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Measurement of Hepatic Iron Concentration
EDITORIAL Measurement of Hepatic Iron Concentration valuation of hepatic iron concentration (HIC) continues to have an important role in assessing the potential for iron-mediated liver disease in patients with hereditary hemochromatosis (HH).1 Furthermore, HIC monitoring in patients receiving iron chelation therapy is important for patients with hemoglobinopathies (eg, thalassemia, sickle cell disease) and myelodysplastic syndromes. Serum ferritin is a reliable indicator of body iron stores in HH, and still is considered suitable for monitoring response to phlebotomy therapy in HH, but is less reliable in non-HH iron overload.1 Accordingly, there has been interest in the noninvasive measurement of HIC in non-HH iron overload for more than 30 years.2 Measurement of hepatic and cardiac iron concentration date back to the 1970s when the first magnetic susceptibility measurements were performed.2 Subsequently, with the development and proliferation of magnetic resonance imaging (MRI), this noninvasive methodology was deemed a better technology for assessing HIC and numerous methods and techniques for measuring HIC by MRI were developed and introduced into the medical literature. From the vantage point of a hepatologist, use of MRI for HIC is limited to a few centers with special interest. Further analysis seemed limited to determining if HIC was normal or whether there was severe iron overload. Correlations between HIC at several levels with an MRI value was lacking. In this issue of Clinical Gastroenterology and Hepatology, a group of Greek investigators have tackled the question of the practical validity of MRI for measurement of HIC by an exhaustive and systematic review of published studies and performance of meta-analysis.3 The methodologic and statistical analyses seem rigorous.4 By detailed review of multiple databases of medical literature, the investigators found a total of 7319 reports from all literature sources. After de-duplication, they further screened 4837 reports and 4744 reports as noneligible using a rigorously predefined set of criteria. Of the remaining 93 reports, further review and analysis eliminated another 73 as inadequate, leaving 20 studies for the systematic review. A total of 819 patients were included in these 20 reports. All included studies used 1.5-T MRI scanners. The main findings of the work by Sarigianni et al3 are surprising and a bit disappointing. Thus, even after carefully selecting the best studies, there was still a high risk of bias in methodologic quality. Methods of patient recruitment were unclear in 8 studies, and blinding of patients’ clinical and liver biopsy results from the MRI assessors was performed in only 12 studies. Different criteria for MRI positivity were present, and in 5 studies
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Clinical Gastroenterology and Hepatology 2015;13:64–65
these were not prespecified. A suitable reference standard was used in all studies, although was not necessarily used in all study subjects. In terms of diagnostic accuracy, MRI sensitivity ranged from 0.00 to 1.00 (median, 0.94), and specificity ranged from 0.50 to 1.00 (median, 0.89). There was substantial heterogeneity among the included studies, which was attributed to differing MRI sequences and thresholds for positivity. Finally, the results for diagnostic accuracy across a range of HIC levels were highly variable and data could not be pooled reliably. Numerous other concerns were discussed by Sarigianni et al.3 Their conclusion was that their systematic review “underlines the paucity of high-quality studies designed to explore the diagnostic accuracy of MRI for liver iron overload.” The caveat is that there is a TS2E protocol called FerriScan from a group in Perth, Australia, that has been approved for MRI estimation of HIC by the Food and Drug Administration.5,6 Needless to say, more work needs to be performed in this area. Given the results of this systematic review and metaanalysis, how should clinicians evaluating and caring for patients with iron overload proceed? When considering a patient with an increased ferritin level who is either a C282Y homozygote or a compound heterozygote (C282Y/H63D), liver biopsy should be performed if the alanine aminotransferase or aspartate aminotransferase level is increased, or if the ferritin level is greater than 1000 ng/mL.7–9 The reason for a biopsy is to assess the degree of fibrosis and whether or not the patient has progressed to cirrhosis. In the absence of an alanine aminotransferase/aspartate aminotransferase increase combined with a ferritin level less than 1000 ng/mL, the likelihood of cirrhosis is negligible. It is important to confirm advanced fibrosis, if present, for further monitoring (surveillance for hepatocellular carcinoma and for varices). Treatment recommendations with phlebotomy remain the same and serum ferritin can be used reliably to monitor response to therapy, aiming to decrease the serum ferritin level to between 50 and 100 ng/mL. If a liver biopsy is performed, analysis for HIC can be obtained by an assay at one of several reference laboratories. Thus, in typical HFE-linked HH, the need for HIC measured by MRI is lacking. When evaluating a patient with iron overload with an increased ferritin level, but who does not have HFE-linked HH, genetic testing for other non-HFE genetic abnormalities (ferroportin, hemojuvelin, hepcidin, and transferrin receptor-2 [TfR2]) can be performed at a DNA diagnostic reference laboratory. The remainder of the assessment and management is as outlined earlier including whether or not a liver biopsy should be performed. Finally, the need for HIC measurement when iron overload is caused by hematologic problems is different
January 2015
than for HH. In this situation, ferritin is not as reliable a predictor of body iron stores, particularly when monitoring response to chelation therapy. Accordingly, a noninvasive, reliable MRI measurement of HIC would be an attractive modality to have. Perhaps increased use and experience with FerriScan would be of greatest utility in this situation. Also, a radiologist with interest in iron measurement is necessary to develop these methods in individual situations. Sarigianni et al3 are to be commended for a thorough systematic review. Unfortunately, the studies available are not of sufficient quality to make firm conclusions about the use of MRI to measure HIC. More studies need to be performed. BRUCE R. BACON, MD Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, Missouri
References 1.
