Maria Grazia Clemente

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

Rotavirus Infects Human Biliary Epithelial Cells and Stimulates Secretion of Cytokines IL-6 and IL-8 via MAPK Pathway

Biliary atresia (BA) is an infantile inflammatory cholangiopathy of unknown etiology although epidemiologic studies and animal models utilizing rotavirus (RV) have suggested a role for viral infection. Proinflammatory and profibrotic cytokines have been detected in infants with BA. The purpose of our study was to investigate the susceptibility of human cholangiocytes (H69 cells) to infection with RRV and to determine if this infection resulted in cytokine secretion. Infection of H69 cells by RRV was noncytolytic and resulted in a time-dependent increase in the release of both infectious virions and cytokines IL-6 and IL-8 into the supernate. The greatest difference in cytokine supernatant levels between infected and mock-infected cells was noted at 24 hours postinfection (h p.i.) for IL-8, 556 ± 111 versus 77 ± 68u2009pg/mL (p < 0.0001), and at 48u2009h p.i. for IL-6, 459 ± 64 versus 67 ± 2u2009pg/mL (p < 0.0001). Production of both cytokines following RRV infection was significantly reduced by pretreating the H69 cells with inhibitors of mitogen-activated protein kinase (MAPK). Conclusion. RRV can infect human cholangiocytes resulting in the production of proinflammatory and profibrotic cytokines via the MAPK pathway. RRV-infected H69 cells could be a useful model system for investigating the viral hypothesis of BA.

An update on the strategies used for the treatment of chronic hepatitis B in children

ABSTRACT Chronic hepatitis B (CHB) in children shows a variety of clinical presentations, which influence its natural course and treatment options. This report provides an overview of the ongoing strategies in pediatric CHB management. Interferon-α represents the first choice of treatment in children showing HBV replication and hepatic inflammation (immune active CHB), while the recommendation is to monitor inactive/immune-tolerant children (normal transaminases and low/absent viral replication). When circumstances preclude the use of Interferon-α and in cases of compensated/decompensated cirrhosis, entecavir for children above 2 years of age or tenofovir for children above 12 years of age are the nucleos(t)ide analogues recommended by the most recent guidelines.

Hepatitis E in Italy: A silent presence

Hepatitis E virus (HEV) was discovered in the 1980s and has been considered as being confined to developing countries. The purpose of this critical review was to determine the reported HEV seroprevalence rates in Italy, to identify predisposing factors and individuals at risk and to assess possible importation of HEV by immigrants. A critical review of 159 articles published in PubMed from 1994 to date was done. Only 27 original reports of 50 or more subjects, written in the English or Italian language, were included. Over three decades, the HEV seroprevalence varied from 0.12% to 49%, with the highest rates being reported from the central region of Italy. Risk factors included ingestion of raw pork or potentially contaminated food. The seroprevalence among immigrants ranged from 15.3% to 19.7% in Apulia. Italy has a population of 60656000; the total number of individuals surveyed was only 21.882 (0.036%). A national epidemiological survey program is needed to capture more comprehensive seroprevalence data.

Intrahepatic bile duct primary cilia in biliary atresia: Primary cilia in biliary atresia

The etiopathogenesis of non‐syndromic biliary atresia (BA) is obscure. The primary aim was to investigate intrahepatic bile duct cilia (IHBC) in BA at diagnosis and its correlation with clinical outcome. The secondary aim was to analyze IHBC in routine paraffin‐embedded liver biopsies using conventional scanning electron microscopy (SEM).

Autoantibodies against CYP-2C19: A Novel Serum Marker in Pediatric De Novo Autoimmune Hepatitis?

Diagnosis of de novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) is challenging especially in the absence of hyper-γ-globulinemia. Circulating autoantibodies are not sensitive nor specific in de novo AIH but when positive increase the diagnostic probability. We report the discovery of novel liver microsomal (LM) autoantibodies against CYP-2C19 in a 9-year-old boy with “de novo” AIH developed 7 years after OLT. Graft dysfunction presented with hypertransaminasemia (up to 400u2009IU/L), while serum γ-globulins remained within the normal range for age. Liver histology and response to high dose prednisone (2u2009mg/kg/day) with the addition of azathioprine therapy further supported the diagnosis of de novo AIH. Autoantibodies investigation by indirect immunofluorescence (IF) on rodent tissues showed a novel staining pattern involving the pericentral liver zone and sparing the renal tissue. Human but not rat liver proteins immunoblotting allowed us to characterize the novel LM antibodies and to identify CYP-2C19 as human antigen. The finding offers insights into the controversial discussion about autoimmunity versus alloreactivity with regard to the pathogenesis of de novo AIH. Correct information on human versus rat tissue antigens tested by methods other than IF for antibodies detection may have significant implications for the correct diagnosis and management of patients followed up after OLT.