The Role of Labile Plasmatic Iron (LPI) In the Assessment of Iron Overload In β-Thalassemic Patients and Its Correlation with MRI Findings

Abstract Abstract 2072 Introduction: The labile plasmatic iron (LPI) represents part of non-transferrin-bound iron (NTBI) capable of entering the tissues and causing oxidative injury. It might be related to certain types of brain damage, especially in those with ischemia, cognitive defects in Alzheimer's disease, endothelial dysfunction in thalassemic children, complications in myelodysplastic syndrome (MDS), in particular infection and tissue injury, and to the increase in mortality rates in transfused and diabetic patients. LPI determination has been used by several authors as a means to monitor the efficacy of different protocols of iron chelation in thalassemic and MDS patients. Efficacy studies of vitamin C and E antioxidant activity, which blocks iron-induced oxidative damage, have also used this methodology. LPI has been suggested as an alternative method to assess iron load. Objective: Establish a correlation between LPI and serum ferritin levels and tissue iron estimated by magnetic resonance imaging (MRI) T2*/R2* in the heart, pancreas and liver. Methods: Data from 83 patients with thalassemia major were analyzed. LPI was measured using a fluorescent method and values <0.5μM were considered normal. Serum ferritin was measured by chemiluminescence and MRI was performed with a General Electric 1.5 T device. Cardiac, pancreatic and liver iron were determined by T2*/R2* methodology, and liver T2* was used to calculate the liver iron concentration (LIC). The statistical analysis was performed using ANOVA. Results: Eighty three patients were studied, of which 44.6% were males and 55.4% females. The median number of red blood cell packs used per year was 29.3±7.4. The mean LPI was 1.04±2.39μM (range 0.001 – 11.45). The mean LIC and serum ferritin were 8.96±3.35 mg/g dry liver weight (1.31-18.34) and 2,928.19 ± 2,398.4 ng/ml (101-12,958), respectively. Cardiac T2* values varied from 3.4 to 59.52ms, of which 33.7% (28) showed cardiac iron overload (T2*<20ms). Pancreatic R2*values varied from 19.8–500 Hz. Considering abnormal pancreatic R2*values >43Hz, 86.3% (69) were classified as pancreatic siderosis. After ANOVA analysis, we found a strong correlation between LPI and LIC (p<0.0007). Conclusion: A strong correlation was found between LPI and liver iron concentration. It is still premature to use this correlation as a predictor of iron overload. However, it might be useful as a complementary method to monitor chelation therapy and does not preclude the MRI studies to assess tissue iron in clinical practice. Disclosures: No relevant conflicts of interest to declare.

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Longitudinal Follow-up From Newborn Screening Reveals Deletional Hemoglobin H Disease and Hemoglobin H Constant Spring Disease Are Distinct Thalassemia Syndromes

Blood ◽

10.1182/blood.v116.21.4260.4260 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4260-4260

Author(s):

Ashutosh Lal ◽

Michael Lee Goldrich ◽

Drucilla Foote ◽

Mahin Azimi ◽

Sylvia Titi Singer ◽

...

Keyword(s):

