Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation?

Wenke Moris; Pauline Verhaegh; Daisy Jonkers; Cees van Deursen; Ger Koek

doi:10.1055/s-0039-1693114

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2019; 39(04): 476-482
DOI: 10.1055/s-0039-1693114

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation?

Authors

Wenke Moris^*

¹Department of Internal Medicine Gastroenterology and Clinical Geriatrics, Zuyderland Medical Center, Heerlen, The Netherlands

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands

³School of Nutrition and Translational Research in Metabolism (NUTRIM) University Maastricht, Maastricht, The Netherlands
Pauline Verhaegh‡^*

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands

³School of Nutrition and Translational Research in Metabolism (NUTRIM) University Maastricht, Maastricht, The Netherlands
Daisy Jonkers

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands

³School of Nutrition and Translational Research in Metabolism (NUTRIM) University Maastricht, Maastricht, The Netherlands
Cees van Deursen

¹Department of Internal Medicine Gastroenterology and Clinical Geriatrics, Zuyderland Medical Center, Heerlen, The Netherlands

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands
Ger Koek

²Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre+, Maastricht, The Netherlands

³School of Nutrition and Translational Research in Metabolism (NUTRIM) University Maastricht, Maastricht, The Netherlands

⁴Department of visceral and transplantation Surgery, Klinikum, RWTH, Aachen, Germany

Abstract

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.

