Clinical and genetic predictors of cardiac dysfunction assessed by echocardiography in patients with hereditary hemochromatosis.

PURPOSE: Hereditary hemochromatosis (HH) may cause iron deposition in cardiac tissue. We aimed to describe the echocardiographic findings in patients with HH and identify risk factors for cardiac dysfunction. METHODS: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at our tertiary care center between August 2000 and July 2022. We defined three primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55%, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') > 15, and 3) global longitudinal strain (GLS) < 18. Multivariable logistic regression was utilized to identify predictors of cardiac dysfunction. RESULTS: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e' > 15 and GLS < 18 was 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. In multivariable analysis, non-White race, age, and hypertension were associated with E/e' > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e' > 15. In patients with LVEF ≥ 55%, the C282Y/H63D genetic mutation was associated with reduced likelihood of E/e' > 15, p = 0.024. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS < 18 in unadjusted analysis. CONCLUSION: We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. Patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations in patients with a normal LVEF.

Association of Genetic Variant Linked to Hemochromatosis With Brain Magnetic Resonance Imaging Measures of Iron and Movement Disorders.

Importance: Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that leads to iron overload. Conflicting results from previous research has led some to believe the brain is spared the toxic effects of iron in HH. Objective: To test the association of the strongest genetic risk variant for HH on brainwide measures sensitive to iron deposition and the rates of movement disorders in a substantially larger sample than previous studies of its kind. Design, Setting, and Participants: This cross-sectional retrospective study included participants from the UK Biobank, a population-based sample. Genotype, health record, and neuroimaging data were collected from January 2006 to May 2021. Data analysis was conducted from January 2021 to April 2022. Disorders tested included movement disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10], codes G20-G26), abnormalities of gait and mobility (ICD-10 codes R26), and other disorders of the nervous system (ICD-10 codes G90-G99). Exposures: Homozygosity for p.C282Y, the largest known genetic risk factor for HH. Main Outcomes and Measures: T2-weighted and T2* signal intensity from brain magnetic resonance imaging scans, measures sensitive to iron deposition, and clinical diagnosis of neurological disorders. Results: The total cohort consisted of 488 288 individuals (264 719 female; ages 49-87 years, largely northern European ancestry), 2889 of whom were p.C282Y homozygotes. The neuroimaging analysis consisted of 836 individuals: 165 p.C282Y homozygotes (99 female) and 671 matched controls (399 female). A total of 206 individuals were excluded from analysis due to withdrawal of consent. Neuroimaging analysis showed that p.C282Y homozygosity was associated with decreased T2-weighted and T2* signal intensity in subcortical motor structures (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen d >1) consistent with substantial iron deposition. Across the whole UK Biobank (2889 p.C282Y homozygotes, 485 399 controls), we found a significantly increased prevalence for movement disorders in male homozygotes (OR, 1.80; 95% CI, 1.28-2.55; P = .001) but not female individuals (OR, 1.09; 95% CI, 0.70-1.73; P = .69). Among the 31 p.C282Y male homozygotes with a movement disorder, only 10 had a concurrent HH diagnosis. Conclusions and Relevance: These findings indicate increased iron deposition in subcortical motor circuits in p.C282Y homozygotes and confirm an increased association with movement disorders in male homozygotes. Early treatment in HH effectively prevents the negative consequences of iron overload in the liver and heart. Our work suggests that screening for p.C282Y homozygosity in high-risk individuals also has the potential to reduce brain iron accumulation and to reduce the risk of movement disorders among male individuals who are homozygous for this mutation.

Quantifying Brain Iron in Hereditary Hemochromatosis Using R2* and Susceptibility Mapping.

BACKGROUND AND PURPOSE: Brain iron dyshomeostasis is increasingly recognized as an important contributor to neurodegeneration. Hereditary hemochromatosis is the most commonly inherited disorder of systemic iron overload. Although there is an increasing interest in excessive brain iron deposition, there is a paucity of evidence showing changes in brain iron exceeding that in healthy controls. Quantitative susceptibility mapping and R2* mapping are established MR imaging techniques that we used to noninvasively quantify brain iron in subjects with hereditary hemochromatosis. MATERIALS AND METHODS: Fifty-two patients with hereditary hemochromatosis and 47 age- and sex-matched healthy controls were imaged using a multiecho gradient-echo sequence at 3T. Quantitative susceptibility mapping and R2* data were generated, and regions within the deep gray matter were manually segmented. Mean susceptibility and R2* relaxation rates were calculated for each region, and iron content was compared between the groups. RESULTS: We noted elevated iron levels in patients with hereditary hemochromatosis compared with healthy controls using both R2* and QSM methods in the caudate nucleus, putamen, pulvinar thalamus, red nucleus, and dentate nucleus. Additionally, the substantia nigra showed increased susceptibility while the thalamus showed an increased R2* relaxation rate compared with healthy controls, respectively. CONCLUSIONS: Both quantitative susceptibility mapping and R2* showed abnormal levels of brain iron in subjects with hereditary hemochromatosis compared with controls. Quantitative susceptibility mapping and R2* can be acquired in a single MR imaging sequence and are complementary in quantifying deep gray matter iron.

