Hyperferritinemia and liver iron content determined with MRI: Reintroduction of the liver iron index.

BACKGROUND: Hyperferritinemia is found in around 12 % of the general population. Analyzing the cause can be difficult. In case of doubt about the presence of major iron overload most guidelines advice to perform a MRI as a reliable non-invasive marker to measure liver iron concentration (LIC). In general, a LIC of ≥ 36 µmol/g dw is considered the be elevated however in hyperferritinemia associated with, for example, obesity or alcohol (over)consumption the LIC can be ≥ 36 µmol/g dw in abscence of major iron overload. So, unfortunately a clear cut-off value to differentiate iron overload from normal iron content is lacking. Previously the liver iron index (LII) (LIC measured in liver biopsy (LIC-b)/age (years)), was introduced to differentiate between patients with major (LII ≥ 2) and minor or no iron overload (LII < 2). Based on the good correlation between the LIC-b and LIC determined with MRI (LIC-MRI), our goal was to investigate whether a LII_MRI ≥ 2 is a good indicator of major iron overload, reflected by a significantly higher amount of iron needed to be mobilized to reach iron depletion. METHODS: We compared the amount of mobilized iron to reach depletion and inflammation-related characteristics in two groups: LII-MRI ≥ 2 versus LII-MRI <2 in 92 hyperferritinemia patients who underwent HFE genotyping and MRI-LIC determination. RESULTS: Significantly more iron needed to be mobilized to reach iron depletion in the LII ≥ 2 group (mean 4741, SD ± 4135 mg) versus the LII-MRI <2 group (mean 1340, SD ± 533 mg), P < 0.001. Furthermore, hyperferritinemia in LII-MRI < 2 patients was more often related to components of the metabolic syndrome while hyperferritinemia in LII-MRI ≥ 2 patients was more often related to HFE mutations. ROC curve analysis showed good performance of LII =2 as cut-off value. However the calculations showed that the optimal cut-off for the LII = 3.4. CONCLUSION: The LII-MRI with a cut-off value of 2 is an effective method to differentiate major from minor iron overload in patients with hyperferritinemia. But the LII-MRI = 3.4 seems a more promising diagnostic test for major iron overload.

Patients with hereditary hemochromatosis reach safe range of transferrin saturation sooner with erythrocytaphereses than with phlebotomies.

INTRODUCTION: For the maintenance treatment of patients with hereditary hemochromatosis (HH), it is advised to keep the transferrin saturation (TSAT) <70% to prevent formation of non-transferrin-bound iron and labile plasma iron. The period of the initial iron depletion may last up to 1 year or longer and during this period, the patient is exposed to elevated TSAT levels. Therapeutic erythrocytapheresis (TE) is a modality which has proven to reduce treatment duration of patients with iron overload from HH. In this study, we investigated the time to reach TSAT <70% for both treatment modalities. METHODS: From a previous randomized controlled trial comparing erythrocytaphereses with phlebotomies (PBMs), we performed an analysis in a subgroup of patients who presented with TSAT >70%. Mann-Whitney U tests were performed to compare the number of treatments and the number of weeks to reach the interim goal of a persistent level of <70% for TSAT between TE and PBM. RESULTS: The period to reach TSAT levels of <70% was statistically significant shorter for the TE group compared to the PBM treatment group (median treatment procedures [IQR] 2.0 (5) vs 16.0 (23), P-value: <.001, and median treatment duration [IQR]: 5.5 (11) vs 19.0 (29) weeks, P-value: .007). CONCLUSION: Patients with HH reach a safe TSAT <70% significantly sooner and with less treatment procedures with TE compared to PBM.

Using the World Apheresis Association Registry Helps to Improve the Treatment Quality of Therapeutic Apheresis.

