piperidines and Hepatitis--Autoimmune

The prevalence of immune‑mediated liver diseases such as autoimmune liver disease or viral hepatitis has increased in recent years, and the side effects of pre‑existing treatments are a worldwide problem. Regulatory T cells (Tregs) and T helper 17 (Th17) cells play important roles in the development of immune‑mediated hepatitis and may serve as potential therapeutic targets. Tofacitinib, a new Janus kinase (JAK) inhibitor, is under investigation for the treatment of rheumatoid arthritis; it is also helpful in treating ulcerative colitis and psoriasis. The roles of tofacitinib were investigated in conferring protection against immune‑mediated liver injury in mice. T cell‑mediated hepatitis was induced by concanavalin A (ConA). The mice in the treatment groups were administered with tofacitinib intragastrically before the ConA injection. Histopathological examination was performed by hematoxylin and eosin (H&E) staining, and the serum transaminase and inflammatory cytokine levels were determined using an automatic biochemistry analysis apparatus or cytometric bead array (CBA) kits. Flow cytometric analysis was used to detect Tregs and Th17 cells. Tofacitinib significantly decreased the hepatic injury induced by ConA and prominently decreased the liver transaminase level. The secretion of several anti‑inflammatory cytokines such as interleukin (IL)‑10 was upregulated in mice from the treatment group, compared to that in mice treated with ConA alone, while the expression of interferon‑γ (IFN‑γ) and tumor necrosis factor‑α (TNF‑α) decreased. Tofacitinib treatment increased the number of Tregs and reduced the number of Th17 cells. Furthermore, tofacitinib could relieve liver fibrosis under conditions of autoimmune hepatitis (AIH). The present results indicated that tofacitinib improved immune‑mediated hepatitis and restored the impaired Treg/Th17 cell ratio, which suggests that it may serve as a novel treatment approach for immune‑mediated liver diseases.

Topics: Animals; Hepatitis, Autoimmune; Interferon-gamma; Interleukin-10; Janus Kinase Inhibitors; Liver; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrimidines; Pyrroles; T-Lymphocytes, Regulatory; Th17 Cells

We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication.

Topics: Adult; Amyotrophic Lateral Sclerosis; Azathioprine; Benzamides; Biopsy; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Piperidines; Prednisone; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Severity of Illness Index; Thiazoles; Time Factors; Treatment Outcome

Remifentanil is a useful adjunct in general anesthesia for high-risk obstetric patients. It provides effective blunting of the rapid hemodynamic changes that may be associated with airway manipulation and surgical stimulation. There have been no previous reports of opioid-related rigidity in the neonate delivered by a parturient receiving intraoperative remifentanil. We present a case of short-lived neonatal rigidity and respiratory depression following remifentanil administration during cesarean section to a parturient with autoimmune hepatitis complicated by cirrhosis, esophageal varices and thrombocytopenia.

Topics: Adult; Analgesia, Obstetrical; Analgesics, Opioid; Blood Pressure; Cesarean Section; Esophageal and Gastric Varices; Female; Heart Rate; Hepatitis, Autoimmune; Humans; Infant, Newborn; Male; Muscle Rigidity; Piperidines; Pregnancy; Remifentanil; Respiratory Insufficiency; Thoracic Wall; Thrombocytopenia

Uridine diphosphate glucuronosyltransferase (UGT) was identified as an antigenic target in a subgroup of liver-kidney microsomal autoantibodies and was termed LKM-3. To evaluate the nature of LKM-3 antibodies, we screened sera from 80 untreated patients with autoimmune hepatitis (AIH) type 1 and 2, primary biliary cirrhosis (PBC), AIH/PBC, hepatitis C virus (HCV) infection, and 12 healthy individuals (controls) against 7 recombinant human UGT isoenzymes (UGT1A1, UGT1A4, UGT1A6, UGT1A7, UGT1A9, UGT1A10, and UGT2B7). Autoantibodies reacting against various UGT isoenzymes were observed in sera from 3 of 18 AIH type 2 and 1 of 27 of the HCV patients. The anti-UGT-positive sera from AIH type 2 patients revealed the strongest immunoreactivity against UGT1A1, the main UGT-isoform involved in the bilirubin glucuronidation. Additionally, these sera were able to block UGT-mediated substrate glucuronidation in vitro. The prevalence for UGT1A1 was shown by 2 independent techniques: (1) UGT1A1 was identified as the main antigen by Western blotting. Preabsorption of sera with UGT1A1 prevented reaction against all tested UGT-isoforms. (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation. In contrast, the serum from the HCV-patient reacted predominately with UGT1A6, and moreover, the immunoreactivity pattern was different from that of the AIH group. To summarize, we show the subtype preference of antibodies against UGT1A1 in a subgroup of AIH type 2 patients. These autoantibodies inhibit UGT-mediated glucuronidation in vitro, but it is unlikely that anti-UGT antibodies will have a marked effect on the patients capacity for drug biotransformation, as serum bilirubin levels in patients remained within the normal range.

Topics: Autoantibodies; Child; Cross Reactions; Female; Flavonoids; Glucuronides; Glucuronosyltransferase; Hepatitis C, Chronic; Hepatitis, Autoimmune; Humans; Hymecromone; Immunosuppressive Agents; Isoenzymes; Liver Cirrhosis, Biliary; Male; Piperidines; Recombinant Proteins; Reference Values