Design of an Ongoing Phase I/II Open-Label, Dose-Escalation Trial Using the Oral Chelator Deferasirox To Treat Iron Overload in HFE-Related Hereditary Hemochromatosis (HH).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2680-2680 ◽  
Author(s):  
A. Pietrangelo ◽  
P. Brissot ◽  
H. Bonkovsky ◽  
C. Niederau ◽  
L. Rojkjaer ◽  
...  
Keyword(s):  
Iron Overload ◽  
Dose Escalation ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Analysis Of Covariance ◽  
Dose Escalation Study ◽  
True Incidence ◽  
Medical Disorders ◽  
Alternative Treatment Option

Abstract HH is a genetic disorder commonly associated with homozygosity for the C282Y HFE mutation and characterized by progressive iron overload through increased intestinal absorption. Organ failure due to iron toxicity may develop. Iron removal by phlebotomy is the preferred treatment and has been demonstrated to prevent or reverse some of the complications of iron overload. However, compliance with a weekly phlebotomy schedule is variable, and some patients are ineligible for phlebotomy due to underlying medical disorders. Thus, if an oral iron chelator such as deferasirox proves to be safe and effective, HH patients will have an alternative treatment option. This is an inter-patient dose-escalation study of deferasirox (5, 10, 15, 20 mg/kg) given daily for 24 weeks to C282Y homozygous HH patients with a pre-treatment serum ferritin (SF) value ≥300 μg/L and ≤2000 μg/L, and transferrin saturation ≥45%. Major exclusion criteria are men with hemoglobin <13 g/dL, women with hemoglobin <12 g/dL, a history of blood transfusion during 6 months prior to study entry, serum creatinine above the upper limit of normal (ULN), and serum ALT ≥2xULN at screening. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include the change in SF from baseline at 24 weeks, the time to normalization of SF (defined as the first occurrence of reduction of SF to <100 μg/L), the longitudinal course of SF, and the pharmacokinetics of deferasirox. It is estimated that at least 40 patients are needed to evaluate safety at all dose levels. Cohorts of 8 patients per dose level will be used in order to detect AEs with a 25% true incidence rate at that dose with 90% power. Safety monitoring will be based on medical review and a 2-parameter Bayesian logistic regression model for dose-dependent probabilities of a severe AE. To assess efficacy, the change from baseline in SF after 24 weeks of treatment will be analyzed by performing an analysis of covariance (ANCOVA). To date, 11 patients (9 men, 2 women; all Caucasian; mean age 56 years) with a mean of 7 years since HH diagnosis have been treated at 5 mg/kg/day for at least 4 weeks. There was a mean of 7 years since HH diagnosis, with 2 patients not having been previously treated. The remaining 9 had been treated with phlebotomy, one of whom had also been treated with deferoxamine. Baseline iron studies and ALT values for the 11 patients treated at 5 mg/kg/day are summarized in the table. The dose of deferasirox has been escalated to 10 mg/kg/day after no patients were seen to experience severe AEs at 5 mg/kg/day. In conclusion, this ongoing study will generate preliminary safety and efficacy data for deferasirox use in iron-overloaded HH patients, indicating whether deferasirox could be an alternative to phlebotomy in selected patients. Parameter n Mean±SD Median Range Normal range SF, ng/mL 11 633.0±428.9 567.0 350–1880 30–400 (men); 15–150 (women) Transferrin saturation, % 11 75.5±19.6 82.0 39–95 20–55 ALT, U/L 11 43.4±33.4 34.0 8–122 0–45

Target TMPRSS6 for the Treatment of Hereditary Hemochromatosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1047-1047
Author(s):  
Sheri Booten ◽  
Daniel Knox ◽  
Luis Alvarado ◽  
Shuling Guo ◽  
Brett P. Monia
Keyword(s):  
Iron Overload ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Common Mutation ◽  
C282y Mutation ◽  
Iron Storage ◽  
Hepcidin Expression ◽  
Iron Deficient

Abstract Abstract 1047 Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ∼50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient's life. Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It's been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of TMPRSS6 in Hfe−/− mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011). Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2–3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ∼50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe−/− iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels. Disclosures: Booten: Isis Pharmaceuticals: Employment. Knox:Isis Pharmaceuticals: Summer Intern. Alvarado:Isis Pharmaceuticals: Employment. Guo:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment.

