Hepatotoxicity of Iron Overload: Mechanisms of Iron-Induced Hepatic Fibrogenesis

ABSTRACT

While iron is a vital requirement for normal cellular physiology, excessive intestinal absorption of iron as seen in hemochromatosis leads to its deposition in parenchymal cells of various organs such as the liver, heart, and pancreas, resulting in cellular toxicity, tissue injury, and organ fibrosis. Cellular injury is induced by iron-generated oxyradicals and peroxidation of lipid membranes. In the liver, lipid peroxidation results in damage to hepatocellular organelles, such as mitochondria and lysosomes, which is thought to contribute to hepatocyte necrosis and apoptosis, and ultimately lead to the development of hepatic fibrogenesis. Hepatic stellate cells are central to the development of hepatic fibrosis, as they can be activated into collagen-producing myofibroblasts. Numerous potential stimuli associated with hepatic iron overload and iron-induced hepatocellular injury have been assessed in an attempt to explain stellate cell transformation in hemochromatosis. Stellate cell activation and fibrosis appear to be regulated by a series of events involving cellular interaction between resident and nonresident cells of the liver, the sequestration of free iron versus the transport and storage of mobilizable iron, and extracellular matrix remodeling as well as intracellular signaling events associated with inflammatory and fibrogenic cytokines.

KEYWORDS

Iron - hepatic fibrosis - hepatic stellate cell - hepatotoxicity - hemochromatosis

REFERENCES

• 1 Olynyk J K, Cullen D J, Aquilia S et al.. A population-based study of the clinical expression of the hemochromatosis gene.  N Engl J Med. 1999;  341 718-724
• 2 Britton R S. Mechanisms of iron toxicity. In: Barton JC, Edwards CQ Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, UK; Cambridge University Press 2000: 229-238
• 3 Powell L W, Jazwinska E, Halliday J W. Primary iron overload. In: Brock JH, Halliday JW, Pippard MJ, Powell LW Iron Metabolism in Health and Disease. Philadelphia, PA; WB Saunders & Co. Ltd 1994: 227-270
• 4 Bacon B R, Britton R S. Hereditary hemochromatosis. In: Feldman M, Scharschmidt BF, Sleisenger MH Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia, PA; WB Saunders & Co. Ltd 1998: 1097-1103
• 5 Niederau C, Fischer R, Purchel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis.  Gastroenterology. 1996;  110 1107-1119
• 6 Olynyk J K, St Pierre T G, Britton R S et al.. Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging.  Am J Gastroenterol. 2005;  100 837-841
• 7 Niederau C, Fischer R, Sonnenberg A et al.. Survival and causes of death in cirrhotic and non-cirrhotic patients with primary hemochromatosis.  N Engl J Med. 1985;  313 1256-1262
• 8 Bassett M L, Halliday J W, Powell L W. Value of hepatic iron measurements in early hemochromatosis and critical level associated with fibrosis.  Hepatology. 1986;  6 24-29
• 9 Hübscher S G. Iron overload, inflammation and fibrosis in genetic haemochromatosis.  J Hepatol. 2003;  38 521-525
• 10 Bacon B R, Britton R S. The pathology of hepatic iron overload: a free radical-mediated process.  Hepatology. 1990;  11 127-137
• 11 Halliwell B, Gutteridge JMC. Free Radical in Biology and Medicine. 2nd ed. Oxford, UK; Oxford University Press 1989: 540
• 12 Pietrangelo A. Iron-induced oxidant stress in alcoholic liver fibrogenesis.  Alcohol. 2003;  30 121-129
• 13 Sies H. Oxidative stress: from basic research to clinical application.  Am J Med. 1991;  91 S31-S38
• 14 Britton R S, Leicester K L, Bacon B R. Iron toxicity and chelation therapy.  Int J Hematol. 2002;  76 219-228
• 15 Iancu T C, Shiloh H. Morphological observations in iron overload: an update.  Adv Exp Med Biol. 1994;  356 255-265
• 16 Iacopetta B J, Morgan E H, Yeoh G C. Receptor-mediated endocytosis of transferrin by developing erythroid cells from the fetal rat liver.  J Histochem Cytochem. 1983;  31 336-344