Cardiac Magnetic Resonance at 3.0 T in Patients With C282Y Homozygous Hereditary Hemochromatosis: Superiority of Radial and Circumferential Strain Over Cardiac T2* Measurements at Baseline and at Post Venesection Follow-up.

BACKGROUND: Iron-overload cardiomyopathy initially manifests with diastolic dysfunction and can progress to dilated cardiomyopathy if untreated. Previous studies have shown that patients with primary and secondary hemochromatosis can have subclinical left ventricle dysfunction with abnormalities on strain imaging. This study aimed to evaluate the relationship between cardiac T2* values and myocardial-wall strain in patients with hereditary hemochromatosis (HH) at the time of diagnosis and after a course of venesection treatment. MATERIALS AND METHODS: Baseline cardiac magnetic resonance (CMR) at 3 T was performed in 19 patients with newly diagnosed HH with elevated serum ferritin levels and repeated after a course of treatment with venesection. Quantitative T2* mapping and strain analysis were performed offline using dedicated relaxometry fitting and feature-tracking software. RESULTS: The majority (84%) of patients had normal baseline myocardial T2* values (mean 19.3 ms, range 8.9 to 31.2 ms), which improved significantly after venesection (mean 24.1 ms, range 11 to 38.1 ms) ( P =0.021). Mean global radial strain significantly improved from 25.0 (range: 15.6 to 32.9) to 28.3 (range: 19.8 to 35.8) ( P =0.001) and mean global circumferential strain improved, decreasing from -15.7 (range: -11.1 to -19.2) to -17.1 (range: -13.0 to -20.1) ( P =0.001). CONCLUSION: Patients with HH may have normal T2* values in the presence of subclinical left ventricle dysfunction, which can be detected by abnormal radial and circumferential strain. As strain imaging improves following venesection in HH, it may serve as a useful biomarker to guide treatment.

Magnetic resonance imaging of neonatal hemochromatosis.

Neonatal hemochromatosis is a rare condition that causes neonatal liver failure, frequently resulting in fetal loss or neonatal death. It is thought that most cases of neonatal hemochromatosis are caused by gestational alloimmune liver disease (GALD), with neonatal hemochromatosis being a phenotype of GALD rather than a disease process. Extrahepatic siderosis in the pancreas, myocardium, thyroid and minor salivary gland is a characteristic feature of neonatal hemochromatosis. There is also sparing of the reticuloendothelial system with no iron deposition in the spleen. Hepatic and extrahepatic siderosis seen in neonatal hemochromatosis is from iron dysregulation secondary to liver damage rather than iron deposition causing the liver damage. The presence of extrahepatic siderosis in the pancreas and thyroid is diagnostic of neonatal hemochromatosis and can be detected noninvasively by multi-echo gradient recalled echo (GRE) T2*-weighted sequence of MRI within hours of birth. This helps to expedite the treatment in the form of intravenous immunoglobulin and exchange transfusion, which improves the survival in these babies. The finding of hepatic siderosis is nonspecific and does not help in the diagnosis of neonatal hemochromatosis because it is seen with other causes of advanced liver disease.

MRI-Based Iron Phenotyping and Patient Selection for Next-Generation Sequencing of Non-Homeostatic Iron Regulator Hemochromatosis Genes.

