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.

Acute heart failure and iron deficiency: a prospective, multicentre, observational study.

AIMS: The prevalence and the natural course of iron deficiency (ID) in acute heart failure (AHF) are still unclear. We investigated the prevalence of ID in unselected patients admitted with AHF on admission, at discharge and up to 3 months thereafter. METHODS AND RESULTS: In this prospective, multicentre, observational study, 742 patients admitted with AHF were enrolled. The main study outcome was the percentage of patients with ID (ferritin <100 µg/L = absolute ID or ferritin 100-299 µg/L and transferrin saturation <20% = functional ID) at admission (T0), after clinical stabilization prior to discharge (T1), and 10 ± 6 weeks after discharge (T2). At T0, ID was present in 71.8% of the patients (44.1% absolute and 27.7% functional ID). At T1 and T2, ID was present in 56.4% (32.4% absolute and 24% functional ID) and 50.3% (36.8% absolute and 13.5% functional ID), respectively. Absolute ID persisted from T0 to T2 in 66% of the patients, while functional ID resolved in 56% of the patients. Ferritin (median [interquartile range] 124 µg/L [56-247] to 150 µg/L [73-277]), transferrin saturation (15% [10-20] to 18% [12-27]), and iron levels (9 µmol/L [6-13] to 11 µmol/L [8-16]) increased significantly (all P < 0.001) from T0 to T1. Transferrin saturation (to 21% [15-29]) and iron levels (to 13 µmol/L [9-17]) also increased significantly (both P < 0.01) from T1 to T2 without iron supplementation. CONCLUSIONS: Iron deficiency is highly prevalent in patients with AHF, but resolves during treatment in some patients, even without iron supplementation. Absolute ID is more likely to persist over time, whereas functional ID often resolves during treatment of AHF, representing probably a reduced iron availability rather than a true deficiency.

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.

Safety of low-volume PEG-asc bowel cleansing preparation for colonoscopy: identifying patients at risk for hypokalemia in a prospective cohort study.

Background and study aims The aim of bowel cleansing preparation should be high-quality results and conformance with safety standards. Previously, we reported that hypokalemia occurred in 23.6 % of patients after bowel preparation in a high-risk population on diuretics or hospitalized and referred for colonoscopy. Here we report on a prospective study in a non-selected colonoscopy cohort to identify patients at risk of developing hypokalemia before and after bowel cleansing with low-volume polyethylene glycol with ascorbic acid (PEG-asc). Patients and methods From January 1 to July 31, 2016, we included all patients undergoing colonoscopy in our institution. Prevalences of hypokalemia before and after PEG-asc bowel cleansing for colonoscopy were calculated and risk factors for developing hypokalemia after PEG-asc bowel cleansing were identified. Results In total, 2011 patients were included in the analysis. Of these, 0.8 % had hypokalemia before bowel cleansing with PEG-asc. After bowel preparation, 5.4 % developed hypokalemia. Of the patients, 281 were considered to have "high cardiac risk." The combination of "high cardiac risk" and hypokalemia was present in 1 % of the initial colonoscopy population. Female sex, colorectal cancer diagnosis, and thiazide use were found to be significant predictors for hypokalemia after use of PEG-asc. No arrhythmias or serious adverse events due to hypokalemia occurred. Conclusions Physicians referring patients for colonoscopy should be aware that "high cardiac risk" patients and those on thiazide diuretics undergoing bowel cleansing for colonoscopy are a risk of developing post-cleansing hypokalemia but it remains to be determined whether their risk of developing life-threatening arrhythmias is truly increased.

Inflammation can increase hepcidin in HFE-hereditary hemochromatosis.

We present a p.C282Y homozygous patient with high hepcidin levels and normal iron parameters during systemic inflammation. This suggests that in the absence of a proper functioning HFE, resulting in blockage of the BMP/SMAD pathway, the innate low hepcidin concentration can be upregulated by inflammation, probably via the JAK/STAT3 pathway.

