Liver iron concentration in patients referred for hyperferritinemia. Multicentre analysis of the different groups according to HFE mutations and transferrin saturation index.

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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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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Rusfertide (PTG-300), a Hepcidin Mimetic, Maintains Liver Iron Concentration in the Absence of Phlebotomies in Patients with Hereditary Hemochromatosis

Blood ◽

10.1182/blood-2021-149197 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 943-943

Author(s):

Kris V Kowdley ◽

Nishit B Modi ◽

Frank Valone ◽

Victor M. Priego ◽

Christopher Ferris ◽

...

Keyword(s):

Adverse Events ◽

Serum Iron ◽

Clinical Laboratory ◽

Hematological Parameters ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Transferrin Saturation ◽

Liver Iron Concentration ◽

Open Label ◽

Liver Iron

Abstract Introduction: Patients with hereditary hemochromatosis (HH) require continued phlebotomies to limit end-organ damage. Approximately 25% of patients in maintenance felt receiving phlebotomies was "inconvenient" or "very inconvenient" (Brisott et al, 2011). Patient compliance with phlebotomies generally declines with time (Hicken et al, 2003), and therapeutic phlebotomies may not be medically suitable for some HH patients. Rusfertide, a peptide mimetic of hepcidin, is an effective regulator of iron distribution and utilization that has demonstrated control of iron in an animal model of HH. Methods: We conducted an open-label, dose-finding efficacy study that investigated subcutaneous rusfertide in HH patients on a stable phlebotomy regimen of 0.25 to 1 phlebotomy per month for at least 6 months. Patients with clinical laboratory abnormalities and those receiving iron chelation therapy or erythrocytapheresis were excluded. Subjects received individually titrated rusfertide doses once or twice a week to maintain transferrin saturation (TSAT) below 45% and were followed for 6 months. Study measures included TSAT, serum iron, transferrin and ferritin, liver iron concentration (LIC) measured by MRI, and adverse events (AEs). Results: Sixteen subjects (10 male/6 female) were enrolled. Mean age and weight were 62.5 years and 88.1 kg, respectively. LIC values were maintained at pre-study levels, with minimal use of phlebotomies during the duration of the study (Figure 1A). Average pre-study phlebotomy rate was 0.27 phlebotomies/month compared to 0.03 phlebotomies/month during the study (p<0.0001; Figure 1B). There was a dose- and concentration-dependent decrease in serum iron and TSAT (Figure 2A and 2B). Transferrin levels were relatively constant over the course of the study. There were no notable changes in hematological parameters such as hematocrit, erythrocytes, leucocytes, or platelets. Rusfertide was generally well tolerated. Adverse events reported in 2 or more subjects included diarrhea, fatigue, injection site reactions (erythema, induration, pain, pruritis), dizziness, and headache. Conclusions: Rusfertide demonstrated a pharmacodynamic effect in reducing TSAT and serum iron, with corresponding significant reduction in the number of phlebotomies, and with LIC maintained at pre-study levels with minimal use of phlebotomies. These data indicate rusfertide was well tolerated in patients with HH and controls LIC, supporting development of rusfertide as a potential treatment for HH. Figure 1 Figure 1. Disclosures Kowdley: PTG: Consultancy, Research Funding. Modi: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gupta: Protagonist Therapeutics: Current Employment.

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The Oral Ferroportin Inhibitor VIT-2763 Improves Erythropoiesis without Interfering with Iron Chelation Therapy in a Mouse Model of β-Thalassemia

International Journal of Molecular Sciences ◽

10.3390/ijms22020873 ◽

2021 ◽

Vol 22 (2) ◽

pp. 873

Author(s):

Naja Nyffenegger ◽

Anna Flace ◽

Cédric Doucerain ◽

Franz Dürrenberger ◽

Vania Manolova

Keyword(s):