• 17 Blight G D, Morgan E H. Ferritin and iron uptake by reticulocytes.  Br J Haematol. 1983;  55 59-71
• 18 Ramm G A, Powell L W, Halliday J W. Effect of colchicine on the clearance of ferritin in vivo.  Am J Physiol. 1990;  258(5 Pt 1) G707-G713
• 19 Ramm G A, Powell L W, Halliday J W. Pathways of intracellular trafficking and release of ferritin by the liver in vivo: the effect of chloroquine and cytochalasin D.  Hepatology. 1994;  19 504-513
• 20 LaRusso N F. Hepatic lysosomes in intracellular digestion and biliary secretion. In: Forte JG Handbook of Physiology: The Gastrointestinal System III. Bethesda, MD; American Physiological Society 1989: 677-691
• 21 Peters T J, O'Connell M J, Ward R J. Role of free-radical mediated lipid peroxidation in the pathogenesis of hepatic damage by lysosomal disruption. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF Free Radicals in Liver Injury. Oxford, UK; IRL Press 1985: 107-115
• 22 Peters T J, Seymour C A. Acid hydrolase activities and lysosomal integrity in liver biopsies from patients with iron overload.  Clin Sci Mol Med. 1976;  50 75-78
• 23 Seymour C A, Peters T J. Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes.  Br J Haematol. 1978;  40 239-253
• 24 O'Connell M J, Ward R J, Baum H, Peters T J. The role of iron in ferritin- and haemosiderin-mediated lipid peroxidation in liposomes.  Biochem J. 1985;  229 135-139
• 25 Hultcrantz R, Ahlberg J, Glaumann H. Isolation of two lysosomal populations from iron-overloaded rat liver with different iron concentration and proteolytic activity.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;  47 55-65
• 26 LeSage G D, Kost L J, Barham S S, LaRusso N F. Biliary excretion of iron from hepatocyte lysosomes in the rat. A major excretory pathway in experimental iron overload.  J Clin Invest. 1986;  77 90-97
• 27 Bacon B R, O'Neill R, Britton R S. Hepatic mitochondrial energy production in rats with chronic iron overload.  Gastroenterology. 1993;  105 1134-1140
• 28 Bacon B R, O'Neill R, Park C H. Iron-induced peroxidative injury to isolated rat hepatic mitochondria.  J Free Radic Biol Med. 1986;  2(5-6) 339-347
• 29 Zhao M, Antunes F, Eaton J W, Brunk U T. Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis.  Eur J Biochem. 2003;  270 3778-3786
• 30 Britton R S, O'Neill R, Bacon B R. Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes.  Gastroenterology. 1991;  101 806-811
• 31 Masini A, Ceccarelli D, Trenti T et al.. Perturbation in liver mitochondrial Ca2+ homeostasis in experimental iron overload: a possible factor in cell injury.  Biochim Biophys Acta. 1989;  1014 133-140
• 32 Walter P B, Knutson M D, Paler-Martinez A et al.. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats.  Proc Natl Acad Sci USA. 2002;  99 2264-2269
• 33 Garcia N, Garcia J J, Correa F, Chavez E. The permeability transition pore as a pathway for the release of mitochondrial DNA.  Life Sci. 2005;  76 2873-2880
• 34 Rauen U, Petrat F, Sustmann R, de Groot H. Iron-induced mitochondrial permeability transition in cultured hepatocytes.  J Hepatol. 2004;  40 607-615
• 35 Kim J S, Qian T, Lemasters J J. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes.  Gastroenterology. 2003;  124 494-503
• 36 Lemasters J J. Rusty notions of cell injury.  J Hepatol. 2004;  40 696-698
• 37 Armstrong J S, Yang H, Duan W, Whiteman M. Cytochrome bc regulates the mitochondrial permeability transition by two distinct pathways.  J Biol Chem. 2004;  279 50420-50428
• 38 Pardo Andreu G, Delgado R, Velho J et al.. Mangifera indica L. extract (Vimang) inhibits Fe2+-citrate-induced lipoperoxidation in isolated rat liver mitochondria.  Pharmacol Res. 2005;  51 427-435
• 39 Nair J, Carmichael P L, Fernando R C et al.. Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson's disease and primary hemochromatosis.  Cancer Epidemiol Biomarkers Prev. 1998;  7 435-440