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.

Severe Ankyrin-R deficiency results in impaired surface retention and lysosomal degradation of RhAG in human erythroblasts.

Ankyrin-R provides a key link between band 3 and the spectrin cytoskeleton that helps to maintain the highly specialized erythrocyte biconcave shape. Ankyrin deficiency results in fragile spherocytic erythrocytes with reduced band 3 and protein 4.2 expression. We use in vitro differentiation of erythroblasts transduced with shRNAs targeting ANK1 to generate erythroblasts and reticulocytes with a novel ankyrin-R 'near null' human phenotype with less than 5% of normal ankyrin expression. Using this model, we demonstrate that absence of ankyrin negatively impacts the reticulocyte expression of a variety of proteins, including band 3, glycophorin A, spectrin, adducin and, more strikingly, protein 4.2, CD44, CD47 and Rh/RhAG. Loss of band 3, which fails to form tetrameric complexes in the absence of ankyrin, alongside GPA, occurs due to reduced retention within the reticulocyte membrane during erythroblast enucleation. However, loss of RhAG is temporally and mechanistically distinct, occurring predominantly as a result of instability at the plasma membrane and lysosomal degradation prior to enucleation. Loss of Rh/RhAG was identified as common to erythrocytes with naturally occurring ankyrin deficiency and demonstrated to occur prior to enucleation in cultures of erythroblasts from a hereditary spherocytosis patient with severe ankyrin deficiency but not in those exhibiting milder reductions in expression. The identification of prominently reduced surface expression of Rh/RhAG in combination with direct evaluation of ankyrin expression using flow cytometry provides an efficient and rapid approach for the categorization of hereditary spherocytosis arising from ankyrin deficiency.

The modified iron avidity index: a promising phenotypic predictor in HFE-related haemochromatosis.

OBJECTIVE: Phenotypes of the HFE-related haemochromatosis vary considerably, making it hard to predict the course of iron accumulation. The aim of this retrospective study was to determine if the Iron Avidity Index (IAI) is a good phenotypic predictor of the number of phlebotomies needed per year during maintenance treatment (NPDMT) in patients with homozygous p.C282Y hereditary haemochromatosis (HH). METHODS: Patients with HH homozygous for p.C282Y, on maintenance treatment for at least 1 year were included. The IAI (ferritin level at diagnosis/age at diagnosis) was calculated. RESULTS: Ninety-five patients were included in the analysis. Linear regression analysis showed the confounding effect of sex on the relationship between IAI and NPDMT. A modified IAI, adjusted for sex, was calculated. As proton pump inhibitor (PPI) use was independently associated with NPDMT, the group was split in PPI- and non-PPI-users. A positive correlation between the modified IAI and the NPDMT was shown in both groups (PPI r = 0.367, P = 0.023; non-PPI r = 0.453, P < 0.001). An ROC was computed to measure the accuracy of the modified IAI to predict who needed 0-2 vs. ≥3 maintenance treatments per year. The AUROC in the PPI and non-PPI group were respectively 0.576 (0.368-0.784) and 0.752 (0.606-0.899). CONCLUSION: The modified IAI is a fairly good predictor in non-PPI-using homozygous C282Y HH patients, to differentiate who needs ≥3 maintenance phlebotomies per year. Therefore, this index might help to select patients that benefit from an alternative less frequent therapy, e.g. erythrocytapheresis.

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.

Proton Pump Inhibitors Reduce the Frequency of Phlebotomy in Patients With Hereditary Hemochromatosis.

