Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis

Kayali, Zeid; Ranguelov, Rostislav; Mitros, Frank A.; Shufelt, Chrisandra; Elmi, Farshad; Rayhill, Stephen C.; Schmidt, Warren N.; Brown, Kyle E.

doi:10.1111/j.1478-3231.2005.01022.x

Cited by 28 publications

(20 citation statements)

References 31 publications

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“…Nevertheless, iron was recently shown to inhibit the activity of HCV RNA dependent RNA polymerase (RdRP) as well as reducing replication in NS replicons (37). Our data clearly support these results, however, a potential antiviral role for iron must be considered in the context of clinical data showing that mild increases in storage iron correlate with progressive HCV liver disease and hepatic decompensation (38;39). Furthermore, a potential role for biliverdin and CO as inhibitors of viral replication through antioxidative behavior requires further study.…”

Section: Discussionsupporting

confidence: 84%

Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury

et al. 2008

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C hronic hepatitis C virus (HCV) infection is a worldwide health problem that can lead to chronic hepatitis, cirrhosis, and end-stage liver disease. 1 The virus has a plus-stranded RNA genome with a single long open-reading frame containing 5Ј and 3Ј flanking nontranslated nucleotide regions that are important for translation and replication. Although wild-type virus grows poorly in cell culture, 2 the development of subgenomic and full-length HCV replicons that stably replicate HCV RNA in permissive human hepatoma cells has provided the opportunity for detailed investigation of HCV cellular activities. 3,4 Standard treatment of patients with chronic HCV includes alpha-interferon and ribavirin for 24 to 48 weeks, depending on HCV genotype. Nearly half of all patients treated fail to achieve sustained viral eradication or relapse after therapy. 5 Consequently, new interest has focused on development of additional treatment options. 6 A major aim of new management strategies is to prevent chronic liver injury from the virus by interference with the viral life cycle or hepatic inflammatory injury at critical points.

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Section: Discussionsupporting

confidence: 84%

Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury

et al. 2008

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“…We recently reported that the presence of stainable iron on an index liver biopsy showing cirrhosis was associated with higher baseline MELD score. 2 Moreover, even when the more advanced degree of liver dysfunction in these patients was taken into account, they tended to decompensate more rapidly than patients without stainable iron. Ganne-Carrié et al 3 have made similar observations in patients with alcoholic cirrhosis.…”

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confidence: 99%

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Bergmann

Mathahs

Broadhurst

et al. 2008

Laboratory Investigation

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Hepatic iron deposition unrelated to hereditary hemochromatosis occurs commonly in cirrhosis but the pathogenesis of this condition is unknown. The aim of this study was to compare the expression of genes involved in the regulation of iron metabolism in cirrhotic (n ¼ 22) and control human livers (n ¼ 5). Transcripts were quantitated by real-time RT-PCR and protein levels were assessed by western blot. Hepatic iron concentrations (HICs) were measured by a spectrophotometric method. Levels of hepcidin mRNA did not differ between controls and cirrhotic livers; there was a highly significant correlation between hepcidin transcript levels and HIC in the latter group. Ferroportin, divalent metal transporter-1 (DMT1), and ferritin heavy chain mRNA levels were significantly higher in cirrhotic human livers than in controls (P ¼ 0.007, 0.039, and 0.025, respectively). By western blot, ferroportin and DMT1 levels were generally diminished in the cirrhotic livers compared to controls; neither correlated with HIC. In contrast, the abundance of ferritin increased with increasing HIC in the cirrhotic livers, whereas transferrin receptor decreased, indicating physiologically appropriate regulation. In conclusion, hepcidin expression appears to be appropriately responsive to iron status in cirrhosis. However, there are complex alterations in DMT1 and ferroportin expression in cirrhotic liver, including decreases in ferroportin and DMT1 at the protein level that may play a role in aberrant regulation of iron metabolism in cirrhosis.

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“…Iron would also be an unlikely choice as a therapeutic agent for HCV since it is usually considered to be a hepatotoxin (Ryter and Tyrrell, 2000) and it seems doubtful whether sufficient intracellular levels of free iron might be achieved in vivo to be useful therapeutically without causing cellular injury. Mild iron accumulation in HCV infected human liver samples has been correlated with more severe liver disease in some but not all studies (Beinker et al, 1996; Kayali et al, 2005, 2007). Some but not all earlier clinical studies with α-interferon treatment regimens suggested that phlebotomy could improve viral clearance and increase sustained virological responses to α-interferon (Di Bisceglie et al, 2000; Fontana et al, 2000; Desai et al, 2008).…”

Section: Direct Antiviral Effects Of Heme and Derivatives On Hcvmentioning

confidence: 98%

Heme and HO-1 Inhibition of HCV, HBV, and HIV

Schmidt¹,

Mathahs²,

Zhu³

2012

Front. Pharmacol.

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Hepatitis C virus, human immunodeficiency virus, and hepatitis B virus are chronic viral infections that cause considerable morbidity and mortality throughout the world. In the decades following the identification and sequencing of these viruses, in vitro experiments demonstrated that heme oxygenase-1, its oxidative products, and related compounds of the heme oxygenase system inhibit replication of all 3 viruses. The purpose of this review is to critically evaluate and summarize the seminal studies that described and characterized this remarkable behavior. It will also discuss more recent work that discovered the antiviral mechanisms and target sites of these unique antiviral agents. In spite of the fact that these viruses are diverse pathogens with quite profound differences in structure and life cycle, it is significant that heme and related compounds show striking similarity for viral target sites across all three species. Collectively, these findings strongly indicate that we should move forward and develop heme and related tetrapyrroles into versatile antiviral agents that could be used therapeutically in patients with single or multiple viral infections.

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Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis

Abstract: The presence of siderosis is associated with more advanced liver dysfunction. Even when the effects of baseline liver function are taken into account, siderosis is associated with decreased survival and more rapid decompensation in cirrhosis.

Cited by 28 publications

References 31 publications

Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury

Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Heme and HO-1 Inhibition of HCV, HBV, and HIV

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