• 40 Hussain S P, Raja K, Amstad P A et al.. Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases.  Proc Natl Acad Sci U S A. 2000;  97 12770-12775
• 41 Bartsch H, Nair J. Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis.  Cancer Detect Prev. 2004;  28 385-391
• 42 Hirota N, Hamazaki M, Williams G M. Resistance to iron accumulation and presence of hepatitis B surface antigen in preneoplastic and neoplastic lesions in human hemochromatotic livers.  Hepatogastroenterology. 1982;  29 49-51
• 43 Deugnier Y M, Charalambous P, Le Quilleuc D et al.. Preneoplastic significance of hepatic iron-free foci in genetic hemochromatosis: a study of 185 patients.  Hepatology. 1993;  18 1363-1369
• 44 Lin E, Adams P C. Biochemical liver profile in hemochromatosis. A survey of 100 patients.  J Clin Gastroenterol. 1991;  13 316-320
• 45 Adams P C, Deugnier Y, Moirand R, Brissot P. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis.  Hepatology. 1997;  25 162-166
• 46 Adams P C. Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis?.  Am J Gastroenterol. 2001;  96 567-569
• 47 Powell L W, Dixon J L, Ramm G A et al.. Cascade screening and opportunistic screening reveal comparable levels of hepatic iron overload and disease in apparently healthy hemochromatosis subjects.  Arch Intern Med. 2005;  , In press
• 48 Fletcher L M, Dixon J L, Purdie D M et al.. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 281-289
• 49 Eisenbach C, Gehrke S G, Stremmel W. Iron, the HFE gene, and hepatitis C.  Clin Liver Dis. 2004;  8 775-785
• 50 [No authors listed.] . Hepatic stellate cell nomenclature.  Hepatology. 1996;  23 193
• 51 Friedman S L. Hepatic stellate cells.  Prog Liver Dis. 1996;  14 101-130
• 52 Ramm G A. Isolation and culture of rat hepatic stellate cells.  J Gastroenterol Hepatol. 1998;  13 846-851
• 53 Friedman S L. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies.  N Engl J Med. 1993;  328 1828-1835
• 54 Reeves H L, Burt A D, Wood S, Day C P. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis.  J Hepatol. 1996;  25 677-683
• 55 Chedid A, Arain S, Snyder A et al.. The immunity of fibrogenesis in alcoholic liver disease.  Arch Pathol Lab Med. 2004;  128 1230-1238
• 56 Ramm G A, Nair V G, Bridle K R et al.. Contribution of hepatic parenchymal and non-parenchymal cells to hepatic fibrogenesis in biliary atresia.  Am J Pathol. 1998;  153 527-535
• 57 Lewindon P J, Pereira T N, Hoskins A C et al.. The role of hepatic stellate cells and transforming growth factor-β₁ in cystic fibrosis liver disease.  Am J Pathol. 2002;  160 1705-1715
• 58 Mathew J, Hines J E, James O F, Burt A D. Non-parenchymal cell responses in paracetamol (acetominophen)-induced liver injury.  J Hepatol. 1994;  20 537-541
• 59 el Hag I A, Hashim F A, el Toum I A et al.. Liver morphology and function in visceral leishmaniasis (Kala-azar).  J Clin Pathol. 1994;  47 547-551
• 60 Inuzuka S, Ueno T, Torimura T et al.. Immunohistochemistry of the hepatic extracellular matrix in acute viral hepatitis.  Hepatology. 1990;  12 249-256
• 61 Tuchweber B, Desmouliere A, Bochaton-Piallat M L et al.. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat.  Lab Invest. 1996;  74 265-278
• 62 Ramadori G, Saile B. Portal tract fibrogenesis in the liver.  Lab Invest. 2004;  84 153-159
• 63 Cassiman D, Libbrecht L, Desmet V et al.. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers.  J Hepatol. 2002;  36 200-209
• 64 Neubauer K, Knittel T, Aurisch S et al.. Glial fibrillary acidic protein-a cell type specific marker for Ito cells in vivo and in vitro.  J Hepatol. 1996;  24 719-730
• 65 Enzan H, Himeno H, Iwamura S et al.. Alpha-smooth muscle actin-positive perisinusoidal stromal cells in human hepatocellular carconima.  Hepatology. 1994;  19 895-903
