Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients

Serum ferritin (SF) and liver iron concentration (LIC), as measured by SQUID biosusceptometry, were assessed in a convenience sample of transfusion independent thalassemia patients (nTx-Thal, n=26), regularly transfused thalassemia (Tx-Thal, n=89), or sickle cell patients (SCD, n=45) to investigate the severity of iron overload and the relationship between SF and LIC in nTx-Thal compared to SCD and Tx-Thal. SF correlated with LIC (RS=0.53, P<0.001), but was found to be a poor predictor for LIC. SF was significantly lower (P<0.001) in nTx-Thal patients than in other groups, despite similar LIC values. The SF-to-LIC ratio was significantly lower in nTx-Thal compared to Tx-Thal and SCD patients (median of 0.32, 0.87, and 1.2, respectively: P<0.001). Due to underestimation of LIC by ferritin levels, chelation treatment may be delayed or misdirected in patients with thalassemia intermedia.     

MRI T2*技术对中、重型β地中海贫血患者心脏及肝脏铁沉积状态的评估

目的：了解中、重型β地中海贫血患者体内铁沉积状况。方法：对39例中、重型β地中海贫血患者的输血、排铁的情况进行统计,检测患者体内铁蛋白水平,并运用MRI T2*技术检测心脏及肝脏铁沉积状况。结果：患者血清铁蛋白水平最低为1500 ng/mL,最高达 11491 ng/mL。肝脏铁重度沉积者15例（38%）,中度沉积者15例（38%）,轻度沉积者7例（18%）,正常者 2例（5%）。 心脏铁重度沉积者7例（18%）,轻度沉积者5例（13%）,正常者27例（69%）。1例出现心律紊乱症状,4例年龄超过20岁者均呈现性腺功能发育不全。大多患者因家庭经济原因未能进行规律输血及排铁治疗,且开始排铁时间较晚。患者血清铁蛋白水平与开始排铁的时间、剂量密切相关。结论：未进行早期规律的输血和排铁治疗的地中海贫血患者,体内铁的沉积发生年龄早,易早期出现重要器官的功能损害而引发相关并发症,应引起临床医师和患者家属的高度重视并制定相应的诊疗措施提高患者的生活质量。     

Serum ferritin,liver iron stores,and liver histology in children with thalassaemia.

Serum ferritin, liver iron stores, and liver histology were studied in 38 children with thalassaemia major who were being treated by regular blood transfusions. There was no correlation between serum ferritin levels and either the number of transfusions or the amount of iron deposited in the liver. However, for a given level of iron stores, ferritin levels were higher in patients with chronic hepatitis (including chronic aggressive and chronic persistent forms) than in those with hepatic siderosis only. We conclude that serum ferritin reflects tissue iron deposits in regularly transfused thalassaemic patients, only in the absence of hepatitis.     

Efficacy of hepatic T2* MRI values and serum ferritin concentration in predicting thalassemia major classification for hematopoietic stem cell transplantation

Liver biopsy has been performed for many decades for classifying the patients with TM. Meanwhile, using non‐invasive methods such as T2* MRI technique has been recently much more considered to determine the hepatic iron overload. Ninety‐three pediatric HSCT candidates with TM who underwent liver biopsy were included in this study. Hepatic T2* MRI values and serum ferritin concentrations were assessed to investigate and determine the useful method in detection of patients with TM class III whom received different conditioning regimens, in comparison with class I and II. Twenty (21.5%) patients were categorized as class III. Hepatic T2* MRI could detect TM class III patients with 60% sensitivity and 87.67% specificity (LR+: 4.867, accuracy: 81.72%), while predictive feature of ferritin values for distinguishing patients with TM class III was not statistically significant (p‐value >0.01). Combination of T2*MRI with age (T2*‐age) could detect TM class III with 85% sensitivity and 72.6% specificity (LR+: 3.1, accuracy: 75.27%).T2*‐age may be considered as an alternative and non‐invasive method to liver biopsy for differentiation and classification of patients with TM before transplantation.     

