The Role of the Liver in Iron Homeostasis and What Goes Wrong?
Main Article Content
Keywords
liver, iron homeostasis, iron overload
Abstract
Iron is an essential mineral that is vital for growth development, normal cellular function, synthesis of hormones and connective tissue, and most importantly, serves as a component of hemoglobin to carry oxygen to body tissues. The body finely regulates the amount of circulating and stored iron within the body to maintain concentration levels within range for optimal physiologic function. Without iron, the ability for cells to participate in electron transport and energy metabolism decreases. Furthermore, hemoglobin synthesis is altered, which leads to anemia and decreased oxygen delivery to tissue. Problems arise when there is too little or too much iron. This review explores the role of the liver in iron physiology, iron overload and discusses the most common causes of primary and secondary hepatic iron overload.
References
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7. Pietrangelo A. Ferroportin disease: Pathogenesis, diagnosis and treatment. Haemotologica. 2017 Dec;102(12):1972. https://doi.org/10.3324/haematol.2017.170720
8. Boyer TD, Manns MP, Sanyal AJ, Zakim D. Zakim and Boyer's hepatology: A textbook of liver disease. Philadelphia, PA: Saunders/Elsevier;2012.
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10. Ganz T Iron metabolism. In: Kaushansky K, Lichtman MA, Prchal JT, et al., editors. Williams hematology. 9th ed. New York: McGraw-Hill; 2015.
11. Fitzsimons E, Cullis J, Thomas D, et al. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br Haematol. 2018;181(3):293–303. https://doi.org/10.1111/bjh.15164
12. Katsarou M, Papasavva M, Latsi R, Drakoulis, N. Hemochromatosis: Hereditary hemochromatosis and HFE gene. Vitam Horm.2019;110:201–22. https://doi.org/ 10.1016/bs.vh.2019.01.010.
13. De Sanctis V. A young adult with unintentional acute parenteral iron intoxication treated with oral chelation: The use of liver ferriscan. Mediterr J Hematol Infect Dis. 2016;9(1):e2017008. https://doi.org/10.4084/mjhid.2017.008
14. De Sanctis V. Liver iron content (LIC) in adults with non-transfusion dependent sickle cell disease (NT-SCD). Correlation with serum ferritin and liver enzymes concentrations. Mediterr J Hematol Infect Dis. 2017;9(1):2017037. https://doi.org/10.4084/mjhid.2017.037
15. Rossi E. Hepcidin- the iron regulatory hormone. Clin Biochem Rev. 2005:26(3); 47–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240030/
16. Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin: From discovery to differential diagnosis. Haematologica. 2008 Jan;93(1):90–7. https://doi.org/10.3324/haematol.11705
17. Billesbolle CB, Azumaya CM, Kretsch RC et al. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature. 2020 Oct;586(7831):807–11. https://doi.org/10.1038/s41586-020-2668-z
18. Bunn H, Heeney MM. Iron homeostasis: Deficiency and overload. In: Aster JC, Bunn H, editors. Pathophysiology of blood disorders. 2nd ed. New York: McGraw-Hill; 2016.
19. Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol.. 2020;5:25. https://doi.org/10.21037/tgh.2019.11.15
20. Armitage AE, Stacey AR, Giannoulatou E, et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV and HCV infections. Proc Natl Acad Sci USA. 2014 Aug 19;111(33):12187–92. https://doi.org/10.1073/pnas.1402351111
21. Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet. 2016;388(10045):706–16. https://doi.org/10.1016/S0140-6736(15)01315-X
22. Adams P, Altes A, Brissot P, et al. Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83–6. https://doi.org/10.1007/s12072-018-9855-0
23. Ganz T. Iron deficiency and overload. In: Kaushansky K, Lichtman MA, Prchal JT, et al., editors. Williams hematology. 10th ed. New York: McGraw-Hill; 2021.
24. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105(3):1337–42. https://doi.org/10.1182/blood-2004-07-2966
25. Kennelly PJ, Murray RK, Jacob M, Varghese J. Plasma proteins & Immunoglobulins. In: Rodwell VW, Bender DA, Botham KM, et al. Harpers illustrated biochemistry. 31 ed. New York: Mcgraw-Hill, 2018.
26. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3–22. https://doi.org/10.1016/j.jhep.2010.03.001
27. Kowdley K, Brown K, Ahn J, Sundaram V. ACG Clinical guideline. Am J Gastroenterol Suppl. 2019;114(8):1202–18.https://doi.org/10.14309/ajg.0000000000000315
28. Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders; 2015.
29. Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary hemochromatosis: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005;143(7):517. https://doi.org/10.7326/0003-4819-143-7-200510040-00010
30. Golfers S, Lewis S, Weisberg IS. Hemochromatosis: Pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert Rev Gastroenterol Hepatol. 2018;12(8):767–78. https://doi.org/10.1080/17474124.2018.1496016
31. Acton R, Barton J, Passmore L, et al. Accuracy of family history of hemochromatosis or iron overload: The hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. 2008;6(8):934–8. https://doi.org/10.1016/j.cgh.2008.04.003
32. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G → A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002; 359: 211–8. https://doi.org/10.1016/S0140-6736(02)07447-0
33. Bacon B, Adams P, Kowdley K, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the study of liver diseases. Hepatology. 2011;54(1):328–43. https://doi.org/10.1002/hep.24330
34. Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2016;10(3):359–70. https://doi.org/10.1586/17474124.2016.1119043
35. Hoffbrand AV, Taher A, Cappellini MD. How I treat transfusional iron overload. Blood 2012; 120:3657. https://doi.org/10.1182/blood-2012-05-370098
36. Lee JW, Yoon SS, Shen ZX, et al. Iron chelation therapy with deferasirox in patients with aplastic anemia: A subgroup analysis of 116 patients from the EPIC trial. Blood 2010; 116:2448. https://doi.org/10.1182/blood-2010-01-261289
37. Boxed warning about deferasirox [Internet]. [Cited 2012 Dec 12]. Available from: https://www.fda.gov/media/91182/download
38. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007; 115:1876. https://doi.org/10.1161/CIRCULATIONAHA.106.648790
39. Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone--toxicity or lack of efficacy? N Engl J Med. 1998; 339:468. https://doi.org/10.1056/NEJM199808133390709
40. Van Aerts RM, van Deursen CT, Koek GH. Proton pump inhibitors reduce the frequency of phlebotomy in patients with hereditary hemochromatosis. Clin Gastroenterol Hepatol. 2016;14(1):147–52. https://doi.org/10.1016/j.cgh.2015.06.043
41. Vanclooster A, van Deursen C, Jaspers R, et al. Proton pump inhibitors decrease phlebotomy need in HFE hemochromatosis: Double-blind randomized placebo-controlled trial. Gastroenterology 2017;153(3):678–80.e2. https://doi.org/10.1053/j.gastro.2017.06.006
42. Hutchinson C, Geissler CA, Powell JJ, et al. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut. 2007;56(9):1291–5. https://doi.org/10.1136/gut.2006.108613
43. Cohen DE, Anania FA. Nonalcoholic fatty liver disease. In: Greenberger NJ, Blumberg RS, Burakoff R, editors. Current diagnosis & treatment: Gastroenterology, hepatology, & endoscopy. 3rd ed. New York: McGraw-Hill; 2016.
44. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011; 140:124. https://doi.org/10.1053/j.gastro.2010.09.038
45. Datz C, Müller E, Aigner E. Iron overload and nonalcoholic fatty liver disease. Minerva Endocrinol. 2017 Jun;42(2):173–83. https://doi.org/10.23736/S0391-1977.16.02565-7
46. Britton LJ, Subramaniam VN, Crawford DH. Iron and nonalcoholic fatty liver disease. World J Gastroenterol., 2016;22(36): 8112–22. https://doi.org/10.3748/wjg.v22.i36.8112
47. Sumida Y, Yoneda M, Hyogo H, et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:257–68. https://doi.org/10.1007/s00535-010-0305-6
48. Aigner E. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol. 2014;7(2):177. https://doi.org/10.4254/wjh.v7.i2.177
49. Musso G, Cassander M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in nonalcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of randomised trials. Diabetologia. 2012; 55(4):885–904. https://doi.org/10.1007/s00125-011-2446-4
50. Bennett TD, Hayward KN, Farris RW, et al. Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. Pediatr Crit Care Med. 2011;12(6):e233–6. https://doi.org/10.1097/PCC.0b013e31820abca8
51. Ravasi G, Pelucchi S, Mariani R, et al. Unexplained isolated hyperferritinemia without iron overload. Am J Hematol. 2017;92(4):338–43. https://doi.org/10.1002/ajh.24641
52. Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401–9. https://doi.org/10.1093/intimm/dxx031
53. Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 2018;13(1):27–49. https://doi.org/10.1146/annurev-pathol-020117-043625
54. Cadenas B, Fita-Torró J, Bermúdez-Cortés M, et al. L-Ferritin: one gene, five diseases; from hereditary hyperferritinemia to hypoferritinemia—Report of new cases. Pharmaceuticals. 2019;12(1):17.https://doi.org/10.3390/ph12010017
2. Chipman J, Laubenbacher R, Torti S. A systems biology approach to iron metabolism. In: Corey S, Kimmel M, Leonard J, editors. A systems biology approach to blood. Advances in experimental medicine and biology. Vol 844. New York, NY: Springer; 2014. p. 201–25. https://doi.org/10.1007/978-1-4939-2095-2_
3. Ded S, Babbitt J. Overview of iron metabolism in health and disease. Hemodial Int. 2017; 21:S6–20. https://doi.org/10.1111/hdi.12542
4. Janson LW, Tischler ME. The big picture. Medical biochemistry. New York: McGraw-Hill; 2012.
5. Milic S, Mikolasevic I, Orlic L, et al. The role of iron and iron overload in chronic liver disease. Med Sci Monit Basic Res. 2016;22:2144–51. https://doi.org/10.12659/MSM.896494
6. Lolascon A, De FL. Mutations in the gene encoding DMT 1: Clinical presentation and treatment. Semin Hematol. 2009;46(4):358–70. https://doi.org/10.1053/j.seminhematol.2009.06.005
7. Pietrangelo A. Ferroportin disease: Pathogenesis, diagnosis and treatment. Haemotologica. 2017 Dec;102(12):1972. https://doi.org/10.3324/haematol.2017.170720
8. Boyer TD, Manns MP, Sanyal AJ, Zakim D. Zakim and Boyer's hepatology: A textbook of liver disease. Philadelphia, PA: Saunders/Elsevier;2012.
9. Bloomer S, Brown K. Iron-induced liver injury: A critical reappraisal. Int J Mol Sci. 2019; 20(9):21–32. https://doi.org/10.3390/ijms20092132
10. Ganz T Iron metabolism. In: Kaushansky K, Lichtman MA, Prchal JT, et al., editors. Williams hematology. 9th ed. New York: McGraw-Hill; 2015.
11. Fitzsimons E, Cullis J, Thomas D, et al. Diagnosis and therapy of genetic haemochromatosis (review and 2017 update). Br Haematol. 2018;181(3):293–303. https://doi.org/10.1111/bjh.15164
12. Katsarou M, Papasavva M, Latsi R, Drakoulis, N. Hemochromatosis: Hereditary hemochromatosis and HFE gene. Vitam Horm.2019;110:201–22. https://doi.org/ 10.1016/bs.vh.2019.01.010.
