In adults, primary sclerosing cholangitis (PSC), a cholestatic liver disease characterized by inflammation/fibrosis of intra/extra-hepatic bile ducts, associates with a milder form of inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). The pediatric PSC-IBD phenotype is less well characterized.
We performed a retrospective, single-center study examining PSC-IBD patients at Texas Children’s Hospital (TCH) between 2000–2015. IBD-phenotype (Modified Montreal Classification), medications, lab values, endoscopic records, and IBD-based hospital admissions were collected. PSC-UC phenotype was compared to UC, non-PSC patients (n=95) from TCH. Elevated gamma-glutamyl transpeptidase (GGT) levels were compared to calcitonin levels and IBD-flare activity, i.e. GI symptoms resulting in office/emergency room visits or hospital admission.
Of thirty-nine PSC-IBD patients, thirty-four (87.2%) had UC (PSC-UC) and five (12.8%) had Crohn’s Disease. Pancolitis was more common in PSC-UC than UC, non-PSC (96.3%, 64%, p=0.0009). PSC-UC patients required less treatment with steroids (76.5%, 91.6%, p=0.0326) or infliximab (8.8%, 37.9%, p=0.0011), and fewer had at least one IBD-related hospital admission (32.4%, 63.2%, p=0.0025) than UC, non-PSC. Progression to colectomy was significantly less (5.8%, 24.2%, p=0.0223) in PSC-UC. Median diagnosis-to-colectomy time tended to be longer in PSC-UC (6.37, 2.5 years, p=0.0792). In two smaller subsets, GGT did not correlate with calprotectin in PSC-UC (n=11, p=0.7922) and less strongly associated with IBD-flares in PSC-UC than UC, non-PSC (n=33, n=67; 15.2%, 41.8%, p=0.0120).
Pediatric PSC appears to associate with milder pancolitic-UC. PSC and IBD activity do not appear to correlate. Our findings may provide useful information towards etiology and management of pediatric PSC-IBD.
As of August 2022, cases of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze 27 samples, including nasopharyngeal swab, stool, plasma, and/or whole blood, from 16 such cases from 6 states (Alabama, California, Florida, Illinois, North Carolina, and South Dakota) presenting from October 1, 2021 to May 22, 2022, in parallel with whole blood samples from 45 controls. Among the 13 cases for whom whole blood was available, adeno-associated virus 2 (AAV2) sequences were detected in 92% (12 of 13) (p<0.001), while adenovirus sequences were detected in 100%, of which 11 (84.6%) were genotyped as human adenovirus type 41 (HAdV-41), one as HAdV-40, and one as HAdV-2. Co-infections of herpesviruses, Epstein-Barr virus (EBV) or human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in all 13 cases. In contrast, AAV2 and HAdV-41 were not detected in any control, and EBV, HHV-6, or EV-A71 were each only detected in one or two of 45 controls (p<0.001). Analysis of assembled AAV2 viral genome sequences identified 35 coding mutations relative to the AAV2 reference genome, predominantly located in the VP1 capsid and assembly-activating protein (AAP) proteins, and AAV2 genomes from cases clustered together by phylogenetic analysis. Our findings of a distinct AAV2 strain in nearly all cases of acute severe hepatitis of unknown etiology in conjunction with one or more infecting helper viruses suggest that disease pathogenesis and/or severity may be related to co-infection with AAV2.
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end-stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 score (FIB-4), and conjugated bilirubin as biomarkers to assess fibrosis severity and risk for LT among children with ALGS and PFIC. This multicenter, cross-sectional study included 64 children with ALGS or PFIC (per genetics or strict clinical criteria) with APRI, FIB-4, and conjugated bilirubin levels collected within ±90 days of their most recent liver biopsy. A single, blinded pathologist staged all biopsies (metavir; F0-F2: nonsevere, F3-F4: severe). Logistic regression and area under the receiver operating characteristic curve analysis (AUC) were used to assess biomarker associations with fibrosis severity and risk for LT. In ALGS, only APRI distinguished F3-F4 (AUC 0.72, P = 0.012), with a cutoff greater than 2.97 demonstrating a sensitivity of 61.5% (95% confidence interval 0.32, 0.86) and specificity of 81.5% (0.62, 0.94). In ALGS, a 50% increase of APRI increased the odds of F3-F4 by 1.31-fold (1.04, 1.65; P = 0.023). In ALGS, APRI (AUC 0.87; P < 0.001) and FIB-4 (AUC 0.84; P < 0.001) were able to predict risk for LT. In PFIC, only APRI distinguished F3-4 (AUC 0.74, P = 0.039), with a cutoff greater than 0.99 demonstrating a sensitivity of 80% (0.44, 0.98) and specificity of 64.3% (0.35, 0.87). In PFIC, only FIB-4 was able predict risk for LT (AUC 0.80; P = 0.002). In ALGS or PFIC, conjugated bilirubin could not distinguish F3-F4 or predict risk for LT. Conclusion: This liver biopsy-validated study suggests that APRI is able to distinguish F3-F4 from F0-F2 in ALGS and PFIC. APRI and FIB-4 may also serve as predictors of risk for LT in ALGS (APRI and FIB-4) and PFIC (FIB-4). (Hepatology Communications 2020;4:1516-1526). A lagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) represent distinct but rare inherited cholestatic disorders that display wide variability in degrees of liver fibrosis, progression of disease, and time to transplant. (1-8) Although genetic analysis is emphasized for either diagnosis, percutaneous liver biopsy has historically been an essential tool for histologic staging and monitoring progression of disease. (9,10) Risks of liver biopsies are relatively low; however, there is still potential for bleeding, patient discomfort, infection, and side effects of anesthesia. (10,11) An autosomal dominant disorder, ALGS is characterized by bile duct paucity and often presents with extrahepatic clinical features such as vertebral abnormalities, renal or cardiac disease, posterior embryotoxon,
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