Laser captured hepatocytes show association of butyrylcholinesterase gene loss and fibrosis progression in hepatitis C-infected drug users

• Published in: Hepatology (Baltimore, Md.) Vol. 56; no. 2; pp. 544 - 554
• Main Authors: Munshaw, Supriya, Hwang, Hyon S., Torbenson, Michael, Quinn, Jeffrey, Hansen, Kasper D., Astemborski, Jacquie, Mehta, Shruti H., Ray, Stuart C., Thomas, David L., Balagopal, Ashwin
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2012; Wiley; Wolters Kluwer Health, Inc
• Subjects: Addictive behaviors; Adult; Adult and adolescent clinical studies; Apnea; Biological and medical sciences; Butyrylcholinesterase - deficiency; Butyrylcholinesterase - genetics; Butyrylcholinesterase - metabolism; Disease Progression; Drug addiction; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene expression; Gene Expression Profiling; Genotype; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - genetics; Hepatitis C, Chronic - pathology; Hepatitis C, Chronic - virology; Hepatocytes - physiology; Hepatocytes - virology; Hepatology; Human viral diseases; Humans; Infectious diseases; Laser Capture Microdissection - methods; Lasers; Liver cirrhosis; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver Cirrhosis - virology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Longitudinal Studies; Male; Medical sciences; Metabolism; Metabolism, Inborn Errors - genetics; Metabolism, Inborn Errors - pathology; Metabolism, Inborn Errors - virology; Middle Aged; Portal System - cytology; Portal System - physiology; Portal System - virology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Substance-Related Disorders - genetics; Substance-Related Disorders - pathology; Substance-Related Disorders - virology; Viral diseases; Viral hepatitis; Human; Drug addiction; Prognosis; Hepatic disease; Infection; Hepatocyte; Viral disease; Fibrosis; Gastroenterology; Laser; Digestive diseases; Evolution; Viral hepatitis C
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.25655

Chronic hepatitis C virus (HCV) infection is complicated by hepatic fibrosis. Hypothesizing that early fibrogenic signals may originate in cells susceptible to HCV infection, hepatocyte gene expression was analyzed from persons with chronic HCV at different stages of liver fibrosis. Four HCV‐infected subjects with precirrhosis liver fibrosis (Ishak fibrosis 3‐5) were matched for age, race, and gender to five HCV‐infected subjects with no evidence of fibrosis (Ishak fibrosis 0). Hepatocytes from each subject were isolated from liver biopsies using laser capture microdissection. Transcriptome profiling was performed on hepatocyte RNA using hybridization arrays. We found that hepatocytes in precirrhosis fibrosis were depleted for genes involved in small molecule and drug metabolism, especially butyrylcholinesterase (BCHE), a gene involved in the metabolism of drugs of abuse. Differential expression of BCHE was validated in the same tissues and cross‐sectionally in an expanded cohort of 143 HCV‐infected individuals. In a longitudinal study, serum BCHE activity was already decreased at study inception in 19 fibrosis progressors compared with 20 fibrosis nonprogressors (P < 0.05). Nonprogressors also had decreased BCHE activity over time compared with initial values, but these evolved a median (range) 8.6 (7.8‐11.4) years after the study period inception (P < 0.05). Laser captured portal tracts were enriched for immune related genes when compared with hepatocytes but precirrhosis livers lost this enrichment. Conclusion: Chronic HCV is associated with hepatocyte BCHE loss years before hepatic synthetic function is impaired. These results indicate that BCHE may be involved in the pathogenesis of HCV‐related fibrosis among injection drug users. (HEPATOLOGY 2012)