scholarly journals Genetic Risk for Hemochromatosis is Associated with Movement Disorders

2021 ◽  
Author(s):  
Robert Loughnan ◽  
Jonathan Ahern ◽  
Cherisse Thompkins ◽  
Clare E Palmer ◽  
Leo Sugrue ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Iron Overload ◽  
Movement Disorders ◽  
Genetic Disorder ◽  
Red Nucleus ◽  
Hereditary Hemochromatosis ◽  
Iron Deposition ◽  
Uk Biobank ◽  
Increased Risk ◽  
The Impact

Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that can lead to iron overload, causing oxidative damage to affected organs. HH type 1 is predominantly associated with homozygosity for the mutation p.C282Y. Previous case studies have reported tentative links between HH and movement disorders, e.g., Parkinson's disease, and basal ganglia abnormalities on magnetic resonance imaging. We investigated the impact of p.C282Y homozygosity: on whole brain T2 intensity differences, a measure of iron deposition, and; on measures of movement abnormalities and disorders within UK Biobank. The neuroimaging analysis (154 p.C282Y homozygotes, 595 matched controls) showed that p.C282Y homozygosity was associated with decreased T2 signal intensity in motor circuits (basal ganglia, thalamus, red nucleus, and cerebellum; Cohen's d > 1) consistent with substantial iron deposition. Across the whole UK Biobank (2,889 p.C282Y homozygotes, 496,968 controls), we found a significant enrichment for movement abnormalities in male homozygotes (OR (95% CI) = 1.82 (1.27-2.61), p=0.001), but not females (OR (95% CI) = 1.10 (0.69-1.78), p=0.71). Among the 31 p.C282Y homozygote males with a movement disorder only 7 had a concurrent HH diagnosis. These findings indicate susceptibility to iron overload in subcortical structures in p.C282Y homozygotes, and confirmed an increased risk of movement abnormalities and disorders in males. Given the effectiveness of early treatment in HH, screening for p.C282Y homozygosity in high risk individuals may offer a potential avenue to reduce iron accumulation in the brain and limit additional risk for the development of movement disorders among males.

scholarly journals Movement Disorders Associated With Hemochromatosis

2016 ◽  
Vol 43 (6) ◽  
pp. 801-808 ◽  
Author(s):  
Niraj Kumar ◽  
Philippe Rizek ◽  
Bekim Sadikovic ◽  
Paul C. Adams ◽  
Mandar Jog
Keyword(s):  
Movement Disorders ◽  
Genetic Disorder ◽  
Red Nucleus ◽  
Hereditary Hemochromatosis ◽  
Gene Mutations ◽  
Iron Deposition ◽  
Homozygous Mutation ◽  
The Third ◽  
London Health ◽  
The Brain

AbstractBackground:Hereditary hemochromatosis (HH) is a genetic disorder causing pathological iron deposition and functional impairment of various organs, predominantly the liver. We assessed patients with HH for the presence of movement disorders.Methods:We reviewed the charts of 616 patients with HH who attended hemochromatosis clinic at London Health Sciences Centre, London, ON, Canada, from 1988 to 2015.Results:We found three HH patients with movement disorders, without any other major systemic manifestation. One had parkinsonism, another had chorea, and the third had tremor. All three patients had evidence of iron deposition in the brain, affecting the basal ganglia in the first two, and the dentate nucleus, red nucleus, and substantia nigra in the third patient. In addition to the C282Y homozygous mutation in theHFEgene, two of our patients had non-HFEgene mutations.Conclusion:HH should be considered in the differential diagnosis of movement disorders with pathological brain iron deposition. We report for the first time chorea in a patient with HH. Non-HFEgene mutations may predispose HH patients to iron deposition in the brain.

A Prognostic Model for Predicting the Impact of Comorbidities on Survival of Patients with Myelodysplastic Syndromes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2453-2453 ◽  
Author(s):  
Matteo G. Della Porta ◽  
Luca Malcovati ◽  
Erica Travaglino ◽  
Cristiana Pascutto ◽  
Margherita Maffioli ◽  
...  
Keyword(s):  
Heart Failure ◽  
Iron Overload ◽  
Myelodysplastic Syndromes ◽  
Cardiac Death ◽  
Multivariable Analysis ◽  
Risk Groups ◽  
Increased Risk ◽  
Secondary Iron Overload ◽  
Transfusion Dependency ◽  
The Impact