13. De Sanctis V. A young adult with unintentional acute parenteral iron intoxication treated with oral chelation: The use of liver ferriscan. Mediterr J Hematol Infect Dis. 2016;9(1):e2017008. https://doi.org/10.4084/mjhid.2017.008
14. De Sanctis V. Liver iron content (LIC) in adults with non-transfusion dependent sickle cell disease (NT-SCD). Correlation with serum ferritin and liver enzymes concentrations. Mediterr J Hematol Infect Dis. 2017;9(1):2017037. https://doi.org/10.4084/mjhid.2017.037
15. Rossi E. Hepcidin- the iron regulatory hormone. Clin Biochem Rev. 2005:26(3); 47–9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1240030/
16. Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin: From discovery to differential diagnosis. Haematologica. 2008 Jan;93(1):90–7. https://doi.org/10.3324/haematol.11705
17. Billesbolle CB, Azumaya CM, Kretsch RC et al. Structure of hepcidin-bound ferroportin reveals iron homeostatic mechanisms. Nature. 2020 Oct;586(7831):807–11. https://doi.org/10.1038/s41586-020-2668-z
18. Bunn H, Heeney MM. Iron homeostasis: Deficiency and overload. In: Aster JC, Bunn H, editors. Pathophysiology of blood disorders. 2nd ed. New York: McGraw-Hill; 2016.
19. Piperno A, Pelucchi S, Mariani R. Inherited iron overload disorders. Transl Gastroenterol Hepatol.. 2020;5:25. https://doi.org/10.21037/tgh.2019.11.15
20. Armitage AE, Stacey AR, Giannoulatou E, et al. Distinct patterns of hepcidin and iron regulation during HIV-1, HBV and HCV infections. Proc Natl Acad Sci USA. 2014 Aug 19;111(33):12187–92. https://doi.org/10.1073/pnas.1402351111
21. Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet. 2016;388(10045):706–16. https://doi.org/10.1016/S0140-6736(15)01315-X
22. Adams P, Altes A, Brissot P, et al. Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatol Int. 2018;12(2):83–6. https://doi.org/10.1007/s12072-018-9855-0
23. Ganz T. Iron deficiency and overload. In: Kaushansky K, Lichtman MA, Prchal JT, et al., editors. Williams hematology. 10th ed. New York: McGraw-Hill; 2021.
24. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105(3):1337–42. https://doi.org/10.1182/blood-2004-07-2966
25. Kennelly PJ, Murray RK, Jacob M, Varghese J. Plasma proteins & Immunoglobulins. In: Rodwell VW, Bender DA, Botham KM, et al. Harpers illustrated biochemistry. 31 ed. New York: Mcgraw-Hill, 2018.
26. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol. 2010;53(1):3–22. https://doi.org/10.1016/j.jhep.2010.03.001
27. Kowdley K, Brown K, Ahn J, Sundaram V. ACG Clinical guideline. Am J Gastroenterol Suppl. 2019;114(8):1202–18.https://doi.org/10.14309/ajg.0000000000000315
28. Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier/Saunders; 2015.
29. Qaseem A, Aronson M, Fitterman N, et al. Screening for hereditary hemochromatosis: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005;143(7):517. https://doi.org/10.7326/0003-4819-143-7-200510040-00010
30. Golfers S, Lewis S, Weisberg IS. Hemochromatosis: Pathophysiology, evaluation, and management of hepatic iron overload with a focus on MRI. Expert Rev Gastroenterol Hepatol. 2018;12(8):767–78. https://doi.org/10.1080/17474124.2018.1496016
31. Acton R, Barton J, Passmore L, et al. Accuracy of family history of hemochromatosis or iron overload: The hemochromatosis and iron overload screening study. Clin Gastroenterol Hepatol. 2008;6(8):934–8. https://doi.org/10.1016/j.cgh.2008.04.003
32. Beutler E, Felitti VJ, Koziol JA, et al. Penetrance of 845G → A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002; 359: 211–8. https://doi.org/10.1016/S0140-6736(02)07447-0
33. Bacon B, Adams P, Kowdley K, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the study of liver diseases. Hepatology. 2011;54(1):328–43. https://doi.org/10.1002/hep.24330
34. Brissot P. Optimizing the diagnosis and the treatment of iron overload diseases. Expert Rev Gastroenterol Hepatol. 2016;10(3):359–70. https://doi.org/10.1586/17474124.2016.1119043