Correlation of serum ferritin levels with hepatic MRI T2 and liver iron concentration in nontransfusion beta-thalassemia intermediate patients: A contemporary issue

Background: Beta-thalassemia intermediate is a genetic disease that is milder than beta-thalassemia major. The T2^* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI of liver and measurement of liver iron concentration for early detection of hepatic iron overload in Beta-thalassemia intermediate patients. Methods: This cross-sectional study was conducted on 108 patients with Beta-thalassemia intermediate who referred to tertiary hospital, Shiraz, Iran. Serum ferritin, hepatic T2 MRI, and liver iron concentration were assessed. Receiver operator characteristic was used to determine the sensitivity and specificity of cut-off value. Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r = ?0.290, p value =.003) and positive correlation with liver iron concentration (r = 0.426, p value <.001) in the patients with Beta-thalassemia intermediate. According to the receiver operator characteristic, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/mL. Calculated sensitivities and specificities were 0.78 and 0.82 for T2 MRI and 0.76 and 0.86 for liver iron concentration, respectively. Conclusion: Serum ferritin levels of around 450 ng/mL might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin could be considered for starting iron chelation therapy in patients with Beta-thalassemia intermediate in areas where T2 MRI is not available.     

重型β地中海贫血肝铁负荷与铁蛋白和影像学检查的临床研究

目的探讨重型β地中海贫血肝铁负荷与血清铁蛋白和股骨头红骨髓影像学面积的相关性,旨在寻求一个无创和便于动态评估机体铁负荷的方法,为正确指导去铁治疗和造血干细胞移植寻求新途径。方法对1999—2005年的65例长期在中山大学附二医院输血治疗并追踪观察的重型β地中海贫血患儿病例进行回顾性分析。比较65例重型β地中海贫血患儿肝纤维化程度、含铁血黄素沉积分级在年龄、性别上的差异,以及与股骨头近端红骨髓影像学面积和铁蛋白间的相关性。结果中国广东地区重型β地中海贫血患儿铁蛋白随肝纤维化程度递增,各纤维化程度在年龄和性别上差异无显著性。股骨头红骨髓影像学面积与肝纤维化程度相关系数为0.70,P<0.05。结论广东地区重型β地中海贫血发展为肝纤维化的平均年限为6.7年;股骨头红骨髓影像学面积可作为动态、准确和无创评估铁负荷的新方法。     

Comparison of whole liver and small region-of-interest measurements of MRI liver R2* in children with iron overload

Background  

Measurement of liver MRI T2* and R2* is emerging as a reliable alternative to liver biopsy for the quantitation of liver iron content. A systematic investigation of the influence of the region-of-interest size and placement has not been conducted.     

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??To study the status of myocardial T2* and liver T2* in β- thalassemia major??β-TM?? patients with iron overload and its relationship with clinical test data. Methods??In June 2010??on a voluntary basis??out of the 80 β-TM patients over 7 years under regular blood transfusion therapy??51 were chosen to receive myocardial MRI T2* ??myocardial T2*?? and liver MRI T2* ??liver T2*?? tests. The results were compared with age??SF??LVEF??transfusion time??chelation time and Hb. Results??Eleven out of 51 cases ??21.6%?? were myocardial iron overload??including 3 mild cases??3 moderate cases and 5 severe cases. Forty-three out of 51 cases ??84.3%?? were liver iron overload??including 14 mild cases??17 moderate cases and 12 severe cases. There was no correlation between myocardial T2* and SF??LVEF or liver T2*. SF was positively correlated with liver T2*??r = 0.558??P < 0.01??. The transfusion time of myocardial T2* > 20 ms group was less than that of myocardial T2* < 20 ms group ??P < 0.05??. There was no statistical significance between the liver iron overload incidence ratios of the two groups ??P > 0.05?? . Two out of 11 myocardial iron overload cases had lower LVEF??18.2%??. Conclusion??The group of TM patients demonstrates lower myocardial iron overload incidence and higher liver iron overload incidence. As SF increases??liver iron overload becomes more severe??myocardial iron overload can not be predicted or determined by examining SF level. There is no correlation between myocardial iron overload and liver iron overload. LVEF can not be a reliable factor to predict myocardial iron overload.     