BACKGROUND AND AIMS: High serum ferritin is frequent among patients with chronic liver disease and commonly associated with hepatic iron overload. Genetic causes of high liver iron include homozygosity for the p.Cys282Tyr variant in homeostatic iron regulator (HFE) and rare variants in non-HFE genes. The aims of the present study were to describe the landscape and frequency of mutations in hemochromatosis genes and determine whether patient selection by noninvasive hepatic iron quantification using MRI improves the diagnostic yield of next-generation sequencing (NGS) in patients with hyperferritinemia. APPROACH AND RESULTS: A cohort of 410 unselected liver clinic patients with high serum ferritin (defined as ≥200 µg/L for women and ≥300 µg/L for men) was investigated by HFE genotyping and abdominal MRI R2*. Forty-one (10%) patients were homozygous for the p.Cys282Tyr variant in HFE. Of the remaining 369 patients, 256 (69%) had high transferrin saturation (TSAT; ≥45%) and 199 (53%) had confirmed hepatic iron overload (liver R2* ≥70 s-1 ). NGS of hemochromatosis genes was carried out in 180 patients with hepatic iron overload, and likely pathogenic variants were identified in 68 of 180 (38%) patients, mainly in HFE (79%), ceruloplasmin (25%), and transferrin receptor 2 (19%). Low spleen iron (R2* <50 s-1 ), but not TSAT, was significantly associated with the presence of mutations. In 167 patients (93%), no monogenic cause of hepatic iron overload could be identified. CONCLUSIONS: In patients without homozygosity for p.Cys282Tyr, coincident pathogenic variants in HFE and non-HFE genes could explain hyperferritinemia with hepatic iron overload in a subset of patients. Unlike HFE hemochromatosis, this type of polygenic hepatic iron overload presents with variable TSAT. High ferritin in blood is an indicator of the iron storage disease, hemochromatosis. A simple genetic test establishes this diagnosis in the majority of patients affected. MRI of the abdomen can guide further genetic testing.

Balanced by iron. Hereditary hemochromatosis and celiac disease.

We present the case of a healthy 14-year-old adolescent who was referred to our hospital for an incidental alteration of the iron profile (Fe 225 ug/dl, transferrin 186 mg/dl, IST 63.93 %, ferritin 253 ng/ml). The blood count, proteinogram and renal, lipid and liver function tests were in the normal range. Abdominal ultrasound was requested with no findings of interest. The genetic analysis for hereditary hemochromatosis (HH) confirmed that the patient was homozygous for the C282Y mutation.

Chelating Polymers for Hereditary Hemochromatosis Treatment.

Hemochromatosis (iron overload) encompasses a group of diseases that are characterized by a toxic hyperaccumulation of iron in parenchymal organs. Currently, only few treatments for this disease have been approved; however, all these treatments possess severe side effects. In this study, a paradigm for hemochromatosis maintenance/preventive therapy is investigated: polymers with negligible systemic biological availability form stable complexes with iron ions in the gastrointestinal tract, which reduces the biological availability of iron. Macroporous polymer beads are synthesized with three different iron-chelating moieties (benzene-1,2-diol, benzene-1,2,3-triol, and 1,10-phenanthroline). The polymers rapidly chelate iron ions from aqueous solutions in vitro in the course of minutes, and are noncytotoxic and nonprooxidant. Moreover, the in vivo biodistribution and pharmacokinetics show a negligible uptake from the gastrointestinal tract (using 125 I-labeled polymer and single photon emission computed tomography/computed tomography), which generally prevents them from having systemic side effects. The therapeutic efficacy of the prepared polymers is successfully tested in vivo, and exhibits a significant inhibition of iron uptake from the gastrointestinal tract without any noticeable signs of toxicity. Furthermore, an in silico method is developed for the prediction of chelator selectivity. Therefore, this paradigm can be applied to the next-generation maintenance/preventive treatment for hemochromatosis and/or other diseases of similar pathophysiology.

Clinical evaluation of infiltrative cardiomyopathies resulting in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction is a very common clinical problem. Its prevalence is increasing with aging of the population. A diverse group of risk factors and etiologies comprise the HFpEF syndrome. No specific therapies have been shown to improve survival for the vast majority of HFpEF cases. Restrictive cardiomyopathies account for a significant portion of HFpEF patients and are characterized by diastolic dysfunction due to infiltration of the myocardium or ventricular hypertrophy. Many of these restrictive diseases occur in the context of myocardial infiltration by other substances such as amyloid, iron or glycogen or endomyocardial fibrosis. These infiltrative diseases usually have important clues in the clinical picture and on cardiac imaging that may allow differentiation from the usual HFpEF phenotype (that is commonly seen in the older, hypertensive patient). Noninvasive diagnosis has replaced endomyocardial biopsy for most instances in the workup of these conditions. Early recognition is important to institute specific therapies and to improve prognosis. In this review, we describe 4 major infiltrative cardiomyopathies (Cardiac Amyloidosis, Sarcoidosis, Hemochromatosis and Fabry disease), and their key imaging features.

