Incidence of amoxycillin-clavulanic acid associated hepatotoxicity in an Australian children's hospital.

OBJECTIVES: Amoxycillin/clavulanic acid is the most common antimicrobial cause of drug-induced liver injury in adults. It is a less common cause of severe drug-related hepatotoxicity in children despite its frequent use. We studied the incidence, characteristics and predictive factors for amoxycillin/clavulanic acid hepatoxicity in children. DESIGN: Retrospective cohort study of children who received oral or intravenous amoxycillin/clavulanic acid at a quaternary children's hospital over a 5-year period. Children were included if they had liver function tests (LFTs) determined at baseline, during and within 3 months after the treatment course. Causality was assessed using the Naranjo criteria for adverse drug reactions and Roussel Uclaf Causality Assessment Method. RESULTS: Of 3271 children prescribed amoxycillin/clavulanic acid, 374 were included. Forty-nine (13%) had LFT abnormalities related to amoxycillin/clavulanic acid. Fourteen (3.6%) fulfilled Common Terminology Criteria for Adverse Events (CTCAE) grade 2 criteria with clinically significant hepatotoxicity. Age <2 years, sepsis, post-gastrointestinal surgical indications, prolonged treatment course of >7 days and higher cumulative amoxycillin (>10 g) and clavulanic acid dose (>1 g) were predictive of hepatotoxicity. The median time to resolution of LFT abnormalities was 4 weeks (range 3-7). CONCLUSIONS: The incidence of amoxycillin/clavulanic acid related LFT abnormalities (CTCAE Grade 2 or above) in children was 3.6%. A prolonged treatment course >7 days, high cumulative amoxycillin (10 g) and clavulanic acid (>1 g) doses, those aged <2 years, and patients with sepsis or post-gastrointestinal surgery were predictive of a higher likelihood of abnormal LFTs. LFT monitoring should be considered in children receiving ≥7 days of treatment, particularly in those with other predisposing factors.

Cystic fibrosis liver disease in the new era of cystic fibrosis transmembrane conductance regulator (CFTR) modulators.

Cystic fibrosis liver disease (CFLD) is characterised by a wide heterogenity of manifestations and severity. It represents a major cause of morbidity in people with cystic fibrosis (PwCF), which will be of increasing relevance as survival increases in the new era of cystic fibrosis care. No medical therapy currently available has evidence to treat or prevent progression of liver disease. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators may be transformative on pulmonary, nutritional and quality of life, but direct effect on long term liver disease outcomes is not yet established. Drug-associated hepatic adverse effects may be common, and clinician familiarity with drug-monitoring recommendations is essential. Longitudinal studies are required to understand the effect of CFTR modulators on the incidence and natural history of CFLD, including with early treatment initiation, in established advanced liver disease, and post liver transplantation.

Current status and future directions of liver transplantation for metabolic liver disease in children.

Orthotopic liver transplantation (OLT) in the care of children with inborn errors of metabolism (IEM) is well established and represent the second most common indication for pediatric liver transplantation in most centers worldwide, behind biliary atresia. OLT offers cure of disease when a metabolic defect is confined to the liver, but may still be transformative on a patient's quality of life reducing the chance of metabolic crises causing neurological damage in children be with extrahepatic involvement and no "functional cure." Outcomes post-OLT for inborn errors of metabolism are generally excellent. However, this benefit must be balanced with consideration of a composite risk of morbidity, and commitment to a lifetime of post-transplant chronic disease management. An increasing number of transplant referrals for children with IEM has contributed to strain on graft access in many parts of the world. Pragmatic evaluation of IEM referrals is essential, particularly pertinent in cases where progression of extra-hepatic disease is anticipated, with long-term outcome expected to be poor. Decision to proceed with liver transplantation is highly individualized based on the child's dynamic risk-benefit profile, their family unit, and their treating multidisciplinary team. Also to be considered is the chance of future treatments, such as gene therapies, emerging in the medium term.

Pediatric Eosinophilic Esophagitis is Associated With Low Baseline Impedance.

BACKGROUND AND AIMS: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder that requires repeat endoscopic evaluation(s) to assess response to treatment. This results in high health care costs and a procedural burden in affected children. Noninvasive alternate modalities to reassess disease activity have not been established. Low baseline impedance measured by multichannel pH impedance (pH-MII) is seen in adults with EoE, in keeping with poor mucosal integrity. We aimed to investigate the relationship between esophageal eosinophilia (or severity of eosinophilic infiltration) and baseline impedance in children with EoE. METHODS: We retrospectively identified 15 children diagnosed with EoE at our institution who had undergone pH-MII within 30 days of 3-level esophageal biopsy. This group were not concurrently prescribed proton pump inhibitors and had negligible reflux parameters on pH-MII. Average impedance baseline was calculated upper, mid, and lower esophageal segments via baseline impedance automated analysis (RIAA) and mean nocturnal baseline impedance (MNBI) methods. Eosinophil count data for upper, mid, and lower esophageal segments in the EoE group was collated. RESULTS: A significantly lower baseline impedance was seen across the esophageal length in children with EoE, compared with 30 controls who had no differences in age or reflux burden on nonparametric testing. A relationship between baseline impedance and eosinophil number at corresponding esophageal segments was not established. CONCLUSIONS: Baseline impedance may be an important, less invasive adjunct in clinical practice to monitor treatment response in children with EoE. Larger prospective cohort studies should delineate optimally predictive baseline impedance thresholds for active and inactive disease.

New Pathogenic Mutations Associated with Diacylglycerol O-Acyltransferase 1 Deficiency.

Diacylglycerol O-acyltransferase 1 deficiency is a recently discovered, rare congenital diarrheal disorder. We report 2 patients with newly described pathogenic mutations in diacylglycerol O-acyltransferase 1 with compound heterozygous inheritance and unusual phenotypes. This included a macrophage activation syndrome-like response seen in one patient, ameliorated with low dietary fat.