Alcohol and Iron

Iron in its free ferrous and ferric states may serve as a physiological regulator of normal intracellular functions but can be a double-edged sword when linked to several pathways of cellular toxicity. In particular, oxidative stress-induced cytotoxicity leading to both necrosis and apoptosis (so-called necrapoptosis) may be promoted by increased intracellular free iron. When hepatocyte iron accumulates to excess in clinical alcohol abuse or in an experimental, combined model of iron and alcohol hepatotoxicity, there is evidence for synergy among the putative pathways of oxidative stress. Just how excess hepatocyte iron accumulates in alcohol excess is unknown, but when the usual safe harbor for intracellular iron, namely the endosomal-lysosomal compartment, is compromised, it becomes a potent source of free, chelatable pro-oxidant iron. In this regard excess iron in alcohol-induced liver damage and alcohol excess in iron-overload disease are powerful cocktails promoting subcellular organelle damage leading to cell death and fibrogenesis. In some experimental circumstances, only the combined insults of both alcohol and iron overload are capable of inducing cell injury and fibrogenesis. There are clinical examples for such relative resistance to each hepatotoxin presented to the liver in isolation that lend support to this concept of synergy of pro-oxidant pathways of liver injury.

KEYWORDS

Alcohol and iron - iron overload - hemochromatosis - oxidative stress - lipid peroxidation - fibrogenesis - necrosis - apoptosis

REFERENCES

• 1 Britton R S. Metal-induced hepatoxicity.  Semin Liver Dis. 1996;  16 3-12
• 2 Niederau C, Fischer R, Purschel A et al.. Long-term survival in patients with hereditary hemochromatosis.  Gastroenterology. 1996;  110 1107-1119
• 3 Bacon B R, Britton R S. The pathology of hepatic iron overload: A free radical-mediated process?.  Hepatology. 1990;  11 127-137
• 4 Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis.  Semin Liver Dis. 1996;  16 13-30
• 5 Pietrangelo A. Mechanisms of liver injury and fibrosis due to iron and copper. American Association for the Study of Liver Diseases (AASLD) Review Course October 2003: 53-58
• 6 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
• 7 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
• 8 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
• 9 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
• 10 Selden C, Owen M, Hopkins J MP et al.. Studies on the concentration and intracellular localization of iron proteins in liver biopsy specimens from patients with iron overload with special reference to their role in lysosomal disruption.  Br J Haematol. 1980;  44 593-603
• 11 O'Connell M J, Ward R J, Baum H, Peters T J. The role of iron in ferritin and haemosiderin-mediated lipid peroxidation in lysosomes.  Biochem J. 1985;  229 135-139
• 12 Hultcrantz R, Ahlberg J, Glaumann H. Isolation of two lysosomal populations from iron-overload rat liver with different iron concentration and proteolytic activity.  Virchows Arch [B]. 1984;  47 55-65
• 13 Myers B M, Prendergast F G, Holman R et al.. Alterations in structure, physicochemical properties, and pH of hepatocyte lysosomes in experimental iron overload.  J Clin Invest. 1991;  88 1207-1215
• 14 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
• 15 Britton R S, Ramm G A, Olynyk J et al.. Pathophysiology of iron toxicity.  Adv Exp Med Biol. 1994;  356 239-253
• 16 Park C H, Bacon B R, Brittenham G M, Tavill A S. Pathology of dietary carbonyl iron overload in rats.  Lab Invest. 1987;  57 555-563