• 66 Torimura T, Ueno T, Inuzuka S et al.. The extracellular matrix in hepatocellular carcinoma shows different localization patterns depending on the differentiation and the histological pattern of tumours: immunohistochemical analysis.  J Hepatol. 1994;  21 37-46
• 67 Ooi L P, Crawford D H, Gotley D C et al.. Evidence that “myofibroblast-like” cells are the cellular source of capsular collagen in hepatocellular carcinoma.  J Hepatol. 1997;  26 798-807
• 68 Bridle K R, Crawford D H, Powell L W, Ramm G A. Role of myofibroblasts in tumour encapsulation of hepatocellular carcinoma in haemochromatosis.  Liver. 2001;  21 96-104
• 69 Schnaper H W, Hayashida T, Hubchak S C, Poncelet A C. TGF-beta signal transduction and mesangial cell fibrogenesis.  Am J Physiol Renal Physiol. 2003;  284 F243-F252
• 70 Haber P S, Keogh G W, Apte M V et al.. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis.  Am J Pathol. 1999;  155 1087-1095
• 71 Neuschwander-Tetri B A, Bridle K R, Wells L D, Marcu M, Ramm G A. Repetitive acute pancreatic injury in the mouse induces procollagen α1(I) mRNA expression colocalized to pancreatic stellate cells.  Lab Invest. 2000;  80 143-150
• 72 Apte M V, Park S, Phillips P A et al.. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells.  Pancreas. 2004;  29 179-187
• 73 Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis.  Semin Liver Dis. 1996;  16 13-30
• 74 Pietrangelo A, Gualdi R, Casalgrandi G et al.. Enhanced hepatic collagen type I mRNA expression into fat-storing cells in a rodent model of hemochromatosis.  Hepatology. 1994;  19 714-721
• 75 Ramm G A, Li SCY, Li L et al.. Chronic iron overload causes activation of rat lipocytes in vivo.  Am J Physiol. 1995;  268 G451-G458
• 76 Ramm G A, Crawford DHG, Powell L W et al.. Hepatic stellate cell activation in genetic hemochromatosis: lobular distribution, effect of increasing hepatic iron and response to phlebotomy.  J Hepatol. 1997;  26 584-592
• 77 Brunt E M, Fazel A, Brown K E. Lack of zonal association between alpha-smooth muscle actin, CD34 and fibrosis in a variety of liver diseases.  Hepatology. 1999;  30 A554
• 78 Guido M, Rugge M, Chemello L et al.. Liver stellate cell in chronic viral hepatitis: the effect of interferon therapy.  J Hepatol. 1996;  24 301-307
• 79 Guido M, Rugge M, Leandro G et al.. Hepatic stellate cell immunodetection and cirrhotic evolution of viral hepatitis in liver allografts.  Hepatology. 1997;  26 310-314
• 80 Geerts A. History, heterogeneity and developmental biology, and functions of quiescent hepatic stellate cells.  Semin Liver Dis. 2001;  21 311-335
• 81 Wake K, Sato T. Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver.  Cell Tissue Res. 1993;  273 227-237
• 82 Ramm G A, Britton R S, O'Neill R et al.. Vitamin A-poor lipocytes: a novel desmin-negative lipocyte subpopulation, which can be activated to myofibroblasts.  Am J Physiol. 1995;  269 G532-G541
• 83 Ratziu V, Friedman S L. Pathobiology and hepatic stellate cells. In: Vidal-Vanaclocha F Functional Heterogeneity of Liver Tissue: From Cell Lineage Diversity to Sub-Popular Compartment-Specific Pathogenesis. Austin, TX; RG Landes 1997: 133-160
• 84 Levy M T, McCaughan G W, Abbott C A et al.. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis.  Hepatology. 1999;  29 1768-1778
• 85 Malarkey D E, Johnson K, Ryan L et al.. New insights into functional aspects of liver morphology.  Toxicol Pathol. 2005;  33 27-34
• 86 MacSween RNM, Desmet V J, Roskams T, Scothorne R J. Developmental anatomy and normal structure. In: MacSween RNM, Burt AD, Portmann BC, Ishak KG, Scheyer PJ, Anthony PP Pathology of the Liver. New York, NY; Churchill Livingston 2002: 1-66
• 87 Sleyster E C, Knook D L. Relation between localisation and function of rat Kupffer cells.  Lab Invest. 1982;  47 484-490
• 88 Armbrust T, Ramadori G. Functional characterisation of two different Kupffer cell populations of normal rat liver.  J Hepatol. 1996;  25 518-528
