the absorption of iron is strictly controlled through hepcidin , while there are no efficient physiologic mechanisms to excrete iron from the body . under conditions where iron metabolism is disturbed , such as in transfusion - dependent patients with thalassemia major ,
myelodysplastic syndromes , aplastic anemia , or sickle cell disease , excessive iron deposition occurs in the liver , heart , and endocrine organs , resulting in reactive oxygen species ( ros ) through the fenton and haber  weiss reaction .
ros can attack components of cells and further induce organ dysfunction , such as liver fibrosis , cirrhosis , hepatic carcinoma , myocarditis , pericarditis , and other diseases . in the liver of chronic hepatitis c ( chc ) patients ,
iron deposition has been found in both hepatocytes and reticuloendothelial cells although the mechanism is not fully clarified . like other viruses , hepatitis c virus ( hcv )
needs constituents of host cells to proliferate , and iron is one of the most important constituents .
many studies have explored the connection between iron overload and hcv life cycle with differing results .
some studies have found that iron promotes hcv replication , while others have shown that iron suppresses hcv replication .
most of the studies suggest the positive role of iron on hcv translation . to summarize the interactions between hcv and iron , and understand the mechanisms of iron overload in chc
, we searched articles published in the pubmed databases up to january 28 , 2017 , to gain an in - depth understanding and knowledge of relevant areas .
in the human body , iron is critical for maintaining the fundamental function of many proteins .
iron in the diet is absorbed through divalent metal transporter 1 ( dmt1 ) , a multi - transmembrane protein , or heme carrier protein 1 on duodenal and jejunal enterocytes .
it is then exported by the ferroportin ( fpn ) to bind to transferrin in the bloodstream , and taken to the erythroblasts for erythropoiesis .
iron that is not utilized can also be stored as ferritin or hemosiderin in enterocytes , macrophages , and hepatocytes .
there are no efficient physiologic mechanisms to excrete iron , a little iron ( about 2 mg per day ) is lost by sloughing of intestinal epithelial cells , desquamation of skin and urinary cells , blood loss , and sweat .
iron homeostasis in the human body is mainly regulated by the hepcidin / fpn and iron - regulatory protein / iron - responsive element ( irp / ire ) systems .
when iron levels increase , hepcidin negatively regulates iron levels by binding to the fpn and promoting the internalization and degradation of fpn .
this reduces the amount of iron absorbed by enterocytes , released by hepatocytes , and recycled from macrophages , and finally reduces transferrin levels in the bloodstream .
in contrast , when iron levels decrease , hepcidin is downregulated to improve transferrin levels .
transferrin receptor 1 ( tfr1 ) and bone morphogenetic protein 6 receptor ( bmp-6r ) can sense transferrin saturation ( ts ) and tissue iron content , respectively , further regulating hepcidin concentration .
hepcidin can also be affected by other factors , including inflammation , erythropoietic activity of the bone marrow , and the oxygen tension within hepatocytes .
while hepcidin regulates systemic iron metabolism transcriptionally and posttranslationally , cellular iron metabolism is regulated by the irp / ire system posttranscriptionally .
the irp / ire system alters the expression of iron - metabolism - related proteins , such as ferritin , fpn , hypoxia - inducible factor 2 ( hif2/epas1 ) , dmt1 , tfr1 , and other proteins .
many studies have found iron deposition in the liver , and in both hepatocytes and reticuloendothelial cells .
were the first to find elevated serum ferritin and iron levels in patients with chronic hepatitis ( both chronic hepatitis b and chc ) .
subsequently , in 1999 , a study of 209 chc patients found liver iron accumulation detected by liver biopsy in 42.1% of patients , the majority of which was mild liver iron accumulation ( 35.4% of the 209 chc patients ) .
those with liver iron accumulation had significantly higher levels of serum iron ( si ) , ferritin , and ts ; liver iron accumulation was also found to have a significant relationship with the severity of histological activity based on metavir classification and cirrhosis . in a study of 100 consecutive patients with hcv infection who underwent liver biopsy ,
19 patients were found to be hepatic iron stain positive , which is associated with stage iii or iv fibrosis .
fifty - five patients had at least one abnormal value of si , ferritin , or ts .
in multivariate analysis , the only independent predictive factor of severe hepatic fibrosis was serum ferritin .
however , elevated serum ferritin can also be caused by hepatic inflammation . in 1994 , a study of 123 chronic hepatitis patients ( including 63 chc patients ) found increased si , iron saturation , and ferritin in chc patients , while no evidence of hepatic iron accumulation could be found in any of these patients . in this study ,
serum ferritin was elevated in the absence of liver iron overload , which indicates that elevated serum ferritin may also be caused by inflammation itself .
thus , elevated ferritin reflects hepatic iron accumulation , as well as hepatic inflammation , and also predicts severe hepatic fibrosis .
in other words , hepatic iron accumulation can lead to elevated ferritin , while elevated ferritin is not only induced by hepatic iron accumulation but also caused by hepatic inflammation .
thus , serum ferritin levels only serve as a reference to evaluate liver iron status in chc patients , and liver biopsy is the gold standard for diagnosis of iron overload .