Iron Overload ◽

Newborn Screening ◽

Serum Ferritin ◽

Iron Concentration ◽

Growth Failure ◽

Liver Iron Concentration ◽

Liver Iron ◽

The Mean ◽

Hemoglobin H Disease

Abstract Abstract 4260 Background: Alpha thalassemia disorders are rapidly increasing in North America. This has resulted in proposals for universal newborn screening (NBS) for hemoglobin H disease. However, the institution of routine newborn screening and construction of guidelines for early intervention requires longitudinal clinical data before setting national goals. Since 1995, California has performed universal screening for alpha thalassemia disorders. The longitudinal follow up of data from patients with hemoglobin H disorders diagnosed in the asymptomatic period provides essential information needed for formulating public health policy. Methods: Hemoglobin H disorders were diagnosed by high performance liquid chromatography with multiplex GAP-PCR assay to determine deletional hemoglobin H disease (deletion of 3 α globin genes, HbH) and the non-deletional hemoglobin H Constant Spring (α0 thalassemia with Constant Spring mutation, HCS). Longitudinal clinical data for all patients from the Northern California Thalassemia Center were analyzed. Ethnicity, growth data, clinic visits, hospitalizations, complications including splenectomy, transfusion, and iron overload were monitored. Quantitative liver iron concentration was determined by ferritometer. Results: 86 patients predominantly diagnosed through NBS were longitudinally followed. Out of these, 60 (70%) had HbH, 23 (27%) had HCS and 3 (3%) had other forms of hemoglobin H disease. The parental ethnicity in HbH was 79% Asian, 6% Hispanic, and 15% African-American (in one or both parents). All patients with HCS were of Asian ethnicity. Longitudinal data for hemoglobin revealed that anemia was more severe in HCS at all ages (p<0.001). Mean hemoglobin in HbH increased from 8.8 g/dL (6.9-10.6 g/dL) at 6 months to 9.4 g/dL (7.9-11.5 g/dL) at 5 years (p<0.001). However, mean hemoglobin in HCS remained unchanged from 7.4 g/dL (5.8-9.9 g/dL) at 6 months to 7.2 g/dL (3.8-8.7 g/dL) at 5 years (p=ns). There was no hemoglobin value <6.7 g/dL in 237 patient-years of observation of 60 patients with HbH. Compared to HbH, red blood cells in HCS had higher mean corpuscular hemoglobin (18.6 versus 16.6 pg, p<0.001) and mean corpuscular volume (65.2 versus 54.0 fL, p<0.001). The mean absolute reticulocyte count was 88.2 ×103/μL in HbH versus 235.1 ×103/μL in HCS (p<0.001), while the mean serum bilirubin was 0.56 mg/dL and 2.60 mg/dL, respectively (p<0.001). Clinical severity and complications were markedly worse in HCS in contrast with HbH. Growth was delayed in HCS with mean weight-for-age Z-score -0.91 compared with -0.06 in HbH (p<0.001). The mean height-for-age Z-score was also lower in HCS (-1.29) compared with HbH (-0.43, p<0.001). The striking susceptibility to acute worsening of anemia with infections requiring urgent blood transfusion was observed in HCS, but not in HbH. The probability of receiving one or more blood transfusion by 20 years was 3% in HbH and 82% in HCS (p<0.001). Transfusions in HCS were required for 13% infants and median transfusion-free survival was 6 years. Splenectomy improved hemoglobin by 2.9 g/dL (0.4 to 4.0 g/dL, p=0.012) and reduced transfusions in HCS. Iron overload, measured by serum ferritin and liver iron concentration, developed during the first decade in HCS and increased during follow up. Median ferritin in HCS between 12 –17 years was 330 ng/mL (66-1420 ng/mL). Serum ferritin in HbH did not increase between 0–18 years (median 40 ng/mL, range 5–182 ng/mL), but older patients showed strong positive correlation between age and ferritin (p<0.001). In patients with HbH or HCS undergoing ferritometer examination, the degree of serum ferritin elevation underestimated the liver iron concentration. Conclusions: Our data support the utility of a universal NBS program, particularly in areas where αCS mutation is prevalent, since young infants with HCS can develop life-threatening anemia. HCS is a serious disease that needs close follow-up by a specialty thalassemia center to plan for emergency and elective transfusions, measure iron overload, monitor growth failure and evaluate the need for splenectomy. In contrast, HbH is asymptomatic during infancy and childhood; its complications are age-dependent, and monitoring for hemosiderosis and growth failure is more important in older children. In summary, HCS should be recognized as a thalassemia syndrome distinct from HbH with a different screening and treatment approach. Disclosures: No relevant conflicts of interest to declare.

