Pathomorphogenesis of Glycogen-Ground Glass Hepatocytic Inclusions (Polyglucosan Bodies) in Children after Liver Transplantation

Seventeen out of 764 liver biopsies from transplanted (Tx) livers in children showed glycogen-ground glass (GGG) hepatocytic inclusions. The inclusions were not present in pre-Tx or in the explanted or donor’s liver. Under the electron microscope (EM), the stored material within the cytosol appeared as non-membrane-bound aggregates of electron-lucent globoid or fibrillar granules, previously described as abnormally structured glycogen and identified as Polyglucosan bodies (PB). The appearance of GGG in our children was analogous to that of PB-GGG occurring in a number of congenital diseases due to gene mutations such as Lafora’s d., Andersen’s d., Adult Polyglucosan Body Disease and glycogenin deficiency. The same type of GGG was previously reported in the liver of patients undergoing transplants, immunosuppressive or antiblastic treatment. To explore the potential mechanism of GGG formation, we examined whether the drugs after whose treatment this phenomenon was observed could have a role. By carrying out molecular docking, we found that such drugs somehow present a high binding affinity for the active region of glycogenin, implicating that they can inactivate the protein, thus preventing its interaction with glycogen synthase (GS), as well as the maturation of the nascent glycogen towards gamma, beta or alfa glycogen granules. We could also demonstrate that PG inclusions consist of a complex of PAS positive material (glycogen) and glycogen-associated proteins, i.e., glicogenin-1 and -2 and ubiquitin. These features appear to be analogous to congenital GGG, suggesting that, in both cases, they result from the simultaneous dysregulation of glycogen synthesis and degradation. Drug-induced GGG appear to be toxic to the cell, despite their reversibility

Albuminuria and insulin resistance in children with biopsy proven non-alcoholic fatty liver disease

Insulin resistance may favor increased urinary albumin excretion (UAE), leading progressively to chronic kidney disease (CKD). A recent study on non-alcoholic fatty liver disease (NAFLD), a condition of insulin resistance, associated this disease with the incidence of CKD in patients with type 2 diabetes. The aim of our study was to determine whether there is an association between insulin resistance and kidney function, based on estimates of UAE and creatinine clearance in children with biopsy-proven NAFLD. Kidney function was assessed in 80 patients with NAFLD and 59 individuals of normal weight matched for age and sex. Insulin resistance was measured by means of the homeostatic model assessment-insulin resistance (HOMA-IR) and limited to NAFLD patients by using the whole-body insulin sensitivity index. The HOMA-IR was found to differ significantly between the two groups (2.69 +/- 1.7 vs. 1.05 +/- 0.45; p = 0.002), while UAE (9.02 +/- 5.8 vs. 8.0 +/- 4.3 mg/24 h; p = 0.9) and creatinine clearance (78 +/- 24 vs. 80 +/- 29 mg/min; p = 0.8) did not. We found a significant but weak inverse correlation between insulin sensitivity and creatinine clearance in NAFLD patients (r (s) = -0.25;p = 0.02). No difference was observed in kidney function between NAFLD children presenting with or without metabolic syndrome, low or normal HDL-cholesterol, and different degrees of histological liver damage (grade of steatosis a parts per thousand yen2, necro-inflammation, and fibrosis). Patients with hypertension had increased levels of UAE (p = 0.04). A longer exposure to insulin resistance may be required to cause the increase in urinary albumin excretion and to enable the detection of the effect of the accelerated atherogenic process most likely occurring in children with fatty liver disease. Longitudinal studies are needed to rule out any causative relationship between insulin resistance and urinary albumin excretion

Severe liver disease in early childhood due to fibrinogen storage and de novo gamma375Argâ\u86\u92Trp gene mutation

We report hypofibrinogenemia and massive hepatic storage of fibrinogen in a child with cryptogenic chronic liver disease. Fibrinogen gene analysis revealed a de novo Aguadilla (c.1201C>T; p.Arg375Trp) mutation. This mutation should be considered in childhood hypofibrinogenemia associated with chronic liver disease. © 2006 Elsevier Inc. All rights reserved

Paraneoplastic pemphigus and Castleman’s disease: a case report and a revision of the literature

Abstract Background In literature, a few reports described an association between paraneoplastic pemphigus (PNP) and Castelman’s disease (CD), but no consensus have been proposed for the diagnostic-therapeutical approach. Aim of this study is to present a case report and explore the relationship between PNP and CD in pediatric patients, focusing on clinical manifestations, histopathological findings, treatment and outcome to find elements for an early diagnosis. Case presentation We present the clinical case of a 13 years old girl with a challenging diagnosis of PNP and CD who underwent therapy at first with Rituximab and then with Siltuximab, for the control of symptoms. Conclusions Reviewing literature, 20 clinical cases have been described in the pediatric age. Diagnosis may be challenging, requiring an average of 3 months (range from 3 weeks to 2 years). In all cases, the initial manifestations were mucocutaneous lesions, especially oral lesions with poor response to conventional treatment. Systemic symptoms may be present as well. Therapeutical approach is still discussed with no consensus. Almost all patients received corticosteroids with poor response. Other drugs including azathioprine, methotrexate, cyclosporine and monoclonal antibodies have been evaluated for the control of the disease. Further studies and experimental trials urge to define the diagnostic criteria and therapy protocol