Iron Overload in C282Y Heterozygotes: Identification of New Rare HFE Gene Mutants and a Step Strategy for Diagnosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1859-1859
Author(s):  
Patricia Aguilar-Martinez ◽  
Severine Cunat ◽  
Fabienne Becker ◽  
Francois Blanc ◽  
Marlene Nourrit ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Hfe Gene ◽  
Compound Heterozygous ◽  
Exon 2 ◽  
High Iron ◽  
Iron Parameters

Abstract Introduction: Homozygozity for the p.Cys282Tyr (C282Y) mutation of the HFE gene is the main genotype associated with the common form of adult hereditary hemochromatosis. C282Y carriers do not usually develop iron overload, unless they have additional risk factors such as liver diseases, a dysmetabolic syndrome or an associated genetic defect. The commonest is the compound heterozygous state for C282Y and the widespread p.His63Asp (H63D) variant allele. However, a few rare HFE mutations can be found on the 6th chromosome in trans, some of which are of clinical interest to fully understand the disorder. Patients and Methods: We recently investigated four C282Y carrier patients with unusually high iron parameters, including increased levels of serum ferritin (SF), high transferrin saturation (TS) and high iron liver content measured by MRI. They were males, aged 37, 40, 42, 47 at diagnosis. Two brothers (aged 40 and 42) were referred separately. The HFE genotype, including the determination of the C282Y, H63D and S65C mutations was performed using PCR-RFLP. HFE sequencing was undertaken using the previously described SCA method (1). Sequencing of other genes (namely, HAMP, HJV/HFE2, SLC40A1, TFR2) was possibly performed in a last step using the same method. Results: We identified three rare HFE mutant alleles, two of which are undescribed, in the four studied patients. One patient bore a 13 nucleotide-deletion in exon 6 (c.[1022_1034del13], p.His341_Ala345>LeufsX119), which is predicted to lead to an abnormal, elongated protein. The two brothers had a substitution of the last nucleotide of exon 2 (c.[340G>A], p.Glu114Lys) that may modify the splicing of the 2d intron. The third patient, who bore an insertion of a A in exon 4 (c.[794dupA],p.[trp267LeufsX80]), has already been reported (1). Discussion: A vast majority of C282Y carriers will not develop iron overload and can be reassured. However, a careful step by step strategy at the clinical and genetic levels may allow to correctly identify those patients deserving further investigation. First, clinical examination and the assessment of iron parameters (SF and TS) allow identifying C282Y heterozygotes with an abnormal iron status. Once extrinsic factors such as heavy alcohol intake, virus or a dysmetabolic syndrome have been excluded, MRI is very useful to authenticate a high liver iron content. Second, HFE genotype must first exclude the presence of the H63D mutation. Compound heterozygozity for C282Y and H63D, a very widespread condition in our area, is usually associated with mild iron overload. Third, HFE sequencing can be undertaken and may identify new HFE variants as described here. The two novel mutations, a frameshift modifying the composition and the length of the C terminal end of the HFE protein and a substitution located at the last base of an exon, are likely to lead to an impaired function of HFE in association with the C282Y mutant. However, it is noteworthy that three of the four patients were diagnosed relatively late, after the 4th decade, as it is the case for C282Y homozygotes. Three further unrelated patients are currently under investigation in our laboratory for a similar clinical presentation. Finally, it can be noted that in those patients who will not have a HFE gene mutant identified, analysis of other genes implicated in iron overload must be performed to search for digenism or multigenism. None of our investigated patients had an additional gene abnormality.

