Hepatocytes with a phenotype of substantial CYP3A4 induction generated from drug-associated fulminant hepatitis-derived induced pluripotent stem cells

Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4). Hepatocytes are often employed to evaluate drug-mediated CYP3A4 induction, but the variation between different cell lots is an issue that needs to be solved. Only a limited number of immortalized hepatocyte cell lines have been reported to date. In this study, we describe the successful generation of hepatocytes from disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with fulminant hepatitis (FH-iPSCs). To examine the CYP3A4 induction potential, FH-iPSCs were induced into hepatocytes. Drug-mediated induction testing revealed that HepaKI exhibited a 57.2-fold increase in CYP3A4 after exposure to rifampicin, relative to control cells. These results suggest that FH-iPSCs are a preferred cell source for in vitro CYP3A4 induction assays.

Human Wharton's jelly-derived mesenchymal stem cells alleviate concanavalin A-induced fulminant hepatitis by repressing NF-κB signaling and glycolysis

Background Fulminant hepatitis is a severe life-threatening clinical condition with rapid progressive loss of liver function. It is characterized by massive activation and infiltration of immune cells into the liver and disturbance of inflammatory cytokine production. Mesenchymal stem cells (MSCs) showed potent immunomodulatory properties. Transplantation of MSCs is suggested as a promising therapeutic approach for a host of inflammatory conditions. Methods In the current study, a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model was used to investigate the effects of transplanting human umbilical cord Wharton's jelly-derived MSCs (hWJ-MSCs) on fulminant hepatitis. Results We showed that hWJ-MSCs effectively alleviate fulminant hepatitis in mouse models, primarily through inhibiting T cell immunity. RNA sequencing of liver tissues and human T cells co-cultured with hWJ-MSCs showed that NF-κB signaling and glycolysis are two main pathways mediating the protective role of hWJ-MSCs on both Con A-induced hepatitis in vivo and T cell activation in vitro. Conclusion In summary, our data confirmed the potent therapeutic role of MSCs-derived from Wharton's jelly of human umbilical cord on Con A-induced fulminant hepatitis, and uncovered new mechanisms that glycolysis metabolic shift mediates suppression of T cell immunity by hWJ-MSCs.

A case report of fulminant hepatitis due to ribociclib with confirmed by liver biopsy in breast cancer

Introduction Breast cancer is the most frequently diagnosed cancer in women worldwide. Ribociclib is now frequently used in the treatment of metastatic hormone-positive and human epidermal growth factor receptor 2 (HER 2)-negative breast cancer. Case Report A 54-year-old woman with breast cancer presented at a clinic in November 2017 with multiple lung and bone metastases. After receiving multiple lines of treatment due to disease progression, ribociclib and fulvestrant were initiated. Grade 4 toxicity was observed due to ribociclib during follow-up, and ribociclib was discontinued permanently. Management & Outcome: Given that liver transaminases and bilirubin elevation persisted despite discontinuation of the treatment, other reasons for liver toxicity were investigated. Abdominal MRI showed no liver metastases, although there was acute hepatitis. A liver biopsy was performed to determine the etiology. The pathology result was compatible with drug-induced acute fulminant toxic hepatitis. After liver biopsy, prednisolone treatment was initiated, after which the laboratory findings normalized. Discussion Although there are reported cases showing improvement in liver enzymes after ribociclib discontinuation, in our case, no recovery from hepatotoxicity was noticed. The treatment was changed to another hormonal pathway therapy option, exemestane. To the best of our knowledge, this is the first case in the literature reporting this rare side effect of ribociclib, which is a liver biopsy-proven fulminant hepatitis.

Peculiarities of clinical course of Wilson's disease in children

Purpose — to discover peculiarities of Wilson disease course in children dependently on the variant of liver affection. Materials and methods. Anamnesis of the disease and clinical and paraclinical peculiarities of the course of the disease with consideration of liver affection severity have been studied in 50 children aged 5–17 years. Results. It was estimated that in 52% of children the disease had a form of chronic hepatitis with minimal clinical symptoms, 44% of patients had liver cirrhosis with predominant signs of edematous and ascitic syndrome and 4% had fulminant hepatitis in a debut of the disease. Complicated family anamnesis was detected in 4% of patients. Syndrome of cytolysis predominated in patients with liver damage in the form of chronic hepatitis (р<0.05). Typical biochemical changes in cirrhotic patients were hepatocellular insufficiency with hypoalbuminemia and coagulopathy, hyperbilirubinemia and minimal hypertransaminasemia (р<0.05). Children with cirrhosis in contrast to patients with chronic hepatitis had reliably lower serum ceruloplasmin concentration and reliably higher excretion of copper with urine. Specific for Wilson disease Kayser—Fleischer rings were found out in 36% of patients only. Conclusions. Wilson's disease in children is characterized by progressing course in the form of either chronic hepatitis or liver cirrhosis or, rarely, fulminant hepatitis. Clinical and paraclinical symptoms of the disease are estimated by the severity of liver affection and vary from a course with minimal symptoms in patients with chronic hepatitis to edematous and ascitic syndrome and hepatocellular insufficiency in patients with cirrhosis and fulminant hepatitis. The research was carried out in accordance with the principles of the Helsinki declaration. The study protocol was approved by the Local Ethics Committee of all participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: Wilson's disease, children, chronic hepatitis, liver cirrhosis, course of the disease.

Everolimus Related Fulminant Hepatitis in Pancreatic Neuroendocrine Tumor With Liver Metastases: A Case Report and Literature Review

BackgroundEverolimus, an immunosuppressant, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs) but has been reported to be related to hepatitis B reactivation. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR).Case PresentationA 45-year-old male had a history of chronic hepatitis B infection. He was found to have a complicated liver cyst incidentally, and then he underwent biopsy, which disclosed a grade 2 neuroendocrine tumor (NET). Subsequent MRI of the abdomen and PET revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases and peripancreatic lymph node metastases. Transarterial chemoembolization (TACE) of the right lobe of the liver was performed, and he started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every month 8 days after the 1st TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. He then underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. He continued everolimus 5 mg twice a day and octreotide 20 mg every month after the operation. Three months later, hepatic failure occurred due to acute hepatitis B flare-up–related fulminant hepatic failure since other possible causes of hepatic failure were excluded. Five days after hepatic failure presented, hepatic failure was apparent, and pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation.ConclusionA literature review of everolimus-related hepatitis B reactivation was conducted. In P-NET patients with chronic hepatitis B who will undergo everolimus treatment, HBV prophylaxis should be considered since fatal hepatitis B reactivation might occur under rare conditions.

Hemophagocytic lymphohistiocytosis in pregnancy evolving towards fulminant hepatitis

Background Hemophagocytic lymphohistiocytosis is a rare disorder, especially in pregnancy, characterized by excessive immune activation leading to hemophagocytic activity. Case Report A 34-year-old woman presented at 31 weeks’ gestation with fever, cytopenias, hyperferritinemia and fulminant hepatitis. Bone marrow biopsy was non-contributory, and no trigger was identified. Liver biopsy confirmed the diagnosis of hemophagocytic lymphohistiocytosis, and she received dexamethasone and etoposide, which was changed to anakinra to allow breastfeeding. Prompt diagnosis and treatment of hemophagocytic lymphohistiocytosis is crucial to the survival of pregnant women, but no consensus exists regarding the most appropriate therapy during pregnancy. Conclusion Hemophagocytic lymphohistiocytosis is life-threatening and associated with significant morbidity and mortality. Important treatment considerations in pregnancy include maternal health, fetal prematurity and treatment toxicity. Anakinra has been successfully used in pregnancy and provides a promising alternative.