HEREDITARY HEMOCHROMATOSIS AND JAK2-POSITIVE POLYCYTHEMIA VERA

A 59-year-old male was diagnosed with JAK2-positive Polycythemia Vera. Subsequently, further lab testing revealed elevated ferritin and iron saturation. Genetic testing for HFE gene mutation screen revealed that the patient was positive for heterozygous C282Y mutation. The patient was ultimately diagnosed with both Polycythemia Vera and Hereditary Hemochromatosis.

CME-Labor 63/Antworten: Eisenstoffwechsel-Diagnostik

Zusammenfassung. Zusammenfassung: Eisenmangel ist häufig und beeinflusst den Verlauf vieler chronischer Erkrankungen. Die Diagnose einer absoluten und manifesten Eisenmangelanämie kann leicht durch Messung der Hämoglobin- und Serumferritinspiegel gestellt werden. Bei entzündlichen Erkrankungen kann die Diagnose durch zusätzliche Laborparameter wie dem löslichen Transferrin-Rezeptor erleichtert werden. Bei mehreren chronischen Erkrankungen wie Herz- oder Niereninsuffizienz gelten je nach Krankheit und Stadium unterschiedliche und höhere Schwellenwerte für Serumferritin, manchmal auch unter zusätzlicher Berücksichtigung der Transferrinsättigung. Die Transferrinsättigung ist zudem wichtig für die Diagnostik der Hämochromatose. Bei Patienten mit Transferrinsättigung >45 % erfordert die Diagnose in der Regel den Nachweis der Homozygotie für die C282Y-Mutation im HFE-Gen.

CME-Labor 63: Eisenstoffwechsel-Diagnostik

Zusammenfassung. Eisenmangel ist häufig und beeinflusst den Verlauf vieler chronischer Erkrankungen. Die Diagnose einer absoluten und manifesten Eisenmangelanämie kann leicht durch Messung der Hämoglobin- und Serumferritinspiegel gestellt werden. Bei entzündlichen Erkrankungen kann die Diagnose durch zusätzliche Laborparameter wie dem löslichen Transferrin-Rezeptor erleichtert werden. Bei mehreren chronischen Erkrankungen wie Herz- oder Niereninsuffizienz gelten je nach Krankheit und Stadium unterschiedliche und höhere Schwellenwerte für Serumferritin, manchmal auch unter zusätzlicher Berücksichtigung der Transferrinsättigung. Die Transferrinsättigung ist zudem wichtig für die Diagnostik der Hämochromatose. Bei Patientinnen und Patienten mit Transferrinsättigung >45 % erfordert die Diagnose in der Regel den Nachweis der Homozygotie für die C282Y-Mutation im HFE-Gen.

Evaluation of a screening program for iron overload andHFE mutations in 50,493 blood donors

Early detection of individuals with hereditary hemochromatosis (HH) is important to manage iron levels and prevent future organ damage. Although theHFE mutations that cause most cases of HH have been identified, their geographic distribution is highly variable, and their contribution to iron overload is not fully understood. All new registered blood donors at the Sahlgrenska University hospital between 1998 and 2015 were included in the study. Donors with signs of iron overload at baseline and subsequent follow-up testing were recommended genotyping of the HFE gene. Of the 50,493 donors that were included in the study, 950 (1.9%) had signs of iron overload on both test occasions. Of the 840 donors with iron overload that performed HFE genotyping, 117 were homozygous for C282Y, and 97 were compound heterozygotes. The prevalence of C282Y homozygosity was 0.23%. Iron overload screening effectively detects individuals at risk of carrying the C282Y mutation of the HFE gene and enables early treatment to prevent HH complications.

Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

Kinetics of Iron Depletion in Hereditary Hemochromatosis

Introduction: Hereditary hemochromatosis (HH) is a genetic disorder that results in an increased accumulation of dietary iron. The only effective treatment is iron depletion by phlebotomy or erytrocytapheresis (EA). The kinetics of iron depletion in response to these treatments has been little studied and its temporal profile and the influence of patient's factors are not fully known. Objective: To describe the kinetics of iron depletion in patients with HH on phlebotomy or EA. Material and methods: Patients in depletive treatment with phlebotomy (once per week) or EA (one every two weeks) were selected for this study if they had no associated inflammatory disorder, at least 3 ferritin determinations were available during treatment, and more than 70% of the established therapeutic schedule was fulfilled. The average reduction of serum ferritin was measured in ng/ml per ml of red blood cells (RBC) removed per Kg of patient's body weight, and was analyzed as natural logarithms (ln). Categorical variables were expressed as proportions and continuous variables, as median and interquartile range (IQR). Results: Median age of the 34 included patients was 51 (44-58) years and 32 (94%) were men. Initial and final ferritin values were 1035 (IQR: 777-1564) ng/ml and 83 (IQR: 50-123) ng/ml, respectively. Transaminase levels were high (ALT> 50 U/L) in 9 patients, and 2 of them had been diagnosed with liver cirrhosis secondary to HH. With regard to genotype, 27 patients were C282Y homozygous, 4 were compound heterozygous (C282Y/H63D), 1 had a TFR2 mutation, and no mutation was found in 2. The average reduction of serum ferritin was 1.04 (IQR: 1.03-1.05) ng/mL per mL of removed RBCs/Kg of patient's body weight. Figure 1 shows the mathematical expression that best described the kinetics of serum ferritin. The rate of serum ferritin reduction, as measured by this mathematical expression, was independent of the initial ferritin level, the total reduction of ferritin, the presence of high transaminase levels or cirrhosis, as well as the patient's age and body mass index. In contrast, the rate of ferritin reduction varied with the genotype; it was significantly lower in patients homozygous for the C282Y mutation than in patients with other genotypes (median: 1.03, IQR: 1.02-1.05 vs. 1.07, IQR: 1.06-1.11 ng/mL per mL of removed RBCs/Kg; p < 0.001; figure 2). Conclusions: In patients with HH and good adhesion to the therapeutic schedule, the reduction of serum ferritin is predictable as a function of the volume of removed RBCs and the patient's weight. Patients homozygous for the C282Y mutation have a slower kinetics of iron depletion. Disclosures No relevant conflicts of interest to declare.

Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects

Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis.

HFE GENE MUTATIONS

Objectives: To determine the frequency of two common HFE Gene Mutations(C282Y & H63D) in an immigrant population (British Pakistanis) in UK. Study Design: Crosssectional study. Setting: University of Lincoln UK. Duration: Duration of study was 12 monthsfrom 01/09/2012 to 31/08/2013. Material and Methods: Two hundred immigrant Pakistani (BP)chromosomes (100 samples; 50 male and 50 female) from major cities of UK and 200 ancestralorigin Pakistani chromosomes (100 samples; 50 male and 50 female) were analysed by PCRRFLPfor the presence of the H63D and C282Y mutations. Results: Eight individuals were foundto be heterozygous for the H63D mutation and one individual was found to be homozygousfor the H63D mutation, therefore, the H63D mutation was observed to have a frequency of 8%in immigrant Pakistani (BP) population sample and similar results were observed in ancestralorigin population from Pakistan. The C282Y mutation was not detected at all. Conclusion: Wefound that our results are close to Saudi-Arabian and Indian population (8.5% & 9.1% H63Dmutation, respectively) and in accordance with the global spread of the H63D mutation.