A Phase I/II, Open-Label, Dose-Escalation Trial of Once-Daily Oral Chelator Deferasirox to Treat Iron Overload in HFE-Related Hereditary Hemochromatosis: Final Results of the Core Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1514-1514 ◽  
Author(s):  
Pradyumna D. Phatak ◽  
Pierre Brissot ◽  
Herbert Bonkovsky ◽  
Mark Wurster ◽  
Lawrie Powell ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Hereditary Hemochromatosis ◽  
Advisory Committees ◽  
The Core ◽  
Upper Limit ◽  
Dose Dependent

Abstract Abstract 1514 Poster Board I-537 Background and aims Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by progressive iron overload through increased intestinal absorption. Phlebotomy treatment is the standard of care, but compliance is variable and some patients are poor candidates due to underlying medical disorders and/or poor venous access. An oral iron chelator such as deferasirox (Exjade®) may provide an alternative treatment option for HH patients. Methods This is an inter-patient dose-escalation study of deferasirox (5, 10, 15 and 20 mg/kg) administered daily for 24 weeks to C282Y HFE homozygous HH patients with a pre-treatment serum ferritin (SF) value of 300–2000 ng/mL, transferrin saturation ≥45% and no known history of cirrhosis. A 6-month extension of this trial has recently been completed. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include change in SF, time to SF normalization (<100 ng/mL), longitudinal course of SF, and pharmacokinetics of deferasirox. Results 49 patients were enrolled and 48 patients were treated (33 men, 16 women; mean age 50.6 years; mean of 3.1 years since HH diagnosis) with deferasirox 5 (n=11), 10 (n=15) or 15 mg/kg/day (n=23) for at least 24 weeks. 37 (75.5%) patients completed the study (10 [90.9%], 11 [73.3%]; 16 [69.6%] patients in the 5, 10 and 15 mg/kg/day groups, respectively. The most common reasons for discontinuation were AEs in 3 (20.0%) patients and 4 (17.4%) patients in the 10 and 15 mg/kg/day groups, respectively. Bayesian analysis and medical review were performed between dose escalations. Meaningful reductions in SF were observed across the first three dose groups (median decrease -31.1%, -52.8% and -55.4% in the 3 groups respectively), and escalation to 20 mg/kg/day was not undertaken. Time course of the SF decline was dose-dependent (Figure). AEs in the core were dose dependent and consistent with the known safety profile of deferasirox. The most common drug-related AEs (≥10% in all patients) reported were diarrhea in 1 (9%), 4 (27%) and 9 (39%) patients, nausea in 0 (0%), 2 (13%) and 4 (17%) patients and abdominal pain in 0 (0%), 2 (13%), 3 (13%) patients in the 5, 10 and 15 mg/kg/day groups, respectively. One patient had ALT >5X upper limit of normal, and 11 patients had serum creatinine ≥33% over baseline and upper limit of normal on two consecutive occasions. All resolved with dose cessation or modification. Conclusions The results from the CORE trial suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden in HH patients. Based on the safety profile, only the 5 and 10 mg/kg/day doses are being considered for further study in this population. The results of the 24 week extension phase will be available at the time of the meeting. Larger studies are required to define the appropriate treatment regimen in HH. Disclosures Phatak: Novartis: Honoraria, Speakers Bureau. Brissot:Novartis: Honoraria, Research Funding. Bonkovsky:Boehringer-Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees; Clinuvel: Consultancy; Lundbeck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Roche: Research Funding; Vertex: Research Funding. Niederau:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adams:Novartis: Honoraria. Griffel:Novartis: Employment, Equity Ownership. Lynch:Novartis Pharmaceuticals: Employment. Schoenborn-Kellenberger:Novartis Pharma AG: Employment.