Therapeutic apheresis (TA) is prescribed to patients that suffer from a severe progressive disease that is not sufficiently treated by conventional medications. A way to gain more knowledge about this treatment is usually by the local analysis of data. However, the use of large quality assessment registries enables analyses of even rare findings. Here, we report some of the recent data from the World Apheresis Association (WAA) registry. Data from >104,000 procedures were documented, and TA was performed on >15,000 patients. The main indication for TA was the collection of autologous stem cells (45% of patients) as part of therapy for therapy. Collection of stem cells from donors for allogeneic transplantation was performed in 11% of patients. Patients with indications such as neurological diseases underwent plasma exchange (28%). Extracorporeal photochemotherapy, lipid apheresis, and antibody removal were other indications. Side effects recorded in the registry have decreased significantly over the years, with approximately only 10/10,000 procedures being interrupted for medical reasons. CONCLUSION: Collection of data from TA procedures within a multinational and multicenter concept facilitates the improvement of treatment by enabling the analysis of and feedback on indications, procedures, effects, and side effects.

A predictive model for estimating the number of erythrocytapheresis or phlebotomy treatments for patients with naïve hereditary hemochromatosis.

BACKGROUND AND AIMS: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient. METHODS: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 µg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately. RESULTS: The linear regression model with the best predictive quality (R2  = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.

How we manage patients with hereditary haemochromatosis.

A number of disorders cause iron overload: some are of genetic origin, such as hereditary haemochromatosis, while others are acquired, for instance due to repeated transfusions. This article reviews the treatment options for hereditary haemochromatosis, with special attention to the use of erythrocytapheresis. In general, therapy is based on the removal of excess body iron, for which ferritin levels are used to monitor the effectiveness of treatment. For many decades phlebotomy has been widely accepted as the standard treatment. Recent publications suggest that erythrocytapheresis, as a more individualized treatment, can provide a good balance between effectiveness, tolerability and costs. Other treatments like oral chelators and proton pomp inhibitors, which are used in selected patients, create the possibility to further individualize treatment of hereditary haemochromatosis. In the future, hepcidin-targeted therapy could provide a more fundamental approach to treatment.

Course of iron parameters in HFE-hemochromatosis patients during initial treatment with erythrocytapheresis compared to phlebotomy.

Current treatment for newly diagnosed patients with hereditary hemochromatosis (HH) and iron overload consist of weekly phlebotomy or less frequent and more personalized erythrocytapheresis. Previous observations during phlebotomy suggest an increase in intestinal iron uptake caused by lowering of hepcidin as a result of intensive bloodletting. It is not known whether such an effect is present or even more pronounced using erythrocytapheresis since a larger amount of iron is extracted per procedure. In this study we aimed to assess the effect of erythrocytapheresis on the course of iron parameters, with special focus on serum hepcidin. We performed a retrospective proof-of-principle observational study, comparing serum iron parameters in 12 males during the depletion phase using either phlebotomy (n = 6) or erythrocytapheresis (n = 6). Decreases in serum ferritin over time were similar for both treatments but more pronounced using erythrocytapheresis when expressed per treatment procedure. Hemoglobin did not change during erythrocytapheresis, whereas during phlebotomy decreased with 10%. Increase of erythropoietin and soluble transferrin receptor and decrease in transferrin saturation were similar for both treatments. Reduction in serum hepcidin was higher (50% versus 25% of initial value) and occurred more early using phlebotomy (10 versus 20 weeks after start). In aggregate, compared to phlebotomy, the less frequent and more personalized erythrocytapheresis leads to a more pronounced decrease in serum ferritin per treatment procedure, without a larger decrease in serum hepcidin. This may be clinically relevant and may prevent an increase in intestinal iron uptake and an ensuing vicious circle of more frequent treatment procedures. J. Clin. Apheresis 31:564-570, 2016. © 2015 Wiley Periodicals, Inc.

Erythrocytapheresis versus phlebotomy in the maintenance treatment of HFE hemochromatosis patients: results from a randomized crossover trial.