MR imaging assessment and quantification of liver iron.

Iron overload is a common clinical problem resulting from hereditary hemochromatosis or secondary hemosiderosis (mainly associated with transfusion therapy), being also associated with chronic liver diseases and metabolic disorders. Excess of iron accumulates in organs like the liver, pancreas and heart. Without treatment, patients with iron overload disorders will develop liver cirrhosis, diabetes and cardiomyopathy. Iron quantification is therefore crucial not only for diagnosis of iron overload but also to monitor iron-reducing therapies. Liver iron concentration is considered the surrogate marker of total body iron stores. Because liver biopsy is invasive and prone to high variability and sampling bias, MR imaging has emerged as a non-invasive method and gained wide acceptance, now being considered the standard of care for assessing iron overload. Nevertheless, there are different MR techniques for iron quantification and there is still no consensus about the best technique or postprocessing tool for hepatic iron quantification, with the choice of imaging technique depending mainly on the local expertise as well on the available equipment and software. Because different methods should not be used interchangeably, it is important to choose one method and use the same one when following up patients over time.

Improvements in cardiac function detected using echocardiography in patients with hereditary haemochromatosis.

BACKGROUND: Hereditary haemochromatosis is often not diagnosed until adulthood. Iron overload cardiomyopathy initially results in diastolic dysfunction and can result in arrhythmias and irreversible cardiac failure if untreated. The aim of this study was to investigate whether patients with newly diagnosed hereditary haemochromatosis without signs of heart failure exhibit subclinical alterations of cardiac function and to determine if cardiac function improved after 1 year of venesection. METHODS: Baseline echocardiography was performed on 25 patients with newly diagnosed hereditary haemochromatosis with elevated serum ferritin levels. The test was repeated after 1 year of treatment with venesection. Tissue Doppler imaging (TDI) and deformation (strain) imaging using speckle tracking were performed. Left atrial force was measured according to the Newtonian principle, in which force (dynes) = mass × acceleration. Left atrial force was calculated by the Manning method expressed as ρ × 0.53 × mitral annular orifice area × (peak A velocity)2. RESULTS: Radial strain showed a significant improvement after 1 year of venesection (increase from 38.8 to 52.6). The LAF showed a significant decrease after 1 year of venesection (median decrease = 0.6 (IQR 0, 1.60), p = 0.0004). Iso-volumetric relaxation time (IVRT) decreased significantly in patients after 1 year of venesection (decrease from 107.4 ± 16.2 to 97.68 ± 15.4 ms, p (0.0187)). CONCLUSION: Among all measurements, radial strain, IVRT and left atrial force were shown to significantly improve following a 1-year course of venesection, suggesting that these parameters could be used to identify subclinical cardiac dysfunction in patients with iron overload secondary to hereditary haemochromatosis and to guide intensification of venesection therapy.

Hemocromatosis genética hepato-cerebral en un paciente con síndrome de piernas inquietas / Hepato-cerebral hereditary hemochromatosis in a patient with restless legs syndrome

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Influence of hereditary haemochromatosis on left ventricular wall thickness: does iron overload exacerbate cardiac hypertrophy?

BACKGROUND: The left ventricular (LV) hypertrophy increases the risk of heart failure. Hypertension and infiltrative cardiomyopathies are the well-known reasons of LV hypertrophy. The growing interest of scientists in this issue affects hereditary haemochromatosis (HH), which is characterised by the excess deposition of iron mostly due to HFE gene mutation. The aim of our study was to investigate the possible influence of HH on LV parameters in patients with early-diagnosed (early HH) and long-lasting and long-treated (old HH) disease. MATERIALS AND METHODS: Thirty nine early HH and 19 old HH patients were prospectively enrolled in the study; age- and sex-matched healthy volunteers constituted the appropriate control groups. All participants had echocardiography performed (including three-dimension volume and mass analysis); the iron turnover parameters were measured at the time of enrolment in every HH patients. RESULTS: Echocardiographic parameters regarding to left atrium (LA), LV thickness, mass and long axis length were significantly higher, whereas LV ejection fraction was lower in early HH in comparison to healthy persons. In old HH patients the differences were similar to those mentioned before, except LV ejection fraction. The presence of hypertension in both HH groups did not influence echo parameters, as well as diabetes in old HH. The strongest correlation in all HH group was found between the time from HH diagnosis and LA, LV thickness and volumes parameters, but the correlations between iron turnover and echo parameters were non-existent. CONCLUSIONS: Hereditary haemochromatosis, not only long-lasting, but also early-diagnosed, could lead to exacerbation of LV wall thickness and cardiac hypertrophy. This effect is not simply connected with hypertension and diabetes that are frequent additional diseases in these patients, but with the time from HH diagnosis.

