Autophagy: A Unique Ultrastructural Feature of Hepatitis C Viral Hepatitis
SD Norwood, G Sidhu, N Cassai, G-Y Yang. Northwestern University Feinberg School of Medicine, Chicago, IL; New York University School of Medicine & New York VA Hospital, New York, NY
Background: Typical histopathological features of chronic hepatitis C virus (HCV) infection are subtle bile duct damage, lymphocyte predominant portal tract inflammation, and mild steatosis. However, the effects of HCV on hepatocytes are uncertain. In vitro experiments have shown that HCV induced the accumulation of autophagosomes in immortalized human hepatocytes, without enhancing protein degradation by autophagosomes, probably indicating a defense mechanism to HCV infection . Here, we report direct evidence of the presence of autophagosomes seen on electron microscopy in HCV biopsy specimens, which were also correlated with HCV viral load, and histologic grade of hepatitis.
Design: 83 liver biopsy specimens, including 71 HCV and 12 non-HCV (5 hepatitis B, 5 cholestatic disease, and 2 autoimmune hepatitis), were analyzed histologically and ultrastructurally. Hepatitis C viral load and genotype were also determined.
Results: On electron microscopy, small double-membraned organelles located in the pericanalicular cytoplasm of hepatocytes and corresponding to autophagosomes (Figure 1) were found in 70 of 71 HCV cases, but not in non-HCV cases. Histologically, the affected hepatocytes lacked lipofuscin. 1 of the 71 HCV biopsies had no autophagosomes, exhibited a non-detectable HCV viral load (< 5,000 copies/ml), and showed extensive lipofuscin deposits. 7 of the 71 HCV biopsies had scanty autophagosomes (defined as < 3 autophagosomes per hepatocyte), exhibited low or non-detectable HCV viral loads (< 100,000 copies/ml), and had mild portal tract inflammation and fibrosis. The remaining HCV biopsies showed numerous autophagosomes (> 10 autophagosomes per hepatocyte), exhibited high viral loads (> 100,000 copies/ml), and most showed severe portal inflammation.
Conclusions: Autophagosomes are a unique ultrastructural feature occurring in HCV-infected hepatocytes, and appear to be useful correlates of HCV viral load, intensity of inflammation and hepatocyte injury. The biological significance of autophagosomes in HCV needs to be further investigated, particularly for its role in HCV pathogenesis.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 261, Wednesday Morning