The role of magnetic resonance imaging‐ T 2* in the evaluation of iron overload early in hereditary hemochromatosis. A cross‐sectional study with 159 patients

The last decade has witnessed a substantial increase in the number of patients diagnosed with hemochromatosis, particularly after some authors postulated that the detection of elevated serum ferritinemia (SF) or high transferrin saturation (TS) could be cost-effective for iron overload screening 1, 2. The use of MRI to measure the iron burden in hereditary hemochromatosis (HH) has only recently been accepted as a diagnostic tool 3-5. We hypothesized that MRI T2* can be a sensitive tool to measure iron overload in patients with HH even at early stages. We examined all medical records of consecutive patients with iron overload seen in a tertiary hospital in Brazil, between 2008 and 2012, with the aim of describing MRI-T2* findings in a large sample of patients, and correlating these with HFE genetic profiles. The local Ethics Committee approved the protocol. We analyzed data from all the 159 patients admitted in the study period with suspected iron overload based on high TS (above 55% in men and 45% in women) and/or SF (> 322 ng/mL), who had undergone MRI-T2* for heart, liver, spleen, and/or pancreas iron overload and had been screened for the presence of HFE mutations by allele-specific PCR (polymerase chain reaction). The calculations of liver iron concentration (LIC) values were based on liver MRI-T2* measurements, using the Thalassemia-Tools software (Cardiovascular Imaging Solutions, London, UK). Mutations in the HFE gene were identified in 109/159 (68.6%) patients. The most common mutation in our sample was H63D, present in 91 patients (57.2%): 14 (8.8%) were homozygous, 69 (43.4%) heterozygous, and 8 (5%) compound heterozygous for C282Y/H63D. For the C282Y mutation, in contrast, only 5 patients (3.1%) were homozygous and 11 (6.9%) were heterozygous. The S65C mutation was detected in heterozygous state in 2 (2.5%) cases. All 159 patients underwent abdominal MRI-T2* and 126 underwent cardiac MRI-T2* too. Only 3 out of 126 cardiac MRIs had a positive T2* result, mild cardiac overload (T2*: 18.98, 19.14, and 19.8 ms). Of these, two patients had the H63D mutation (1 homozygous and 1 heterozygous) and one patient did not have any of the mutations studied. In the liver, 61 (38.4%) patients had iron overload (T2*: < 11.4 ms and LIC > 2.0 mg/g) of which 57 (35.8%) were light (T2*: 3.83–11.4 ms and LIC: 2.01–6.86 mg/g), and four (2.5%) moderate (T2*: 2.0–3.8 ms and LIC: 7.06–13.56 mg/g). Of these patients with liver overload, 27.9% were C282Y carriers (8.2% homozygous, 11.5% heterozygous, and 8.2% compound heterozygous C282Y/H63D), and 50.8% carried the H63D mutation (14.8% in homozygosis and 36.1% in heterozygosis). Only 12 (19.7%) patients with liver overload did not have the HFE mutation. The presence of C282Y mutation (in either homo or heterozygosis), compound heterozygous (C282/H63D), and H63D in homozygosis was significantly associated with a higher frequency of iron overload in the liver as measured by T2* (P = 0.001). However, this was not true in patients with H63D in heterozygosis or absence of mutation (P = 0.42), in which overload frequency was 68.4% and 29.1%, respectively. Pancreatic overload was diagnosed in 33 patients (21%), and 56 patients (35.7%) had splenic overload (Table 1). The presence of the C282Y was associated with an overall higher frequency of iron overload. There was also a relatively high frequency (37.3%) of abnormal T2* values in H63D mutants both in the liver and in the spleen, and the frequency of splenic iron overload in H63D mutants was similar to that associated with the C282Y mutation. SF results were available for 152 patients. Median SF was 647 ng/mL (72–13,625), and in 138 patients (90.8%) SF was abnormally high. Overall, in 28 patients (18.2%) serum levels were higher than 1,000 ng/mL, in 80 patients (54%) they varied from 501 to 1,000 ng/mL and in 30 (20.3%) they ranged from 324 to 500 ng/mL. Serum TS was obtained from 94 patients, with a median of 42% (31–57) and elevated results in 32 (34%) of the tests. Considering MRI findings as standard, SF was the most sensitive test (sensitivity 94.7%, specificity 11.8%), whereas TS was the most specific (sensitivity 34%, specificity 65.4%), indicating that they might be complementary. Sensitivity and specificity values were similar in patients with and without HFE mutation. Iron overload prevalence was different according to the affected organ or the type of HFE mutation; over 50% of patients with liver iron overload carried the H63D mutation, and two out of three patients who had cardiac iron overload were also H63D carriers. A total of 38% of the H63D carriers presented with iron overload in the liver and spleen and 22% in the pancreas, showing that this mutation alone might correlate with iron overload. It is worth noticing, however, that the absence of HFE mutations does not rule out the presence of other mutations associated with hereditary hemochromatosis. Our study demonstrates, in a large sample of Brazilian patients, that MRI-T2* is a non-invasive, accurate, and sensitive technique for the detection of low levels of iron overload in patients with HH type 1. Excessive iron stores in the liver were detected in 39% of patients, showing that iron accumulation begins in the liver 6. Given the observation that MRI is an accurate and safe tool to measure iron stores in these organs, we believe that this technology should be incorporated in the investigation of suspected cases of hemochromatosis and contribute to guide therapeutic decisions such as phlebotomy. Reijâne A. Assis,1 Fernando U. Kay,2 Fabiana M. Conti,1 Paulo V. Campregher,1 Gilberto Szarf,2 Michelli S. Diniz,3 Morgani Rodrigues,1 Ricardo Helman,1 Marcelo B.G. Funari,2John Wood,4 Nelson Hamerschlak1* 1Department of Hematology, Hospital Israelita Albert Einstein, São Paulo, Brazil; 2Imaging Department, Hospital Israelita Albert Einstein, São Paulo, Brazil; 3Clinical Research Institute, Hospital Israelita Albert Einstein, São Paulo, Brazil; 4Division of Cardiology, University of Southern California, Children's Hospital, Los Angeles, California