scholarly journals Liver iron overload is associated with elevated SHBG concentration and moderate hypogonadotrophic hypogonadism in dysmetabolic men without genetic haemochromatosis

2011 ◽  
Vol 165 (2) ◽  
pp. 339-343 ◽  
Author(s):  
Alain Gautier ◽  
Fabrice Lainé ◽  
Catherine Massart ◽  
Laure Sandret ◽  
Xavier Piguel ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Concentration ◽  
Multivariable Analysis ◽  
Sex Hormone Binding Globulin ◽  
Total Testosterone ◽  
Liver Iron ◽  
Hypogonadotrophic Hypogonadism ◽  
Liver Iron Overload ◽  
The Relationship ◽  
Hormonal Levels

AimsTo assess the relation between moderate iron overload on sex hormone binding globulin (SHBG) levels and gonadotroph function in men with dysmetabolic iron overload syndrome and the effects of phlebotomy.MethodsThe relationship between magnetic resonance imaging assessed liver iron concentration (LIC) and plasma ferritin levels with total testosterone, bioavailable testosterone (BT), SHBG and LH levels, were studied in 50 men with moderate dysmetabolic iron excess, in the absence of genetic haemochromatosis, who were randomised to phlebotomy therapy or to normal care.ResultsFour patients (8%) had low total testosterone (<10.4 nmol/l) and 13 patients (26%) had low BT (<2.5 nmol/l). In the entire population, those with LIC above the median (90 μmol/l) had a higher mean SHBG (P=0.028), lower LH (P=0.039) than those with LIC below the median. In multivariable analysis (adjusted for age, and fasting insulin) LIC was significantly associated with SHBG (positively) and LH (negatively). Patients in the highest quartile of SHBG had higher LIC (P=0.010) and higher ferritinaemia (P=0.012) than those in the three other quartiles. Iron depletion by venesection did not significantly improve any hormonal levels.ConclusionsHypogonadism is not infrequent in men with dysmetabolic iron overload syndrome. Liver iron excess is associated with increased plasma SHBG and moderate hypogonadotrophic hypogonadism. Phlebotomy therapy needs further investigation in symptomatic hypogonadal men with dysmetabolic iron excess.

Whole Liver Iron Overload Measurement by Magnetic Iron Detector (MID). A Non Cryogenic Bio-Susceptometer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1547-1547
Author(s):  
Mauro Marinelli ◽  
Piergiorgio Beruto ◽  
Barbara Gianesin ◽  
Antonella Lavagetto ◽  
Martina Lamagna ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Reduction ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Large Error ◽  
Liver Iron ◽  
Heterogeneous Distribution ◽  
Ferritin Concentration ◽  
Liver Iron Overload ◽  
Liver Needle Biopsy

Abstract Accurate assessment of body-iron accumulation is essential for diagnosis and therapy of iron-overload in diseases such as thalassemia, hereditary hemochromatosis and other forms of severe congenital or acquired anemias. At present, the gold standard to determine liver-iron concentration (LIC) is the invasive liver needle biopsy. This technique might lead to large error, in assessing iron burden, due to the heterogeneous distribution of iron deposition in the liver. SQUID bio-susceptometer and MRI are currently the only non-invasive validated methods for LIC measurements. The susceptometer presented herein, named Magnetic Iron Detector (MID), measures directly the iron overload in the whole liver. All of its components operate at room temperature. Since February 2005 about 150 patients and 90 healthy volunteers have been measured and the measures were obtained in blind. The local Ethics Committee approved the study and all subjects gave informed consent. The result of correlations with the LIC measurements by SQUID susceptometry (Dr. A. Piga, Turin) in 43 patients showed a R 0.86 (Fig 1). In 2 patients, affected by Congenital Hemocromatosis, we correlated the LIC measurement by MID with the assessment of the expected iron depletion obtained with the phlebotomy therapy R 0.94 (Fig 2). All the measurements were correlated with the serum-ferritin concentration values R 0.72. We obtained correlation with the LIC measurement by liver biopsy in 7 patients R 0.89, further measures are in progress. The reproducibility of the iron overload of the same patients, measured after a relatively short lapse of time, is better than 0.5g. In conclusion the data obtained shows that MID is a reliable instrument for the diagnosis of the liver iron overload and for the follow-up of the chelation therapy. It is simpler to operate being manageable directly in the Clinical Center and more affordable than competing techniques. Fig. 1 LIC measured by MID vs LIC measured by SQUID Fig. 1. LIC measured by MID vs LIC measured by SQUID Fig. 2 The iron reduction of two hemochromatosis patients, under phebotomy therapy, compare with the reduction measured by the MID. Fig. 2. The iron reduction of two hemochromatosis patients, under phebotomy therapy, compare with the reduction measured by the MID.

