Mycophenolate Mofetil Hepatotoxicity Associated With Mitochondrial Abnormality in Liver Transplant Recipients and Mice.

OBJECTIVES: Mycophenolate mofetil (MMF) is a widely used immunosuppressive agent. MMF hepatotoxicity has been reported in non-transplant and renal transplant patients with minimal histologic description. This is the first study describing detailed histology and ultrastructure of MMF hepatotoxicity. METHODS: Four liver-transplant recipients (Cases 1-4) were suspected to have MMF hepatotoxicity. Cases 1-3 (two females and one male; 4-17 years) had multiple biopsies for liver function test (LFT) abnormalities. Case 4 (female; 16 years) had a surveillance biopsy. Electron-microscopic examination (EM) was requested on Cases 1-3 for unexplained, persistent LFT elevation and histologic abnormalities despite therapy and Case 4 for unexplained histologic abnormalities despite a stable clinical course. To confirm the pathologic changes in the human allografts, livers from MMF-treated and untreated mice were also reviewed. RESULTS: While the allograft biopsies showed nonspecific histologic changes, EM revealed unequivocal mitochondrial abnormalities similar to those seen in primary and secondary mitochondrial disorders. In Cases 1 and 2, LFTs improved after stopping and reducing MMF, respectively. In Case 3, pre- and post-MMF treatment biopsies were performed and only the post-MMF biopsy demonstrated mitochondrial abnormalities. Mitochondrial abnormality in Case 4 was subclinical. The mouse study confirmed that MMF caused various stress changes in the mitochondria; number of mitochondria/cell (mean ± standard deviation; untreated group: 58.25 ±â€Š8.426; MMF-treated group: 76.37 ±â€Š18.66), number of lipid droplets/cell (untreated: 0.9691 ±â€Š1.150; MMF-treated: 3.649 ±â€Š4.143) and sizes of mitochondria (µm, untreated: 0.8550 ±â€Š0.3409; MMF-treated: 0.9598 ±â€Š0.5312) were significantly increased in hepatocytes in the MMF-treated mice compared with the untreated mice (P < 0.0001). CONCLUSIONS: Although MMF is safe for the majority of patients, MMF can cause mitochondrial stress, which may trigger more severe mitochondrial abnormalities in a small subset. MMF hepatotoxicity should be considered for MMF-treated patients with unexplained, persistent LFT abnormalities and nonspecific histologic findings. EM should be requested for these cases.

Autoimmune Gastritis in Pediatrics: A Review of 3 Cases.

OBJECTIVES: To bring heightened awareness to a condition, autoimmune gastritis (AIG), which is a well-established entity in adults; however, rarely described in pediatrics. Currently, the literature describes AIG in pediatric patients who also suffer from other autoimmune disorders, which precedes the diagnosis of AIG, and often presents with unexplained anemia. Additionally, there have been case reports describing patients with immunodeficiencies and AIG, which progress to gastric adenocarcinoma. AIG is a histopathologic diagnosis, demonstrating chronic inflammatory process with loss of parietal cells with or without intestinal metaplasia and enterochromaffin-like cell hyperplasia. Management of these patients includes nutritional replacement as well as routine surveillance endoscopy with biopsy in search of metaplastic and dysplastic changes. METHODS: We queried the pathology database at Children's Hospital Los Angeles (CHLA) for cases with a final diagnosis of AIG and for those with a differential diagnosis that includes AIG in the diagnostic comment. All cases that were identified were selected as long as they did not only meet the histopathologic criteria, but also the biochemical criteria for this condition. RESULTS: Of the 3 patients, 2 were referred to gastroenterology for the evaluation of iron-deficiency anemia in the context of diabetes mellitus and Addison's disease; and diabetes mellitus and Hashimoto's thyroiditis. AIG was confirmed on the biopsies, which showed a reduction in parietal cell mass, pseudopyloric metaplasia and enterochromafin-like cell hyperplasia. Both patients were treated with iron replacement therapy. The third patient presented with symptomatic anemia and diagnosed with pernicious anemia without other autoimmune disorders. She was successfully treated with oral vitamin supplementation. In this case, serial gastric biopsies demonstrated stable intestinal metaplasia without evidence of dysplasia. CONCLUSION: Although AIG is rare in children, pediatric gastroenterologists and pathologists should have a heightened suspicion for this entity in those patients with a history of autoimmune disorders and/or pernicious anemia.

Pediatric Nonalcoholic Fatty Liver Disease.

Obesity has led fatty liver disease to become the most common chronic liver disease in children worldwide. Pediatric professional organizations have agreed that screening for fatty liver disease in children is the need of the hour. Once identified, prevention is key through appropriate dietary and activity prescriptions. Research continues to identify key pathways and genetic risk factors that predispose certain children to the more severe manifestations of this silent epidemic. We hope these novel observations lead to breakthrough treatments for these children that are severely impacted, such that they may no longer need liver transplantation as young adults.

Clinicopathologic Characteristics of Late Acute Antibody-mediated Rejection in Pediatric Liver Transplantation.