Nitric oxide affects serum ferritin levels in children with iron deficiency

In iron deficiency, serum levels of ferritin decrease. The lack of iron has been thought to be the main factor in this decrease, but another potential factor is nitric oxide, which has been shown to affect ferritin metabolism in vitro. The aim of this study was therefore to evaluate in children with iron deficiency the relation of serum ferritin, nitric oxide degradation products (nitrate and nitrite), and endothelin-1, a protein closely related to nitric oxide function. A total of 80 children were included in the study (39 with iron deficiency, 41 controls). Serum levels of ferritin, nitrate, nitrite, and endothelin-1 were measured in all participants. In children with iron deficiency, nitrate and nitrite levels were significantly higher (p < .009 and .01, respectively). Also, serum ferritin was negatively correlated with serum levels of nitrate and nitrite (p = .034, r = -.254 for nitrate and p = .01, r = -.593 for nitrite). No statistical relationship was found between serum ferritin and endothelin-1.     

血清铁蛋白在缺铁性贫血并感染中的诊断价值

目的 研究血清铁蛋白(SF)在并感染的缺铁性贫血(IDA)患儿中的诊断价值。方法 采用酶联免疫吸附试验,检测60例感染性疾病IDA患儿SF,其中38例骨髓铁染色显示铁缺乏患儿为A组[Hb(62.9±21.3)g／L],22例未做骨穿检查患儿为B组[Hb(83.3±16.4)g／L];同时检测20例患同类感染性疾病Hb正常患儿为对照组。结果 对照组SF为(170±150)μg／L,A组和B组分别为(40±32)μg／L、(53±37)μg/L,A、B组均明显低于对照组(P均<0.01)。在有骨髓铁染色作为金标准A组中,若分别以SF<14μg／L、<60μg／L、<100μg／L作为诊断界点,诊断缺铁敏感度分别为15.8％、73.7％、92.1％,约登指数分别为0.26、0.52、0.57,以SF<100μg／L为诊断界值准确性最好;在B组中若以同样几个界点作为判断缺铁标准,其敏感度分别为18.2％、63.6％、95.5％,约登指数为0.18、0.43、0.61,与A组相似。结论 在并感染性疾病的贫血患儿中,建议可将SF<100μg／L作为判断IDA的依据。     

Noninvasive measurement of liver iron concentration at MRI in children with acute leukemia: initial results

Background  

Routine assessment of body iron load in patients with acute leukemia is usually done by serum ferritin (SF) assay; however, its sensitivity is impaired by different conditions including inflammation and malignancy.     

Quantification of liver iron overload by T2 quantitative magnetic resonance imaging in thalassemia: impact of chronic hepatitis C on measurements

PURPOSE: Measurement of liver T2 values seems to be an accurate and sensitive magnetic resonance imaging (MRI) method for the quantification of liver hemosiderosis in multiple transfused patients with thalassemia. Because many of these patients have coexistent chronic hepatitis C virus (HCV) infection, the effect of inflammatory changes on liver T2 values was assessed. MATERIALS AND METHODS: Liver MRI studies of 35 HCV+ and 17 HCV- patients with beta-thalassemia, 9 HCV+ patients without thalassemia, and 10 healthy controls of the same age range (13 to 32 years) were reviewed. Iron status was assessed by serum ferritin in all patients, and determination of liver iron concentration (LIC) was available in 16 HCV+ patients with thalassemia. Histologic activity index (HAI) and grades of siderosis were evaluated in all HCV+ patients with thalassemia. RESULTS: Patients with thalassemia had significantly lower T2 values (P < 0.0001) than subjects without thalassemia, whereas no difference existed between HCV+ patients without thalassemia and healthy controls. In HCV+ patients, LIC correlated more nearly with T2 values (r = 0.93) than with serum ferritin (r = 0.73). T2 values were not influenced by HAI score or fibrosis. CONCLUSION: Liver T2 values were found to be more accurate than serum ferritin in predicting liver iron overload and were not influenced by the presence of chronic hepatitis C. Therefore, MRI could serve as a noninvasive alternative to liver biopsy for the quantification of hemosiderosis in HCV+ patients with thalassemia.     

Quantitative MRI for hepatic fat fraction and T2* measurement in pediatric patients with non-alcoholic fatty liver disease

Background

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. The gold standard for diagnosis is liver biopsy. MRI is a non-invasive imaging method to provide quantitative measurement of hepatic fat content. The methodology is particularly appealing for the pediatric population because of its rapidity and radiation-free imaging techniques.

