with unremarkable laboratory results and no need for medication.
PubMed: 38685896
DOI: 10.17235/reed.2024.10461/2024