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Comparing the Value of Serum Ferritin, Transfusion History and Magnetic Resonance Imaging for the Prediction of Iron Overload In MDS and AML Patients Undergoing Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.3493.3493 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3493-3493

Author(s):

Martin Wermke ◽

Jan Moritz Middeke ◽

Nona Shayegi ◽

Verena Plodeck ◽

Michael Laniado ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Content ◽

Iron Concentration ◽

Transferrin Saturation ◽

Resonance Imaging ◽

Liver Iron Concentration ◽

Liver Iron ◽

Liver Iron Content ◽

Transfusion History

Abstract Abstract 3493 An increased risk for GvHD, infections and liver toxicity after transplant has been attributed to iron overload (defined by serum ferritin) of MDS and AML patients prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the reason for this observation is not very well defined. Consequently, there is a debate whether to use iron chelators in these patients prior to allo-HSCT. In fact, serum ferritin levels and transfusion history are commonly used to guide iron depletion strategies. Both parameters may inadequately reflect body iron stores in MDS and AML patients prior to allo-HSCT. Recently, quantitative magnetic resonance imaging (MRI) was introduced as a tool for direct measurement of liver iron. We therefore aimed at evaluating the accurateness of different strategies for determining iron overload in MDS and AML patients prior to allo-HSCT. Serologic parameters of iron overload (ferritin, iron, transferrin, transferrin saturation, soluble transferrin receptor) and transfusion history were obtained prospectively in MDS or AML patients prior to allo-SCT. In parallel, liver iron content was measured by MRI according to the method described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006), respectively. A total of 20 AML and 9 MDS patients (median age 59 years, range: 23–74 years) undergoing allo-HSCT have been evaluated so far. The median ferritin concentration was 2237 μg/l (range 572–6594 μg/l) and patients had received a median of 20 transfusions (range 6–127) before transplantation. Serum ferritin was not significantly correlated with transfusion burden (t = 0.207, p = 0.119) but as expected with the concentration of C-reactive protein (t = 0.385, p = 0.003). Median liver iron concentration measured by MRI was 150 μmol/g (range 40–300 μmol/g, normal: < 36 μmol/g). A weak but significant correlation was found between liver iron concentration and ferritin (t = 0.354; p = 0.008). The strength of the correlation was diminished by the influence of 5 outliers with high ferritin concentrations but rather low liver iron content (Figure 1). The same applied to transfusion history which was also only weakly associated with liver iron content (t = 0.365; p = 0.007). Levels of transferrin, transferrin saturation, total iron and soluble transferrin receptor did not predict for liver iron concentration. Our data suggest that serum ferritin or transfusion history cannot be regarded as robust surrogates for the actual iron overload in MDS or AML patients. Therefore we advocate caution when using one of these parameters as the only trigger for chelation therapy or as a risk-factor to predict outcome after allo-HSCT. Figure 1. Correlation of Liver iron content with Ferritin. Figure 1. Correlation of Liver iron content with Ferritin. Disclosures: No relevant conflicts of interest to declare.

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Myocardial and Hepatic Iron Overload and Cardiac Function In Sickle/Thalassemia Patients Of Italian Origin

Blood ◽

10.1182/blood.v122.21.2252.2252 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2252-2252

Author(s):

Antonella Meloni ◽

Giovan Battista Ruffo ◽

Daniele De Marchi ◽

Antonio Cardinale ◽

Anna Pietrapertosa ◽

...

Keyword(s):