Bacon BR, Adams PC, Kowdley KV, et al. American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328–343.
2.
Brittenham GM, Farrel DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 1982; 307:1671–1675.
Editorial
65
3.
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;13:55–63.
4.
Kanwal F, White D. “Systematic reviews and meta-analyses” in Clinical Gastroenterology and Hepatology. Clin Gastroenterol Hepatol 2012;10:1184–1186.
5.
St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005;105:855–886.
6.
St Pierre TG, El-Beshlawy A, Elalfy M, et al. Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration. Magn Reson Med 2014;71:2215–2223.
7.
Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115:929–936. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130:953–962.
8.
9.
Morrison ED, Brandhagen DJ, Phatak PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003; 138:627–633.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.09.003
E
Clinical Gastroenterology and Hepatology 2015;13:64–65
these were not prespecified. A suitable reference standard was used in all studies, although was not necessarily used in all study subjects. In terms of diagnostic accuracy, MRI sensitivity ranged from 0.00 to 1.00 (median, 0.94), and specificity ranged from 0.50 to 1.00 (median, 0.89). There was substantial heterogeneity among the included studies, which was attributed to differing MRI sequences and thresholds for positivity. Finally, the results for diagnostic accuracy across a range of HIC levels were highly variable and data could not be pooled reliably. Numerous other concerns were discussed by Sarigianni et al.3 Their conclusion was that their systematic review “underlines the paucity of high-quality studies designed to explore the diagnostic accuracy of MRI for liver iron overload.” The caveat is that there is a TS2E protocol called FerriScan from a group in Perth, Australia, that has been approved for MRI estimation of HIC by the Food and Drug Administration.5,6 Needless to say, more work needs to be performed in this area. Given the results of this systematic review and metaanalysis, how should clinicians evaluating and caring for patients with iron overload proceed? When considering a patient with an increased ferritin level who is either a C282Y homozygote or a compound heterozygote (C282Y/H63D), liver biopsy should be performed if the alanine aminotransferase or aspartate aminotransferase level is increased, or if the ferritin level is greater than 1000 ng/mL.7–9 The reason for a biopsy is to assess the degree of fibrosis and whether or not the patient has progressed to cirrhosis. In the absence of an alanine aminotransferase/aspartate aminotransferase increase combined with a ferritin level less than 1000 ng/mL, the likelihood of cirrhosis is negligible. It is important to confirm advanced fibrosis, if present, for further monitoring (surveillance for hepatocellular carcinoma and for varices). Treatment recommendations with phlebotomy remain the same and serum ferritin can be used reliably to monitor response to therapy, aiming to decrease the serum ferritin level to between 50 and 100 ng/mL. If a liver biopsy is performed, analysis for HIC can be obtained by an assay at one of several reference laboratories. Thus, in typical HFE-linked HH, the need for HIC measured by MRI is lacking. When evaluating a patient with iron overload with an increased ferritin level, but who does not have HFE-linked HH, genetic testing for other non-HFE genetic abnormalities (ferroportin, hemojuvelin, hepcidin, and transferrin receptor-2 [TfR2]) can be performed at a DNA diagnostic reference laboratory. The remainder of the assessment and management is as outlined earlier including whether or not a liver biopsy should be performed. Finally, the need for HIC measurement when iron overload is caused by hematologic problems is different
January 2015
than for HH. In this situation, ferritin is not as reliable a predictor of body iron stores, particularly when monitoring response to chelation therapy. Accordingly, a noninvasive, reliable MRI measurement of HIC would be an attractive modality to have. Perhaps increased use and experience with FerriScan would be of greatest utility in this situation. Also, a radiologist with interest in iron measurement is necessary to develop these methods in individual situations. Sarigianni et al3 are to be commended for a thorough systematic review. Unfortunately, the studies available are not of sufficient quality to make firm conclusions about the use of MRI to measure HIC. More studies need to be performed. BRUCE R. BACON, MD Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, Missouri
References 1.
Bacon BR, Adams PC, Kowdley KV, et al. American Association for the Study of Liver Diseases. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011; 54:328–343.
2.
Brittenham GM, Farrel DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 1982; 307:1671–1675.
Editorial
65
3.
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;13:55–63.
4.
Kanwal F, White D. “Systematic reviews and meta-analyses” in Clinical Gastroenterology and Hepatology. Clin Gastroenterol Hepatol 2012;10:1184–1186.
5.
St Pierre TG, Clark PR, Chua-anusorn W, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005;105:855–886.
6.
St Pierre TG, El-Beshlawy A, Elalfy M, et al. Multicenter validation of spin-density projection-assisted R2-MRI for the noninvasive measurement of liver iron concentration. Magn Reson Med 2014;71:2215–2223.
7.
Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998;115:929–936. Bacon BR, Olynyk JK, Brunt EM, et al. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130:953–962.
8.
9.
Morrison ED, Brandhagen DJ, Phatak PD, et al. Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis. Ann Intern Med 2003; 138:627–633.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.09.003