HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2302020820v1 230/2/479    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alústiza, J. M. Articles by Recondo, J. A. Search for Related Content PubMed PubMed Citation Articles by Alústiza, J. M. Articles by Recondo, J. A.

MR Quantification of Hepatic Iron Concentration¹

¹ From OSATEK, Alta Tecnología Sanitaria S.A., Paseo Dr Beguiristain 109, 20014 San Sebastián, Basque Country, Spain (J.M.A., J.A.R.); Donostia Hospital, San Sebastián, Spain (J.A., C.A., J.I.E., M.G.B., F.M.); Mendaro Hospital, Spain (A.C.); Alto Deba Hospital, Arrasate-Mondragón, Spain (P.O.); and Bidasoa Hospital, Hondarribia, Spain (J.B.). The members of the Group and their affiliations are listed at the end of this article. Received July 1, 2002; revision requested September 4; final revision received May 19, 2003; accepted June 13. Address correspondence to J.M.A. (e-mail: rm.donostia@osatek.es).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To evaluate the accuracy of magnetic resonance (MR) imaging in the quantification of hepatic iron concentration.

MATERIALS AND METHODS: Between April 1999 and June 2001, 112 patients were recruited prospectively. All had undergone liver biopsy and hepatic iron concentration quantification with spectrophotometry, followed by MR imaging. MR imaging involved use of four gradient-echo sequences and one spin-echo sequence. Signal intensity (SI) was measured on images obtained with each sequence by means of regions of interest placed in the liver and paraspinal muscle to obtain the liver-to-muscle SI ratio. The relationship between hepatic iron concentration and SI ratio for each sequence was analyzed with multiple linear regression. Receiver operating characteristic analysis was performed to find the diagnostic thresholds.

RESULTS: Sixty-eight patients had normal hepatic iron levels (<36 µmol/g), 23 had hemosiderosis (36–80 µmol/g), and 21 had hemochromatosis (>80 µmol/g). With all sequences, an inverse linear relationship between iron concentration and SI ratio was apparent. The authors generated a mathematic model to estimate the iron concentrations from MR imaging data (r = 0.937). For estimated concentrations of more than 85 µmol/g, the positive predictive value for hemochromatosis was 100%; for those less than 40 µmol/g, the negative predictive value for hemochromatosis was 100%. For estimated concentrations of more than 58 µmol/g, the positive predictive value for iron overload was 100%; for those less than 20 µmol/g, the negative predictive value for iron overload was 100%.

CONCLUSION: MR imaging is a useful and noninvasive diagnostic tool for quantification of hepatic iron concentration.

© RSNA, 2003

Index terms: Hemochromatosis, 761.659 • Liver, biopsy, 761.1261 • Liver, diseases, 761.659 • Magnetic resonance (MR), comparative studies, 761.121411, 761.121412

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Hereditary hemochromatosis is a common autosomal recessive disease that is characterized by an increase in the gastrointestinal absorption of iron, which can lead to deposits of iron in the liver, pancreas, heart, skin, and joints (1).

In 1996, Feder et al (2) cloned the HFE gene from hemochromatosis and discovered the two mutations of the gene that cause the disease: C282Y and H63D. This has aided in diagnosis, but the prevalence of these mutations varies greatly with geographic location. There is a decreasing gradient of occurrence from north to south (3,4) with a variable percentage of patients with negative genetic findings that can reach 40% (1,5). In 1999 (6), a new mutation was discovered, S65C, which constitutes a less serious form of the disease.

The standard method of diagnosis of this disease is the quantification of hepatic iron concentration by means of liver biopsy with spectrophotometry (7) because the disease originates from the higher overload of iron in the liver. The patient is considered to have hemochromatosis when the iron index (micromoles per gram of iron in dry liver divided by patient age in years) is greater than 1.9 (1), or, according to other authors, when the hepatic iron concentration is greater than 80 µmol/g (5,8,9). If the hepatic iron concentration is between 36 and 80 µmol/g, iron overload is present, and the patient has hemosiderosis. It should also be taken into account that young people and women with hemochromatosis can have a hepatic iron index with values between 1.5 and 1.9 (10). Hepatic biopsy is also important in the prognosis of the disease, which depends on the presence or absence of cirrhosis. Hepatic biopsy is recommended in all patients except those who are C282Y homozygotes, those who have serum ferritin levels lower than 1,000 µg/L, those without hepatomegaly, those younger than 40 years, and those with normal serum aminotransferase levels (1,11,12).