Abstract Myelodysplastic syndromes (MDS) occur mainly in older persons, and these patients are likely to have comorbidities. We studied the impact of comorbidities on non-leukemic death (NLD) and overall survival (OS) in MDS patients with the aim of developing a specific prognostic index. Eight hundred forty consecutive patients receiving a diagnosis of MDS at Policlinico San Matteo, Pavia, Italy, between 1992 and 2006 were retrospectively evaluated. One or more comorbidities were present in 455/840 (54%) patients: the older the age, the higher their prevalence (P<0.001). Cardiac disease was observed in 25% of patients, liver disease in 16%, diabetes in 11%, prior solid tumor in 10%, nephropathy and pulmonary disease in 4%. Non-leukemic causes of death included cardiac failure (63%), infection (24%) and hemorrhage (7%). In a Cox analysis with age, sex, WHO category, cytogenetics and transfusion-dependency as time-dependent covariates, the presence of one or more comorbidities significantly affected both the risk of NLD (HR=1.91, P=0.001) and OS (HR=1.51, P=0.01), while it did not influence the risk of leukemic progression. The negative effect of comorbidities on OS was more evident in patients without excess of blasts (HR=1.8 P=0.007), while it retained a borderline significance in patients with more advanced disease (P=0.05). By including comorbidities as distinct entities in multivariable analysis, cardiac failure, liver or pulmonary disease, and solid tumors were found to independently affect the risk of NLD (HR=3.7, HR=2.08, HR=2.07 HR=2.23, respectively; P values from <0.001 to 0.033). Based on results of uni- and multivariable analysis, we developed a prognostic model for predicting the effect of comorbidities on NLD and OS. For each comorbidity, risk scores were estimated from the coefficients of the Cox regression. This MDS-specific comorbidity index (MDS-CI) allowed us to identify 3 groups of patients with different probability of NLD and OS (HR 2.78, P<0.001; HR 1.67 P=0.001), and provided a better stratification than the available non MDS-specific indices. Focusing on WPSS categories [J Clin Oncol2007; 25:3503–10], MDS-CI significantly stratified survival of patients with very-low, low and intermediate risk groups (P<0.001), while it had no effect in high and very-high risk groups. We then investigated the relationship between transfusion-dependency, secondary iron overload and comorbidities. Heart failure (28% vs. 18% P=0.001) and cardiac death (69% vs 55% P=0.03) were significantly more frequent in transfusion-dependent patients. In a Cox analysis with time-dependent covariates, transfusion-dependent patients showed an increased risk of NLD (HR=2.12 P=<0.001), heart failure (HR 1.34 P=0.03), and cardiac death (HR 2.99 P=0.01). The development of secondary iron overload significantly affected the risk of NLD and OS (HR=1.25 and 1.16 respectively, P<0.001), and this effect was maintained after adjusting for transfusion burden. Iron overload specifically increased the risk of developing heart failure (HR=1.17, P<0.001). In summary, the presence of non-hematological comorbidities significantly worsens the survival of MDS patients. Transfusion-dependency and secondary iron overload are associated with an increased risk of cardiac complications and cardiac death. The MDS-CI might be a useful tool for clinical decision making in patients with myelodysplastic syndromes.

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.

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.

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.

scholarly journals Susceptibility-weighted MR imaging (SWI) of basal ganglia iron deposition in the early and advanced stages of Parkinson's disease

2019 ◽  
Vol 11 (2) ◽  
pp. 30-36
Author(s):  
A. G. Trufanov ◽  
A. A. Yurin ◽  
A. B. Buriak ◽  
S. A. Sandalov ◽  
M. M. Odinak ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Substantia Nigra ◽  
Caudate Nucleus ◽  
Globus Pallidus ◽  
Red Nucleus ◽  
Regions Of Interest ◽  
Iron Deposition ◽  
Left Caudate

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease and the first one among the nosological entities of parkinsonism. Susceptibility-weighted imaging (SWI), magnetic resonance imaging (MRI) pulse sequence, which allows the in vivo estimation of the values of iron deposition in different areas of the brain, is a potential technique for the early diagnosis of PD and for the study of the pathogenesis of its complications.Objective: to compare the values of iron deposition in the basal ganglia in Stages II and III PD and to determine the relationship of clinical findings to the level of iron deposition according to the SWI findings.Patients and methods. Twenty-four patients with Hoehn and Yahr Stages II (n=24) and III (n=12) PD were examined. All the patients underwent brain MRI on a Siemens TrioTim (3T) MRI scanner by using pulse sequences T1, T2, SWI and subsequently quantifying the iron deposition (SPIN software). The accumulation of iron is visualized as an area of reduced signal intensity on SWI, and its estimation in accordance with the SPIN program has accordingly a smaller value. The regions of interest on both sides were the dentate nucleus, substantia nigra, red nucleus, putamen, globus pallidus, and head of the caudate nucleus. The examination protocol also included tests using the following scales: the Unified Parkinson's Disease Rating Scale (UPDRS), the Mini-Mental State Examination (MMSE), Frontal Assessment Batter (FAB), Freezing of Gait (FOG), Gait and Balance Scale (GABS), the Epworth Daytime Sleepiness Scale, the Parkinson's Disease Quality of Life Questionnaire (PDQ), the Beck Depression Inventory, and the Clock-Drawing Test.Results and discussion. The investigators found significant (p<0.05) correlations between the clinical picture and the level of iron deposition in the regions of interest in patients with Stage II PD: FOG – left caudate nucleus (r=-0.94); GABS – left caudate nucleus (r=-0.94); and in patients with stage III of the disease: UPDRS (full) – left red nucleus (r=-0.82), right globus pallidus (r=-0,80), left putamen (r=-0,96); UPDRS (Section 2) – left red nucleus (r=-0.77), left globus pallidus (r=-0.84); UPDRS (Section 3) – right putamen (r=-0,85), right globus pallidus (r=-0.78), left globus pallidus (r=-0,92); FOG – left globus pallidus (r=-0.81); GABS – left red nucleus (r=-0.96), left putamen (r=0.82), right putamen (r=-0.89), left globus pallidus (r=-0.82), right globus pallidus (r=-0.85), left caudate nucleus (r=-0.82), right caudate nucleus (r=-0.89); Beck Depression Inventory – right substantia nigra (r=-0.82).Conclusion. SWI measurement of the values of iron deposition in the structures of the extrapyramidal system in PD provides an additional insight into the pathological processes occurring in them.