µXRF and LA-ICP-TQMS for quantitative bioimaging of iron in organ samples of a hemochromatosis model.

Hereditary hemochromatosis is the most common autosomal recessive genetic disorder of the iron metabolism. Iron accumulation in various organs, especially in liver and pancreas leads to diseases and may cause organ failure. In this study, methods for elemental bioimaging by means of quantitative micro X-ray fluorescence analysis (µXRF) and laser ablation-inductively coupled plasma-triple quadrupole mass spectrometry (LA-ICP-TQMS) were developed and applied to investigate the pathophysiological development of iron accumulation in murine tissue based on animals with an iron-overload phenotype caused by a hepatocyte-specific genetic mutation. The use of an external calibration with matrix-matched gelatin standards enables the quantification of iron by means of µXRF without the typically used fundamental parameters method or Monte Carlo simulation, which becomes more imprecise when analyzing thin tissue sections. A fast, non-destructive screening of the iron concentration and distribution with a spatial resolution of 25 µm in liver samples of iron-overload mice was developed. For improved limits of detection and higher spatial resolution down to 4 µm, LA-ICP-TQMS was used with oxygen as reaction gas. By monitoring the mass shift of 56Fe to 56Fe16O, a limit of detection of 0.5 µg/g was obtained. With this method, liver and pancreas samples of iron-overload mice as well as control mice were successfully analyzed. The high spatial resolution enabled the analysis of the iron distribution in different liver lobules. Compared to the established Prussian blue staining, both developed methods proved to be superior due to the possibility of direct iron quantification in the tissues.

Prenatal imaging features suggestive of liver gestational allo immune disease.

We report prenatal imaging features of four cases of neonatal hemochromatosis due to an alloimmune disease. All cases exhibited intra uterine growth restriction (IUGR) without arguments for a vascular etiology, associated with oligohydramnios. Placental hydrops was present in 75% of cases. Splenomegaly was identified in one case. Other causes of NH have been ruled out during diagnostic workup including karyotype, detection of IGFBP-1 to evaluate a premature rupture of membranes, maternal serologic tests. MRI was performed in two cases and showed an atrophic liver associated with a low signal intensity on T2-sequence in one case. Prenatal NH was suspected in this later case and the fetus was successfully treated with two IVIG (intravenous immunoglobulins) perfusions performed during pregnancy followed by exchange transfusion and IVIG after birth. The child is doing well with normal liver function tests after 17 months of follow up. Our aim was to highlight the importance of suggesting NH-GALD when facing IUGR with oligohydramnios, ascites, placental hydrops, splenomegaly on prenatal ultrasound with negative work up for placental vascular pathologies and infectious fetopathies. MRI might be of a good help, showing an atrophic liver but enhancing iron overload in hepatic and extrahepatic tissue is helpful but not constant.

Iron-Containing Abdominal Pathologies: Exploiting Magnetic Susceptibility Artifact on Dual-Echo Gradient-Echo Magnetic Resonance Imaging.

A multitude of pathologic entities involve abnormal iron deposition in the abdomen. These lesions demonstrate decreased signal on longer magnetic resonance sequences with longer echo time due to T2* effect. Dual-echo gradient-echo sequences demonstrate increased susceptibility artifact with longer echo sequences. In this article, the spectrum of iron-containing abdominal pathologies is illustrated, with their characteristic distributions. Included is a brief discussion of the physics of magnetic resonance imaging of iron-containing lesions.

Quantification of liver iron overload disease with laser ablation inductively coupled plasma mass spectrometry.

BACKGROUND: Hereditary hemochromatosis is the most frequent, identified, genetic disorder in Caucasians affecting about 1 in 1000 people of Northern European ancestry, where the associated genetic defect (homozygosity for the p.Cys282Tyr polymorphism in the HFE gene) has a prevalence of approximately 1:200. The disorder is characterized by excess iron stores in the body. Due to the incomplete disease penetrance of disease-associated genotype, genetic testing and accurate quantification of hepatic iron content by histological grading of stainable iron, quantitative chemical determination of iron, or imaging procedures are important in the evaluation and staging of hereditary hemochromatosis. METHODS: We here established novel laser ablation inductively coupled plasma mass spectrometry protocols for hepatic metal bio-imaging for diagnosis of iron overload. RESULTS: We demonstrate that these protocols are a significant asset in the diagnosis of iron overload allowing iron measurements and simultaneous determination of various other metals and metalloids with high sensitivity, spatial resolution, and quantification ability. CONCLUSIONS: The simultaneous measurement of various metals and metalloids offers unique opportunities for deeper understanding of metal imbalances. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a highly powerful and sensitive technique for the analysis of a variety of solid samples with high spatial resolution. We conclude that this method is an important add-on to routine diagnosis of iron overload and associated hepatic metal dysbalances resulting thereof.