Nevertheless, hepatic biopsy has associated risks inherent to the technique (7), as well as a certain variability of the results, especially in cases of hepatic cirrhosis (13). It is therefore important to have an alternative noninvasive method available that permits quantification of hepatic iron concentration without having to revert to hepatic biopsy (1,7,14,15).

Various articles in the literature (7,15–22) have focused on the use of magnetic resonance (MR) imaging in the quantification of hepatic iron concentration with variable results. The iron overload causes a decrease of SI in liver parenchyma on T2-weighted MR images. A correlation exists between the magnitude of SI decrease and the degree of iron overload. From a technical point of view, it is widely accepted that gradient-echo MR sequences are the most sensitive for mild degrees of iron overload (2,7,14–17,19,22,23). To be able to quantify low as well as high degrees of iron overload, however, it is necessary to use and compare results from different sequences (9,15–17,22,24).

The purpose of this study was to evaluate the accuracy of MR imaging in the quantification of hepatic iron concentration.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patients
Between April 1999 and June 2001, hepatic MR images were obtained prospectively in 112 patients who had previously undergone liver biopsy, the results of which were independent of the biopsy results obtained in the present study.

Consecutive patient recruitment was performed by the gastroenterology and internal medicine departments of six hospitals that serve a population of 700,000 patients. All patients gave their written informed consent before entry into the study. The Clinical Research Ethics Committee of the Hospital Donostia reviewed and approved the study protocol. Eighty-four of the patients were men (mean age, 45.3 years ± 12.4), and 28 were women (mean age, 48.8 years ± 12.4). Ages ranged from 27 to 75 years. Indications for liver biopsy were chronic hepatitis C, persistent high levels of serum aminotransferase, or iron metabolism abnormalities.

The time interval between biopsy and MR imaging was less than a month in all cases. The hepatic iron concentration was quantified from liver biopsy fragments by using spectrophotometry with a graphite atomic absorption camera (Perkin-Elmer 5100; Boston, Mass) in Reference laboratory (in Barcelona, Spain). On the day of MR imaging, iron metabolism analysis was performed (including serum ferritin and serum iron levels and percentage saturation of transferrine) and serum aminotransferase levels were assessed.

Patients were classified according to hepatic iron concentration in the following way (5,9): normal concentration, less than 36 µmol/g; hemosiderosis, 36–80 µmol/g; hemochromatosis, more than 80 µmol/g.

Liver Biopsy
Liver biopsy was performed in the right lobe of the liver with a 14-gauge Tru-cut needle (Allegiance Healthcare, Ill). Most of the specimen was placed in a 10% buffered formaldehyde saline solution, processed routinely, embedded in paraffin, and sectioned. The embedded sections were stained with hematoxylin-eosin, Masson trichrome, and Perls Prussian blue stains. Another portion of the biopsy specimen was dried, weighted, ashed, and submitted for hepatic iron concentration measurement with spectrophotometry.

MR Imaging Techniques
MR images were obtained with a 1.5-T system (Gyroscan ACS-NT; Philips, Best, the Netherlands) and analyzed by a radiologist (J.M.A., with 15 years of experience) who was blinded to liver biopsy results and clinical information.

We used the MR imaging technique proposed by Gandon et al from the University of Rennes, France (14,23). The technique consisted of four gradient-echo sequences (T1 weighted, intermediate weighted, T2 weighted, and long echo time T2 weighted) and one T1-weighted spin-echo sequence, details of which are shown in Table 1.

The University of Rennes Web site (14) allows calculation of the hepatic iron concentration in each patient by means of the input of the SI measurements obtained for each sequence. This calculation was performed in all cases.

Statistical Analysis
The relationship between liver-to-muscle SI ratio of each sequence and hepatic iron concentration was analyzed by means of a scatterplot. These results were inspected for linearity and goodness of fit.

After hepatic iron concentration logarithmic transformation, the relationship between iron concentration and SI measurements obtained with the different sequences was modeled by using a backward stepwise multiple linear regression technique. The hepatic iron concentration estimated with this model was submitted to receiver operating characteristic analysis. We calculated the area under the curve and the estimated threshold of hepatic iron concentration that gave the greatest predictive value for diagnosis of hemochromatosis and iron overload.

The correlation between hepatic iron concentrations calculated by using the University of Rennes Web-based application (14) and those obtained by means of liver biopsy were analyzed by using the Pearson correlation coefficient.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Of the 112 patients, 68 had normal levels (without hepatic iron overload), 23 had hemosiderosis, and 21 had hemochromatosis.