Role of Magnetic Ressonance Imaging – T2* in Hereditary Hemochromatosis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2096-2096
Author(s):  
Reijane Alves de Assis ◽  
Fernando Uliana Kay ◽  
Paulo Vidal Campregher ◽  
Gilberto Szarf ◽  
Fabiana Mendes Conti ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Conflicts Of Interest ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Laboratory Data ◽  
Surrogate Marker ◽  
Control Group ◽  
Double Mutation ◽  
H63d Mutation

Abstract Abstract 2096 Introduction: Hereditary hemochromatosis (HH) is an autossomic recessive disorder characterized by increased iron absorption. Magnetic resonance imaging – T2* (MRI-T2*) has become a reliable and robust methodology to directly assess the iron burden, with better results in transfusional hemosiderosis compared to indirect methods, such as serum ferritin and transferrin saturation (TS). However, little is known about its role in HH. Objectives: Describe the demographic profile of HH type 1 patients as to the type of the HFE mutation and correlate laboratory parameters to MRI-T2*results. Methods: We collected data from patients with a positive HFE gene mutation who performed abdominal and/or cardiac MRI-T2* in our institution from 2004 to 2011. Images retrieved from the digital archive were analyzed by two blinded independent radiologists using the Thalassemia-Tools software (Cardiovascular Imaging Solutions, London, UK). Laboratory data available within 6 months before or after the MRI study were analyzed using the t-Student test, Exact Fisher's test analysis and multivariate analyses. Results: We analyzed 81 patients, 76 (93%) males and 5 (6.2%) females, with a median age of 48 years (21–80). Liver, pancreatic and splenic MRI-T2*values and LIC calculation were performed in 80 patients, and cardiac T2* assessment in 57 patients. The inter-observer T2* variation coefficient was 5%. Serum ferritin was abnormal in 70 patients (90.9%), while TS was abnormal in 34% of the tests. In our study sample, the H63D mutation was present in 70 patients (86.4%): 11 (13.6%) were homozygous, 59 (72.8%) heterozygous and 7 (8.6%) double heterozygous for C282Y/H63D. Only three patients (3.7%) were homozygous and 6 (7.4%) were heterozygous only for the C282Y mutation. The S65C mutation was detected in heterozygous state in 2 (2.5%) of cases. Two out 57 cases had a positive T2* result and were classified as light cardiac overload (T2*:18.98 e 19.14 ms). Both had the H63D mutation (1 homozygous and 1 heterozygous). Thirty seven out of 80 patients (46.3%) had liver overload in abdominal MRI (T2*: 3.8–11.4ms), being 33 (41.3%) light overload and four (5%) moderate overload (T2*:1.8–3.8ms). We found that 77.8% of patients with liver overload were C282Y carriers, of which 57.2% had double mutation and 40.3% had H63D mutation in hetero or homozigosity. Pancreatic overload was found in 20 patients (25.1%), while 30 patients (37.5%) had splenic overload. There was a slight correlation (r: 0.365) between liver T2* and splenic T2* (p=0.001). The presence of C282Y and H63D mutations was statistically associated with a higher frequency of abnormal liver T2* (p=0.017 and p=0.042, respectively). The H63D mutation was associated with iron accumulation in the liver (p=0,037) and homozygous carriers showed higher levels of liver overload (p=0,038). Conclusion: In our study, serum ferritin was a better surrogate marker for iron overload than ST. In addition, up to 40.3% of patients with H63D mutation had evidence of hepatic iron overload by MRI. These findings differ from the currente literature. The higher RMI positivity might be due to a higher sensitivity to detect lower levels of organic iron. Despite the lack of a control group and laboratory tests or MRI in all the cases studied, our results suggest that RMI-T2* is a promising methodology to guide the therapeutic management of HH patients. The clinical impact of this finding must be investigated in further studies. Disclosures: No relevant conflicts of interest to declare.