Cardiac Function ◽

Iron Overload ◽

Conflicts Of Interest ◽

Iron Concentration ◽

Hepatic Iron ◽

Liver Iron ◽

Hepatic Iron Overload ◽

The Mean ◽

Magnetic Resonance Imaging Mri ◽

Italian Origin

Abstract Introduction Sickle-thalassemia results from the combined heterozygosity for sickle-cell and β-thalassemia genes. This study evaluates myocardial and hepatic iron overload and cardiac function in Italian patients and explores their correlation with transfusions, age and sex. Methods Fifty-nine sickle-thalassemia patients (29 males, mean age 35.6±14.1 years), enrolled in the MIOT network underwent magnetic resonance imaging (MRI). T2* value for all 16 myocardial segments and global heart T2* value were calculated. Hepatic T2* value was converted into liver iron concentration (LIC). Cine images were acquired to quantify biventricular volumes and ejection fraction (EF). Results 55 (93%) patients had all segmental T2* values normal (>20 ms). Of the 4 patients with abnormal segmental T2* values, all showed an heterogeneous myocardial iron overload (some segments with T2*>20 ms and other with T2*<20 ms) and only one had a global T2*<20 ms. The mean global heart T2* value was 34.4±6.2 ms. The mean LIC was 5.9±6.5 mg/g/dw and 30 patients (50.8%) had a pathological value (≥ 3 mg/g dw). There was a statistically significant positive correlation between global heart T2* and age but with poor linearity (R=0.368; P=0.004) and there was not a significant correlation between age and LIC. Males and females had comparable global heart T2* values and LIC values. Twenty patients were regularly transfused, 32 received sporadic transfusions while 7 were not transfused. The comparison among the three groups is shown in Table 1. We did not find significant differences in the global heart T2* value while patients regularly transfused had significantly higher LIC than sporadically transfused patients. Biventricular volumes indexed by body surface area and ejection fractions were comparable among the groups. Conclusions In respect of MIO, the sickle/thalassemia patients are similar to patients with homozygous SCD for which iron overloading is relatively rare. Hepatic iron overload may develop also in no regularly-transfused patients, maybe due to increased absorption of iron from the digestive tract, characteristic of both SCD and thalassemia intermedia patients. This finding underlines the importance to monitor by MRI also no regularly transfused sickle/thalassemia patients. Disclosures: No relevant conflicts of interest to declare.

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The Effect of Chronic Viral Hepatitis on Serum Ferritin Level in Thalassemia Patients

Blood ◽

10.1182/blood-2019-125010 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4819-4819

Author(s):

Natthapat Rujeerapaiboon ◽

Adisak Tantiworawit ◽

Pokpong Piriyakhuntorn ◽

Thanawat Rattanathammethee ◽

Sasinee Hantrakool ◽

...

Keyword(s):

Viral Load ◽

Iron Overload ◽

Viral Hepatitis ◽

Serum Ferritin ◽

Serum Ferritin Level ◽

Conflicts Of Interest ◽

Ferritin Level ◽

Iron Concentration ◽

Chronic Viral Hepatitis ◽

The Mean

Background: Serum ferritin is widely used as a marker of iron overload in thalassemia patients. However, the ferritin level is affected by active infections or inflammation. The association between viral hepatitis and serum ferritin level in thalassemia patients is still unclear. This study aimed to determine the effect of chronic viral hepatitis on serum ferritin level in thalassemia patients. Methods: This was a cross-sectional study in thalassemia patients aged ≥15 years-old at Chiang Mai University hospital. We expected that thalassemic patients in our clinic have a mean serum ferritin of 767 ng/mL with a standard deviation of 210 ng/mL. As a result, we have to enroll a total of 28 patients to demonstrate 30% difference of mean serum ferritin when the power was set at 80% with alpha level of 0.05. Information on chronic viral hepatitis, mean serum ferritin and liver iron concentration (LIC) as measured by T2* MRI were collected. Chronic viral hepatitis status was confirmed by either HBV DNA or HCV RNA testing. Patients were categorized to hepatitis and non-hepatitis group. Serum ferritin levels were compared between two groups. LIC measurement was used as a gold standard for iron overload. Subgroup analysis was performed according to iron overload and transfusion requirement status. Categorical and continuous variables were compared using the Chi-squared test and T-test, respectively. The correlation between viral loads and mean serum ferritin levels was analyzed by Pearson's correlation. Result: Of 32 thalassemia patients (25 non-transfusion dependent [NTDT] and 7 transfusion dependents [TDT]), 13 patients had chronic viral hepatitis (7 with hepatitis B and 6 with hepatitis C infections). The LIC between hepatitis and non-hepatitis groups were not significantly different (7.28 [SD 4.7] vs 9.08 [SD 5.2] mg Fe/g, p=0.19). In the higher LIC group (≥ 5 mg Fe/g), the mean serum ferritin level was higher in the hepatitis group than non-hepatitis group (1,776 [SD 488] vs 967 [SD 860] ng/mL, p=0.03). For the lower LIC group (<5 mg Fe/g), the mean ferritin levels were not significantly different between the hepatitis and non-hepatitis groups (646 [SD 224] vs 459 [SD 205] ng/mL, p=0.22). The correlation between the viral load and mean ferritin level in NTDT group showed a significant linear correlation with R=0.7 (p=0.04). Conclusions: We observe a higher serum ferritin level among thalassemia patients who concurrently have chronic viral hepatitis. Chronic viral hepatitis is a possible cause of a falsely high ferritin level in these patient population. Furthermore, the viral load is positively correlated with serum ferritin level. Disclosures No relevant conflicts of interest to declare.