Table 2 shows patient ages and serum ferritin levels, percentage saturation of transferrine, and serum iron and serum aminotransferase levels in the different groups of patients. The sex distribution between patients with normal levels and those with abnormal levels was not different (P = .102, ² test).

View larger version (135K): [in this window] [in a new window] [Download PPT slide]   Figure 1. A-C, Transverse MR images of the liver in three patients with different degrees of iron overload shown with various MR sequences. D, Scatterplots of liver-to-muscle SI ratio and hepatic iron concentration for each MR sequence. A, Patient without iron overload. B, Patient with hemosiderosis. C, Patient with hemochromatosis. D, Scatterplots for all sequences show inverse linear correlation of liver-to-muscle (L/M) SI ratio with hepatic iron concentration (HIC) (in micromoles per gram), with maximal decrease of liver SI with most T2-weighted (T2) MR sequences. IW = intermediate weighted, SE = spin echo, T1 = T1 weighted, T2+ = long echo time T2 weighted.

where T2 is the SI measurement value on T2-weighted MR images and IW is the SI measurement value on intermediate-weighted MR images. The inclusion of the liver-to-muscle SI ratio from other sequences does not improve the results of this linear regression.

View larger version (25K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Scatterplot shows hepatic iron concentration (HIC) (in micromoles per gram) calculated with MR imaging (HIC-Est) versus that determined with spectrophotometry at liver biopsy (r = 0.937).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

In agreement with results of previous studies (8,9,15,16,22,24), our findings show that use of one MR imaging sequence is not enough to enable evaluation of all levels of iron overload. From the sequences that were used in the present study, T2- and intermediate-weighted MR sequences were sufficient for the evaluation of all degrees of iron overload present in our series. These results were not improved when data from other sequences were taken into account. This agrees with the results of Guyader and Gandon (9).

There was good correlation between quantification of hepatic iron concentration with spectrophotometry and that with MR imaging. However, 13% of patients were classified incorrectly. This result correlates with that in other published studies (7,14,16). Clinical interest categorization of estimated hepatic iron concentrations would undoubtedly be improved with the addition of other clinical data, such as patient age.

The reduced number of patients with hemochromatosis (19% of patients) is a limiting factor of this work, which means that the 95% CI of these results is better used to confirm the absence of iron overload than to confirm the presence of hemochromatosis.

An interesting aspect of our work is that we used the MR imaging sequences proposed by Gandon et al (14), and we obtained similar results with a high correlation index (r = 0.957). This constitutes a forceful positive argument for the reproducibility of the technique.

The method proposed by Gandon et al (14,23) consists of different MR sequences adaptable to machines with different magnetic field intensities (0.5, 1.0, and 1.5 T). It is a rational and interesting means of homogenization of the sequence parameters in studies aimed at quantifying hepatic iron concentration. Our work was simplified greatly by the fact that these precise parameters were available; however, the technique should still be evaluated in other centers in studies such as this one.

One of the most important problems in the quantification of hepatic iron concentration with MR imaging is the necessity to calibrate each machine so that the results can be reproducible between different MR imaging centers (7,15,17). Our work highlights this problem when values obtained with the University of Rennes Web-based method and our own estimated values are compared. We commented earlier that the correlation between the two sets of results is good, but if each of them is compared separately with the true hepatic iron concentration value, some differences can be seen.

The calibration of each machine with use of specific phantoms would allow correction of these differences and eliminate the need for extensive calibration studies with human patients (6). In our opinion, this will be necessary to achieve a practical, widely used, simple, and standardized technique.

The presence of iron metabolism abnormalities is frequently observed in the course of different hepatopathies (viral hepatitis, alcoholic liver disease, etc). In most of these cases, there is no real iron overload, or in some cases, only a weak overload. The group of patients that did not exhibit iron overload in the present study did, however, exhibit greater irregularities during iron analysis than would be expected from a healthy population. This results from the type of patients recruited for the study; most had viral hepatitis or alcoholic liver disease. However, MR imaging showed normal levels in all patients. This indicates that MR imaging could be of help in this type of situation, with discrete irregularities in iron metabolism for the differential diagnosis of iron overloads, which has also been proposed in previous studies (7,15–17).

MR imaging could prove very useful in the study of patients with inconclusive analytic and genetic irregularities and in cases where quantification of hepatic iron concentration is not sufficiently conclusive (eg, young double heterozygote with hepatic iron concentration values that do not reach the range for hereditary hemochromatosis).

In conclusion, MR imaging is a very useful and noninvasive diagnostic tool that allows quantification of hepatic iron concentration in all possible levels of iron overload. More studies are still necessary to achieve greater reproducibility of the technique.

