Steatohepatitis/Metabolic Liver Disease
Article first published online: 14 MAR 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 57, Issue 5, pages 1806–1813, May 2013
How to Cite
Maliken, B. D., Nelson, J. E., Klintworth, H. M., Beauchamp, M., Yeh, M. M. and Kowdley, K. V. (2013), Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology, 57: 1806–1813. doi: 10.1002/hep.26238
Potential conflict of interest: Nothing to report.
This work was supported by the National Institutes of Health (grant nos.: R01DK087696, K24DK02957, and K24DK02957.S1; to K.V.K.).
- Issue published online: 22 APR 2013
- Article first published online: 14 MAR 2013
- Accepted manuscript online: 16 JAN 2013 11:28AM EST
- Manuscript Accepted: 26 NOV 2012
- Manuscript Revised: 21 NOV 2012
- Manuscript Received: 24 AUG 2012
The aim of this study was to examine the relationship between the presence of hepatic iron deposition, apoptosis, histologic features, and serum markers of oxidative stress (OS) and cell death in nonalcoholic fatty liver disease (NAFLD). Clinical, biochemical, metabolic, and independent histopathologic assessment was conducted in 83 unselected patients with biopsy-proven NAFLD from a single center. Apoptosis and necrosis in serum was quantified using serum cytokeratin 18 (CK18) M30 and M65 enzyme-linked immunosorbent assays and in liver by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in situ. Serum malondialdehyde (MDA) and thioredoxin-1 (Trx1) levels were measured to evaluate OS. Presence of reticuloendothelial system (RES) cell iron in the liver was associated with nonalcoholic steatohepatitis (P < 0.05) and increased hepatic TUNEL staining (P = 0.02), as well as increased serum levels of apoptosis-specific (M30; P = 0.013) and total (M65; P = 0.006) CK18 fragments, higher MDA (P = 0.002) and lower antioxidant Trx1 levels (P = 0.012), compared to patients without stainable hepatic iron. NAFLD patients with a hepatocellular (HC) iron staining pattern also had increased serum MDA (P = 0.006), but not M30 CK18 levels or TUNEL staining, compared to subjects without stainable hepatic iron. Patients with iron deposition limited to hepatocytes had a lower proportion of apoptosis-specific M30 fragments relative to total M65 CK18 levels (37% versus ≤25%; P < 0.05). Conclusions: Presence of iron in liver RES cells is associated with NASH, increased apoptosis, and increased OS. HC iron deposition in NAFLD is also associated with OS and may promote hepatocyte necrosis in this disease. (HEPATOLOGY 2013)