BACKGROUND: An early and accurate diagnosis of liver antibody-mediated rejection (AMR) followed by timely intervention is important for clinical management but remains challenging. The aim of this study was to assess the clinicopathologic characteristics and outcomes of late acute AMR in pediatric liver transplantation recipients. METHODS: We performed a retrospective review of 739 ABO-identical/compatible allograft liver biopsies from 199 pediatric transplantation recipients. RESULTS: Based on Banff 2016 AMR criteria, 3 recipients fulfilled the criteria for definite for late acute AMR, 2 met the criteria for suspicious for AMR, and 2 were indeterminate for AMR. We further assessed the clinicopathologic characteristics of these 7 patients. All 7 patients had at least 1 biopsy with a histopathologic pattern compatible with acute AMR. Additionally, we observed accompanied moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury in all 7 patients; periportal/perivenular hepatocyte necrosis was seen in 6 of 7 patients; and arteritis was seen in 3 of 7 patients. In each case, microvascular C4d deposition was present in at least 1 biopsy. Posttransplant donor specific anti-HLA antibodies were detected in 5 patients. Two of 7 patients were retransplanted, and 2 died after developing refractory AMR. The remaining 5 patients were alive with stable graft function at a median follow-up of 4.1 years. CONCLUSIONS: Our data suggest that acute AMR in pediatric liver grafts is rare, can develop late, and may be associated with graft loss or patient death. The recurrent histopathologic findings of moderately to markedly dilated portal/central veins and endothelialitis disproportionate to the degree of bile duct injury are features that appear unique to pediatric acute AMR of liver grafts.

Severe Late-Onset Acute Cellular Rejection in a Pediatric Patient With Isolated Small Intestinal Transplant Rescued With Aggressive Immunosuppressive Approach: A Case Report.

Small intestinal transplantation is performed for patients with intestinal failure who failed other surgical and medical treatment. It carries notable risks, including, but not limited to, acute and chronic cellular rejection and graft malfunction. Late severe acute intestinal allograft rejection is associated with increased risk of morbidity and mortality and, in the majority of cases, ends with total enterectomy. It usually results from subtherapeutic immunosuppression or nonadherence to medical treatment. We present the case of a 20-year-old patient who underwent isolated small bowel transplant for total intestinal Hirschsprung disease at age 7. Due to medication nonadherence, she developed severe late-onset acute cellular rejection manifested by high, bloody ostomy output and weight loss. Ileoscopy showed complete loss of normal intestinal anatomic landmarks and ulcerated mucosa. Graft biopsies showed ulceration and granulation tissue with severe architectural distortion consistent with severe intestinal graft rejection. She initially received intravenous corticosteroids and increased tacrolimus dose without significant improvement. Her immunosuppression was escalated to include infliximab and finally antithymocyte globulin. Graft enterectomy was considered repeatedly; however, clinical improvement was noted eventually with evidence of histologic improvement and salvage of the graft. The aggressive antirejection treatment was complicated by development of post-transplant lymphoproliferative disorder that resolved with reducing immunosuppression. Her graft function is currently maintained on tacrolimus, oral prednisone, and a periodic infliximab infusion. We conclude that a prompt and aggressive immunosuppressive approach significantly increases the chance of rescuing small bowel transplant rejection.

Utility of hepatobiliary scintigraphy in diagnosing or excluding biliary atresia in premature neonates and full-term infants with conjugated hyperbilirubinemia who received parenteral nutrition.

PURPOSE: Hepatobiliary scintigraphy (HBS) is used to aid in the diagnosis of Biliary Atresia in full-term infants with conjugated hyperbilirubinemia. There is little information on the utility of the HBS in premature infants with conjugated hyperbilirubinemia and infants with parenteral nutrition associated cholestasis (PNAC). The purpose of this study is to assess the utility of HBS in differentiating Biliary Atresia and PNAC in premature neonates and full-term infants who received parenteral nutrition (PN). MATERIALS AND METHODS: Retrospective data collection and analysis on infants who developed conjugated hyperbilirubinemia and had HBS performed during their stay at level IV neonatal intensive care unit between 2005 and 2015. RESULTS: A total of 20 patients with exposure to PN had HBS; two patients were confirmed to have Biliary Atresia. There were no statistically significant differences between patients with Biliary Atresia versus PNAC in demographics, days on PN, or gamma glutamyl-transferase levels. Stool color was statistically significantly different between the two groups; patients with Biliary Atresia had acholic stools more consistently than patients without Biliary Atresia. HBS had 100% sensitivity, 17% specificity, positive-predictive value of 12%, and a negative-predictive value (NPV) of 100%. CONCLUSIONS: These data indicate that the ability of HBS to aid in diagnosing Biliary Atresia is poor in a population of preterm neonates and full-term infants with PNAC. Although there is 100% sensitivity, the poor specificity (17%) should be acknowledged when utilizing HBS to diagnose Biliary Atresia in this vulnerable patient population. NPV of 100% is helpful in ruling out Biliary Atresia in this population.