• 17 Rauen U, Petrat F, Sustmann R, de Groon H. Iron-induced mitochondrial permeability transition in cultured hepatocytes.  J Hepatol. 2004;  40 607-615
• 18 LeMasters J L. Rusty notions of cell injury.  J Hepatol. 2004;  40 696-698
• 19 Tavill A S, Bacon B R. Hemochromatosis: how much iron is too much?.  Hepatology. 1986;  6 142-145
• 20 Summers K M, Halliday J W, Powell L W. Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index.  Hepatology. 1990;  12 20-25
• 21 Bassett M L, Halliday J W, Powell L W. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis.  Hepatology. 1986;  6 24-29
• 22 Sallie R, Reed W D, Shilkin K B. Confirmation of the efficacy of the hepatic iron index in differentiating genetic haemochromatosis from alcoholic liver disease complicated by alcoholic haemosiderosis.  Gut. 1991;  32 207-210
• 23 Beaton M, Guyader D, Deugnier Y et al.. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis.  Hepatology. 2002;  36 673-678
• 24 Morrison E D, Brandhagen D J, Phatak P D et al.. Serum ferritin levels predict advanced hepatic fibrosis among U. S. patients with phenotypic hemochromatosis.  Ann Intern Med. 2003;  138 627-633
• 25 Pietrangelo A, Rocchi E, Schiaffonoti L et al.. Liver gene expression during chronic dietary iron overload in rats.  Hepatology. 1990;  11 798-804
• 26 Pietrangelo A, Borella F, Casalgrandi G et al.. Antioxidant activity of silybin in vivo during long-term iron overload in rats.  Gastroenterology. 1995;  109 1941-1949
• 27 Houglum K, Grant A R, Crawford D HG et al.. Excess iron induces hepatic oxidative stress and transforming growth factor B1 in genetic hemochromatosis.  Hepatology. 1997;  26 605-610
• 28 Parola M, Robino G, Dianzani M U. 4-hydroxy-2, 3-alkenals as molecular mediators of oxidative stress in the pathogenesis of liver fibrosis.  Int J Mol Med. 1999;  4 425-432
• 29 Zhou X Y, Tomatsu S, Fleming R E et al.. HFE gene knockout produces mouse model of hereditary hemochromatosis.  Proc Natl Acad Sci USA. 1998;  95 2492-2497
• 30 Bell H, Skinningsrud A, Raknerud N, Try K. Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver disease.  J Intern Med. 1994;  236 315-322
• 31 Sabesin S M, Thomas L B. Parenchymal siderosis in patients with preexisting portal cirrhosis. A pathologic entity simulating idiopathic and transfusional hemochromatosis.  Gastroenterology. 1964;  46 477-485
• 32 Powell L W. Normal human iron storage and its relation to ethanol consumption.  Australas Ann Med. 1966;  15 110-115
• 33 Lundvall O, Weinfeld A, Lundin P. Iron stores in alcohol abusers.  Acta Med Scand. 1969;  185 259-269
• 34 Jacobovits A, Morgan M Y, Sherlock S. Hepatic siderosis in alcoholics.  Dig Dis Sci. 1979;  24 305-310
• 35 MacDonald R A. Primary hemochromatosis: inherited or acquired?.  Prog Hematol. 1966;  5 324-353
• 36 Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic hemochromatosis. Demonstration of recessive transmission and early detection by family HLA typing.  N Engl J Med. 1977;  297 1017-1021
• 37 Simon M, Bourel M, Genetet B et al.. Idiopathic hemochromatosis and iron overload in alcoholic liver disease: differentiation by HLA phenotype.  Gastroenterology. 1977;  73 655-658
• 38 Simon M, Alexandre J L, Bourel M et al.. Heredity of idiopathic haemochromatosis: a study of 106 families.  Clin Genet. 1977;  11 327-341
• 39 Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic haemochromatosis: demonstration of recessive transmission and early detection by family HLA typing.  N Engl J Med. 1977;  297 1017-1022
• 40 Finch S C, Finch C A. Idiopathic hemochromatosis, an iron storage disease. A. Iron metabolism in hemochromatosis.  Medicine. 1955;  34 381-430
• 41 Milder M S, Cook J D, Stray S, Finch C A. Idiopathic hemochromatosis, an interim report.  Medicine (Baltimore). 1980;  59 34-49