so far , plenty of studies have been devoted to exploring the mechanism as to how hcv leads to iron overload .
it is generally accepted that hcv alters iron metabolism by reducing the level of hepcidin .
fujita et al . measured hepcidin messenger rna ( mrna ) levels in liver samples from 56 patients with hcv infection , and revealed that the expression of hepcidin is strongly correlated with serum ferritin and the degree of iron deposition in liver tissues .
the hepcidin - to - ferritin ratio was significantly lower in hcv(+ ) patients than hbv(+ ) patients or controls .
girelli et al . detected s - hepcidin ( the 25-amino acid bioactive peptide in serum ) levels in 81 untreated chc patients and 57 controls with a rigorous definition of normal iron status and found that s - hepcidin was significantly lower in chc patients than in controls . in chc patients , s - hepcidin levels
examined the determinants of serum hepcidin and liver hepcidin mrna levels and their association with histological lesions in 96 patients with chc and 30 controls ; they concluded that serum hepcidin was significantly lower in patients with chc compared to healthy controls , and that liver hepcidin mrna levels did not differ between patients and controls .
a study using fl - n/35 transgenic mice harboring the hcv polyprotein also found decreased hepcidin expression in the liver , accompanied by an increase in fpn expression in the duodenum , spleen , and liver .
this suggests that hcv proteins may directly lead to increased duodenal iron absorption , macrophage iron release , and hepatic iron accumulation .
elevated duodenal fpn levels and a significant relationship between hcv and hepcidin in chc patients were also found by other studies .
all of these studies suggest that hepcidin may play a pivotal role in the pathogenesis of iron overload in patients with chc .
kohjima et al . analyzed iron - metabolism - related gene expression profiles in 100 patients with chc ( genotype 1b , n = 50 ; genotype 2 , n = 50 ) and 18 living donors of liver transplantation .
they found that expression of genes related to iron absorption ( transferrin , and dmt1 ) , iron export ( fpn ) , cellular iron metabolism ( irp1 and irp2 ) , and hepcidin - regulation ( bmpr1 , bmpr2 , and hemojuvelin ) were significantly higher , indicating that hcv affects the expression of iron - metabolism - related genes , leading to iron accumulation in hepatocytes .
besides , patients with a sustained virological response ( svr ) had significantly lower transcription and protein expression levels of hepcidin , fpn , bmpr2 , and hemojuvelin before therapy , indicating the importance of hepatocytic iron retention for viral response during pegylated interferon plus ribavirin treatment .
almost all hcv proteins , including core , e1 , e2 , ns3 , ns4a , ns4b , and ns5a , have been shown to regulate hepcidin expression through signal transducer and activator of transcription 3 , mitogen - activated protein kinase , or bmp / smad signaling pathways , and increased histone deacetylase activity , which further clarifies the mechanism of decreased levels of hepcidin caused by hcv .
like other viruses , hcv needs constituents of host cells to replicate and translate , and iron is one of the most important constituents . it is indispensable for several basic metabolic processes in viruses , as well as in mammalian cells , as described in many studies .
were the first to analyze the effect of iron on hcv replication in vitro . in 2000 , they cultured a nonneoplastic hcv - infected human hepatocyte line ( ph5ch8 ) treated with feso4 and proved that iron can promote hcv replication in liver cells . in 2016 , foka et al . found that iron - overloaded macrophages was infected with hcv when co - cultured with hcv - infected human hepatoma cell line ( huh7.5 ) .
these iron overloaded macrophages also enhanced hcv replication in co - cultured hcv - infected huh7.5 cells through reversed ferritin  flow  from macrophages to huh7.5 cells .
macrophages without overloaded iron was also infected with hcv and enhance hcv replication in huh7.5 cells , but the rate of infection was slower and the effect on hcv replication was weaker . on the other hand , several studies have found that iron suppresses hcv replication .
a study using huh7 cells in 2005 concluded that iron could inhibit hcv replication by inactivating the rna polymerase ns5b , without significant effect on translation .
fillebeen et al . concluded that iron could decrease hcv replication by reducing the activity of ns5b in huh7.5.1 cells , similar to the result of the study in 2005
. a later study , in 2011 , again found that increased iron status and down - regulated hepcidin inhibited hcv replication .
. this may be due to different cell types . besides , in clinical practice , chc with primary or secondary iron overload have different prognoses .
chc patients with hereditary iron overload due to hemochromatosis gene mutations have increased svrs to antiviral therapy , when excess iron deposits in parenchymal cells and macrophages become iron deficient .
in contrast , iron overload secondary to chc or other chronic liver diseases significantly aggravates the disease , when excess iron deposits in macrophages .
it seems that the iron content of macrophages is associated with the clinical outcome of disease , because iron overload may impair the immune function of macrophages through oxidative stress .
although the role of iron in promoting or suppressing hcv replication is debatable , there are few controversies about the effect of iron on hcv translation .
apart from a group in the usa that reported that iron suppresses hcv translation through increasing heme oxygenase-1 in vitro and another group that found no effect of iron on hcv translation , all other studies confirm the positive role of iron on hcv translation , but the mechanisms are not fully understood .