	APPENDIX

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Although iron overload is a continuum, the receiver operating characteristic curve also yields intermediate points from the diagnostic test, which have been categorized into four groups of clinical interest (Table A1).

	ACKNOWLEDGMENTS

 
We thank Ander Arzubía (manager of OSATEK, 1994–2001), who supported this project from the beginning; Marga Lasa (staff head nurse), for her work with the patients; and David Pérez, who collected and processed all patient data. Members of the Study Group: José Artetxe, MD, Cristina Agirre, MD, Manuel García-Bengoechea, MD, José I. Emparanza, PhD, Fernando Mújica, MD, Luis F. Alzate, MD, Jose A. Arriola, MD, Pilar López, MD, Angel Cosme, MD, Joaquín Lapaza, MD, Isabel Montalvo, MD, Fernando Neira, MD, Juan I. Arenas, MD, María D. De Juan, MD, Julio Torrado, MD, Ana Muñagorri, MD, Maite Recasens, MD, and Santiago Merino, MD, Donostia Hospital, San Sebastián, Spain; José M. Alústiza, MD, José A. Recondo, MD, OSATEK, San Sebastián, Spain; Agustín Castiella, MD, Pilar Bernardo, MD, Alberto García-Zamalloa, MD, Lourdes Legasa, MD, Mario Ugarte, MD, Ainhoa Galardi, MD, Malen Almeida, MD, Mendaro Hospital, Spain; Begoña Ibarra, MD, Manuel Alvarez, MD, Nuestra Señora de la Antigua Hospital, Zumárraga, Spain; Pedro Otazua, MD, Alto Deba Hospital, Arrasate-Mondragón, Spain; Jesús Barrio, MD, María L. Rincón, MD, Bidasoa Hospital, Hondarribia, Spain; Javier Yerobi, MD, Blanca Loidi, MD, Nuestra Señora de La Asunción Hospital, Tolosa, Spain.

	FOOTNOTES

 
Abbreviation: SI = signal intensity

Author contributions: Guarantors of integrity of entire study, J.M.A., A.C., J.I.E.; study concepts, J.M.A., J.A., J.I.E., A.C., J.A.R.; study design, J.M.A., J.A., A.C., J.I.E., M.G.B., P.O., J.A.R.; literature research, J.M.A., A.C., C.A.; clinical studies, J.A., A.C., P.O., F.M., J.B.; data acquisition, C.A.; data analysis/interpretation, J.A., J.I.E.; statistical analysis, J.I.E.; manuscript preparation, J.M.A., J.A., C.A., A.C., J.I.E.; manuscript definition of intellectual content and editing, J.M.A., J.I.E., J.A., A.C.; manuscript revision/review, P.O., F.M., J.B., M.G.B.; manuscript final version approval, J.M.A., J.A., C.A., A.C., J.I.E.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 