Keywords

iron overload - DIOS - ferritin - NAFLD - inflammation

Full Text

References

References
1 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64 (01) 73-84
2 Manousou P, Kalambokis G, Grillo F. , et al. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int 2011; 31 (05) 730-739
3 Neuschwander-Tetri BA. Fatty liver and the metabolic syndrome. Curr Opin Gastroenterol 2007; 23 (02) 193-198
4 Lindsay RS, Howard BV. Cardiovascular risk associated with the metabolic syndrome. Curr Diab Rep 2004; 4 (01) 63-68
5 Koh KK, Han SH, Quon MJ. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J Am Coll Cardiol 2005; 46 (11) 1978-1985
6 Moirand R, Mendler MH, Guillygomarc'h A, Brissot P, Deugnier Y. Non-alcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload?. J Hepatol 2000; 33 (06) 1024-1026
7 Trombini P, Piperno A. Ferritin, metabolic syndrome and NAFLD: elective attractions and dangerous liaisons. J Hepatol 2007; 46 (04) 549-552
8 Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol 2017; 29 (09) 401-409
9 Worwood M. Ferritin. Blood Rev 1990; 4: 259-269
10 Adams PC, Reboussin DM, Barton JC. , et al; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005; 352 (17) 1769-1778
11 Brissot P, Pietrangelo A, Adams PC, de Graaff B, McLaren CE, Loréal O. Haemochromatosis. Nat Rev Dis Primers 2018; 4: 18016
12 Valenti L, Canavesi E, Galmozzi E. , et al. Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2010; 53 (05) 927-933
13 Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK. ; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2005; 143 (07) 517-521
14 Nelson JE, Wilson L, Brunt EM. , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53 (02) 448-457
15 Valenti L, Fracanzani AL, Bugianesi E. , et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010; 138 (03) 905-912
16 Deugnier Y, Bardou-Jacquet É, Lainé F. Dysmetabolic iron overload syndrome (DIOS). Presse Med 2017; 46 (12 Pt 2): e306-e311
17 Akin K, Beyler AR, Kaya M, Erden E. The importance of iron and copper accumulation in the pathogenesis of non-alcoholic steatohepatitis. Turk J Gastroenterol 2003; 14: 228-233
18 Duseja A, Das R, Nanda M. , et al. Nonalcoholic steatohepatitis in Asian Indians is neither associated with iron overload nor with HFE gene mutations. World J Gastroenterol 2005; 11: 393-395
19 Uraz S, Aygun C, Sonsuz A, Ozbay G. Serum iron levels and hepatic iron overload in nonalcoholic steatohepatitis and chronic viral hepatitis. Dig Dis Sci 2005; 50: 964-969
20 George DK, Goldwurm S, MacDonald GA. , et al. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114 (02) 311-318
21 Valenti L, Dongiovanni P, Piperno A. , et al. Alpha 1-antitrypsin mutations in NAFLD: high prevalence and association with altered iron metabolism but not with liver damage. Hepatology 2006; 44 (04) 857-864
22 Kowdley KV, Belt P, Wilson LA. , et al; NASH Clinical Research Network. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012; 55 (01) 77-85
23 Aigner E, Theurl I, Theurl M. , et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 2008; 87 (05) 1374-1383
24 Aigner E, Theurl I, Haufe H. , et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology 2008; 135 (02) 680-688
25 Valenti L, Rametta R, Dongiovanni P. , et al. The A736V TMPRSS6 polymorphism influences hepatic iron overload in nonalcoholic fatty liver disease. PLoS One 2012; 7 (11) e48804
26 Bugianesi E, Manzini P, D'Antico S. , et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39 (01) 179-187
27 Yoneda M, Nozaki Y, Endo H. , et al. Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis (NASH) independent of HFE gene mutation. Dig Dis Sci 2010; 55 (03) 808-814
28 Bonkovsky HL, 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 (03) 421-429
29 Chitturi S, Weltman M, Farrell GC. , et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002; 36 (01) 142-149
30 Valenti L, Dongiovanni P, Fracanzani AL. , et al. Increased susceptibility to nonalcoholic fatty liver disease in heterozygotes for the mutation responsible for hereditary hemochromatosis. Dig Liver Dis 2003; 35 (03) 172-178
31 Zamin Jr I, Mattos AA, Mattos AZ, Migon E, Bica C, Alexandre CO. Prevalence of the hemochromatosis gene mutation in patients with nonalcoholic steatohepatitis and correlation with degree of liver fibrosis. Arq Gastroenterol 2006; 43 (03) 224-228
32 Deguti MM, Sipahi AM, Gayotto LC. , et al. Lack of evidence for the pathogenic role of iron and HFE gene mutations in Brazilian patients with nonalcoholic steatohepatitis. Braz J Med Biol Res 2003; 36 (06) 739-745
33 Lin TJ, Lin CL, Wang CS, Liu SO, Liao LY. Prevalence of HFE mutations and relation to serum iron status in patients with chronic hepatitis C and patients with nonalcoholic fatty liver disease in Taiwan. World J Gastroenterol 2005; 11 (25) 3905-3908
34 Rametta R, Dongiovanni P, Pelusi S. , et al. Hepcidin resistance in dysmetabolic iron overload. Liver Int 2016; 36 (10) 1540-1548
35 Tsuchiya H, Ashla AA, Hoshikawa Y. , et al. Iron state in association with retinoid metabolism in non-alcoholic fatty liver disease. Hepatol Res 2010; 40 (12) 1227-1238
36 Uysal S, Armutcu F, Aydogan T, Akin K, Ikizek M, Yigitoglu MR. Some inflammatory cytokine levels, iron metabolism and oxidan stress markers in subjects with nonalcoholic steatohepatitis. Clin Biochem 2011; 44 (17-18): 1375-1379
37 Boga S, Alkim H, Alkim C. , et al. The relationship of serum hemojuvelin and hepcidin levels with iron overload in nonalcoholic fatty liver disease. J Gastrointestin Liver Dis 2015; 24 (03) 293-300
38 Dongiovanni P, Lanti C, Gatti S. , et al. High fat diet subverts hepatocellular iron uptake determining dysmetabolic iron overload. PLoS One 2015; 10 (02) e0116855
39 Hoki T, Miyanishi K, Tanaka S. , et al. Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology 2015; 62 (03) 751-761
40 Zimmermann A, Zimmermann T, Schattenberg J. , et al. Alterations in lipid, carbohydrate and iron metabolism in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome. Eur J Intern Med 2011; 22 (03) 305-310
41 Barisani D, Pelucchi S, Mariani R. , et al. Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload. J Hepatol 2008; 49 (01) 123-133
42 Fujita N, Miyachi H, Tanaka H. , et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 2009; 18 (02) 424-432
43 Kleiner DE, Brunt EM, Van Natta M. , et al; Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41 (06) 1313-1321
44 Hagström H, Nasr P, Bottai M. , et al. Elevated serum ferritin is associated with increased mortality in non-alcoholic fatty liver disease after 16 years of follow-up. Liver Int 2016; 36 (11) 1688-1695
45 Canbakan B, Senturk H, Tahan V. , et al. Clinical, biochemical and histological correlations in a group of non-drinker subjects with non-alcoholic fatty liver disease. Acta Gastroenterol Belg 2007; 70 (03) 277-284
46 Koruk M, Tayşi S, Savaş MC, Yilmaz O, Akçay F, Karakök M. Serum levels of acute phase proteins in patients with nonalcoholic steatohepatitis. Turk J Gastroenterol 2003; 14 (01) 12-17
47 Sumida Y, Nakashima T, Yoh T. , et al. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol 2003; 38 (01) 32-38
48 Parikh P, Patel J, Ingle M, Sawant P. Serum ferritin levels predict histological severity in patients with nonalcoholic fatty liver disease in India. Indian J Gastroenterol 2015; 34 (03) 200-208
49 Utzschneider KM, Largajolli A, Bertoldo A. , et al. Serum ferritin is associated with non-alcoholic fatty liver disease and decreased B-cell function in non-diabetic men and women. J Diabetes Complications 2014; 28 (02) 177-184
50 Rakha EA, Adamson L, Bell E. , et al. Portal inflammation is associated with advanced histological changes in alcoholic and non-alcoholic fatty liver disease. J Clin Pathol 2010; 63 (09) 790-795
51 Loguercio C, De Simone T, D'Auria MV. , et al; Italian AISF Clinical Group. Non-alcoholic fatty liver disease: a multicentre clinical study by the Italian Association for the Study of the Liver. Dig Liver Dis 2004; 36 (06) 398-405
52 Oh S, Shida T, Yamagishi K. , et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 2015; 61 (04) 1205-1215
53 Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42 (04) 413-418
54 Beaton MD, Chakrabarti S, Adams PC. Inflammation is not the cause of an elevated serum ferritin in non-alcoholic fatty liver disease. Ann Hepatol 2014; 13 (03) 353-356
55 Adams LA, Crawford DH, Stuart K. , et al. The impact of phlebotomy in nonalcoholic fatty liver disease: a prospective, randomized, controlled trial. Hepatology 2015; 61 (05) 1555-1564
56 Adams PC, Barton JC. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. J Hepatol 2011; 55 (02) 453-458
57 Pietrangelo A. Iron and the liver. Liver Int 2016; 36 (Suppl. 01) 116-123
58 Maliken BD, Nelson JE, Klintworth HM, Beauchamp M, Yeh MM, Kowdley KV. Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease. Hepatology 2013; 57 (05) 1806-1813
59 Murali AR, Gupta A, Brown K. Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease. Hepatol Res 2018; 48 (03) E30-E41
60 Chalasani N, Younossi Z, Lavine JE. , et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018; 67 (01) 328-357
61 Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet 2016; 388 (10045): 706-716
62 Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 1986; 6 (01) 24-29

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