HFE Gene Mutations in AAT Deficiency and HCV Cirrhosis
M Lam, M Torbenson, M Yeh, P Vivekanandan, L Ferrell. UCSF, San Francisco, CA; Johns Hopkins, Baltimore, MD; Univ of Washington, Seattle, CA
Background: HFE gene mutations for C282Y and H63D are seen in 11.6% and 27.4% of US Caucasians, respectively. Studies have suggested an increased risk for advanced fibrosis in chronic hepatitis C (HCV) patients with these mutations. Cirrhotic patients without HFE defects may also have iron overload, causing cardiac failure on rare occasion post liver transplant. To further examine the association between HFE mutations and iron overload in cirrhosis, we examined endstage HCV and alpha-1 antitrypsin deficiency (AAT), the latter noted for its variable clinical phenotype, to determine if HFE mutations may be enriched or enhance iron overload.
Design: Charts were reviewed for 45 AAT and 33 HCV cirrhotic explants for evidence of iron overload; iron was graded by iron stain, scale 0-4; AAT was confirmed by PASD or immunostain. Analysis for C282Y, H63D, and other rare HFE mutations was performed by PCR and sequencing. Statistical analysis of iron grade between groups was performed.
Results: Analysis showed a similar frequency of mutations in HCV cirrhotics compared to expected for the general population, with total frequencies of C282Y=15% and H63D=27% (C282Y/wt=4; C282Y/H63D=1; H63D/H63D=2; H63D/wt=6). Total frequencies for AAT were C282Y=2% and H63D=42% (C282Y/wt=1; H63D/H63D=2; H63D/wt=17). The frequency of H63D mutations in AAT vs expected was higher (42% vs 27%) but not statistically significant, p=0.119. Iron stains on 44 AAT showed: 0+(N=8), 1+(N=18), 2+(N=5), 3+(N=11), 4+(N=2); on 33 HCV showed: 0+(N=0), 1+(N=9), 2+(N=16), 3+(N=8), 4+(N=0); no statistical difference noted. Other rare mutations identified include one S65C mutation in HCV and one novel A271S mutation in AAT; this patient had 4+ iron in the liver explant and later developed heart failure with cardiac iron. No other patients developed heart failure, regardless of degree of iron in the liver explant or HFE mutation status.
Conclusions: We were unable to confirm a greater than expected frequency of HFE mutations in HCV or AAT cirrhotics. Although H63D mutations are high (42%) in patients with AAT, this was not statistically significant, and its role in AAT cirrhosis is unclear. A novel A271S HFE mutation was found in one AAT case with heart failure and cardiac iron deposits; this suggests that HFE testing for the C282Y and H63D mutations in AAT and HCV patients without clinical signs of iron overload pretransplant is not predictive of significant iron overload and risk for cardiac failure following transplant.
Category: Liver & Pancreas
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 208, Monday Morning