title: Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease.
abstract: Fibrinogen storage disease (FSD) is a rare autosomal-dominant hereditary disorder characterized by hypofibrinogenemia and accumulation of fibrinogen aggregates within the hepatocellular endoplasmatic reticulum (ER). Some FSD patients present with elevated amino-transferases and fibrosis/cirrhosis similar to alpha-1-antitrypsin deficiency (ATD), also an ER storage disease. Pharmacological stimulation of autophagy has been shown to mediate clearance of protein aggregates and halt progression of liver fibrosis in in vivo models of ATD. Our aim was to evaluate the presence of autophagy and a possible response to autophagy-enhancing therapy in patients with FSD. Hepatic fibrosis was assessed by transient elastography in 2 newly identified FSD families with fibrinogen Aguadilla and Brescia mutations, encompassing 8 affected members. Available liver biopsies were assessed for autophagy. Two patients, who had had elevated alanine amino-transaminase levels (2-5 above upper limit of normal), were treated with the autophagy enhancer carbamazepine (CBZ). Transient elastography did not show evidence of significant fibrosis in any affected family members. Quantitative electron microscopy of one patient showed a 5.15-fold increase of late stage autophagocytic vacuoles compared to control livers. CBZ at low anticonvulsive treatment levels led to rapid normalization of alanine-aminotransferase and decrease of caspase-cleaved and uncleaved cytokeratin-18 fragments (M30 and M65). These effects reversed after discontinuation of treatment. Response to CBZ may be mediated by pharmacologically enhanced autophagy resulting in reduction of aggregate-related toxicity in FSD. These results suggest clinical applicability of pharmacological stimulation of autophagy in FSD, but potentially also in other related disorders.
authors.affiliation: Institute of Pathology, Hannover Medical School, Hannover, Germany. florian.puls@nhs.net
authors.forename: Florian
authors.initials: F
authors.lastname: Puls
authors.forename: Imeke
authors.initials: I
authors.lastname: Goldschmidt
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
authors.forename: Clemens
authors.initials: C
authors.lastname: Agne
authors.forename: Verena
authors.initials: V
authors.lastname: Bröcker
authors.forename: Maximilian
authors.initials: M
authors.lastname: Dämmrich
authors.forename: Ulrich
authors.initials: U
authors.lastname: Lehmann
authors.forename: Jens
authors.initials: J
authors.lastname: Berrang
authors.forename: Eva-Doreen
authors.initials: ED
authors.lastname: Pfister
authors.forename: Hans Heinrich
authors.initials: HH
authors.lastname: Kreipe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
mesh_terms: D000347:Afibrinogenemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000187:drug effects; D002220:Carbamazepine / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D054459:Elasticity Imaging Techniques; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D010375:Pedigree; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D002220:Carbamazepine; D005340:Fibrinogen
keywords: ALT; AST; ATD; Autophagy; CBZ; Cirrhosis; ER; EVG; Elastic Van Gieson; Elasticity imaging techniques; FGC; FSD; Fibrinogen; Fibrinogen storage disease; H&E; INR; IQR; OM; TEM; alpha-1-antitrypsin deficiency; aspartate aminotransferase; carbamazepine; endoplasmatic reticulum; fibrinogen gamma chain; fibrinogen storage disease; hematoxylin/eosin; international normalized ratio; interquartile range; n.t.; not tested; original magnification; serum alanine aminotransferase; transmission electron microscopy