Molecular overview of progressive familial intrahepatic cholestasis

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Inpatient use of racemic epinephrine for children admitted with croup

Background Pediatric patients with croup are frequently admitted if they require two doses of racemic epinephrine(RE)in the emergency department(ED).We aimed to identify factors associated with the need for additional therapy(>2 RE doses)among pediatric patients with croup.Methods We performed a single-center retrospective study of consecutive patients admitted from the ED with a diagnosis of croup between January 1,2011 and December 31,2015.Primary outcome was need for>2 doses of RE.Secondary out-comes included time to third RE and 72-hour return visits.We performed logistic regression to identify factors associated with use of>2 RE doses during hospitalization,and survival analysis to identify time to dosing of 3rd RE from 2nd RE.Results Of 353 included admissions[250(70.8%)males,median age 1.48,interquartile range 0.97-2.51 years],106/353(30.0%)required>2 RE.In univariate logistic regression,only recent use of steroids within 1 day prior to presentation(4.18,1.48-11.83;P=0.007)was associated with need for>2 RE.Survival from third RE was 0.74(95%CI 0.69-0.78),which was similar to the survival at 12 hours(0.70,95%CI 0.65-0.75).Return visits occurred in 19(5.4%)patients,of whom 12/19(63.2%)were given RE.Conclusions Patients hospitalized for croup with recent use of steroids prior to ED presentation have a greater need for>2 RE during hospitalization.The majority who require inpatient RE will do so within 8-12 hours.These data provide informa-tion for risk stratification and duration of monitoring for patients hospitalized with croup.