Threshold Ferritin Values to Predict Control of Liver Iron Burden in Thalassemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4824-4824
Author(s):  
Ashutosh Lal ◽  
Marcela G Weyhmiller ◽  
Elliott Vichinsky
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Roc Analysis ◽  
Conflicts Of Interest ◽  
False Negative ◽  
Iron Concentration ◽  
False Negative Rate ◽  
Operating Characteristics ◽  
Liver Iron ◽  
The Relationship

Abstract Transfusion-dependent (TD) and non-transfusion dependent (NTD) forms of thalassemia are associated with progressive iron overload reflected by increase in serum ferritin and liver iron concentration (LIC). Despite the adoption of non-invasive methods, measurement of LIC is available to only a minority of patients or can only be performed annually. Maintenance of low systemic iron usually depends on frequent determination of ferritin, a less reliable marker whose level can vary among individuals with similar LIC. We evaluated the relationship between LIC and ferritin in TD and NTD (including un-transfused (NT) or intermittently transfused (TI)) individuals to determine the validity of average annual ferritin to identify inadequate control of liver iron (defined as LIC >7 mg/g dry-liver-weight). After excluding individuals with active hepatitis C virus infection, the LIC (measured by Ferritometer) and serum ferritin values were available from 115 TD (729 observations), 36 TI (139 observations) and 14 NT (28 observations) individual patients. The median (range) ferritin and LIC were 1,684 (91-14,155) ng/mL and 10.2 (0.14- 59.4) mg/g for TD, 469 (50-4,536) ng/mL and 8.8 (2.4-33.1) mg/g for TI, and 407 (30-1,061) ng/mL and 5.7 (1.3-22.8) mg/g for NT groups, respectively. The slope of the regression line between ferritin and LIC was significantly different between the 3 groups (p=0.019), being lowest in TD, intermediate in TI, and highest in NT. The predicted LIC for ferritin level of 1000 ng/mL was 8.1 mg/g for TD, 12.1 mg/g for TI, and 13.5 mg/g for NT groups. Receiver operating characteristics (ROC) analysis showed that in NTD group (NT+TI), a ferritin threshold of >200, >300 and >500 ng/mL failed to correctly identify 7%, 21% and 38% of individuals with LIC >7 mg/g, respectively. In contrast, in the TM group, these ferritin values were associated with false negative rate of 0%, 0% and 2%, respectively. In a subgroup analysis restricted to TM patients with ferritin <1,000 ng/mL, LIC varied from 0.14 mg/g to 21.1 mg/g. ROC analysis in this subgroup showed no ability of ferritin to discriminate between individuals with LIC <3 mg/g or ≥3 mg/g (AUC 0.54, P=n.s.). In conclusion, transfusions significantly alter the relationship between serum ferritin and LIC in thalassemia. In TM individuals, ferritin levels do not identify those with very low LIC. NTD patients with seemingly safe serum ferritin levels may have clinically significant hemosiderosis and be at risk for organ injury. These relationships should be factored into making decisions about screening or treatment of iron overload in untransfused or intermittently transfused individuals with thalassemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Association of vitamin D deficiency and bone mass with liver and heart iron overload in transfusion dependent thalassemia

2020 ◽  
Vol 7 (7) ◽  
pp. 1544
Author(s):  
Anjali Verma ◽  
Alok Khanna ◽  
Babita Jangra ◽  
Sanjiv Nanda ◽  
Surender Verma
Keyword(s):  
Vitamin D ◽  
Bone Mass ◽  
Iron Overload ◽  
Vitamin D Deficiency ◽  
Mass Density ◽  
Iron Concentration ◽  
Bone Mass Density ◽  
Liver Iron ◽  
Vitamin D Levels ◽  
Liver Iron Overload