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Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

Case Reports in Oncology ◽

10.1159/000507756 ◽

2020 ◽

Vol 13 (2) ◽

pp. 712-715

Author(s):

Mustafa A. Al-Tikrity ◽

Mohamed A. Yassin

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Ferritin Level ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Hfe Gene ◽

Liver Iron Concentration ◽

C282y Mutation ◽

Liver Iron ◽

T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

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Serum Ferritin a Predictor of Iron Overload in Patients with Thalassemia and Sickle Cell Disease?.

Blood ◽

10.1182/blood.v104.11.3789.3789 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3789-3789 ◽

Cited By ~ 1

Author(s):

Zahra Pakbaz ◽

Roland Fischer ◽

Richard Gamino ◽

Ellen B. Fung ◽

Paul Harmatz ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Iron Concentration ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron ◽

Iron Stores ◽

Significant Difference

Abstract Introduction: Monitoring iron overload by serum ferritin in patients with hemosiderosis is still a routine practice although its limitations are widely studied and well known. Using non-invasive liver iron assessment by quantitative MRI or by biomagnetic liver susceptometry (BLS) with SQUID biomagnetometers would be the better alternative, however, these methods are available at only a few centers worldwide. Objective: To determine the relationship between serum ferritin (SF) and liver iron concentration (LIC), measured by BLS at CHRCO, in patients with different types of hemosiderosis. Methods and Patients: A total of 97 patients with thalassemia (TM: 3 to 52 y, 54% females) and 39 patients with sickle cell disease (SCD: 5 to 49 y, 60% female) were prospectively assessed for LIC and SF. Both tests were performed within 2 weeks of each other. Most patients with TM and SCD were chronically transfused, while 10 b-thalassemia intermedia (TI), 5 HbE/β-thalassemia (HbE), and 5 SCD patients were not on transfusion programs. LIC was measured by LTc SQUID biosusceptometer system (Ferritometer®, Model 5700, Tristan Technologies, San Diego, USA) under the standardized Hamburg-Torino-Oakland protocol. A non-parametric test (U-test) was utilized to analyze differences between SF and LIC data. Results: In chronically transfused TM and SCD patients, the median SF and LIC were very similar (Table I). In TI&HbE patients, ferritin results were disproportionately low with respect to LIC. In order to improve prediction of iron stores by SF, the SF/LIC ratio was calculated. There was a significant difference between the median ratios of the two groups of transfused and non- transfused thalassemia patients, 0.82 vs. 0.32 [μg/l]/[μg/gliver], respectively (p < 0.01). In SCD patients the ratio is significantly (p < 0.01) higher. Conclusion: Present data confirm ferritin to be a poor predictor of liver iron stores both in sickle cell disease and thalassemia. Relying only on ferritin to monitor iron overload in patients with hemosiderosis can be misleading, especially, in sickle cell disease and non-transfused thalassemia patients. Taking into account disease specific ferritin-LIC relations, could improve the prediction of iron stores. However, assessment of liver iron stores is the ultimate method to initiate and adjust chelation treatment in order to avoid progressive organ injury. Table I. Median values and ranges ( − ) of serum ferritin (SF) and liver iron concentration (LIC) in transfused (Tx) and non-transfused (non-Tx) hemosiderosis patients. Patient group n SF μg/l] LIC [mg/gliver ] SF:LIC Thalassemia Tx 82 1721 (209–8867) 3424 (364–7570) 0.82 (0.3–1.8) TI &HbE non-Tx 15 766 (52–2681) 2174 (226–5498) 0.32 (0.1–1.4) SCD Tx 34 2757 (400–9138) 1941 (518–6670) 1.2 (0.6–3.3)