Mouse Model ◽

Iron Overload ◽

Chelation Therapy ◽

Iron Concentration ◽

Transferrin Saturation ◽

Iron Chelation ◽

Iron Chelator ◽

Liver Iron Concentration ◽

Ineffective Erythropoiesis ◽

Liver Iron

In β-thalassemia, ineffective erythropoiesis leads to anemia and systemic iron overload. The management of iron overload by chelation therapy is a standard of care. However, iron chelation does not improve the ineffective erythropoiesis. We recently showed that the oral ferroportin inhibitor VIT-2763 ameliorates anemia and erythropoiesis in the Hbbth3/+ mouse model of β-thalassemia. In this study, we investigated whether concurrent use of the iron chelator deferasirox (DFX) and the ferroportin inhibitor VIT-2763 causes any pharmacodynamic interactions in the Hbbth3/+ mouse model of β-thalassemia. Mice were treated with VIT-2763 or DFX alone or with the combination of both drugs once daily for three weeks. VIT-2763 alone or in combination with DFX improved anemia and erythropoiesis. VIT-2763 alone decreased serum iron and transferrin saturation (TSAT) but was not able to reduce the liver iron concentration. While DFX alone had no effect on TSAT and erythropoiesis, it significantly reduced the liver iron concentration alone and in the presence of VIT-2763. Our results clearly show that VIT-2763 does not interfere with the iron chelation efficacy of DFX. Furthermore, VIT-2763 retains its beneficial effects on improving ineffective erythropoiesis when combined with DFX in the Hbbth3/+ mouse model. In conclusion, co-administration of the oral ferroportin inhibitor VIT-2763 and the iron chelator DFX is feasible and might offer an opportunity to improve both ineffective erythropoiesis and iron overload in β-thalassemia.

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The Diversity of Liver Diseases among Outpatient Referrals for Elevated Serum Ferritin

Canadian Journal of Gastroenterology ◽

10.1155/2006/357340 ◽

2006 ◽

Vol 20 (7) ◽

pp. 467-470 ◽

Cited By ~ 18

Author(s):

Karen Wong ◽

Paul C Adams

Keyword(s):

Liver Biopsy ◽

Serum Ferritin ◽

Liver Diseases ◽

Tertiary Care ◽

Iron Concentration ◽

Transferrin Saturation ◽

Elevated Serum ◽

Liver Iron Concentration ◽

Liver Iron ◽

Ferritin Concentration

BACKGROUND: The aim of the present study was to examine the diversity of liver diseases in outpatients referred because of elevated serum ferritin.METHODS: A retrospective review was performed of outpatient referrals for serum ferritin elevations made to a tertiary care centre liver clinic between 1999 and 2005. Information regarding serum ferritin, transferrin saturation, liver biopsy, liver iron concentration and final diagnosis was extracted. Patients were stratified into two groups based on ferritin concentration: ferritin concentration 300 μg/L to 1000 μg/L, and ferritin concentration greater than 1000 μg/L.RESULTS: A total of 482 charts were reviewed, of which 119 (25%) had ferritin concentrations greater than 1000 μg/L.HFE-linked hemochromatosis, nonalcoholic steatohepatitis and alcohol-related liver disease were the top three diagnoses.HFE-linked hemochromatosis accounted for 28% to 42% of the diagnoses in all subgroups. The percentage of patients diagnosed withHFE-linked hemochromatosis was similar in the ferritin 300 μg/L to 1000 μg/L and the ferritin greater than 1000 μg/L groups (P=0.067). Among patients with ferritin greater than 1000 μg/L, 63% underwent a liver biopsy. Of those with an elevated liver iron concentration (greater than 35 μmol/g dry weight), 71% had a transferrin saturation greater than 50% (88% of C282Y homozygotes and 43% of non-C282Y homozygotes). In non-C282Y homozygotes with an elevated serum ferritin concentration greater than 1000 μg/L, 64% did not have iron overload on liver biopsy.CONCLUSION:HFE-linked hemochromatosis accounted for less than one-half of the diagnoses in an outpatient population referred for elevated ferritin, suggesting a need to search further for an alternate cause.

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Evaluating the Volumetric Liver Fat Fraction in Patients Referred for Investigation of Hyperferritinemia

Blood ◽

10.1182/blood-2019-128122 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3539-3539

Author(s):

Aoife Dervin ◽

Perla Eleftheriou ◽

Deepak Suri ◽

Sara Trompeter ◽

Maciej W Garbowski ◽

...