Background: Transfusion dependent thalassemia patients are reported to have Vitamin D insufficiency/deficiency in many countries. Vitamin D hydroxylation occurs in the liver; whether liver iron overload interferes with this step has not been addressed till date. This study helps to establish an association between liver iron concentration (LIC) and heart iron concentration (MIC) with vitamin D levels and Bone Mass Density in these patients.Methods: A cross sectional study was done by including transfusion dependent Thalassemia patients (TM) if they had an assessment of Liver and cardiac iron done by T2*MRI and bone mineral density by DEXA. Clinical data regarding age, gender, type of iron chelation therapy and laboratory data of S. ferritin and Vitamin D was collected. Data was assessed using appropriate statistical methods.Results: Among 40 TM patients were taken and mean age was 17.6 years. Vitamin D deficiency was identified in 26(65%). 20 out of them had an LIC>7mg/g DW and 6 had MIC>1.65mg/g DW. There was a significant association between LIC>7mg/g and vitamin D level<20 ng/ml and a significant inverse correlation between LIC and vitamin D, suggesting that liver iron overload may indeed affect vitamin D metabolism. Osteopenia was present in 32.5% and osteoporosis was present in 27.5 % of all TM patients. Reduced Bone Mass Density was also found to be linked with iron over load.Conclusions: Regular monitoring of vitamin D levels and supplementation is required in patients with severe liver and heart iron load. More studies are needed to confirm these results.

Transient Elastography May Predict Liver Iron Overload in Adult Thalassaemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5407-5407 ◽  
Author(s):  
Vasilios Perifanis ◽  
Efthimia Vlachaki ◽  
Emmanouil Sinakos ◽  
Ioanna Tsatra ◽  
Maria Raptopoulou-Gigi ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Iron Overload ◽  
Hepatic Fibrosis ◽  
Transient Elastography ◽  
Iron Concentration ◽  
Thalassaemia Major ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Liver Iron Overload ◽  
T2 Mri

Abstract Although it is life saving, transfusion therapy has resulted in the majority of thalassemia patients being at risk for hemosiderosis-induced organ damage. Liver Iron Concentration (LIC) assessed by liver biopsy is considered the most accurate and sensitive method for determining body iron burden in patients with iron overload. The development of liver fibrosis is more closely related to liver iron concentration. Transient elastography (FibroScan, FS), which measures liver stiffness (LS), is a novel, noninvasive method to assess liver fibrosis. Whether FS is useful in the detection of preexisting liver iron overload in patients presenting with thalassaemia major without chronic viral hepatitis, is unclear. On the other hand, Magnetic Resonance Imaging (MRI) is a relatively inexpensive, widely available but more time consuming method that has long been considered as a useful tool for the non-invasive estimation of tissue iron content in multiple transfused patients with thalassemia. Aim: To study the prevalence and severity of liver fibrosis of transfusion dependent thalassaemia major patients, and correlate the MRI.LIC with the measurements of FS. Methods-Patients: The applicability for FS (Echosens, Paris, France) was defined as at least 10 valid measures and a success rate (number of valid measures/total number of LS Measures, LSM) ≥60% and a ratio of interquartile range/stiffness ≤0,2. Most subjects with FS scores below 5.1 kilopascals (kPa) are considered to have minimal fibrosis (grade F0 or F1, METAVIR score) according to the literature. The cut off FS values for diagnosing different stages of hepatic fibrosis were defined as &gt; 7.9kPa for F≥2, &gt; 10.3kPa for F≥3 and &gt; 11.9kPa for F=4. A total of 43 thalassaemic patients 23 males/20 females, median age 26,8±4,9 years, regularly transfused (pre-transfusion haemoglobin 9,7g/dl) were included in the study. All patients were hepatitis C virus (HCV) negative and chelated with different drugs (13 on deferasirox, 12 on deferiprone, 5 on desferrioxamine and 13 on combined therapy). Median ferritin levels were 1552±1576ng/ml. Liver tests (AST, ALT, γGT and Alkaline Phosphatase) were done simultaneously to all patients. Twenty-two of the 43 patients underwent liver iron determination (LIC) simultaneously by two methods: T2* Magnetic Imaging (T2*MRI) assessment and by calculation of MR-Hepatic Iron Concentration (MR.HIC) values (based on an algorithm developed by Gandon et al (Lancet 2004), using liver to muscle ratios in five axial gradient-echo sequences). T-test was used in statistical analysis to compare means. Results: Applicability of LSM was 100%. Overall median LSM was 8,25±6,05kPa (range 4–40,3kPa). Nineteen (44,1%) patients had FS&lt;6,1kPa (notably 8/19 patients below 5,1kPa), 13 (30,2%) had &lt;7,9kPa, 4 (9,3%) had &lt;10,3kPa, 2 (4,7%) had &lt;11,9kPa and 5 (11,7%) above 11,9kPa. Total FS correlated with Ferritin (r=0,39, p=0,008). Using the cutt-off value of 6,1 kPa for FS measurements, patients were divided in two groups with different ferritin levels: A (&lt;6,1kPa) 1039±758ng/ml vs B (&gt;6,1kPa) 1833±1742ng/ml, p&lt;0,03. FS values of the three different major therapy groups did not differ significantly. FS (22pts) correlated negatively with T2*MRI results (r=−0,39, p=0,07) and positively with MR.HIC results (r=0,49, p=0,02). There was no correlation with liver function tests. Conclusions: Severe haemosiderosis and hepatic fibrosis are common in patients with thalassaemia major despite the use of chelation therapy and the absence of HCV. Elastography has several characteristics that make it a desirable method for assessing hepatic fibrosis. In addition to being noninvasive and painless, it is also quick, inexpensive, and produces consistent results. It can also be useful as an alternative to check for liver iron overload, as abnormal results predict heavy liver iron overload. Further longitudinal and prospective studies are necessary to confirm these preliminary data.