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Liver Iron Concentration Measurements Using MRI R2 in MDS Patients in a Deferasirox (Exjade®, ICL670) Phase II Study.

Blood ◽

10.1182/blood.v108.11.4846.4846 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4846-4846 ◽

Cited By ~ 1

Author(s):

Peter L. Greenberg ◽

Charles A. Schiffer ◽

Charles Asa Koller ◽

Barinder Kang ◽

Jodie Decker ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Serum Iron ◽

Iron Concentration ◽

Transferrin Saturation ◽

Ongoing Study ◽

Liver Iron Concentration ◽

Liver Iron ◽

Calculated Creatinine Clearance ◽

L 14

Abstract Introduction: Approximately 60% of patients with myelodysplastic syndromes (MDS) require ongoing red blood cell transfusions, which can lead to significant iron overload and associated morbidities. Historically, many of these patients have not received iron chelation therapy due to burdensome administration of deferoxamine. Deferasirox (Exjade®, ICL670) is a once-daily, oral iron chelator recently approved for the treatment of chronic iron overload due to blood transfusions. This ongoing study is designed to evaluate the efficacy and safety of deferasirox in Low/Int-1-risk MDS patients. In addition, this is the first prospective, multicenter trial to evaluate liver iron concentration (LIC) using the MRI R2 parameter in this population. Methods: This ongoing study will enroll 30 patients at three US centers. Deferasirox will be administered at 20–30 mg/kg/day for 12 months. Iron burden is being monitored by monthly serum ferritin evaluations, and LIC by MRI R2 at baseline, 6 and 12 months. Serum iron, transferrin, transferrin saturation, labile plasma iron (LPI), and urinary hepcidin are being assessed throughout the study. In addition, serum creatinine, calculated creatinine clearance, echocardiograms and hematological status are being monitored. In this report, we are presenting the baseline data for the currently enrolled patients. Results: As of May 2006, 14 patients (9 male, 5 female; aged 55–81 years) were enrolled. All patients were Caucasian with equal distribution of Low- and Int-1-risk MDS. The mean interval from MDS diagnosis to screening was 4 years, ranging from <1 to 12 years. The table summarizes baseline iron parameters in these patients: Parameter n Mean ± SD Median Range Normal range n/a, not applicable LIC, mg Fe/g dw 14 21.8 ± 11.0 23.5 3.8–40.5 <1.3 Serum ferritin,μg/L 14 4645 ± 3804 3534.5 1433–15380 20–360 Serum iron, μg/dL 14 205.9 ± 26.5 200 165.9–252.0 50–160 Transferrin, mg/dL 14 143 ± 19 142.5 106–172 200–400 Transferrin saturation, % 14 113.8 ± 8.5 114 95–124 15–50 LPI, μmol/L 14 0.7 ± 0.7 0.6 0–1.9 0 Num. of lifetime transfusions 14 106.3 ± 115.5 47.5 30–352 n/a Renal function: Calculated creatinine clearance at baseline was normal (>80 mL/min) in 46% of patients, mildly impaired (50–80 mL/min) in 46% and moderately impaired (30–50 mL/min) in 8% of patients. Hematological parameters: neutropenia (<1800/μL): 1 patient; thrombocytopenia (<100,000/μL): 3 patients; neutropenia and thrombocytopenia: 1 patient. Concurrent therapies: Revlimid: 2 patients; and hydroxyurea: 1 patient. Conclusions: Baseline iron burden in these patients demonstrates a high degree of iron overload, as measured by LIC via MRI, as well as serum ferritin, serum iron and transferrin saturation. Based on NCCN guidelines for the management of iron overload, the degree of iron overload observed meets criteria for treatment. This ongoing study is assessing the safety and efficacy of deferasirox in this population.