Objective

To develop a multi-point Dixon MRI method with multi-interference models (multi-fat-peak modeling and bi-exponential T2* correction) for accurate hepatic fat fraction (FF) and T2* measurements in pediatric patients with NAFLD.

Materials and methods

A phantom study was first performed to validate the accuracy of the MRI fat fraction measurement by comparing it with the chemical fat composition of the ex-vivo pork liver-fat homogenate. The most accurate model determined from the phantom study was used for fat fraction and T2* measurements in 52 children and young adults referred from the pediatric hepatology clinic with suspected or identified NAFLD. Separate T2* values of water (T2*_W) and fat (T2*_F) components derived from the bi-exponential fitting were evaluated and plotted as a function of fat fraction. In ten patients undergoing liver biopsy, we compared histological analysis of liver fat fraction with MRI fat fraction.

Results

In the phantom study the 6-point Dixon with 5-fat-peak, bi-exponential T2* modeling demonstrated the best precision and accuracy in fat fraction measurements compared with other methods. This model was further calibrated with chemical fat fraction and applied in patients, where similar patterns were observed as in the phantom study that conventional 2-point and 3-point Dixon methods underestimated fat fraction compared to the calibrated 6-point 5-fat-peak bi-exponential model (P?W (27.9?±?3.5 ms) decreased, whereas T2*_F (20.3?±?5.5 ms) increased; and T2*_W and T2*_F became increasingly more similar when fat fraction was higher than 15–20%. Histological fat fraction measurements in ten patients were highly correlated with calibrated MRI fat fraction measurements (Pearson correlation coefficient r?=?0.90 with P?=?0.0004).

Conclusion

Liver MRI using multi-point Dixon with multi-fat-peak and bi-exponential T2* modeling provided accurate fat quantification in children and young adults with non-alcoholic fatty liver disease and may be used to screen at-risk or affected individuals and to monitor disease progress noninvasively.     

MRI as an alternative to serum ferritin for diagnosis of iron overload in children in the context of immune response after stem cell transplantation

Multiple blood cell transfusions may cause iron overload or even liver fibrosis, requiring early diagnosis and intervention. SF is the standard for estimating iron levels in the body, but it also increases with inflammation. We hypothesized that T₂* magnetic resonance (MR) relaxometry is a more accurate alternative for follow‐up in pediatric patients before and after allogenic SCT. Twenty‐three children (mean age 10.2 years, 10 female, 13 male) were evaluated prospectively before SCT as well as at least 1 year after SCT with T₂* relaxometry on a 1.5 T MR‐scanner to estimate liver iron concentrations from the T₂* values (“MR‐Fe”). The results were compared with SF, while also considering CRP, and correlated with the number of transfusions. Overall, 24.3 transfusions were administered in average, mainly within 100 days of SCT (mean 10.5 units). Both MR‐Fe and SF increased after SCT and decreased in the absence of new transfusions 1 year later without chelate therapy. This suggests regeneration of LP and iron loss, although the original states were not reached. Additionally, simultaneous peaks of CRP and SF were observed directly after SCT. MR‐Fe did neither reveal these peaks nor was it associated with CRP (P = .39). We postulate that these early CRP and SF peaks after SCT are probably related to inflammatory reactions and not to iron overload. Thus, SF is not reliable for iron overload diagnosis after SCT in every condition. Beside this interaction, SF and MR‐Fe revealed similar accuracy. MRI, however, has practical and economical disadvantages in routine estimation of iron.     

Red blood cell distribution width is not a reliable biomarker for low iron stores in children with cystic fibrosis

Low iron stores in children, absolute iron deficiency (AID), can lead to impaired neurodevelopment and requires iron therapy. In the presence of infection/inflammation, like in cystic fibrosis (CF), serum ferritin (SF) is not a reliable biomarker for AID. Red blood cell distribution width (RDW) is a promising alternative reported not to be influenced by infection in healthy children. Currently, there are no data on the diagnostic capacity of RDW to detect AID in pediatric CF patients. This was a prospective observational study that investigated iron status biomarkers in 53 Dutch pediatric CF patients. AID was defined using World Health Organization criteria for SF in stable patients (no recent pulmonary exacerbation) and C-reactive protein (CRP) ≤10 mg/l. Patients with AID had higher RDW levels than patients without AID (p = 0.019). An RDW ≥13.2% showed the following test statistics: sensitivity 100%; specificity 39.4%; positive predictive value 20%; and negative predictive value 100%. Furthermore, we found a correlation between RDW and CRP in the total group that originated from the stable patients (r = 0.308; p = 0.042). In conclusion, the diagnostic capacity of RDW for detecting AID in pediatric CF patients seems limited because RDW levels might also be influenced by chronic infection/inflammation in these patients.     