• 89 Olynyk J K, Clarke S L. Isolation and primary culture of rat Kupffer cells.  J Gastroenterol Hepatol. 1998;  13 841-849
• 90 Olynyk J K, Clarke S L. Iron overload impairs pro-inflammatory cytokine responses by Kupffer cells.  J Gastroenterol Hepatol. 2001;  16 438-444
• 91 Bykov I, Ylipaasto P, Eerola L, Lindros K O. Functional differences between periportal and perivenous Kupffer cells isolated by digitonin-collagenase perfusion.  Comp Hepatol. 2004;  3(suppl 1) S34
• 92 Esterbauer H. Cytotoxicity and genotoxicity of lipid-oxidation products.  Am J Clin Nutr. 1993;  57 779S-785S discussion 785S-786S
• 93 Houglum K, Filip M, Witztum J L, Chojkier M. Malondialdehyde and 4-hydroxynonenal proteins adducts in plasma and liver of rats with iron overload.  J Clin Invest. 1990;  86 1991-1998
• 94 Parkkila S, Niemela O, Britton R S et al.. Vitamin E decreases hepatic levels of aldehyde-derived peroxiodation products in rats with iron overload.  Am J Physiol. 1996;  270 G376-G384
• 95 Khan M F, Wu X, Tipnis U R et al.. Protein adducts of malondialdehyde and 4-hydroxynonenal in livers of iron loaded rats: quantitation and localization.  Toxicology. 2002;  173 193-201
• 96 Brown K E, Kinter M T, Oberley T D et al.. Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload.  Free Radic Biol Med. 1998;  24 545-555
• 97 Hultcrantz R, Ericsson J L, Hirth T. Levels of malondialdehyde production in rat liver following loading and unloading with iron.  Virchows Arch B Coll Pathol Incl Mol Pathol. 1984;  45 139-146
• 98 Brown K E, Poulos J E, Li L et al.. Effect of vitamin E supplementation on hepatic fibrogenesis in chronic dietary iron overload.  Am J Physiol. 1997;  272(1 Pt 1) G116-G123
• 99 Bacon B R, Tavill A S, Brittenham G M et al.. Hepatic lipid peroxidation in vivo in rats with chronic iron overload.  J Clin Invest. 1983;  71 429-439
• 100 Livrea M A, Tesoriere L, Pintaudi A M et al.. Oxidant stress and antioxidant status in b-thalassemia major: iron overload and depletion of lipid-soluble antioxidants.  Blood. 1996;  88 3608-3614
• 101 Young I S, Trouton T G, Torney J J et al.. Antioxidant status and lipid peroxidation in hereditary haemochromatosis.  Free Radic Biol Med. 1994;  16 393-397
• 102 Houglum K, Ramm G A, Crawford DHG et al.. Excess iron induced hepatic oxidant stress and transforming growth factor β1 in genetic haemochromatosis.  Hepatology. 1997;  26 605-610
• 103 Niemela O, Parkkila S, Britton R S et al.. Hepatic lipid peroxidation in hereditary haemochromatosis and alcoholic liver injury.  J Lab Clin Med. 1999;  133 451-460
• 104 Dabbagh A J, Mannion T, Lynch S M, Frei B. The effect of iron overload on rat plasma and liver oxidant stress, in vivo.  Biochem J. 1994;  300 799-803
• 105 Dresow B, Albert C, Zimmerman I, Nielson P. Ethane exhalation and vitamin E/ubiquinol status as markers of lipid peroxidation in ferrocene iron-loaded rats.  Hepatology. 1995;  21 1099-1105
• 106 von Herbay A, de Groot H, Hegi U et al.. Low vitamin E content in liver of patients with alcoholic liver disease, haemochromatosis and Wilson's disease.  J Hepatol. 1994;  20 41-46
• 107 Paradis V, Mathurin P, Kollinger M et al.. In situ detection of lipid peroxidation in chronic hepatitis C: correlation with pathological features.  J Clin Pathol. 1997;  50 401-406
• 108 Macdonald G A, Bridle K R, Ward P J et al.. Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominantly in acinar zone 3.  J Gastroenterol Hepatol. 2001;  16 599-606
• 109 Lee K S, Buck M, Houglum K, Chojkier M. Activation of hepatic stellate cells by TGF-α and collagen type I is mediated by oxidative stress through c-myb.  J Clin Invest. 1995;  96 2461-2468
• 110 Parola M, Pinzani M, Casini A et al.. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells.  Biochem Biophys Res Commun. 1993;  194 1044-1050