• 42 Powell L W. Iron storage in relatives of patients with haemochromatosis and in relatives of patients with alcoholic cirrhosis and haemochromatosis. A comparative study of 27 families.  Q J Med. 1965;  34 427-442
• 43 Beutler E, Felitti V, Koziol J A et al.. Penetrance of 845G→A (C282Y) HFE hereditary haemochromatosis mutation in the USA.  Lancet. 2002;  359 211-218
• 44 LeSage G D, Baldus W P, Fairbanks V F et al.. Hemochromatosis: genetic or alcohol-induced?.  Gastroenterology. 1983;  84 1471-1477
• 45 Cederbaum A I. Oxygen radical generation by microsomes: role of iron and implications for alcohol metabolism and toxicity.  Free Radic Biol Med. 1989;  7 559-567
• 46 Ekstrom G, Ingelman-Sundberg M. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P450 (P-459 IIE1).  Biochem Pharmacol. 1989;  38 1313-1319
• 47 Morimoto M, Hagbjork A L, Nanji A A et al.. Role of cytochrome P450 2E1 in alcoholic liver disease pathogenesis.  Alcohol. 1993;  10 459-464
• 48 Ekstrom G, Cronholm T, Ingelman-Sundberg M. Hydroxyl-radical production of ethanol oxidation by liver microsomes isolated from ethanol treated rats.  Biochem J. 1986;  233 755-761
• 49 Niemela O, Parkkila S, Britton R S et al.. Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury.  J Lab Clin Med. 1999;  133 451-460
• 50 Bacon B, Tavill A. Role of the liver in normal iron metabolism.  Semin Liver Dis. 1984;  4 181-192
• 51 Reif D W. Ferritin as a source of iron for oxidative damage.  Free Radic Biol Med. 1992;  12 417-427
• 52 Shaw S. Lipid peroxidation, iron mobilization and radical generation induced by alcohol.  Free Radic Biol Med. 1989;  7 541-547
• 53 French S W. The mechanism of organ injury in alcoholics: implications for therapy.  Alcohol Alcohol Suppl. 1991;  1 57-63
• 54 Sanchez J, Casas M, Rama R. Effect of chronic ethanol administration on iron metabolism in the rat.  Eur J Haematol. 1988;  41 321-325
• 55 Fairweather-Tait S J, Southon S, Piper Z. The effect of alcoholic beverages on iron and zinc metabolism in the rat.  Br J Nutr. 1988;  60 209-215
• 56 Sadrzadeh S MH, Nanji A A, Price P L. The oral iron-chelator, 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats.  J Pharmacol Exp Ther. 1994;  269 632-636
• 57 Hultcrantz R, Bissell D M, Roll F J. Iron mediates production of a neutrophil chemoattractant by rat hepatocytes metabolizing ethanol.  J Clin Invest. 1991;  87 45-49
• 58 Tsukamoto H, Towner S J, Ciafalo L M et al.. Ethanol-induced liver fibrosis in rats fed high fat diet.  Hepatology. 1986;  6 814-822
• 59 Tsukamoto H, Matsuoka M, French S W. Experimental models of hepatic fibrosis.  Semin Liver Dis. 1990;  10 56-65
• 60 Tsukamoto H, Horne W, Kamimura S et al.. Experimental liver cirrhosis induced by alcohol and iron.  J Clin Invest. 1995;  96 620-630
• 61 Adams P C, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria.  Gastroenterology. 1998;  114 319-323
• 62 Powell L W, Summers K M, Board P G et al.. Expression of hemochromatosis in homozygous subjects. Implication for early diagnosis and prevention.  Gastroenterology. 1990;  98 1625-1632
• 63 Adams P C, Frei J V, Bradley C, Lam D. Hepatic iron and iron absorption in hemochromatosis.  Clin Invest Med. 1990;  13 256-258
• 64 Cotler S, Bronner M, Press D et al.. End-stage liver disease without hemochromatosis associated with elevated hepatic iron index.  J Hepatol. 1998;  29 257-262
• 65 Feder J N, Gnirke A, Thomas W et al.. A novel MHC class I-like gene mutation in patients with hereditary haemochromatosis.  Nat Genet. 1996;  13 399-408
• 66 Bacon B R, Powell L W, Adams P C et al.. Molecular medicine and hemochromatosis: at the crossroads.  Gastroenterology. 1999;  116 193-207
