Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease.

BACKGROUND & AIMS: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. METHODS: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. RESULTS: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. CONCLUSIONS: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

Coagulation Factors as Predictive Markers of Poor Outcomes in Children with Acute Liver Failure.

BACKGROUND: In children, acute liver failure (ALF) is a severe condition associated with high mortality if an emergency liver transplantation (LT) is impossible. Clinical laboratory parameters and different scores or criteria are used to predict ALF evolution in children. We aimed to assess the role of coagulation factors as predictive markers of poor outcomes in children with ALF. METHODS: The prospective study included 40 children with ALF, diagnosed based on the Pediatric ALF study group criteria. Patients with emergency LT or deceased were considered with poor outcomes. For all patients, we analyzed clinical and laboratory parameters (including plasma level of factor V (FV), factor VII (FVII), and INR). We calculated the PELD (Pediatric End-stage Liver Disease) and MELD (Model for End-stage Liver Disease) scores, King's College Hospital (KCH), and Clichy criteria. We analyzed their performance in predicting a poor outcome. RESULTS: FV and FVII levels were significantly lower in children with poor outcomes than survivors (18.92 ± 19.95% vs. 10.72 ± 10.21%, p = 0.00139, respectively 46.51 ± 26.05% vs. 10.72 ± 10.21%, p = 0.00014). These parameters varied with ALF etiology, being the lowest in metabolic and infectious causes. The maximum value of INR (INR-max) was higher in children with poor outcomes than survivors (7.05 ± 3.20 vs. 2.96 ± 1.82, p = 0.000007), as it also was for the PELD/MELD score (30.06 ± 15.55 vs. 15.77 ± 9.64, p = 0.00092). FVII, FV, and INR-max had an excellent performance in predicting the poor outcome with an area under the ROC curve of 0.894, 0.816, and 0.861, respectively. KCH criteria had a higher sensitivity than Clichy criteria (92.86% vs. 50%) but lower specificity (53.85% vs. 95%). CONCLUSIONS: Our results support the role of coagulation factors (INR, FV, and FVII) as predictive markers for the fatal evolution of children with ALF and underlined the need for monitoring along with the usual liver function tests in children with ALF.

European Society for Pediatric Gastroenterology Hepatology and Nutrition's Educational Offer and the Training Syllabus.

The basic knowledge necessary for a European pediatric gastroenterologist/hepatologist/nutritionist is set-out in the training syllabus (TS) of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). We retrospectively compared the topics covered in ESPGHAN's training events between 2013 and 2016 with the basic knowledge TS items. Thirty-six initiatives including e-learning were identified. Twelve (33%) courses focused on gastroenterology, 9 (25%) on hepatology, and 10 (28%) on nutrition. Five (14%) courses covered >1 field and were classified "General." The initiatives covered 12 of 57 (21%) TS items; 31 of 57 items (54%) were partially covered; and 14 of 57 (25%) not covered. Five of 9 e-learning courses covered gastroenterology topics, whereas none covered hepatology topics. ESPGHAN's 3-year educational offer partially met the training needs listed in the TS. A coordinated educational program covering all TS items would harmonize training within Europe and would provide trainees with a professional portfolio for employment purposes.

Clinical significance of the antinuclear antibodies in chronic viral hepatitis B in children.

BACKGROUND: The presence of autoantibodies is frequent in chronic viral hepatitis evolution. Defining the role of autoimmunity in disease evolution or response to interferon treatment is still in debate, both in children and in adults. There are few studies about the influence of autoimmunity in children with chronic viral hepatitis. The aim of our study was to establish the clinical significance of antinuclear autoantibodies (ANA) in chronic hepatitis B in children. METHODS: We have studied 80 children with chronic hepatitis B (30 female; mean age 12.31 +/- 4.13 years). For each patient we performed haematological and biochemical tests and in 41 patients we analyzed the liver histology. The immunological parameters analyzed were: circulating immune complexes (CIC), complement, and the serum levels of immunoglobulin G, A, and M. We analysed by indirect fluorescence the presence of ANA and other autoantibodies. The response to treatment (hepatoprotectors, interferon and Lamivudine) was established depending on seroconversion to HBeAb and HBsAb. RESULTS: Positive ANA were found at baseline in 15% of the patients and during follow-up in 21.25%. In ANA-positive patients compared to those without autoantibodies we found lower levels of haemoglobin and platelet numbers (p = 0.0245, p = 0.0236, respectively), higher gamma-glutamyl-transferase level (p = 0.040) and higher CIC level (p = 0.0155). During interferon treatment 13.79% of those who initially tested ANA-negative presented ANA, compared to 2.56% in those without interferon (p = 0.042). There was no difference in response to interferon treatment according to the presence of ANA (p = 0.4201). CONCLUSIONS: Searching for ANA in children with chronic hepatitis B is a key element in describing the evolution of these patients, especially when considering interferon therapy. Interferon treatment stimulates the development of ANA, but their presence does not influence the response to this particular treatment. The role of autoimmune processes in the evolution and response to treatment of chronic hepatitis B patients remains controversial.