Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comparative Study
. 2013 May;57(5):1806-13.
doi: 10.1002/hep.26238. Epub 2013 Mar 14.

Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease

Bryan D Maliken  1 , James E Nelson, Heather M Klintworth, Mary Beauchamp, Matthew M Yeh, Kris V Kowdley
Affiliations
Comparative Study

Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease

Bryan D Maliken et al. Hepatology. 2013 May.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest: None

Figures

Fig. 1
Fig. 1. Quantification of TUNEL staining in patients with hepatic iron deposition
TUNEL staining was performed and positive nuclei were counted and normalized to the number of cells per field by two blinded investigators in liver tissue of NAFLD patients with or without iron staining. Values are presented as mean ± SEM. P values are shown and significant differences are indicated by the arrow (Mann-Whitney test).
Fig. 2
Fig. 2. Differences in oxidative stress markers based on presence of iron deposition
Serum levels of the lipid peroxidation byproduct, malondialdehyde (MDA, white bars, left axis), and antioxidant enzyme thioredoxin-1 (Trx1, black bars, right axis) are shown together. Values are presented as mean ± SEM. P values are shown and significant differences are indicated by the arrow (Mann-Whitney test).
Fig. 3
Fig. 3. The effect of hepatic iron deposition on serum CK-18 levels
Serum levels of fragmented (M30, white bars) and total (M65, black bars) CK-18 were determined by ELISA and are shown according to the presence of either HC or RES iron staining. Levels are shown relative to the level of total M65 CK18 in patients without iron staining. P values are shown and significant differences are indicated by the arrow (Mann-Whitney test).
Fig. 4
Fig. 4. Proportion of CK18 fragments due to apoptosis or necrosis according to hepatic iron pattern
The percentage of CK-18 fragments due to apoptosis and necrosis, calculated using the following equation: [%apoptosis = (M30/M65)*100] or %necrosis=100-[(M30 CK-18/M65 CK-18)*100] were significantly different among groups (p=0. 047). Values are presented as mean ± SEM. Statistical analysis was performed using the Kruskal-Wallis test.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tiniakos DG, Vos MB, Brunt EM. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol. 2010;5:145–171. - PubMed
    1. Nelson JE, Klintworth H, Kowdley KV. Iron metabolism in Nonalcoholic Fatty Liver Disease. Curr Gastroenterol Rep. 2012;14:8–16. - PubMed
    1. Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, Unalp-Arida A, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology. 2011;53:448–457. - PMC - PubMed
    1. Eaton JW, Qian M. Molecular basis of cellular iron toxicity. Free Radic Biol Med. 2002;32:833–840. - PubMed
    1. Dizdaroglu M, Jaruga P, Birincioglu M, et al. Free radical induceddamage to DNA: mechanisms and measurement. Free RadicBiolMed. 2002;32:1102–1115. - PubMed

Publication types

MeSH terms