expression of hcv is predominantly controlled at the translational level , which involves the interaction between cellular translation initiation factors and a specific mrna stem - loop structure  the internal ribosome entry site ( ires )  within the 5 untranslated region .
iron is reported to stimulate the expression of eukaryotic initiation factor 3 ( eif3 ) , thus enhancing hcv ires - dependent translation both in hepg2 cells and hcv - infected patients , whereas iron chelation reverses it in vitro .
another group also found that hepatic iron load promotes hcv translation initiation in vitro with the mechanism involving iron - dependent increased expression of eif3 .
expression of another element , la protein , is also significantly increased by hepatic iron load which can promote hcv translation .
expression of both eif3 and la protein can be partially inhibited by the iron chelator deferoxamine .
cho et al . also found that iron changes the affinities of common cellular factors to hcv ires which modulates hcv ires - dependent translation . in summary
, iron can regulate hcv ires - dependent translation by increasing expression levels of associated factors .
translation of both hcv 1b and hcv 2b is significantly increased after iron treatment , while translation of hcv 6a shows little difference .
compared with subtype 1b , hcv 6a has a modified eif3 binding site within hairpin iii .
it is reported that hepatic iron levels are higher in patients infected with subtype 1b than those in patients infected with subtypes 2a or 2b , which may explain the different responses of hcv genotypes to iron overload .
nowadays , liver biopsy is the gold standard for diagnosis of hepatic iron overload , and there are no uniform diagnostic criteria about extracellular iron concentration .
most of the studies described in the paper used cell models incubated in ferric or ferrous iron solutions with maximum concentrations ranging from 50 to 300 mol / l , whether they reach the standard of iron overload is difficult to judge . therefore , whether these results from in vitro research could be suggestive to understand the effect of iron on hcv is still debatable .
each part of iron metabolism , including absorption , restoration , recycling , and utilization , is regulated by hepcidin and the ire / irp system .
there is no efficient way to eliminate iron from the body , so any abnormality in the process of iron metabolism may lead to excessive iron burden . the relationship between hcv and iron overload
many studies have observed iron overload in patients with chc , and most suggest that decreased hepcidin expression , as well as increased hcv protein - mediated expression of other iron metabolism - related genes , play a role . as to the detailed mechanism of hcv proteins inducing iron overload , there is still much to discover . in turn , as an essential element for all living bodies , iron can also affect the life cycle of hcv .
nearly all studies so far confirm the positive role of iron on hcv translation , while the role of iron in promoting or suppressing hcv replication is still unclear . more work is needed to understand this , and the mechanisms by which iron affects hcv life cycle .
iron chelation therapy can reverse the negative effect of iron overload , which offers important information for clinical application .
hcv reduces the levels of hepcidin , and elevates the levels of fpn , resulting in elevated iron absorbed by enterocytes and iron deposition in hepatocytes and macrophages .
although the role of iron in hcv replication is disputable , it is strongly suggested the positive effect of iron on hcv translation by increasing expression of both eif3 and la protein , and changing the affinities of common cellular factors to hcv ires .
hcv : hepatitis c virus ; fpn : ferroportin ; si : serum iron ; ts : transferrin saturation ; ires : internal ribosome entry site ; eif3 : eukaryotic initiation factor 3 ;  : upregulated ;  : downregulated .
this work was supported by grants from the 215 project of beijing municipal commission of health and family planning ( no .
303 - 01 - 005 - 0068 ) and the basic - clinic cooperative foundation of capital medical university ( no .
this work was supported by grants from the 215 project of beijing municipal commission of health and family planning ( no .
303 - 01 - 005 - 0068 ) and the basic - clinic cooperative foundation of capital medical university ( no .
 objective : the aim of this study was to summarize the interactions between hepatitis c virus ( hcv ) infection and iron overload , and to understand the mechanisms of iron overload in chronic hepatitis c ( chc ) and the role iron plays in hcv life cycle.data sources : this review was based on data in articles published in the pubmed databases up to january 28 , 2017 , with the keywords  hepatitis c virus  ,  iron overload  ,  iron metabolism  ,  hepcidin  ,  translation  , and  
 replication.study selection : articles related to iron metabolism , iron overload in patients with chc , or the effects of iron on hcv life cycle were selected for the review.results:iron overload is common in patients with chc . 
 the mechanisms involve decreased hepcidin levels caused by hcv through signal transducer and activator of transcription 3 , mitogen - activated protein kinase , or bone morphogenetic protein / smad signaling pathways , and the altered expression of other iron - metabolism - related genes . 
 some studies found that iron increases hcv replication , while other studies found the opposite result . 
 most of the studies suggest the positive role of iron on hcv translation , the mechanisms of which involve increased expression levels of factors associated with hcv internal ribosome entry site - dependent translation , such as eukaryotic initiation factor 3 and la protein.conclusion:the growing literature demonstrates that chc leads to iron overload , and iron affects the hcv life cycle in turn . 
 further research should be conducted to clarify the mechanism involved in the complicated interaction between iron and hcv . 
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