BACKGROUND: Phlebotomy is standard maintenance treatment of patients with hereditary hemochromatosis (HH). Erythrocytapheresis, which selectively removes red blood cells, provides a new, potentially more effective treatment option. Our aim was to evaluate the effectiveness of erythrocytapheresis over phlebotomy for maintenance therapy in patients with HH. STUDY DESIGN AND METHODS: We conducted a two-treatment-arms, randomized, crossover clinical trial, involving 46 patients, treated for 1 year with either erythrocytapheresis or phlebotomy to keep the ferritin level at not more than 50 µg/L. After 1 year, patients were switched to the other treatment modality. Primary endpoint was the number of treatment procedures per treatment year. Secondary endpoints were intertreatment intervals, several aspects of health-related quality of life, costs, and patient discomfort as well as preference for one of both treatments. RESULTS: The mean number of required treatment procedures per treatment year was significantly higher using phlebotomy versus erythrocytapheresis (3.3 vs. 1.9; mean difference, 1.4; 95% confidence interval, 1.1-1.7). The median intertreatment time was 2.3 times longer for erythrocytapheresis. There was no significant difference in overall health assessed by SF-36 and EQ-5D, respectively, between both treatments arms. The number of self-reported swollen joints was significantly higher during phlebotomy treatment. The mean treatment costs of one treatment year were 235€ for phlebotomy versus 511€ for erythrocytapheresis. Eighty percent of patients preferred erythrocytapheresis as treatment method. CONCLUSION: Erythrocytapheresis significantly reduced the number of treatment procedures per treatment year, although the mean treatment costs per year are higher in our health care system. It is the preferred treatment for the majority of patients.

[Erythrocytapheresis for hereditary haemochromatosis]. / Erytrocytaferese voor hereditaire hemochromatose.

With a prevalence of 0.4%, hereditary haemochromatosis is the most common autosomal-recessive genetic disease in Northern Europe. Hereditary haemochromatosis is characterized by an increase in the absorption of iron. This consequently leads to the excessive deposition of iron in tissues and organs with resultant functional impairment. Early-stage treatment can prevent complications resulting from the accumulation of iron. The standard treatment for hereditary haemochromatosis is phlebotomy, whereby 500 ml of whole blood is removed once a week until serum ferritin levels of 50-100 µg/l are achieved. After this, the patient must undergo lifelong maintenance treatment consisting of 3-6 phlebotomies per year on average. An alternative treatment is erythrocytapheresis, the selective removal of erythrocytes by way of apheresis. This procedure makes it is possible to collect more erythrocytes than during phlebotomy, resulting in significantly fewer treatment sessions being needed for the initial removal of overabundant iron.

Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial.

BACKGROUND: Standard treatment of newly diagnosed HFE hemochromatosis patients is phlebotomy. Erythrocytapheresis provides a new therapeutic modality that can remove up to three times more red blood cells per single procedure and could thus have a clinical and economic benefit. STUDY DESIGN AND METHODS: To compare the number of treatment procedures between erythrocytapheresis and phlebotomy needed to reach the serum ferritin (SF) target level of 50 µg/L, a two-treatment-arms, randomized trial was conducted in which 38 newly diagnosed patients homozygous for C282Y were randomly assigned in a 1:1 ratio to undergo either erythrocytapheresis or phlebotomy. A 50% decrease in the number of treatment procedures for erythrocytapheresis compared to phlebotomy was chosen as the relevant difference to detect. RESULTS: Univariate analysis showed a significantly lower mean number of treatment procedures in the erythrocytapheresis group (9 vs. 27; ratio, 0.33; 95% confidence interval [CI], 0.25-0.45; Mann-Whitney p < 0.001). After adjustments for the two important influential factors initial SF level and body weight, the reduction ratio was still significant (0.43; 95% CI, 0.35-0.52; p < 0.001). Cost analysis showed no significant difference in treatment costs between both procedures. The costs resulting from productivity loss were significantly lower for the erythrocytapheresis group. CONCLUSION: Erythrocytapheresis is highly effective treatment to reduce iron overload and from a societal perspective might potentially also be a cost-saving therapy.

Red cell concentrates of hemochromatosis patients comply with the storage guidelines for transfusion purposes.

