Cystic fibrosis hepatobiliary involvement: an update on imaging in diagnosis and monitoring.

Analysis of the liver using imaging for persons with cystic fibrosis (CF) continues to evolve as new medical therapies are developed improving and extending life. In the 2010s, therapies targeted at modulating protein folding became available to those with CF. Therapeutic options have continued to expand, now providing both correction of protein folding and stabilization for most gene mutations that code for the CF transmembrane receptor protein (CFTR). Today, approximately 80% of persons with CF are eligible for highly effective modulator therapy. With these advancements, the impact of CF on the liver has become more complex, adding metabolism of CFTR modulators to intrinsic CF hepatobiliary involvement (CFHBI) and adding not previously appreciated vascular changes within the liver due to increased longevity in persons with CF. A combination of serum biomarkers and imaging is needed to add clarity to the diagnosis and monitoring of the severity of liver disease. A substantial portion of persons with CF will develop at least CFHBI and a subset will develop advanced cystic fibrosis-associated liver disease (aCFLD); therefore, diagnosis and monitoring need to begin in childhood. In this review, we cover the use of and need for imaging, including elastography, ultrasound, and magnetic resonance imaging (MRI), in diagnosing and monitoring CFHBI and its associated complications.

Intrahepatic Cholangiolitis in Cystic Fibrosis (ICCF): An Under-Appreciated Cause of Persistent Cholestasis in Infancy.

Liver histology in infants with cystic fibrosis (CF) and persistent cholestasis is seldom reported in detail. We extend previous observation of a distinctive intrahepatic cholangiopathy (ICCF) to 3 additional infants homozygous for CFTR pathological variants and a fourth infant with a heterozygous CFTR variant, summarizing our experience in 10 infants with CFTR variants and persistent cholestasis. Cholangiograms demonstrate abnormal extrahepatic ducts in 2 infants with CF, 1 with uniform dilatation interpreted as a choledochal cyst and the other with narrow patent ducts. Liver histology in 3 CF homozygotes had prominent ductular reaction with a focally destructive cholangiolitis (inflammation of small bile ducts). The CFTR heterozygote had generalized portal edema with ductular reaction and paucity but no cholangitis. Cholestasis slowly subsided in all infants. ICCF is characterized by severe ductular reaction, prominent cholangiocyte injury, and multifocal necrotizing cholangiolitis. Local aggregates of portal ceroid might suggest previous bile leakage from damaged ducts. ICCF in liver biopsies from infants with cystic fibrosis and persistent cholestasis is unrelated to the specific CFTR genotype. Liver biopsy findings and intraoperative cholangiogram help rule out biliary atresia. ICCF is an early manifestation of CF, a likely prototype for pathogenesis of cystic fibrosis liver disease later in life.

Hypoplasia of Extrahepatic Biliary Tree and Intrahepatic Cholangiolopathy in Cystic Fibrosis Imperfectly Mimic Biliary Atresia in 4 Infants With Cystic Fibrosis and Kasai Portoenterostomy.

Four male infants with cystic fibrosis and prolonged neonatal jaundice underwent Kasai procedure to relieve biliary obstruction due to apparent biliary atresia. The excised remnants had viscid mucus accumulation in hypoplastic gallbladders and distended peribiliary glands. Main hepatic ducts were narrow and/or malformed. Microscopic differences between the gallbladder and extrahepatic bile ducts in cystic fibrosis and sporadic biliary atresia were unequivocal, despite some histologic overlap; no erosive or fibro-obliterative lesions typical of biliary atresia were seen. Common in liver, biopsies were small duct cholangiopathy with intense focal cholangiolitis and massive accumulation of ceroid pigment within damaged cholangiocytes, and in portal macrophages, portal fibrosis, and unequivocal features of large duct obstruction were inconspicuous compared with biliary atresia. Plugs of bile in small ducts tended to be pale and strongly periodic acid-Schiff-reactive in cystic fibrosis. Distinguishing the liver lesion from that of biliary atresia is challenging but possible. Liver biopsies from 2 additional infants with cystic fibrosis and prolonged jaundice that spontaneously resolved showed a similar small duct cholangiopathy. Small gallbladders and extrahepatic ducts challenge surgical judgment as findings in liver biopsies challenge the pathologist. The decision to perform a Kasai procedure is reasonable when mimicry of biliary atresia is grossly complete. We hypothesize that a disorder of bile volume/flow during development and/or early infancy linked to the CFTR mutation alone or in combination with the stresses of neonatal intensive care causes destructive cholangiolitis and intrahepatic reduction of bile flow with secondary hypoplasia of extrahepatic biliary structures.