• 111 Bedossa P, Houglum K, Trautwein C, Holstege A, Chojkier M. Stimulation of collagen alpha 1 (I) gene expression is associated with lipid peroxidation in hepatocellular injury: a link to tissue fibrosis?.  Hepatology. 1994;  19 1262-1271
• 112 Maher J J, Neuschwander-Tetri B A. Manipulation of glutathione stores in rat hepatic stellate cells does not alter collagen synthesis.  Hepatology. 1997;  26 618-623
• 113 Montosi G, Garuti C, Martinelli S, Pietrangelo A. Hepatic stellate cells are not subject to oxidant stress during iron-induced fibrogenesis in rodents.  Hepatology. 1998;  27 1611-1622
• 114 Olynyk J K, Khan N A, Ramm G A et al.. Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells.  J Gastroenterol Hepatol. 2002;  17 785-790
• 115 Maher J J, Tzagarakis C, Gimenez A. Malondialdeyhde stimulates collagen production by hepatic lipocytes only upon activation in primary culture.  Alcohol Alcohol. 1994;  29 605-610
• 116 Apte M. Oxidative stress: does it “initiate” hepatic stellate cell activation or only “perpetuate” the process?.  J Gastroenterol Hepatol. 2002;  17 1045-1048
• 117 Zhang A S, Xiong S, Tsukamoto H, Enns C A. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes.  Blood. 2004;  103 1509-1514
• 118 Bridle K R, Frazer D M, Anderson G J, Ramm G A. Gene expression of iron transporters in activated rat hepatic stellate cells.  J Clin Gastroenterol. 2002;  34 A347
• 119 Ramm G A, Britton R S, O'Neill R, Bacon B R. Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.  J Clin Invest. 1994;  94 9-15
• 120 Bridle K R, Crawford DHG, Ramm G A. Identification and characterization of the hepatic stellate cell transferrin receptor.  Am J Pathol. 2003;  162 1661-1667
• 121 Moss D, Fargion S, Fracanzani A L et al.. Functional roles of the ferritin receptors of human liver, hepatoma, lymphoid and erythroid cell.  J Inorg Biochem. 1992;  47 219-227
• 122 Ramm G A, Britton R S, O'Neill R et al.. Rat liver ferritin selectively inhibits the expression of α-smooth muscle actin in cultured rat lipocytes.  Am J Physiol. 1996;  270 G370-G375
• 123 Ruddell R G, Rutherford P S, Barwood J M et al.. Ferritin upregulates the expression of NFκB-dependent genes associated with hepatic stellate cell activation via PI3-kinase, PKC-ζ and MAPK.  Hepatology. 2004;  40 A269
• 124 Saile B, Matthes N, Knittel T, Ramadori G. Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells.  Hepatology. 1999;  30 196-202
• 125 Ruiz I G, de la Torre P, Diaz T et al.. Sp family of transcription factors is involved in iron-induced collagen alpha1 (I) gene expression.  DNA Cell Biol. 2000;  19 167-178
• 126 Gardi C, Arezzini B, Fortino V, Comporti M. Effect of free iron on collagen synthesis, cell proliferation and MMP-2 expression in rat hepatic stellate cells.  Biochem Pharmacol. 2002;  64 1139-1145
• 127 Benedetti A, Di Sario A, Casini A et al.. Inhibition of the NA(+)/H(+) exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study.  Gastroenterology. 2001;  120 545-556
• 128 Benyon R C, Arthur M J. Extracellular matrix degradation and the role of hepatic stellate cells.  Semin Liver Dis. 2001;  21 373-384
• 129 Castera L, Hartmann D J, Chapel F et al.. Serum laminin and type IV collagen are accurate markers of histologically severe alcoholic hepatitis in patients with cirrhosis.  J Hepatol. 2000;  32 412-418
• 130 Guechot J, Laudat A, Loria A et al.. Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis.  Clin Chem. 1996;  42 558-563
• 131 Walsh K M, Timms P, Campbell S et al.. Plasma levels of matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases-1 and -2 (TIMP-1 and TIMP-2) as non-invasive markers of liver disease in chronic hepatitis C: comparison using ROC analysis.  Dig Dis Sci. 1999;  44 624-630
• 132 Pereira T N, Lewindon P J, Smith J L et al.. Serum markers of hepatic fibrogenesis in cystic fibrosis liver disease.  J Hepatol. 2004;  41 576-583