BACKGROUND: Therapeutic phlebotomy is the preferred treatment for iron overload associated with hemochromatosis. In the Netherlands, red blood cell concentrates (RCCs) from hemochromatosis patients are not used for transfusion purposes. In this study, their storage performance was compared with that of control donors as a first step in the evaluation of their potential usefulness for transfusion. STUDY DESIGN AND METHODS: RCCs were obtained from hemochromatosis patients and regular donors, either by apheresis or by whole-blood collection, and stored up to 50 days under routine Dutch blood bank conditions. Weekly samples were taken for determination of hematologic, biophysical, and biochemical variables. RESULTS: Most variables displayed the same storage-related changes in RCCs originating from hemochromatosis patients as in those from regular donors. In all RCCs, hemolysis remained well below the guideline limit of 0.8 percent for up to 6 weeks of storage, and the glucose concentration remained above the required 5 mmol per L up to 5 weeks of storage. After 4 weeks of storage, the mean ATP level remained above the required limit of 75 percent of the starting value in all RCCs as well. The major difference was a larger mean cell volume in hereditary hemochromatosis RBCs up to 50 days of storage. CONCLUSIONS: RCCs from hemochromatosis patients comply with the in vitro quality requirements for transfusion. This paves the way for the final step, namely, the establishment of the 24-hour RBC posttransfusion recovery.

Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of hereditary hemochromatosis - A pilot study.

Hereditary Hemochromatosis (HH) is a genetic disorder of iron metabolism, resulting in excessive iron overload. Currently, phlebotomy is the standard effective treatment that prevents progression of tissue damage. Aim of the therapy is to reach ferritin levels between 20 and 50mugl(-1). In patients with total iron stores of more than 30g, intensive treatment by means of weekly phlebotomies during 2-3 years is required to reach this aim. More recently mechanical removal of erythrocytes through therapeutic erythrocytapheresis (TE) has become a new therapeutic modality. By means of TE, up to 1000ml erythrocytes per session can be removed, depending on patient characteristics, compared to 250ml erythrocytes per phlebotomy. Thus, TE potentially offers a more efficient method of removing iron overload with less procedures in a shorter treatment period. In a pilot study between 2002 and 2005, results from a group of HH patients treated with TE (N=6) were compared to the results of a historical control group of HH patients (N=6) treated with phlebotomy. The results showed a reduction of almost 70% in both the total number and the duration of treatments in the TE group. Although, the procedure costs compared on the basis of a single TE session were higher, the total costs for the whole treatment were comparable or cheaper with the use of TE. Future prospective studies are needed to compare both therapies in a randomized setting.

Decreased responsiveness and development of activation markers of PLTs stored in plasma.

BACKGROUND: Circulating PLTs have a low activation state and high responsiveness, which ensures adequate hemostatic activity at sites of vessel wall damage. PLTs collected for transfusion purposes preferably have retained these properties to restore impaired hemostasis with thrombocytopenia. STUDY DESIGN AND METHODS: We determined activation properties and coagulant activity of PLT-plasma preparations that were pooled or collected from single donors via apheresis. RESULTS: In comparison to freshly isolated PLTs, both apheresis and pooled PLTs exhibited slow exposure of CD62 upon storage, followed by surface appearance of procoagulant phosphatidylserine (PS) but not activated integrin alpha IIb beta 3. During storage, thrombin- and ADP-induced Ca2+ signal generation consistently decreased in apheresis and pooled PLTs, which was accompanied by lower agonist-induced CD62 exposure and alpha IIb beta 3 activation. In flowing whole blood, stored apheresis PLTs showed lower collagen-induced Ca2+ responses and strikingly diminished participation in thrombus formation. Both apheresis and pooled PLT-plasma concentrates exhibited high tissue factor-triggered thrombin generation, which was insensitive to PLT inhibition and attributable to PS-exposing microparticles. CONCLUSION: PLTs stored in plasma develop surface activation markers but, simultaneously, show markedly decreased responsiveness toward physiologic agonists. The plasma contains high coagulant activity, which is no longer PLT (activation)-dependent.