• 67 Bacon B R, Olynyk J K, Brunt E M et al.. HFE genotype in patients with hemochromatosis and other liver diseases.  Ann Intern Med. 1999;  130 953-962
• 68 Adams P C, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings.  Hepatology. 1996;  23 724-727
• 69 Fletcher L, Dixon J, Purdie D et al.. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis.  Gastroenterology. 2002;  122 281-289
• 70 Ioannou G N. The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia.  Gastroenterology. 2004;  126 1293-1301
• 71 Regoeczi E, Chindemi P A, Debanne M T. Transferrin glycans: a possible link between alcoholism and alcoholic siderosis.  Alcohol Clin Exp Res. 1984;  8 287-292
• 72 Beguin Y, Bergamschi G, Huebers H, Finch C A. The behavior of asialotranferrin-iron in the rat.  Am J Hematol. 1988;  29 204-210
• 73 Rouach H, Houze P, Gentil M et al.. Effects of acute ethanol administration on the uptake of [59]Fe-labeled transferrin by rat liver and cerebellum.  Biochem Pharmacol. 1994;  47 1835-1841
• 74 Chapman R W, Morgan M Y, Boss A M, Sherlock S. Acute and chronic effects of alcohol on iron absorption.  Dig Dis Sci. 1983;  28 321-327
• 75 Bonkovsky H L, Banner B F, Lambrecht R W, Rubin R B. Iron in liver diseases other than hemochromatosis.  Semin Liver Dis. 1996;  16 65-82
• 76 Milman N, Graudal N, Hegnhoj J et al.. Relationships among serum iron status markers, chemical and histochemical liver iron content in 117 patients with alcohol and non-alcohol hepatic disease.  Hepatogastroenterology. 1994;  41 20-24
• 77 Grace N D, Greenberg M S. Phlebotomy in the treatment of iron overload: a controlled trial (a preliminary report.)  Gastroenterology. 1971;  60 744 (Abst)
• 78 MacPhail A P, Simon M O, Torrance J D et al.. Changing patterns of dietary iron overload in black South Africans.  Am J Clin Nutr. 1979;  32 1272-1278
• 79 Issacson C, Seftel H, Keeley K J, Bothwell T H. Siderosis in the Bantu. The relationship between iron overload and cirrhosis.  J Lab Clin Med. 1961;  58 845-853
• 80 Gordeuk V R, Mukabi J, Hasstedt J et al.. Iron overload in Africa: interaction between a gene and dietary iron content.  N Engl J Med. 1992;  326 95-100
• 81 Bacon B R, Farahvash M J, Janney C G, Neuschwander-Tetri B A. Nonalcoholic steatohepatitis: an expanded clinical entity.  Gastroenterology. 1994;  107 1103-1109
• 82 George D K, Goldwurm S, MacDonald G A et al.. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis.  Gastroenterology. 1998;  114 311-318
• 83 Bonkovsky H L, Jawaid Q, Tortorelli K et al.. Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis.  J Hepatol. 1999;  31 421-429
• 84 Rocchi E, Gilbertini P, Cassanelli M et al.. Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda.  J Lab Clin Med. 1986;  107 36-42
• 85 Rocchi E, Gilbertini P, Cassanelli M et al.. Liver iron overload and desferrioxamine treatment of porphyria cutanea tarda.  Dermatologica. 1991;  182 27-31
• 86 Edwards C Q, Griffen L M, Goldgar D E et al.. HLA-linked hemochromatosis alleles in sporadic porphyria cutanea tarda.  Gastroenterology. 1989;  97 972-981
• 87 Roberts A G, Whatley S D, Morgan R R et al.. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda.  Lancet. 1997;  349 321-323
• 88 Bonkovsky H L. Iron as a comorbid factor in chronic viral hepatitis.  Am J Gastroenterol. 2002;  97 1-3
• 89 Tung B Y, Emond M J, Bronner M P et al.. Hepatitis C, iron status, and disease severity: relationship with HFE mutations.  Gastroenterology. 2003;  124 318-326
• 90 Pietrangelo A. Hemochromatosis gene modifies course of hepatitis C viral infection.  Gastroenterology. 2003;  124 1509-1523