Target TMPRSS6 Using Antisense Technology for the Treatment of Hereditary Hemochromatosis and β-Thalassemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 481-481 ◽  
Author(s):  
Shuling Guo ◽  
Carla Casu ◽  
Sara Gardenghi ◽  
Sheri Booten ◽  
Andy Watt ◽  
...  
Keyword(s):  
Treatment Group ◽  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Transferrin Saturation ◽  
Control Group ◽  
Mrna Levels ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Antisense Technology

Abstract Abstract 481 Hepcidin, the master regulator of iron homeostasis, is a peptide that is mainly expressed and secreted by the liver. Low levels of hepcidin are associated with increased iron absorption. In conditions in which hepcidin is chronically repressed, such as hereditary hemochromatosis and b-thalassemia, patients suffer from iron overload and very severe pathophysiological sequelae associated with this condition. Hepcidin expression is regulated predominantly at the transcriptional level by multiple factors. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor of hepcidin expression. It has been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of Tmprss6 expression in hereditary hemochromatosis (Hfe−/−) mice ameliorates the iron overload phenotype (Finberg et al. Nature Genetics, 2008; Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg et al., Blood, 2011). It has also been demonstrated that hepcidin up-regulation using either a hepcidin transgene or Tmprss6−/− significantly improves iron overload and anemia in a mouse model of β-thalassemia intermedia (th3/+ mice) (Gardenghi et al. JCI, 120:4466, 2010; Nai et al. Blood, 119: 5021, 2012). In this report, we have examined whether reduction of Tmprss6 expression using antisense technology is an effective approach for the treatment of hereditary hemochromatosis and β-thalassemia. Second generation antisense oligonucleotides (ASOs) targeting mouse Tmprss6 were identified. When normal male C57BL/6 mice were treated with 25, 50 and 100mg/kg/week ASO for four weeks, we achieved up to >90% reduction of liver Tmprss6 mRNA levels and up to 5-fold induction of hepcidin mRNA levels in a dose-dependent manner. Dose-dependent reductions of serum iron and transferrin saturation were also observed. ASOs were well tolerated in these animals. In Hfe−/− mice (both males and females), ASOs were administrated at 100 mg/kg for six weeks. This treatment normalized transferrin saturation (from 92% in control animals to 26% in treatment group) and significantly reduced serum iron (from >300ug/dl in control group to <150ug/dl in treatment group), as well as liver iron accumulation. Histopathological evaluation and Prussian's Perl Blue staining indicated that iron was sequestered by macrophages, which led to an increase in spleen iron concentration. The mouse model of thalassemia intermedia that we utilized mimics a condition defined as non-transfusion dependent thalassemia (NTDT) in humans. These patients exhibit increased iron absorption and iron overload due to ineffective erythropoiesis and suppression of hepcidin; iron overload is the most frequent cause of morbidity and mortality. Th3/+ animals exhibit ineffective erythropoiesis, characterized by increased proliferation and decreased differentiation of the erythroid progenitors, apoptosis of erythroblasts due to the presence of toxic hemichromes, reticulocytosis and shorter lifespan of red cells in circulation, leading to splenomegaly, extramedullary hematopoiesis and anemia (∼ 8 g/dL; Libani et al, Blood 112(3):875–85, 2008). Five month old th3/+ mice (both males and females) were treated with Tmprss6 ASO for six weeks. In th3/+ mice, ∼85% Tmprss6 reduction led to dramatic reductions of serum transferrin saturation (from 55–63% in control group down to 20–26% in treatment group). Liver iron concentration (LIC) was also greatly reduced (40–50%). Moreover, anemia endpoints were significantly improved with ASO treatment, including increases in red blood cells (∼30–40%), hemoglobin (∼2 g/dl), and hematocrit (∼20%); reduction of splenomegaly (∼50%); decrease of serum erythropoietin levels (∼50%); improved erythroid maturation as indicated by a strong reduction in reticulocyte number (50–70%) and in a normalized proportion between the pool of erythroblasts and enucleated erythroid cells. Hemichrome analysis showed a significant decrease in the formation of toxic alpha-globin/heme aggregates associated with the red cell membrane. This was consistent with a remarkable improvement of the red cell distribution width (RDW) as well as morphology of the erythrocytes. In conclusion, these data demonstrate that targeting TMPRSS6 using antisense technology is a promising novel therapy for the treatment of hereditary hemochromatosis and β-thalassemia. Disclosures: Guo: Isis Pharmaceuticals: Employment. Booten:Isis Pharmaceuticals: Employment. Watt:Isis Pharmaceuticals: Employment. Freier:Isis Pharmaceuticals: Employment. Rivella:Novartis Pharmaceuticals: Consultancy; Biomarin: Consultancy; Merganser Biotech: Consultancy, Equity Ownership, Research Funding; Isis Pharma: Consultancy, Research Funding. Monia:Isis Pharmaceuticals: Employment.