Opportunistic Screening for Hereditary Hemochromatosis With Unenhanced CT: Determination of an Optimal Liver Attenuation Threshold.

OBJECTIVE: The purpose of this study was to assess whether a specific liver attenuation threshold for unenhanced CT allows both sensitive opportunistic detection of unsuspected hereditary hemochromatosis and low overall screening test-positive rates. MATERIALS AND METHODS: We used a standard ROI placement method on unenhanced CT studies of 3357 consecutive adults (mean age, 57.0 years) with no symptoms of liver disease who underwent colorectal screening. Hepatic attenuation (in HU) was measured to assess test-positive rates at various liver attenuation thresholds. To assess sensitivity, unenhanced hepatic CT attenuation was also measured in 12 patients with hereditary hemochromatosis (mean age, 48.3 years), who were homozygous for the HFE C282Y mutation. All scans were obtained at 120 kV. Serum ferritin levels were recorded for the hereditary hemochromatosis cohort. RESULTS: Mean liver attenuation ± SD among screened adults was 59.4 ± 12.7 HU, compared with 78.7 ± 13.1 HU (range, 59-105 HU) in the hereditary hemochromatosis cohort (p < 0.001). Screening test-positive rates were 30.6% (n = 1028) at 65 HU, 8.2% (n = 275) at 70 HU, 1.2% (n = 39) at 75 HU, and 0.2% (n = 7) at 80 HU. Corresponding sensitivities for hereditary hemochromatosis at these thresholds were 83.3% (10/12) at 65, 70, and 75 HU; and 50.0% (6/12) at 80 HU. Serum ferritin levels were elevated in all patients with hereditary hemochromatosis (mean, 1678 ng/mL; range, 477-3991 ng/mL). CONCLUSION: An unenhanced CT liver attenuation threshold of 75 HU was sensitive (83.3%) for hereditary hemochromatosis while maintaining an acceptably low screening test-positive rate (1.2%). An unexplained liver attenuation of 75 HU or more on unenhanced CT should trigger appropriate laboratory investigation for iron overload; early intervention with phlebotomy can limit or prevent organ damage in patients with hemochromatosis.

Inter-method reproducibility of biexponential R2 MR relaxometry for estimation of liver iron concentration.

PURPOSE: To assess the reproducibility of biexponential R2 -relaxometry MRI for estimation of liver iron concentration (LIC) between proprietary and nonproprietary analysis methods. METHODS: This single-center retrospective study, approved by investigational review board and compliant with the Health Insurance Portability and Accountability Act, included 40 liver MRI exams in 38 subjects with suspected or known iron overload. From spin-echo images of the liver, acquired at 5 different echo times (TE = 6-18 ms), biexponential R2 maps were calculated using 1 proprietary (FerriScan, Resonance Health Ltd., Claremont WA, Australia) and 3 nonproprietary (simulated annealing, nonlinear least squares, dictionary search) analysis methods. Each subject's average liver R2 value was converted to LIC using a previously validated calibration curve. Inter-method reproducibility for liver R2 and LIC were assessed for linearity using linear regression analysis and absolute agreement using intraclass correlation and Bland-Altman analysis. For point estimates, 95% confidence intervals were calculated; P values < 0.05 were considered statistically significant. RESULTS: Linearity between the proprietary and nonproprietary methods was excellent across the observed range for R2 (20-312 s-1 ) and LIC (0.4-52.2 mg/g), with all coefficients of determination (R2 ) ≥ 0.95. No statistically significant bias was found (slope estimates ∼ 1; intercept estimates ∼ 0; P values > 0.05). Agreement between the 4 methods was excellent for both liver R2 and LIC (intraclass correlations ≥ 0.97). Bland-Altman 95% limits of agreement in % difference between the proprietary and nonproprietary methods were ≤ 9% and ≤ 16% for R2 and LIC, respectively. CONCLUSION: Biexponential R2 -relaxometry MRI for LIC estimation is reproducible between proprietary and nonproprietary analysis methods.