Glutamine Synthetase Immunostaining in Regressed Cirrhosis
Rouba Hadi, Kseniya Shin, Nicholas Reder, Lindsay Alpert, Lisa Koch, Won-Tak Choi, John Hart, Maria Westerhoff. University of Washington, Seattle, WA; University of Chicago, Chicago, IL; University of California San Francisco, San Francisco, CA
Background: The prevailing view that cirrhosis is irreversible has been challenged. It is now accepted that varying degrees of regression can be achieved if the agent of injury is removed. The advent of drugs that cure hepatitis C (HCV) has also made regression a leading topic of clinical interest; it can potentially obviate long-term hepatocellular carcinoma surveillance. Therefore it is important for pathologists to recognize regressed cirrhosis (RC). In the normal liver, glutamine synthetase immunostaining (GS) is expressed around central veins (CV). In RC, although fibrous bands between portal tracts (PT) & CV may largely be resorbed, the abnormal PT-CV adherence often remains. Hence we hypothesized that aberrant GS positivity adjacent to PT (PT-GS+) would help recognize RC.
Design: We performed GS on 52 livers (26 explants, 9 biopsies, 17 resections), including 14 RC, 15 normal, 5 nodular regenerative hyperplasia (NRH), and 18 cirrhotic livers. Etiologies of liver disease in RC and cirrhotic groups included 4 cryptogenic, 17 HCV, 2 AIH, 2 HBV, 2 NASH, and 5 ETOH. Qualification for RC required histologic features as previously described: curved delicate incomplete septa, PT-CV adhesions, and PT “remnants” (PTs with no venous branch). 12/14 RC had baseline cirrhosis established based on previous biopsy (9) or signs of cirrhosis based on physical exam, laboratory & radiological findings. In the RC group, 3 had HCV treatment with viral eradication, 1 had HBV treatment, and 2 ETOH cirrhosis pts stopped drinking ETOH.
Results: The average age was 57 (M=31, F=21). All RC (100%) had areas of aberrant PT-GS+, indicating that PT-CV approximation had occurred (p<0.0003 compared to all other categories). No normal cases had PT-GS+, but all had the expected CV-GS+. Half of cirrhosis cases had areas showing regression, including PT-GS+. Cirrhotic cases that did not show regression had almost complete loss of GS or only focal perivenular GS, as previously reported. Only 1 NRH showed PT-GS+. Overall, PT GS+ showed highly significant differences between the 4 categories (p<0.00001).
Conclusions: This study shows that aberrant PT-GS+ is present in RC and can be useful in identifying regression. It validates previous literature that areas of regression are found in many cirrhotic livers. It also underscores the inadequacy of current staging systems to indicate RC, and affirm clinicians’ high suspicion for cirrhosis that have then histologically regressed. In conclusion, pathologists can use GS to help diagnose RC.