• 133 Rosenberg W M, Voelker M, Thiel R et al.. Serum markers detect the presence of liver fibrosis: a cohort study.  Gastroenterology. 2004;  127 1704-1713
• 134 Roberts F D, Sandford N L, Bradbear R A et al.. Serum procollagen-III-peptide: failure to reflect the extent of hepatic fibrosis.  J Gastroenterol Hepatol. 1986;  1 27-32
• 135 Jensen P D, Heickandorff L, Helweg-Larsen H M et al.. Serum procollagen III peptide concentration in iron overload.  Eur J Haematol. 1996;  57 157-164
• 136 George D K, Ramm G A, Walker N I et al.. Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis.  J Hepatol. 1999;  31 47-52
• 137 George D K, Ramm G A, Powell L W et al.. Evidence for altered hepatic matrix degradation in genetic haemochromatosis.  Gut. 1998;  42 715-720
• 138 Guyader D, Jacquelinet C, Moirand R et al.. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.  Gastroenterology. 1998;  115 929-936
• 139 Beaton M, Guyader D, Deugnier Y et al.. Non-invasive prediction of cirrhosis in C282Y-linked hemochromatosis.  Hepatology. 2002;  36 673-678
• 140 Friedman S L. Liver fibrosis-from bench to bedside.  J Hepatol. 2003;  38 S38-S53
• 141 Stål P, Broome U, Scheynius A et al.. Kupffer cell iron overload induces intercellular adhesion molecule-1 expression on hepatocytes in genetic haemochromatosis.  Hepatology. 1995;  21 1308-1316
• 142 Bridle K R, Crawford DHG, Fletcher L M et al.. Evidence for a submorphological inflammatory process in the liver in haemochromatosis.  J Hepatol. 2003;  38 426-433
• 143 Deugnier Y M, Loreal O, Turlin B et al.. Liver pathology in genetic haemochromatosis: a review of 135 homozygous cases and their bioclinical correlations.  Gastroenterology. 1992;  102 2050-2059
• 144 Arthur M J. Iron overload and liver fibrosis.  J Gastroenterol Hepatol. 1996;  11 1124-1129
• 145 Reimao R, Porto G, de Sousa M. Stability of CD4/CD8 ratios in man: new correlation between CD4/CD8 profiles and iron overload in idiopathic haemochromatosis patients.  C R Acad Sci III. 1991;  313 481-487
• 146 Porto G, Vicente C, Teixeira M A et al.. Relative impact of HLA phenotype and CD4-CD8 ratios on the clinical expression of hemochromatosis.  Hepatology. 1997;  25 397-402
• 147 Cardoso E M, Hagen K, de Sousa M, Hultcrantz R. Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli.  Eur J Clin Invest. 2001;  31 45-53
• 148 Fabio G, Zarantonello M, Mocellin C et al.. Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients.  J Hepatol. 2002;  37 753-761
• 149 Cardoso C S, de Sousa M. HFE, the MHC and hemochromatosis: paradigm for an extended function for MHC class I.  Tissue Antigens. 2003;  61 263-275
• 150 Arosa F A, Oliveira L, Porto G et al.. Anomalies of the CD8+ T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8 + CD28- T cells.  Clin Exp Immunol. 1997;  107 548-554
• 151 Cardoso C, Porto G, Lacerda R et al.. T-cell receptor repertoire in hereditary hemochromatosis: a study of 32 hemochromatosis patients and 274 healthy subjects.  Hum Immunol. 2001;  62 488-499
• 152 Crispe I N. Hepatic T cells and liver tolerance.  Nat Rev Immunol. 2003;  3 51-62
• 153 Gressner A M, Lahme B, Brenzel A. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells.  Hepatology. 1995;  22 1507-1518
• 154 Pinzani M, Marra F. Cytokine receptors and signaling in hepatic stellate cells.  Semin Liver Dis. 2001;  21 397-416
• 155 Sugiyama M, Ichida T, Sato T et al.. Expression of activin A is increased in cirrhotic and fibrotic rat livers.  Gastroenterology. 1998;  114 550-558
• 156 Napoli J, Bishop G A, McGuinness P H et al.. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines.  Hepatology. 1996;  24 759-765
• 157 Thompson K, Maltby J, Fallowfield J et al.. Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis.  Hepatology. 1998;  28 1597-1606
• 158 Roberts F D, Charalambous P, Fletcher L et al.. Effect of chronic iron overload on procollagen gene expression.  Hepatology. 1993;  18 590-595