Serum Ferritin and Liver Iron Concentration in Patients with Iron Overload.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3833-3833
Author(s):  
Zahra Pakbaz ◽  
Roland Fischer ◽  
Ellen Fung ◽  
Peter Nielsen ◽  
Rainer Engelhardt ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Chelation Therapy ◽  
Iron Concentration ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Transfusion Therapy ◽  
Poor Predictor ◽  
The Individual ◽  
The Relationship

Abstract Despite its limitations, serum ferritin (SF) is commonly used to monitor chelation therapy in primary and secondary hemochromatosis. To better predict liver iron concentration (LIC), we prospectively investigated the relationship between SF and LIC in a total of 421 patients with primary (HFE-1 associated, n=241) or secondary hemochromatosis (n=180), consisting of chronically transfused thalassemia (Tx-Thal: n=89) or sickle cell disease patients (Tx-SCD: n=45) and transfusion independent thalassemia patients (nTx-Thal: n=26). In all patients, LIC was measured by SQUID biosusceptometry. SF correlated with LIC (RS = 0.51–0.83, p &lt; 0.001) but was a poor predictor for LIC. SF was significantly lower (p &lt; 0.001) in nTx-Thal and HFE-1 patients despite similar LIC (421 – 5524 μg/g-liver) and it was higher in Tx-SCD compared to Tx-Thal (p = 0.03). In order to improve the value of SF, we calculated the SF/LIC ratio for each group. SF/LIC remained stable over time in patients whose therapy did not change. In iron loaded patients without blood transfusion therapy (nTx-Thal and HFE-1), the median SF/LIC ratio was significant lower (0.32 and 0.43) as compared to transfused patients (Tx-Thal: 0.87, HCV-Thal: 0.99, Tx-SCD: 1.2), probably, indicating differences in the secretion of ferritin into plasma. We conclude that SF alone can mislead the iron unloading therapy as it underestimates LIC in nTx-Thal patients and overestimates LIC in Tx-SCD patients. Once the initial LIC value is obtained and the individual SF/LIC ratio is determined in a patient, the ratio together with SF may be more useful than SF alone to monitor iron overload and predict LIC.

SF3B1 Mutation Is an Independent Predictor of Parenchymal Iron Overload in Myelodysplastic Syndromes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1678-1678 ◽  
Author(s):  
Ilaria Ambaglio ◽  
Valeria Pinto ◽  
Domenico Girelli ◽  
Chiara Elena ◽  
Natascia Campostrini ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Loading ◽  
Wild Type ◽  
Liver Iron ◽  
Ring Sideroblasts ◽  
Cardiac Iron Overload ◽  
Liver Iron Overload ◽  
Multivariable Regression ◽  
The Relationship ◽  
Rbc Transfusion