1. Adams P, Brissot P, Powell LW. EASL International Consensus Conference on Haemochromatosis. J Hepatol 2000; 33:485-504.[CrossRef][Medline]
2. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like is mutated in patients with hereditary hemochromatosis. Nat Genet 1996; 13:399-408.[CrossRef][Medline]
3. Merryweather-Clarke AT, Pointon JJ, Juanolle AM, Rochette J, Robson KJ. Geography of HFE C282Y and H63D mutations. Genet Test 2000; 4:183-198.[CrossRef][Medline]
4. de Juan MD, Reta A, Castiella A, Pozueta J, Prada A, Cuadrado E. HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls. Eur J Hum Genet 2001; 9:961-964.[CrossRef][Medline]
5. Powell LW, George KG, McDonnell SM, Kowdley KV. Diagnosis of hemochromatosis. Ann Intern Med 1998; 129:925-931.[Abstract/Free Full Text]
6. Mura C, Raguenes O, Férec C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 1999; 93:2502-2505.[Abstract/Free Full Text]
7. Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Rijcken TH, Stark DD. Hepatic iron concentration: noninvasive estimation by means of MR imaging techniques. Radiology 1999; 212:227-234.[Abstract/Free Full Text]
8. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999; 341:1986-1995.[Free Full Text]
9. Guyader D, Gandon Y. Quantification of iron overload. Bull Acad Natl Med 2000; 184:337-348.[Medline]
10. Pietrangelo A. Hemochromatosis 1998: is one enough? J Hepatol 1998; 29:502-509.[CrossRef][Medline]
11. Ramrakhiani S, Bacon BR. Hemochromatosis: advances in molecular genetics and clinical diagnosis. J Clin Gastroenterol 1998; 27:41-46.[CrossRef][Medline]
12. Guyader D, Jacquelinet C, Moirand R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology 1998; 115:929-936.[CrossRef][Medline]
13. Villeneuve JP, Bilodeau M, Lepage R, Cote J, Lefebvre M. Variability in hepatic iron concentration measurement from needle-biopsy specimens. J Hepatol 1996; 25:172-177.[CrossRef][Medline]
14. Gandon Y. Iron and liver 2003. Available at: www.radio.univ-rennes1.fr. Accessed November 7.
15. Gandon Y, Guyader D, Heautot JF, et al. Hemochromatosis: diagnosis and quantification of liver iron with gradient-echo MR imaging. Radiology 1994; 193:533-538.[Abstract/Free Full Text]
16. Ernst O, Sergent G, Bonvarlet P, Canva-Delcambre V, Paris JC, L’Herminé C. Hepatic iron overload: diagnosis and quantification with MR imaging. AJR Am J Roentgenol 1997; 168:1205-1208.[Abstract/Free Full Text]
17. Ernst O, Rose C, Sergent G, L’Herminé C. Hepatic iron overload: diagnosis and quantification with MR imaging at 1.5 T (letter). AJR Am J Roentgenol 1999; 172:1141-1142.[Medline]
18. Lawrence SP, Caminer SJ, Yavorski RT, et al. Correlation of liver density by magnetic resonance imaging and hepatic iron levels: a noninvasive means to exclude homozygous hemochromatosis. J Clin Gastroenterol 1996; 23:113-117.[CrossRef][Medline]
19. Gomori JM, Horev G, Tamary H, et al. Hepatic iron overload: quantitative MR imaging. Radiology 1991; 179:367-369.[Abstract/Free Full Text]
20. Bonetti MG, Castriota-Scanderbeg A, Criconia GM, et al. Hepatic iron overload in thalassemic patients: proposal and validation of an MRI method of assessment. Pediatr Radiol 1996; 26:650-656.[CrossRef][Medline]
21. Chezmar JL, Nelson RC, Malko JA, Bernardino ME. Hepatic iron overload: diagnosis and quantification by noninvasive imaging. Gastrointest Radiol 1990; 15:27-31.[CrossRef][Medline]
22. Kreeftenberg HG, Jr, Mooyaart EL, Huizenga JR, Sluiter WJ. Quantification of liver iron concentration with magnetic resonance imaging by combining T1-, T2-weighted spin echo sequences and a gradient echo sequence. Neth J Med 2000; 56:133-137.[CrossRef][Medline]
23. Gandon Y, Deugnier Y, Aube C, Auberti P, Guyader D, Boudou A. Detection and quantification of liver iron overload using MRI: multicentric validation (abstr). Radiology 1998; 209(P):294.
24. Rocchi E, Cassanelli M, Borghi A, et al. Magnetic resonance imaging and different levels of iron overload in chronic liver disease. Hepatology 1993; 17:997-1002.[CrossRef][Medline]

This article has been cited by other articles:

				J. S. Hankins, M. B. McCarville, R. B. Loeffler, M. P. Smeltzer, M. Onciu, F. A. Hoffer, C.-S. Li, W. C. Wang, R. E. Ware, and C. M. Hillenbrand R2* magnetic resonance imaging of the liver in patients with iron overload Blood, May 14, 2009; 113(20): 4853 - 4855. [Abstract] [Full Text] [PDF]

				J. M. Alustiza and A. Castiella Liver Fat and Iron at In-Phase and Opposed-Phase MR Imaging Radiology, February 1, 2008; 246(2): 641 - 641. [Full Text] [PDF]

				O. Papakonstantinou, T. G. Maris, S. Kostaridou, V. Ladis, A. Vasiliadou, and N. C. Gourtsoyiannis Abdominal Lymphadenopathy in {beta}-Thalassemia: MRI Features and Correlation with Liver Iron Overload and Posttransfusion Chronic Hepatitis C Am. J. Roentgenol., July 1, 2005; 185(1): 219 - 224. [Abstract] [Full Text] [PDF]

				A. Castiella, J. M. Alustiza, J. Artetxe, and A. Pietrangelo Hereditary Hemochromatosis N. Engl. J. Med., September 16, 2004; 351(12): 1263 - 1264. [Full Text] [PDF]

This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2302020820v1 230/2/479    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Alústiza, J. M. Articles by Recondo, J. A. Search for Related Content PubMed PubMed Citation Articles by Alústiza, J. M. Articles by Recondo, J. A.