BACKGROUND & AIMS: Patients with hereditary hemochromatosis (HH) need frequent phlebotomies to reduce iron overload. Proton pump inhibitors (PPIs) were reported to reduce the need for phlebotomies in patients homozygous for the C282Y mutation in HFE. We investigated the effects of PPI treatment on numbers of phlebotomies in these patients. METHODS: We conducted a retrospective study of patients with HH homozygous for the C282Y mutation by using the database and medical records from Atrium Medical Centrum Parkstad in Brunssum, The Netherlands. In a paired group analysis of 12 patients, we compared mean serum levels of ferritin and number of phlebotomies needed each year during the periods of 3 years before and 3 years after the start of PPI therapy. We compared these results with those from a group who received PPIs for at least 2 years (n = 9) and a group who never received PPIs (n = 36). RESULTS: We found a significant reduction in median number of phlebotomies after patients began taking PPIs vs. before (0.50 vs. 3.17, P < .002). Patients who received PPIs for at least 2 years needed significantly fewer phlebotomies than patients in the paired group before they started taking PPIs (1.25 vs. 3.17, P < .001). The number of phlebotomies in the group who never received PPIs was significantly higher than in the paired group after they started taking PPIs (3.0 vs. 0.5, P < .001). CONCLUSIONS: On the basis of a retrospective analysis, in patients with HH homozygous for the C282Y mutation in HFE, treatment with PPIs for 2 or more years significantly reduced the number of phlebotomies required to maintain serum levels of ferritin below 100 µg/L.

[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.

Preparation before colonoscopy: a randomized controlled trial comparing different regimes.

BACKGROUND AND AIM: A good bowel preparation is essential for optimal visualization of the large intestine. Several preparations with a difference in composition and volume are available. We compared five methods for bowel cleansing quality and patients' acceptability. PATIENTS AND METHODS: Adult ambulatory outpatients scheduled for elective colonoscopy were randomized to receive 4-l polyethylene glycol (PEG) solution (Klean-prep), 2-l PEG solution+ascorbic acid (Moviprep), or a sodium phosphate (NaP) solution, Phosphoral. Patients with the PEG solutions were also randomized to receive simethicone (Aeropax), to investigate whether this improves the bowel cleansing efficacy. Before colonoscopy patients completed a questionnaire about the acceptability and tolerability of the preparation. Endoscopists blinded to the type of preparation gave a bowel cleansing score. RESULTS: Data were available for 461 patients. 2-l PEG+ascorbic acid was noninferior to 4-l PEG in bowel cleansing quality of rectosigmoid and colon. NaP was noninferior to 4-l PEG in bowel cleansing quality of rectosigmoid but inferior for the whole colon. Compliance was significantly less in the group with 4-l PEG compared with the 2-l PEG and NaP group. No difference was found for abdominal cramps. Taste was significantly better in the 2-l PEG group. Simethicone did not improve the bowel cleansing quality. CONCLUSION: 2-l PEG+ascorbic acid was noninferior to the 4-l PEG solution in bowel cleansing quality and was better in taste and compliance. NaP was inferior to 4-l PEG in bowel cleansing quality. Addition of simethicone gave no improvement.

Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: the HEmochromatosis FAmily Study.

BACKGROUND/AIMS: In families of patients with clinically detected hereditary hemochromatosis (HH) early screening has been suggested to prevent morbidity and mortality. Here, we aim to identify determinants for iron overload in first-degree family members of C282Y homozygous probands with clinically detected HH. METHODS: Data on HFE-genotype, iron parameters, demographics, lifestyle factors and health, were collected from 224 Dutch C282Y homozygous patients with clinically diagnosed HH and 735 of their first-degree family members (FDFM), all participating in the HEmochromatosis FAmily Study (HEFAS). RESULTS: The best predictive multivariable model forecasted 45% of variation of the serum ferritin levels. In this model severity of iron overload in the proband significantly predicted serum ferritin levels in FDFM. Other significant determinants in this model consisted of C282Y homozygosity, compound heterozygosity, age at testing for serum ferritin and supplemental iron intake, whereas a low body mass index showed a protective effect. CONCLUSIONS: This study provides a model to assess the risk of development of iron overload for relatives of probands with HH. These results might be instrumental in the development of an optimal strategy for future family screening programs.

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.