Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Malrotation of the Intestine and Chronic Volvulus as a Cause of Protein-Losing Enteropathy in Infancy

Protein-losing enteropathy in children is caused by intestinal metabolic, inflammatory, or infectious processes, or by lymphatic obstruction (intestinal lymphangiectasia). In this report, a 17-month-old child is presented with protein-losing enteropathy due to intestinal malrotation and chronic midgut volvulus causing lymphatic obstruction and spillage of lymph in the intestine and the peritoneum. This report should alert the pediatrician that intestinal malrotation should be added to the wide list of possible causes of protein-losing enteropathy in children. Pediatrics 2012;129:e515-e51

Autoimmune hepatitis type-2 and Epstein-Barr virus infection in a toddler: art of facts or an artifact?

Epstein-Barr virus (EBV) can cause frequently asymptomatic (or anicteric) and self-limited hepatitis, while occasionally may result in considerable cholestatic hepatitis. Herein, we describe the case of a previously healthy toddler (26 month old girl) with prolonged cholestasis, elevated serum transaminases, EBV serology compatible with recent EBV infection and positive anti liver kidney microsomal antibody type 1 which is characteristic of new-onset autoimmune hepatitis type 2. Liver biopsy was also typical of autoimmune hepatitis as attested by the presence of portal inflammation with predominant T-lymphocytes and plasma cells and interface hepatitis. Persistent EBV-related hepatitis was excluded by the absence of viral inclusions and steatosis on liver specimens and negative liver EBV-PCR. In conclusion, our case strongly suggests that in children with prolonged cholestatic hepatitis, positive EBV serology cannot exclude the presence of other causes of liver disease. In this context, autoimmune hepatitis should be considered as an alternate diagnosis, particularly when there is specific liver-related autoantibody detection. In such conditions, liver biopsy seems mandatory in an attempt to achieve a correct and timely diagnosis of a potentially catastrophic disease as autoimmune hepatitis. Although some cases of autoimmune hepatitis type 1 following EBV infection have been reported in adults, to the best of our knowledge, the present case of autoimmune hepatitis type 2 after EBV infection represents the first case in children ever reported in the English literature

Dental Caries and Periodontal Disease in Children and Adolescents with Inflammatory Bowel Disease: A Case-Control Study

Background:Previous reports have demonstrated a higher prevalence of dental caries and periodontal disease in adults with inflammatory bowel disease (IBD), but similar data in children and adolescents do not exist. The aim of the study was to evaluate the status of dental caries, oral hygiene, gingival status and periodontal treatment needs of children with IBD.Methods:In this case-control study, 55 children on remission from a single outpatient IBD clinic, aged 4 to 18 years (12.27 3.67 yr) and 55 matched systemically healthy controls of a dental practice were assessed prospectively. The evaluation included medical history, dental questionnaire in both groups, and previous and current medical therapy of children with IBD. Additionally, the decayed, missing, and filled tooth (dmf-t or DMF-T), simplified gingival, plaque control record and community periodontal treatment needs indices were evaluated.Results:Children with IBD compared with controls had a statistically significant (P &lt; 0.001) higher dmf-t (2.95 versus 0.91) or DMF-T (5.81 versus 2.04) index and a higher gingival inflammation (simplified gingival, 40% versus 24%) although the respectively dental plaque index showed no significant difference (plaque control record, 42% versus 41%). Also, the community periodontal treatment needs was significantly higher compared with controls (P &lt; 0.001); most of the patients with IBD needed treatment of gingivitis (47% versus 4%), and none of them had healthy periodontium (0% versus 69%).Conclusions:The results of this case-control study demonstrate a higher frequency of dental caries, more clinical signs of gingival inflammation, and increased periodontal treatment needs in children and adolescents with IBD despite similar oral hygiene status

HEPATITIS C TREATMENT CONCOMITANT TO CHEMOTHERAPY AS “SALVAGE” THERAPY IN CHILDREN WITH HEMATOLOGIC MALIGNANCIES

In patients with malignancies, chronic hepatitis C reactivation or severe flare is uncommon and antiviral treatment is deferred mainly due to underlying bone marrow and immune suppression. We report the use of antiviral treatment concomitantly to chemotherapy in 3 children with hematologic malignancies, chronic hepatitis C, and significant liver dysfunction