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Correlation of Serum Ferritin Levels and Liver Iron Concentration Determined by R2* MRI in Patients with Thalassemia Intermedia.

Blood ◽

10.1182/blood.v110.11.3818.3818 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3818-3818

Author(s):

Ali Taher ◽

F. El Rassi ◽

H. Ismaeel ◽

S. Koussa ◽

A. Inati

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Care Center ◽

Iron Concentration ◽

Iron Chelation ◽

Thalassemia Intermedia ◽

Liver Iron Concentration ◽

Liver Iron ◽

Cross Sectional ◽

Transfusion Therapy

Abstract Background: Unlike patients with thalassemia major (TM), those with thalassemia intermedia (TI) do not require regular blood transfusion therapy but remain susceptible to iron overload due to increased intestinal iron uptake triggered by ineffective erythropoiesis. TI patients can accumulate 1–3.5 g of excess iron per year, and effective monitoring of iron burden is an important element of patient management. Assessment of serum ferritin (SF) levels is a convenient and widely used method, and a correlation between SF and liver iron concentration (LIC) has been demonstrated in patients with TM. SF levels may, however, be a poor indicator of LIC in patients with TI and the limited data available on the SF:LIC correlation prove equivocal; in fact, reports suggest a discrepancy between LIC and SF in patients with TI. This is the largest study to use R2* MRI to evaluate the SF:LIC correlation in patients with TI. Methods: This was a cross-sectional study of randomly selected, infrequently/non-transfused TI patients treated at a chronic care center in Hazmieh, Lebanon. Patient charts were reviewed and a medical history was compiled. Blood samples were taken for SF assessment, and LIC was determined by R2* MRI. Results: Data from 74 TI patients were included in this analysis (33 male, 41 female; mean age 26.5 ± 11.5 years). Of this group, 59 (79.7%) patients were splenectomized, 20 were transfusion-naive, 45 had received several transfusions in their lifetime but none in the past year, and 9 patients were regularly transfused 2–4 times per year. Overall mean SF values were 1023 ± 780 ng/mL (range 15–4140); mean LIC levels were 9.0 ± 7.4 mg Fe/g dry weight [dw] (range 0.5–32.1). In contrast to previous findings, a significant positive correlation between mean LIC and SF values was seen in the whole group (R=0.64; P<0.001), and in a subset of splenectomized patients (R=0.62; P<0.001). In comparison with data obtained from a randomly selected group of patients with TM treated at the center, SF levels in TI were seen to be significantly lower, while the mean LIC values were similar in both groups of TI and TM. For a given LIC, SF values were lower in patients with TI than those with TM (Figure). Conclusions: Evaluation of iron levels shows that many patients with TI have SF and LIC levels above the recommended threshold levels, indicating a risk of significant morbidity/mortality. Similar to TM, a significant correlation between SF and LIC was observed in patients with TI; however, the relationship between SF and LIC was different between TI and TM (for the same LIC, the SF values in TI were lower than those in TM). Therefore, use of the current threshold for iron overload based on SF values in TM will lead to significant underestimation of the severity of iron overload in patients with TI. This may result in delayed chelation therapy, and expose patients to morbidity and mortality risks associated with iron overload. Disease-specific management approaches are therefore required in patients with TI. This includes either regular assessments of LIC, ideally by non-invasive R2* MRI, or lowering the SF threshold for initiating iron chelation in patients with TI. Figure Figure

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Liver Iron Concentration By MRI In Chronically Transfused Children With Sickle Cell Anemia In The Twitch Trial

Blood ◽

10.1182/blood.v122.21.780.780 ◽

2013 ◽

Vol 122 (21) ◽

pp. 780-780

Author(s):

John C. Wood ◽

Zora R. Rogers ◽

Isaac Odame ◽

Janet Kwiatkowski ◽

Margaret Lee ◽

...