• 159 Houglum K, Bedossa P, Chojkier M. TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload.  Am J Physiol. 1994;  267(5 Pt 1) G908-G913
• 160 Parkes J G, Templeton D M. Modulation of stellate cell proliferation and gene expression by rat hepatocytes: effect of toxic iron overload.  Toxicol Lett. 2003;  144 225-233
• 161 Osterreicher C H, Datz C, Stickel F et al.. TGF-beta1 codon 25 gene polymorphism is associated with cirrhosis in patients with hereditary hemochromatosis.  Cytokine. 2005;  31 142-148
• 162 Powell E E, Edwards-Smith C J, Hay J L et al.. Host genetic factors influence disease progression in chronic hepatitis C.  Hepatology. 2000;  31 828-833
• 163 Dixon J B, Bhathal P S, Jonsson J R et al.. Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese.  J Hepatol. 2003;  39 967-971
• 164 Fargion S, Valenti L, Dongiovanni P et al.. Tumor necrosis factor alpha promoter polymorphisms influence the phenotypic expression of hereditary hemochromatosis.  Blood. 2001;  97 3707-3712
• 165 Distante S, Elmberg M, Foss Haug K B et al.. Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.  Scand J Gastroenterol. 2003;  38 871-877
• 166 Pietrangelo A. Iron, oxidative stress and liver fibrogenesis.  J Hepatol. 1998;  28(Suppl 1) 8-13
• 167 Poli G. Pathogenesis of liver fibrosis: role of oxidative stress.  Mol Aspects Med. 2000;  21 49-98
• 168 Britton R S, Ramm G A, Olynyk J et al.. Pathophysiology of iron toxicity.  Adv Exp Med Biol. 1994;  356 239-253
• 169 Gualdi R, Casalgrandi G, Montosi G et al.. Excess iron into hepatocytes is required for activation of collagen type I gene during experimental siderosis.  Gastroenterology. 1994;  107 1118-1124
• 170 Pietrangelo A, Gualdi R, Casalgrandi G et al.. Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents.  J Clin Invest. 1995;  95 1824-1831
• 171 Pietrangelo A, Montosi G, Garuti C et al.. Iron-induced oxidant stress in nonparenchymal liver cells: mitochondrial derangement and fibrosis in acutely iron-dosed gerbils and its prevention by silybin.  J Bioenerg Biomembr. 2002;  34 67-79
• 172 Svegliati Baroni G, D'Ambrosio L, Ferretti G et al.. Fibrogenic effect of oxidative stress on rat hepatic stellate cells.  Hepatology. 1998;  27 720-726
• 173 Olynyk J K, Britton R S, Stephenson A H et al.. An in vitro model for the study of phagocytosis of damaged hepatocytes by rat Kupffer cells.  Liver. 1999;  19 418-422
• 174 Kondo H, Saito K, Grasso J P, Aisen P. Iron metabolism in the erythrophagocytosing Kupffer cell.  Hepatology. 1988;  8 32-38
• 175 Sibille J C, Kondo H, Aisen P. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein.  Hepatology. 1988;  8 296-301
• 176 Leicester K L, Olynyk J K, Brunt E M et al.. CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis.  Liver Int. 2004;  24 446-451
• 177 Xiong S, She H, Sung C K, Tsukamoto H. Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease.  Alcohol. 2003;  30 107-113
• 178 Xiong S, She H, Tsukamoto H. Signaling role of iron in NF-kappa B activation in hepatic macrophages.  Comp Hepatol. 2004;  3(suppl 1) S36
• 179 George D K, Goldwurm S, MacDonald G A et al.. Increased hepatic iron in non-alcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology. 1998;  114 311-318
• 180 Olynyk J K, Reddy K R, Di Bisceglie A M et al.. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C.  Gastroenterology. 1995;  108 1104-1109
• 181 Brown K E, Dennery P A, Ridnour L A et al.. Effect of iron overload and dietary fat on indices of oxidative stress and hepatic fibrogenesis in rats.  Liver Int. 2003;  23 232-242
• 182 Tavill A S, Qadri A M. Alcohol and iron.  Semin Liver Dis. 2004;  24 317-325
• 183 Stuart K A, Anderson G J, Frazer D M et al.. Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis.  Hepatology. 2004;  39 492-499
• 184 Bonkovsky H L. Iron in non-hemochromatosis liver disease.  Semin Liver Dis. 2005;  25 461-472