35. Hoffbrand AV, Taher A, Cappellini MD. How I treat transfusional iron overload. Blood 2012; 120:3657. https://doi.org/10.1182/blood-2012-05-370098
36. Lee JW, Yoon SS, Shen ZX, et al. Iron chelation therapy with deferasirox in patients with aplastic anemia: A subgroup analysis of 116 patients from the EPIC trial. Blood 2010; 116:2448. https://doi.org/10.1182/blood-2010-01-261289
37. Boxed warning about deferasirox [Internet]. [Cited 2012 Dec 12]. Available from: https://www.fda.gov/media/91182/download
38. Tanner MA, Galanello R, Dessi C, et al. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007; 115:1876. https://doi.org/10.1161/CIRCULATIONAHA.106.648790
39. Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone--toxicity or lack of efficacy? N Engl J Med. 1998; 339:468. https://doi.org/10.1056/NEJM199808133390709
40. Van Aerts RM, van Deursen CT, Koek GH. Proton pump inhibitors reduce the frequency of phlebotomy in patients with hereditary hemochromatosis. Clin Gastroenterol Hepatol. 2016;14(1):147–52. https://doi.org/10.1016/j.cgh.2015.06.043
41. Vanclooster A, van Deursen C, Jaspers R, et al. Proton pump inhibitors decrease phlebotomy need in HFE hemochromatosis: Double-blind randomized placebo-controlled trial. Gastroenterology 2017;153(3):678–80.e2. https://doi.org/10.1053/j.gastro.2017.06.006
42. Hutchinson C, Geissler CA, Powell JJ, et al. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut. 2007;56(9):1291–5. https://doi.org/10.1136/gut.2006.108613
43. Cohen DE, Anania FA. Nonalcoholic fatty liver disease. In: Greenberger NJ, Blumberg RS, Burakoff R, editors. Current diagnosis & treatment: Gastroenterology, hepatology, & endoscopy. 3rd ed. New York: McGraw-Hill; 2016.
44. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: A prospective study. Gastroenterology. 2011; 140:124. https://doi.org/10.1053/j.gastro.2010.09.038
45. Datz C, Müller E, Aigner E. Iron overload and nonalcoholic fatty liver disease. Minerva Endocrinol. 2017 Jun;42(2):173–83. https://doi.org/10.23736/S0391-1977.16.02565-7
46. Britton LJ, Subramaniam VN, Crawford DH. Iron and nonalcoholic fatty liver disease. World J Gastroenterol., 2016;22(36): 8112–22. https://doi.org/10.3748/wjg.v22.i36.8112
47. Sumida Y, Yoneda M, Hyogo H, et al. A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol. 2011;46:257–68. https://doi.org/10.1007/s00535-010-0305-6
48. Aigner E. Dysregulation of iron and copper homeostasis in nonalcoholic fatty liver. World J Hepatol. 2014;7(2):177. https://doi.org/10.4254/wjh.v7.i2.177
49. Musso G, Cassander M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in nonalcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of randomised trials. Diabetologia. 2012; 55(4):885–904. https://doi.org/10.1007/s00125-011-2446-4
50. Bennett TD, Hayward KN, Farris RW, et al. Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. Pediatr Crit Care Med. 2011;12(6):e233–6. https://doi.org/10.1097/PCC.0b013e31820abca8
51. Ravasi G, Pelucchi S, Mariani R, et al. Unexplained isolated hyperferritinemia without iron overload. Am J Hematol. 2017;92(4):338–43. https://doi.org/10.1002/ajh.24641
52. Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401–9. https://doi.org/10.1093/intimm/dxx031
53. Al-Samkari H, Berliner N. Hemophagocytic lymphohistiocytosis. Annu Rev Pathol. 2018;13(1):27–49. https://doi.org/10.1146/annurev-pathol-020117-043625
54. Cadenas B, Fita-Torró J, Bermúdez-Cortés M, et al. L-Ferritin: one gene, five diseases; from hereditary hyperferritinemia to hypoferritinemia—Report of new cases. Pharmaceuticals. 2019;12(1):17.https://doi.org/10.3390/ph12010017
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Sep 18, 2021
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The Role of the Liver in Iron Homeostasis and What Goes Wrong?. (2021). Journal of Renal and Hepatic Disorders, 5(2), 26-33. https://doi.org/10.15586/jrenhep.v5i2.110
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Review Hepatology
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