In-hospital Pediatric Endoscopic Retrograde Cholangiopancreatography Is Associated With Shorter Hospitalization for Children With Choledocholithiasis.

OBJECTIVES: Children with choledocholithiasis are frequently managed at tertiary children's hospitals that do not have available endoscopic retrograde cholangiopancreatography (ERCP) proceduralists. We hypothesized that patients treated at hospitals without ERCP proceduralists would have a longer hospital length of stay (LOS) than those with ERCP proceduralists. METHODS: Charts were reviewed for patients who underwent cholecystectomy and ERCP at 3 tertiary children's hospitals over 10 years. Trauma and complicated pancreatitis patients were excluded. Comparisons between patients requiring and not requiring transfer for ERCP were made using Wilcoxon rank-sum tests for continuous variables and Fisher's exact tests for categorical variables. RESULTS: One hundred and sixty-four children underwent ERCP for suspected choledocholithiasis: 79 (48%) in the transfer group and 85 (52%) in the no transfer group.Median LOS was longer for patients requiring transfer (7 vs 5 days, P < 0.0001). One-third (34%) of the transfer patients had magnetic resonance cholangiopancreatography compared to only 7% that did not require transfer (P < 0.0001). Among the 123 patients who underwent ERCP before cholecystectomy, 53% required (66/123) transfer and 47% (57/123) did not. Transfer group patients had longer median hospital LOS (P < 0.0001), more days between admission and ERCP (P < 0.0001), and more days between ERCP and surgery (P = 0.0004). CONCLUSIONS: Overall median LOS was significantly shorter for patients who underwent ERCP at the admitting facility. Patients who underwent ERCP before cholecystectomy at hospitals without available ERCP proceduralists incurred longer LOS. There is a need for more pediatric proceduralists appropriately trained to perform ERCP in children.

Ketamine inhibits tumor necrosis factor secretion by RAW264.7 murine macrophages stimulated with antibiotic-exposed strains of community-associated, methicillin-resistant Staphylococcus aureus.

BACKGROUND: Infections caused by community-associated strains of methicillin-resistant Staphylococcus aureus (CA-MRSA) are associated with a marked and prolonged host inflammatory response. In a sepsis simulation model, we tested whether the anesthetic ketamine inhibits the macrophage TNF response to antibiotic-exposed CA-MRSA bacteria via its antagonism of N-methyl-D-aspartate (NMDA) receptors. RAW264.7 cells were stimulated for 18 hrs with 105 to 107 CFU/mL inocula of either of two prototypical CA-MRSA isolates, USA300 strain LAC and USA400 strain MW2, in the presence of either vancomycin or daptomycin. One hour before bacterial stimulation, ketamine was added with or without MK-801 (dizocilpine, a chemically unrelated non-competitive NMDA receptor antagonist), APV (D-2-amino-5-phosphono-valerate, a competitive NMDA receptor antagonist), NMDA, or combinations of these agents. Supernatants were collected and assayed for TNF concentration by ELISA. RESULTS: RAW264.7 cells exposed to either LAC or MW2 in the presence of daptomycin secreted less TNF than in the presence of vancomycin. The addition of ketamine inhibited macrophage TNF secretion after stimulation with either of the CA-MRSA isolates (LAC, MW2) in the presence of either antibiotic. The NMDA inhibitors, MK-801 and APV, also suppressed macrophage TNF secretion after stimulation with either of the antibiotic-exposed CA-MRSA isolates, and the effect was not additive or synergistic with ketamine. The addition of NMDA substrate augmented TNF secretion in response to the CA-MRSA bacteria, and the addition of APV suppressed the effect of NMDA in a dose-dependent fashion. CONCLUSIONS: Ketamine inhibits TNF secretion by MRSA-stimulated RAW264.7 macrophages and the mechanism likely involves NMDA receptor antagonism. These findings may have therapeutic significance in MRSA sepsis.