Abstract Somatic mutations of RNA splicing machinery were identified in myelodysplastic syndromes (MDS), and a strong association was found between SF3B1 mutation and disease phenotype with ring sideroblasts. Recent studies showed that this mutation identifies a distinct group of MDS with ring sideroblasts, characterized by isolated erythroid dysplasia with a high degree of expanded but ineffective erythropoiesis, resulting in inappropriately low hepcidin levels. In this work we analyzed the relationship between SF3B1 mutation, body iron status, hepcidin level and liver and cardiac iron overload detected with MRI T2* in patients with MDS. We studied 34 patients with MDS diagnosed according to WHO criteria 2008 at the Department of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy and at Ospedale Galliera, Genova, Italy (8 patients with RA or RCMD, 20 with RARS or RCMD-RS, 6 with RAEB-1 or -2). Serum hepcidin-25 measurements were performed by a validated Mass Spectrometry based method (SELDI-TOF MS). SF3B1 mutations were analyzed on DNA from circulating granulocytes on an Illumina HiSeq. Magnetic Resonance Imaging (MRI) examinations were performed with a validated scanner using a gradient echo T2* technique. Somatic mutations of SF3B1 were detected in 19 of 34 patients, with a median variant allele frequency of 0.40 (range 0.12-0.54). Ten of 19 SF3B1-mutated and 10 of 15 SF3B1 wild-type patients (67%) were RBC transfusion-dependent (median number of RBC transfusions 32, range 7-490). Variable hepcidin levels were found in the patients studied (median value 13.24 nM, range 3.25-75.56, versus 29.19 nM, range 3.26-66.15, in SF3B1-mutated and SF3B1 wild-type patients, respectively). We calculated the hepcidin to ferritin ratio, as a measure of adequacy of hepcidin levels relative to body iron stores, which was inversely related to the SF3B1 mutation (median value 0.015 nmol/mcg, range 0.004-0.035, versus 0.035, range 0.002-0.17, in SF3B1-mutated and SF3B1 wild-type patients, respectively, P=.04). In a multivariable regression model adjusted for RBC transfusion requirement, the hepcidin to ferritin ratio was independently associated with SF3B1 mutation (P=.042), indicating a blunted hepcidin response to iron overload in SF3B1-mutated patients. We then investigated the relationship between SF3B1 mutation status and parenchymal iron overload estimated by liver and cardiac MRI. Median hepatic T2* in the study population was 7 ms, ranging from 1.49 to 30.08. Focusing the analysis on patients with RBC transfusion-dependency, a higher prevalence of hepatic iron overload (defined as MRI T2* values less than 6.3 ms) was observed in SF3B1-mutated compared with SF3B1 wild-type patients (9/10 versus 5/10 respectively). In a multivariable regression analysis adjusted for RBC transfusion history, SF3B1 mutation was an independent predictor of hepatic T2* value (P=.038). When the analysis was limited to patients without RBC transfusion need, two SF3B1-mutated patients showed a liver iron overload, associated with mild increased in AST and ALT values. Cardiac iron overload defined as MRI T2* values less than 10 ms was detected in two out of 10 patients receiving more than 50 RBC units, both of them carrying SF3B1 mutation. In conclusion, our study shows that MDS patients carrying a somatic mutation of SF3B1 have inappropriately low hepcidin levels, resulting in parenchymal iron loading due to excessive iron absorption and reticuloendothelial release. These results suggest that SF3B1 mutation may be associated with liver iron overload even in untransfused patients, as observed in congenital iron loading anemias. These results may be relevant for decision-making concerning treatment of transfusion iron overload in MDS patients. Disclosures No relevant conflicts of interest to declare.

Comparison of 3 Tfr2-deficient murine models suggests distinct functions for Tfr2-α and Tfr2-β isoforms in different tissues

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3382-3389 ◽  
Author(s):  
Antonella Roetto ◽  
Ferdinando Di Cunto ◽  
Rosa Maria Pellegrino ◽  
Emilio Hirsch ◽  
Ornella Azzolino ◽  
...  
Keyword(s):  
Iron Overload ◽  
Transcriptional Control ◽  
Iron Homeostasis ◽  
Transmembrane Protein ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Liver Iron ◽  
Liver Iron Overload ◽  
Diferric Transferrin ◽  
Main Regulator

Abstract Transferrin receptor 2 (TFR2) is a transmembrane protein that is mutated in hemochromatosis type 3. The TFR2 gene is transcribed in 2 main isoforms: the full-length (α) and a shorter form (β). α-Tfr2 is the sensor of diferric transferrin, implicated in the modulation of hepcidin, the main regulator of iron homeostasis. The function of the putative β-Tfr2 protein is unknown. We have developed a new mouse model (KI) lacking β-Tfr2 compared with Tfr2 knockout mice (KO). Adult Tfr2 KO mice show liver iron overload and inadequate hepcidin levels relative to body iron stores, even though they increase Bmp6 production. KI mice have normal transferrin saturation, liver iron concentration, hepcidin and Bmp6 levels but show a transient anemia at young age and severe spleen iron accumulation in adult animals. Fpn1 is strikingly decreased in the spleen of these animals. These findings and the expression of β-Tfr2 in wild-type mice spleen suggest a role for β-Tfr2 in Fpn1 transcriptional control. Selective inactivation of liver α-Tfr2 in KI mice (LCKO-KI) returned the phenotype to liver iron overload. Our results strengthen the function of hepatic α-Tfr2 in hepcidin activation, suggest a role for extrahepatic Tfr2 and indicate that β-Tfr2 may specifically control spleen iron efflux.

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