UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Methods to determine hepatic iron content

Author
Maria Isabel Fiel, MD, FAASLD
Section Editor
Keith D Lindor, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG, AGAF

INTRODUCTION

Hereditary hemochromatosis, hematopoietic stem cell transplantation, myelodysplastic syndrome, chronic liver disease, dialysis, and blood transfusions for sickle cell disease and thalassemia can all cause iron to accumulate in the liver [1,2]. Iron overload is not just limited to the liver, but can also accumulate in other organs, particularly the heart and endocrine organs, resulting in end-organ damage and dysfunction [3]. Hemosiderosis is a commonly used term for iron accumulation in tissues from any cause. (See "Approach to the patient with suspected iron overload".)

Excess oxygen radicals and injury from tissue peroxidation are the main reasons why iron overload causes tissue damage [1,4]. Reducing the degree of iron overload is therefore paramount for most of these diseases to achieve successful treatment. Assessment of total body iron stores can be used to tailor titration of chelation therapy or phlebotomy in an attempt to reduce iron overload and its attendant complications [5]. Phlebotomy has been shown to slow the progression to cirrhosis in hereditary hemochromatosis, and it also reduces the risk of developing hepatocellular carcinoma [6]. The complications of fibrosis and cirrhosis developing in patients increase when there is significant iron overload, which is defined as hepatic iron concentration (HIC) greater than three times the upper limit of normal (greater than 90 micromol/g dry weight). Liver fibrosis may be reversible with phlebotomy therapy [7].

In the past, the diagnosis for hereditary hemochromatosis was based on results of liver biopsy specimens and hepatic iron content and distribution [5]. Since the discovery of the HFE gene mutation (substitution by tyrosine for cysteine at amino acid 282; C282Y) and two other genetic mutations (aspartate for histidine [H63D] and cysteine for serine [S65C]), the diagnosis of hereditary hemochromatosis has become more straightforward [2]. Tests for the HFE gene are performed when serum ferritin and transferrin saturation are elevated. However, a small number of individuals with hereditary hemochromatosis may be missed with these genetic tests [3]. Additionally, phenotypic penetrance in hereditary hemochromatosis is variable with regard to the degree of iron overload and the risk of liver disease, fibrosis, and cirrhosis [8]. As a result, a positive genetic test does not ensure that iron overload had developed. (See "Clinical manifestations and diagnosis of hereditary hemochromatosis", section on 'Making the diagnosis of HH'.)

Determination of the HIC is the most definitive proof of iron overload. It can be used to estimate the total iron burden and the approximate amount of phlebotomy required for a patient with iron overload [1,9-11]. The HIC can also detect mild iron overload, which may be missed with less sensitive modalities [12]. An elevated serum ferritin level alone is often not adequate for estimating total iron burden, particularly if coexisting inflammation is present. The hepatic iron index is calculated based on the HIC and in the past was used to make a diagnosis of hereditary hemochromatosis; however, most patients can now be diagnosed by genetic testing [5].

This topic will review the tests that can be done to determine hepatic iron content, with a focus on the HIC. The approach to a patient with suspected iron overload and the diagnosis of hereditary hemochromatosis are discussed separately. (See "Approach to the patient with suspected iron overload" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

            