Hereditary Hemochromatosis in an Adult Due to H63D Mutation: The Value of Estimating Iron Deposition By MRI T2* and Dissociation Between Serum Ferritin Concentration and Hepatic Iron Overload

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4891-4891
Author(s):  
Mohamed A. Yassin ◽  
Ashraf T Soliman ◽  
Vincenzo Desanctis ◽  
Sandara Abusamaan ◽  
Ahmed Elsotouhy ◽  
...  
Keyword(s):  
Iron Overload ◽  
Basal Ganglion ◽  
Serum Ferritin ◽  
Normal Values ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Deposition ◽  
Ferritin Concentration ◽  
H63d Mutation ◽  
Serum Ferritin Concentration

Abstract Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive intestinal absorption of dietary iron, causing iron overload in different organs, especially the liver. Hemochromatosis may not be recognized until later in life. Patients are usually asymptomatic but may present with a variety of signs and symptoms. These include: hyper-pigmented skin, hepatomegaly, arthralgia, diabetes mellitusand/or heart failure/arrhythmia. The risk of HH related morbidity in HFE compound homozygotes patients (H63D /H63D) is considered rare, we report a male patient with H63D mutation who developed impaired glucose tolerance, and high hepatic enzymes due to significant iron accumulation in the liver as well as Parkinsonian-like syndrome due to iron deposition in the basal ganglia. A 40 year old Qatari male was referred for evaluation of a rise in hemoglobin and hematocrit values with normal MCV, total leucocyte and platelet counts. The patient was asymptomatic with normal vital signs, no depigmentation or hepato-splenomegaly. Hematologic findings included a hemoglobin concentration of Hb 16.5 g/dL, hematocrit 53%, mean corpuscular volume (MCV) 93 fL/red cell, leucocyte count of 7200/ μL and a platelet count of 199000/μL. His serum ferritin was 359 μg/l ( normal values: < 336 μg/l), serum iron: 37 μmol/l ( normal values <28.6μmol/l), fasting transferrin saturation: 64% (normal < 50%). A random glucose 6.5 and 6.4 mmol/L (normal values 5.5mmol/L ), A1C of 5,4 %, normal creatinine and electrolytes, alanine aminotransferase (ALT) of 66 U/l (normal < 40U/l), mild elevation of bilirubin 39 umol/l (normal <24umol/l), normal U&E Hepatitis B and C antibodies were negative. OGTT revealed impaired glucose tolerance. Thyroid function, morning serum cortisol, LH and FSH and serum total testosterone concentrations were in the normal range. A diagnosis of polycythemia vera was excluded on the basis of WHO Criteria 2008. The polymerase chain restriction assay was negative for the common mutation (C282Y) but positive for H63 D mutation. Family screening confirmed HH in his brother (homozygous), whereas his mother, two brothers and the sister were carriers (heterozygous). His four offspring were carriers. This suggested an autosomal recessive mode of inheritance. Conventional MRI study showed a normal liver size with diffuse fatty changes and focal areas of fatty sparing with some evidence of iron deposition. Whereas, T2-star (T2*) sequences showed a diffuse and significant decrease in liver signal intensity. A LIC liver concentration of 27 mg Fe/g dry wt was found (normalvalues:< 2 mg Fe/g dry wt; severe iron overload: ≥15 mg Fe/g dry wt). No significant iron deposition in the spleen, heart or pancreas was observed. At the age of 41 years the patient complained of tremors in both hands and arms while sitting or standing still (resting tremor) that improved with hands movements. A brain MRI revealed iron deposition in the basal ganglion. It was concluded that basal ganglionicn iron deposition mediated the neurological decline. Currently, the transferrin saturation and serum ferritin levels are within normal. Discussion: This is the first case of HH secondary to H63 D among an Arab family and the first reported case of Parkinsonism tremors secondary to this mutation. The H63D HFE variant is less frequently associated with HH, but its role in the neurodegenerative diseases has received a great attention. An accurate evaluation of iron overload is necessary to establish the diagnosis of HH and to guide iron chelation in HH by determination of liver iron concentration (LIC) by means of T2* MRI. Although serum ferritin concentration was only mildly increased a significant siderosis in the liver was detected by MRI T2* technique occurred. Liver siderosis was associated with mild impairment of liver function (increased serum ALT and bilirubin ). Conclusion: Our data further confirm that serum ferritin levels are not an accurate measure of total body iron stores in HH. Iron deposition in the liver and basal ganglion occurred despite mild elevation of ferritin. changes in basal ganglion may present by parkinsonian like tremors in these patients Use,T2* MRI should be encouraged in patients with HH for better evaluation of Iron overload and avoidance of Complications since serum ferritin can be misleading in these conditions. Disclosures Yassin: Qatar National research fund: Patents & Royalties, Research Funding. Aldewik:Qatar Ntional Research Fund: Patents & Royalties, Research Funding.