Magnetic Ressonance Image T2* for the Evaluation of Iron Overload in Patients with Hereditary Hemochromatosis. A New Guide for the Indication of Therapeutic Phlebotomies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3716-3716
Author(s):  
Nelson Hamerschlak ◽  
Laercio Rosemberg ◽  
Alexandre Parma ◽  
Frederico R. Moreira ◽  
Assir F. Fernanda ◽  
...  
Keyword(s):  
Iron Overload ◽  
Laboratory Tests ◽  
Ferritin Level ◽  
Hereditary Hemochromatosis ◽  
Iron Deposition ◽  
European Ancestry ◽  
Liver Iron ◽  
Actual Evaluation ◽  
Invasive Method ◽  
Liver Biopsies

Abstract Hereditary hemochromatosis is highly prevalent in those with northern European ancestry (1 in 8 individuals are heterozygous and 1 in 100 – 200 are homozygous). It is characterized by laboratory tests as ferritin &gt; 150 ng/mL, transferrine saturation &gt; 40% and HFE mutations (C282Y and H63D). Presently the indications for treatment (therapeutic phlebotomies, TP) are based solely on the ferritin levels. It is possible that patients with moderate or even high levels of ferritin do not have iron overload. Performing liver biopsies would be an option for the actual evaluation, though invasive and risky. A non-invasive method to evaluate this deposition would be helpful in order to determine which patients actually demand TP. To evaluate if the use of Magnetic Ressonance Image (MRI) is a method for measuring tissue iron and could be a new guide for the indication of therapeutic phlebotomies, nineteen patients (mean age 43,47 y.o, +/− 9,85, gender = 16 male, 3 female) with hereditary hemochromatosis were scanned with T2- star (T2*) (GE equipment, Milwaukee, USA). The median of ferritin level was 594 (21–9300) The MRI method was previously validated to chemical estimation of iron in thalassemic major patients undergoing liver biopsies. The evaluated organs were liver and heart. All patients were in normal range of myocardial T2*. The images of four patients (25%), showed liver iron deposition. Eleven patients who presented serum ferritin levels below 600 ng/ml showed no liver iron deposition. Just one among five patients (20%), who presented ferritin levels between 601 and 1000 ng/ml showed hepatic iron overload. The three patients with ferritin levels higher than 1000 ng/ml had liver iron deposition quantified using liver T2* MRI techique. MRI T2* showed that some patients who would have an indication for TP based on laboratory tests, might avoid these procedures based on image results of internal organs. These patients can have an image follow up in order to decide when would be the appropriate time to start TP. This method can also be used to evaluate the efficacy of TP in patients who have already received this treatment. A larger group of patients would have to be evaluated in order to validate these results.

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 &lt;13 g/dL, women with hemoglobin &lt;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 &lt;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

Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4456-4462 ◽  
Author(s):  
Marnie J. Wood ◽  
Lawrie W. Powell ◽  
Grant A. Ramm
Keyword(s):  
Liver Disease ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Genetic Mutation ◽  
Iron Loading ◽  
Genetic Modifiers ◽  
Increased Risk ◽  
Recent Developments ◽  
History Of ◽  
Severe Liver Disease

Abstract Hereditary hemochromatosis is a genetic disorder of iron metabolism leading to inappropriate iron absorption and iron loading in various organs especially the liver. Despite the genetic mutation being relatively common in those of Anglo Celtic descent, cirrhosis of the liver occurs in only a small proportion of affected individuals. The risk of hepatic fibrosis and cirrhosis relates to the degree of iron loading with threshold hepatic iron concentrations being identified from population studies. However, other environmental and possibly genetic factors appear to modify this risk. Excess alcohol consumption appears to be one of the most important cofactors with steatosis and coexistent viral infection also implicated. Genetic polymorphisms in genes associated with fibrogenesis, antioxidant activity, and inflammation have been investigated in several different forms of chronic liver disease. The variability in the expression of these genes that predispose patients with hemochromatosis to increased risk of severe liver disease is the subject of ongoing investigations. Clearly the progression of iron loading to cirrhosis marks a crucial stage in the natural history of a patient's disease and therefore therapy and prognosis. This review explores recent developments in knowledge of environmental and genetic modifiers of this process.

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