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Fri Apr 15 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Brissot P, Troadec MB, Bardou-Jacquet E, et al. Current approach to hemochromatosis. Blood Rev 2008; 22:195.
  2. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 2010; 139:393.
  3. Bardou-Jacquet E, Ben Ali Z, Beaumont-Epinette MP, et al. Non-HFE hemochromatosis: pathophysiological and diagnostic aspects. Clin Res Hepatol Gastroenterol 2014; 38:143.
  4. O'Brien J, Powell LW. Non-alcoholic fatty liver disease: is iron relevant? Hepatol Int 2012; 6:332.
  5. Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328.
  6. Kowdley KV, Trainer TD, Saltzman JR, et al. Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study. Gastroenterology 1997; 113:1270.
  7. Nadakkavukaran IM, Gan EK, Olynyk JK. Screening for hereditary haemochromatosis. Pathology 2012; 44:148.
  8. Bacon BR, Britton RS. Clinical penetrance of hereditary hemochromatosis. N Engl J Med 2008; 358:291.
  9. Olynyk JK, Luxon BA, Britton RS, Bacon BR. Hepatic iron concentration in hereditary hemochromatosis does not saturate or accurately predict phlebotomy requirements. Am J Gastroenterol 1998; 93:346.
  10. Salgia RJ, Brown K. Diagnosis and management of hereditary hemochromatosis. Clin Liver Dis 2015; 19:187.
  11. Ali S, Pimentel JD, Munoz J, et al. Iron overload in allogeneic hematopoietic stem cell transplant recipients. Arch Pathol Lab Med 2012; 136:532.
  12. Sarigianni M, Liakos A, Vlachaki E, et al. Accuracy of magnetic resonance imaging in diagnosis of liver iron overload: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2015; 13:55.
  13. Wood MJ, Gadd VL, Powell LW, et al. Ductular reaction in hereditary hemochromatosis: the link between hepatocyte senescence and fibrosis progression. Hepatology 2014; 59:848.
  14. Jakobovits AW, Morgan MY, Sherlock S. Hepatic siderosis in alcoholics. Dig Dis Sci 1979; 24:305.
  15. Harrison-Findik DD. Role of alcohol in the regulation of iron metabolism. World J Gastroenterol 2007; 13:4925.
  16. Larson AM, Taylor SL, Bauermeister D, et al. Pilot study of the relationship between histologic progression and hepatic iron concentration in chronic hepatitis C. J Clin Gastroenterol 2003; 37:406.
  17. Nelson JE, Wilson L, Brunt EM, et al. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53:448.
  18. 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; 138:905.
  19. Turlin B, Mendler MH, Moirand R, et al. Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients. Am J Clin Pathol 2001; 116:263.
  20. Aigner E, Theurl I, Theurl M, et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 2008; 87:1374.
  21. Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011; 31:260.
  22. Boaru SG, Merle U, Uerlings R, et al. Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease. J Cell Mol Med 2015; 19:806.
  23. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95:1565.
  24. Aarsand AK, Boman H, Sandberg S. Familial and sporadic porphyria cutanea tarda: characterization and diagnostic strategies. Clin Chem 2009; 55:795.
  25. Liu LU, Phillips J, Bonkovsky H. Porphyria Cutanea Tarda, Type II. In: GeneReviews, Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (Eds), University of Washington, Seattle 2013.
  26. Olynyk JK, Trinder D, Ramm GA, et al. Hereditary hemochromatosis in the post-HFE era. Hepatology 2008; 48:991.
  27. European Association For The Study Of The Liver. EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010; 53:3.
  28. Urru SA, Tandurella I, Capasso M, et al. Reproducibility of liver iron concentration measured on a biopsy sample: a validation study in vivo. Am J Hematol 2015; 90:87.
  29. Gandon Y, Olivié D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363:357.
  30. Deugnier Y, Margules S, Brissot P, et al. Comparative study between biochemical and histological methods and image analysis in liver iron overload. J Clin Pathol 1982; 35:45.
  31. Olynyk JK, O'Neill R, Britton RS, Bacon BR. Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: diagnostic implications. Gastroenterology 1994; 106:674.
  32. Butensky E, Fischer R, Hudes M, et al. Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis. Am J Clin Pathol 2005; 123:146.
  33. Beilby JP, Prins AW, Swanson NR. Determination of hepatic iron concentration in fresh and paraffin-embedded tissue. Clin Chem 1999; 45:573.
  34. Brissot P, Bourel M, Herry D, et al. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Gastroenterology 1981; 80:557.
  35. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999; 130:953.
  36. Cheng R, Barton JC, Morrison ED, et al. Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes. J Clin Gastroenterol 2009; 43:569.
  37. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol 2000; 33:485.
  38. Angelucci E, Brittenham GM, McLaren CE, et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000; 343:327.
  39. Adams PC. Is there a threshold of hepatic iron concentration that leads to cirrhosis in C282Y hemochromatosis? Am J Gastroenterol 2001; 96:567.
  40. Powell LW, Dixon JL, Ramm GA, et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006; 166:294.
  41. Cotler SJ, Bronner MP, Press RD, et al. End-stage liver disease without hemochromatosis associated with elevated hepatic iron index. J Hepatol 1998; 29:257.
  42. Nash S, Marconi S, Sikorska K, et al. Role of liver biopsy in the diagnosis of hepatic iron overload in the era of genetic testing. Am J Clin Pathol 2002; 118:73.
  43. Sanches-Rocha L, Serpa B, Figueiredo E, et al. Comparison between multi-echo T2* with and without fat saturation pulse for quantification of liver iron overload. Magn Reson Imaging 2013; 31:1704.
  44. Banerjee R, Pavlides M, Tunnicliffe EM, et al. Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease. J Hepatol 2014; 60:69.
  45. Wood JC. Estimating tissue iron burden: current status and future prospects. Br J Haematol 2015; 170:15.
  46. Brunt EM, Olynyk JK, Britton RS, et al. Histological evaluation of iron in liver biopsies: relationship to HFE mutations. Am J Gastroenterol 2000; 95:1788.
  47. Deugnier YM, Loréal O, Turlin B, et al. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology 1992; 102:2050.
  48. SCHEUER PJ, WILLIAMS R, MUIR AR. Hepatic pathology in relatives of patients with haemochromatosis. J Pathol Bacteriol 1962; 84:53.
  49. Tavassoli H, Mahjoub F, Jahanzad E, et al. Introducing a new histologic scoring system for iron deposition in liver of thalassemic patients, compared with atomic absorption spectrometry. Exp Toxicol Pathol 2015; 67:365.