Keyword(s):

Iron Overload ◽

Research Funding ◽

Iron Concentration ◽

Altman Analysis ◽

Liver Iron Concentration ◽

Limits Of Agreement ◽

Advisory Committees ◽

Liver Iron ◽

Markers Of Inflammation ◽

Tissue Iron

Abstract Introduction Chronic transfusion therapy represents the standard of care for sickle cell anemia (SCA) patients with abnormal transcranial Doppler (TCD) ultrasound or prior stroke. While effective, monthly transfusions produce iron overload and toxicity if not controlled with chelation therapies. Liver iron concentration (LIC) is a powerful surrogate for total body iron stores. Unfortunately, liver biopsy is not suited for longitudinal analysis because it is invasive, expensive, and prone to sampling variability. MRI transverse relaxation rates, R2 and R2*, are highly correlated with LIC and have mostly supplanted liver biopsy for iron quantification in clinical practice and clinical trials. Since R2 and R2* have different sensitivity to the size and scale of tissue iron distribution, we compared the agreement of LIC values predicted by R2 and R2* in children with SCA and transfusional iron overload from the prospective multicenter TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial (ClinicalTrials.gov; NCT01425307). Methods 133 patients underwent LIC assessment using both R2 and R2* techniques at 22 MRI sites. All sites used 1.5 Tesla magnets and torso phased array coils. Images for R2 measurements were collected on validated scanners and analyzed centrally according to the FerriScan” protocol (Resonance Health, Western Australia, see St Pierre, T.G., et al. Blood,105, 855-861, 2005). Images for R2* assessment were collected using multiple-echo gradient echo sequences (see Wood, J.C., et al. Blood,106, 1460-1465, 2005). Images were analyzed centrally at Children's Hospital Los Angeles, using an exponential-plus-constant fit to the signal decay. Bland-Altman analysis on log-transformed LIC values was used to test agreement between LICR2 and LICR2*; the residuals of this relationship were probed for association with transfusion/chelation history, markers of inflammation, and markers of hemolysis. Results Figure 1A illustrates the scattergram between LICR2* and LICR2. The variance of the disagreement between the two techniques increases with LIC, so log-transformation was performed prior to Bland Altman analysis. LICR2* was systematically higher than LICR2 below about 5 mg Fe/g dw and systematically lower above 5 mg Fe/g dw. Bland Altman comparison of the log-transformed data (Figure 1B) reveals a downward trend (r2 of 0.203, p<0.0001). After correcting for the trend, 95% limits of agreement were -0.42 to 0.42, translating to 95% limits of agreement of the ratio of the two LIC measurements of 0.66 to 1.52. After controlling for mean log LIC, differences in log LIC values were not associated with transfusion or chelation history, markers of inflammation, or markers of hemolysis. Discussion Systematic bias is present between LICR2 and LICR2* in a cohort of children with SCA and transfusional iron overload. Even after correcting these differences, LICR2 and LICR2* also demonstrate significant intrasubject variability, comparable to the error both techniques displayed with respect to biopsy, precluding use of these metrics interchangeably. This implies that LICR2 and LICR2* have potentially clinically significant deviations from true LIC. Rather than sampling or MRI measurement errors, which are consistently < 10% in multiple studies, these disparities likely reflect calibration bias introduced by intersubject differences in tissue iron distribution. Longitudinal LIC determination should lessen their impact, however, and the changes in LIC predicted by R2 and R2* will be compared using one and two year data from the TWiTCH trial. Disclosures: Wood: Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Kwiatkowski:Shire: Consultancy; Resonance Health: Research Funding. St. Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood.v128.22.4824.4824 ◽

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.

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