Asymptomatic hemochromatosis subjects: genotypic and phenotypic profiles

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3707-3711 ◽  
Author(s):  
Ronald L. Sham ◽  
Richard F. Raubertas ◽  
Caroline Braggins ◽  
Joseph Cappuccio ◽  
Margaret Gallagher ◽  
...  
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Entire Group ◽  
Iron Loading ◽  
Asymptomatic Patients ◽  
Liver Biopsies ◽  
The Relationship ◽  
Genotypic Profile ◽  
Compound Heterozygotes

Screening for hereditary hemochromatosis (HHC) by means of transferrin saturation (TS) levels has been advocated and will identify many patients who are asymptomatic. The purposes of this study were (1) to determine HFE genotypes among asymptomatic HHC patients and correlate this profile with the degree of iron overload and (2) to evaluate the relationship between mobilized iron (mob Fe), age, serum ferritin (SF), and quantitative hepatic iron (QHI) in this population. One hundred twenty-three asymptomatic HHC patients were evaluated; all had quantitative phlebotomy to determine mob Fe and genotyping for C282Y and H63D mutations. Liver biopsies with QHI determinations were performed on 72 of the 123 patients. Of the entire group, 60% were homozygous for C282Y, and 13% were compound heterozygotes (C282Y/H63D). Among asymptomatic patients, the prevalence of homozygous C282Y is lower compared with previous studies that include clinically affected patients. Of those patients with more than 4 g mob Fe, 77% were homozygous C282Y. Asymptomatic patients with lower iron burdens frequently had genotypes other than homozygous C282Y. There was no correlation between age and mob Fe in these patients; however, there was a correlation between mob Fe and both SF (r = 0.68) and QHI (r = 0.75). In conclusion, asymptomatic patients with moderate iron overload had a different genotypic profile than was seen in advanced iron overload. The significance of identifying patients with modest degrees of iron loading, who may not be homozygous for C282Y, must be addressed if routine TS screening is to be implemented.