Epigenetics in paediatric gastroenterology, hepatology, and nutrition: Present trends and future perspectives

Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of "modern" pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition

Acute Hepatitis of Unknown Aetiology Among Young Children: Research Agenda by the ESPGHAN Hepatology Committee

In April 2022, an increased incidence of acute hepatitis cases of unknown aetiology among previously healthy children across the United Kingdom was described. Since, more than 200 cases from United Kingdom and hundreds more from all across the world have been reported. The majority of affected children were younger than six years of age. The clinical presentation was nonspecific with diarrhoea and vomiting usually preceding the appearance of jaundice, abdominal pain, nausea and malaise. Approximately 10% have required liver transplantation. An infectious aetiology has been considered likely given the epidemiological and clinical features of the reported cases. More than 60% of the children tested were diagnosed with adenovirus infection although a clear aetiological connection has still to be demonstrated. No link with SARS-CoV-2 infection and COVID-19 vaccine was found. What is not clear to date is whether the high number of acute hepatitis cases reported is related to a true increase in incidence or heightened awareness following on from the initial reports from the United Kingdom. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition developed a paper on the current outbreak of acute hepatitis of unknown aetiology recognizing its importance and the need of approaching the current situation with a scientifically rigorous approach. The aims of the paper are to summarize the current knowledge and to identify the most pertinent issues regarding the diagnosis and management of this condition and the research questions raised

Epigenetics in Paediatric Gastroenterology, Hepatology, and Nutrition: Present Trends and Future Perspectives

Epigenetics can be defined as stable, potentially heritable changes in the cellular phenotype caused by mechanisms other than alterations to the underlying DNA sequence. As such, any observed phenotypic changes including organ development, aging, and the occurrence of disease could be driven by epigenetic mechanisms in the presence of stable cellular DNA sequences. Indeed, with the exception of rare mutations, the human genome-sequence has remained remarkably stable over the past centuries. In contrast, substantial changes to our environment as part of our modern life style have not only led to a significant reduction of certain infectious diseases but also seen the exponential increase in complex traits including obesity and multifactorial diseases such as autoimmune disorders. It is becoming increasingly clear that epigenetic mechanisms operate at the interface between the genetic code and our environment, and a large body of existing evidence supports the importance of environmental factors such as diet and nutrition, infections, and exposure to toxins on human health. This seems to be particularly the case during vulnerable periods of human development such as pregnancy and early life. Importantly, as the first point of contact for many of such environmental factors including nutrition, the digestive system is being increasingly linked to a number of “modern” pathologies. In this review article, we aim to give a brief introduction to the basic molecular principals of epigenetics and provide a concise summary of the existing evidence for the role of epigenetic mechanisms in gastrointestinal health and disease, hepatology, and nutrition

Management of Hepatitis B Virus Infection and Prevention of Hepatitis B Virus Reactivation in Children With Acquired Immunodeficiencies or Undergoing Immune Suppressive, Cytotoxic, or Biological Modifier Therapies :

Reactivation of hepatitis B virus (HBV) is a known complication of immune-suppressive, cytotoxic, and biological modifier therapies in patients currently infected with HBV or who have had past exposure to HBV. Nowadays, newer and emerging forms of targeted biologic therapies are available for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions and solid-organ, bone marrow, or haematologic stem cell transplant but there is currently a lack of a systematic approach to the care of patients with or at risk of HBV reactivation. The Hepatology Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) together with a working group of ESPGHAN members with clinical and research expertise in viral hepatitis developed an evidence-based position paper on reactivation of HBV infection in children identifying pertinent issues addressing the diagnosis, prevention, and treatment of this condition. Relevant clinical questions were formulated and agreed upon by all the members of the working group. Questions were answered and positions were based on evidence resulting from a systematic literature search on PubMed and Embase from their inception to July 1, 2019. A document was produced and the working group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique. A recommendation was accepted provided upon agreement by at least 75% of the working group members. This position paper provides a comprehensive update on the diagnosis, prevention and treatment of HBV reactivation in children