Effect of iron saturation on the bacteriostasis of human serum: in vivo does not correlate with in vitro saturation

Human serum inhibits the growth of a variety of human pathogens. One of the serum bacteriostatic components is transferrin, the major iron-binding protein. In the presence of transferrin, free iron, which is required for bacterial nucleoprotein synthesis, is unavailable and bacterial growth is inhibited. In an in vitro system, we tested the hypothesis that serum with highly saturated transferrin allows free iron to be available for rapid bacterial growth. We first confirmed the finding that addition of ionic iron sufficient to saturate transferrin in normal sera inhibits the bacteriostatic activity for Escherichia coli. In contrast, no differences were found in the growth rate of E. coli in sera from individuals representing the entire range of transferrin saturation found in humans (iron-deficient, normal, and thalassemic). This finding supports the thesis that iron added in vitro is more easily extracted than in vivo, where it is tightly bound to transferrin, and does not support the contention that ordinary iron treatment predisposes infants to infection.     

Red cell exchange does not appear to increase the rate of allo- and auto-immunization in chronically transfused children with sickle cell disease

Background

Allo‐ and auto‐antibody development is a well recognized complication of chronic red cell transfusion (RCT) in sickle cell disease (SCD). Limited matching of Rh (C, c, D, E, e) and K red cell antigens reduces the incidence of immunization.

Procedure

We reviewed our experience with red cell allo‐ and auto‐immunization in pediatric SCD patients receiving chronic and/or exchange transfusions, to evaluate the rate of immunization after limited red cell antigen matching and specifically during red cell exchange (RCE) transfusion. A retrospective chart review of the patients with SCD followed at our center between 2002 and 2006, who were started on chronic RCT before or during that time period, was conducted.

Results

Of the 93 patients who met study criteria, 23 (24%) developed antibodies during chronic red cell transfusions. Thirty‐four antibodies (15 auto‐antibodies, 18 allo‐antibodies) developed after the institution of limited red cell antigen matching. The rate of allo‐ and auto‐immunization per unit of red cell exposure after limited phenotyping was 1.5%, comparable to other published data. Fifteen patients underwent RCE, utilizing a total of 2,289 packed red cell units. None developed antibodies during RCE.

Conclusion

We conclude that limited red cell antigen matching is an effective strategy for reducing the incidence of allo‐ and auto‐immunization in chronically transfused children with SCD. RCE does not appear to increase the risk of allo‐ or auto‐immunization, despite exposure to more red cell units. Pediatr Blood Cancer 2011; 57: 294–296. © 2011 Wiley‐Liss, Inc.     

Liver transplantation from a deceased donor with β‐thalassemia intermedia is not contraindicated: A case report

The use of extended criteria donors who might have previously been deemed unsuitable is an option to increase the organ supply for transplantation. This report presents a pediatric case of a successful liver transplantation from a donor with β‐thalassemia intermedia. A patient, 6‐year‐old female, with a diagnosis of cryptogenic liver cirrhosis underwent deceased donor liver transplantation from a thalassemic donor. Extreme hyperferritinemia was detected shortly after transplantation. The most probable cause of hyperferritinemia was iron overload secondary to transplantation of a hemosiderotic liver. Hepatocellular injury due to acute graft rejection might have contributed to elevated ferritin levels by causing release of stored iron from the hemosiderotic liver graft. Iron chelation and phlebotomy therapies were started simultaneously in the early postoperative period to avoid iron‐related organ toxicity and transplant failure. Follow‐up with monthly phlebotomies after discharge yielded a favorable outcome with normal transplant functions. Thalassemia intermedia patients can be candidates of liver donors to decrease pretransplant waitlist mortality. After transplantation of a hemosiderotic liver, it is important to monitor the recipient in terms of iron overload and toxicity. Early attempts to lower iron burden including chelation therapy and/or phlebotomy should be considered to avoid organ toxicity and transplant failure.