scholarly journals Hemochromatosis - modern condition of the problem

2018 ◽  
Vol 90 (3) ◽  
pp. 107-112
Author(s):  
N B Voloshina ◽  
M F Osipenko ◽  
N V Litvinova ◽  
A N Voloshin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Iron Overload ◽  
Therapeutic Intervention ◽  
Clinical Observation ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Hereditary Factors ◽  
Life Threatening ◽  
Common Genetic Disorder ◽  
Modern Condition

The iron overload syndrome can be associated with various acquired states and hereditary factors. Hereditary hemochromatosis is the most common genetic disorder. Without therapeutic intervention the disease can lead to the development of life-threatening complications such as cirrhosis, hepatocellular carcinoma. The article presents data on pathogenesis, diagnosis and treatment of hereditary hemochromatosis. Own clinical observation is given.

A High Through-Put Screen Identifies MCP-1 (CCL2) As a Novel Regulator of Iron Homeostasis and a Modifier of Hereditary Hemochromatosis Disease Severity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 685-685
Author(s):  
Martina U. Muckenthaler ◽  
Maja Vujic Spasic ◽  
Katarzyna Mleczko-Sanecka ◽  
Mingang Zhu ◽  
Rainer Pepperkok ◽  
...  
Keyword(s):  
Iron Overload ◽  
Mrna Expression ◽  
Disease Severity ◽  
Iron Homeostasis ◽  
Expression Profiles ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Human Cells ◽  
Liver Iron ◽  
Deficient Mice

Abstract Abstract 685 To identify genes that modify the severity of human iron disorders we pre-selected 74 genes from gene expression profiles of cells and tissues with altered iron levels and assessed whether siRNA-mediated knock-down of these genes affects uptake of transferrin, a key cellular process to acquire iron. This screen identifies the monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, as a critical suppressor of transferrin receptor mRNA expression in human cells. We next analyzed CCL2-deficient mice and demonstrate profound alterations of parameters of systemic iron homeostasis. Specifically, CCL2 knock-out mice show decreased serum iron levels and transferrin saturation, strong iron-overload in the spleen and duodenum as well as mild iron accumulation in the liver. Iron imbalance in CCL2−/− mice is unlikely explained by an impairment of the major control system of systemic iron homeostasis, the hepcidin/ferroportin regulatory system: hepcidin mRNA expression is unaltered and splenic ferroportin protein expression is strongly increased in CCL2−/− mice, as would be expected as a consequence of splenic iron overload. We speculate that increased iron absorption from the plasma, possibly mediated by inappropriately high levels of TfR1 in the spleen, duodenum and liver, may be responsible for tissue iron overload. It is of note that CCL2 levels are strongly decreased in Hfe-deficient mice and patients with Hfe-associated Hereditary Hemochromatosis (HH). We therefore asked whether CCL2 levels could modify disease severity of HH. Analysis of 51 HH patients, all homozygous for the C282Y HFE mutation, confirms significantly lower MCP-1 levels in the serum compared to a group of 23 sex- and age-matched normal controls. Importantly, CCL2 levels in HH patients show a significant negative correlation with liver iron overload at the time point of diagnosis. Furthermore, low CCL2 concentrations are significantly associated with the HLA-A3 genotype and the CD8+ T lymphocyte phenotype, both traits previously shown to correlate with iron overload in HH patients. These patient data and the data from CCL2-deficient mice suggest that appropriate CCL2 expression is required to prevent iron overload. Taken together our data demonstrate the power of siRNA screens to identify novel regulators of iron metabolism in human cells that are critically involved in maintaining systemic iron homeostasis in the mouse and that play a role in modifying hepatic iron overload in the frequent iron overload disorder Hereditary Hemochromatosis. Disclosures: No relevant conflicts of interest to declare.

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