Keyword(s):

Genetic Testing ◽

Magnetic Resonance ◽

Serum Ferritin ◽

Iron Concentration ◽

Transferrin Saturation ◽

Liver Fat ◽

Liver Iron Concentration ◽

Liver Iron ◽

Male Ratio ◽

Fat Fraction

Introduction Elevated serum ferritin (hyperferritinemia, HF) can result from increased iron load, increased inflammation or from liver damage. In the most common forms of hereditary hemochromatosis (HH), elevated ferritin is usually seen with elevated transferrin saturations, [1,2]. In patients with HF but without raised liver iron concentration (LIC, mg/g dry wt [dw]), increased liver fat (hepatic steatosis, HS), either in isolation or as part of a metabolic syndrome, needs to be considered. HS is important to identify as it may progress to chronic liver damage and is potentially reversible with lifestyle interventions. Hepatic fat can now be quantified with magnetic resonance imaging (Hepafat-Scan®)[3]. Here, we evaluate the usefulness of this method in the diagnosis and subsequent management of patients referred with HF. Methods A total of 132 patients (median age 48 years, range 21-86 ; female: male ratio 1:2.5) referred for investigation of HF and who underwent estimation of liver iron concentration (LIC) by R2-MRI (FerriScan®) over a four-year period (January 2015 - December 2018) are included in this analysis. Data on patient demographics, presenting serum ferritin (SF) and transferrin saturation were obtained. Genetic testing for C282Y and H63D was also performed. Genetic testing for rarer forms of haemochromatosis was confined to patients with unexplained raised LIC. Patients with iron overload secondary to chronic iron ingestion or blood transfusion were excluded from this analysis. Results Patients were subdivided by genetic diagnosis: C282Y homozygote (26, 19.7%), C282Y/H63D (18, 13.6%), H63D homozygote (10, 7.6%), C282Y heterozygote (8, 6.1%), H63D heterozygote (18, 13.6%), autosomal dominant ferroportin disease (4, 3%) and negative HFE gene testing (48, 36.4%). There was no statistical difference between mean presenting SF (p= 0.307) between the different groups. C282Y homozygotes, and those with autosomal ferroportin disease had a significantly higher LIC than others (p<0.001). C282Y homozygotes and compound heterozygotes had a significantly higher transferrin saturation than other groups (p<0.001). SF positively correlated with LIC (p<0.001). After genetic testing and LIC quantification, 32 patients underwent a HepaFat-Scan®. Median age was 63 years, range 23 - 74 years; female: male ratio 1:3.5. 54.5% had a volumetric liver fat fraction (VLFF) > 5%. 7.4% of patients, who did not undergo Hepafat-Scan®, had HS based on sonographic findings. Patients with definitive evidence of HS as defined by VLFF >5% had mean LIC of 1.36mg/g dw, and a higher mean presenting SF of 926 µg/L than those with HS <5% (NS, p= 0.47). Those with VLFF <5% had a mean presenting SF of 783 mg/ml and mean LIC of 2.2 mg/g dw. In patients with LIC ≤3mg/g dw (n= 91, mean 1.6), mean presenting SF was 728 mg/ml. 28 of these patients went onto have a Hepafat-Scan®, 16 of which (57.1%) had confirmed steatosis with VLFF >5%. In patients with LIC >3mg/g dw (n= 41, mean LIC 6.9), mean presenting SF was significantly higher at 1056 mg/ml (p=0.021). 4 patients with LIC >3mg/g dw also had a Hepafat-Scan®, with 1 patient having VLFF >5%. Patients with confirmed steatosis were referred for specialist hepatology consultation. Conclusion In patients referred for investigation of HF, demonstrable steatosis (VLFF >5%) by Hepafat-Scan® is remarkably high (13.3% of all referred patients and 54% of patients who received Hepafat-Scan®). The Hepafat-Scan® data show that HS is generally confined to patients with low LIC (≤3mg/g dw) (Figure 1) reflecting the selective decision pathway adopted of excluding hepatic siderosis before proceeding to Hepafat-Scan®. SF is significantly higher in non-iron overloaded patients with HS (VLFF >5%) than those without HS (Figure 1). Estimation of HS should be considered in the diagnostic pathway of patients referred for investigation of HF, particularly when LIC values are not found to be meaningfully increased. References 1. Cullis JO et al. Investigation and management of a raised serum ferritin. British Journal of Haematology 2018; 181:331-340 2. St Pierre TG et al. Noninvasive measurement and imaging of liver iron concentration using proton magnetic resonance. Blood. 2005; 105(2):855-61 3. St Pierre TG et al. Stereological Analysis of Liver Biopsy Histology Sections as a Reference Standard for Validating Non-Invasive Liver Fat Fraction Measurement by MRI. PLoS ONE August 2016; 11(8):e0160789 Disclosures Eleftheriou: Novartis: Honoraria. Garbowski:Imara: Consultancy; Vifor Pharma: Consultancy. St. Pierre:Resonance Health Ltd: Consultancy, Other: Share ownership. Porter:Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria; Bluebird bio: Consultancy, Honoraria. Drasar:Novartis: Honoraria.

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