scholarly journals SAT-354 Isolated Hypoparathyroidism: A Rare Initial Manifestation of Hereditary Hemochromatosis (HH)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Zainab Shaheen ◽  
Kevin McCann ◽  
Rodhan Abass Khthir
Keyword(s):  
Vitamin D ◽  
Hereditary Hemochromatosis ◽  
Organ Damage ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Level ◽  
Initial Manifestation ◽  
Iron Saturation ◽  
History Of ◽  
Classic Form

Abstract Background: We present a case of hypoparathyroidism diagnosed in a patient as initial manifestation of hereditary hemochromatosis. As per our literature search, it is very rarely reported as an isolated abnormality in HH. Case: A 27 year old male with history of seizure disorder, well controlled on Oxcarbazepine, referred for evaluation of chronic hypocalcemia. His PMH includes cerebral palsy, with good functional capacity and mild cognitive impairment. He denied muscle spasm, perioral numbness, bone pain, muscle weakness or fracture. He was taking calcium carbonate 600mg bid and vitamin D 50,000 IU q2monthly. There was no family history of any Ca disorders. Physical exam was unremarkable. Laboratory evaluation revealed Ca levels ranging from 7.6 to 8.5mg/dl with intact PTH values ranging from 11 to 22pg/ml. His ionized calcium was also low. Patient’s 24 hr urinary Ca was 122mg/24hrs. In this case, he did initially have hypomagnesemia and vitamin d deficiency, which could potentially explain low calcium. But even after supplementing Vitamin D and Mg, patient’s Ca remained low. His kidney function was normal. Hemoglobin was in range of 14-15g/dl. To further evaluate the cause of hypoparathyroidism, iron saturation and iron levels were also sent. His iron saturation % was high at 89% with iron level of 286 ug/dl. His ferritin was 224 ng/ml and TIBC was 265 ug/dl. A sample was sent for genetic analysis to rule out hemochromatosis. Homozygous mutations in C282Y gene were found. A diagnosis of hereditary hemochromatosis was made. His other entire hormonal axis was intact. In this case, patient’s hypoparathyroidism is likely an initial manifestation of his HH. Discussion: Hereditary Hemochromatosis (HH) is a genetic disease characterized by an excessive (unregulated) entry of iron into the bloodstream with increased iron deposition in the parenchymal cells of a variety of organs leading to their failure. A defect in the hemochromatosis gene (HFE) is the most common form of HH, also known as the classic form or type 1 HH, where the principal mutation is represented by a substitution of tyrosine for cysteine at position 282 of the HFE gene (C282Y) as seen in our case. According to the genetic forms, the clinical manifestation usually ranges from simple biochemical abnormalities to severe organ damage and disease such as liver cirrhosis, arthritis, DM, cardiomyopathy and hypogonadism. There are reports of hypoparathyroidism from iron overload seen in thalassemia patients and patients who receive long term blood transfusions. In our literature review, this is the first documented case of HH initially manifesting as hypoparathyroidism. As HH is not uncommon in Caucasians, the work up for hemochromatosis as a possible cause of endocrinopathies should be kept in the differential diagnosis. It will help in early diagnosis & treatment which can reverse the effects of the disease leading to better outcomes.

Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 39-50
Author(s):  
Gary M. Brittenham ◽  
Günter Weiss ◽  
Pierre Brissot ◽  
Fabrice Lainé ◽  
Anne Guillygomarc'h ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Full Range ◽  
Hereditary Hemochromatosis ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Regulatory Proteins ◽  
Heme Metabolism ◽  
Clinical Consequences ◽  
And Storage

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism

Hematology ◽  
2000 ◽  
Vol 2000 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Gary M. Brittenham ◽  
Günter Weiss ◽  
Pierre Brissot ◽  
Fabrice Lainé ◽  
Anne Guillygomarc'h ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Transferrin Receptor ◽  
Full Range ◽  
Hereditary Hemochromatosis ◽  
Laboratory Evaluation ◽  
Hfe Gene ◽  
Iron Regulatory Proteins ◽  
Heme Metabolism ◽  
Clinical Consequences ◽  
And Storage

Abstract This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation. In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation. In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice. In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.

Hemochromatosis: the new blood donor

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 645-650 ◽  
Author(s):  
Susan F. Leitman
Keyword(s):  
Large Population ◽  
Hereditary Hemochromatosis ◽  
Cost Effective ◽  
Organ Damage ◽  
Hfe Gene ◽  
C282y Mutation ◽  
Physician Practices ◽  
Blood Center ◽  
Cost Effective Approach ◽  
Genotype Screening

Abstract Hereditary hemochromatosis (HH) due to homozygosity for the C282Y mutation in the HFE gene is a common inherited iron overload disorder in whites of northern European descent. Hepcidin deficiency, the hallmark of the disorder, leads to dysregulated intestinal iron absorption and progressive iron deposition in the liver, heart, skin, endocrine glands, and joints. Survival is normal if organ damage is prevented by early institution of phlebotomy therapy. HH arthropathy is the symptom most affecting quality of life and can be debilitating. Genotype screening in large population studies has shown that the clinical penetrance of C282Y homozygosity is highly variable and can be very low, with up to 50% of women and 20% of men showing a silent phenotype. Targeted population screening for the HFE C282Y mutation is not recommended at present, but might be reconsidered as a cost-effective approach to management if counseling and care were better organized and standardized. Referral of patients to the blood center for phlebotomy therapy and use of HH donor blood for transfusion standardizes treatment, minimizes treatment costs, and may benefit society as a whole. Physician practices should be amended such that HH subjects are more frequently referred to the blood center for therapy.

scholarly journals Case Report: Guitarist’s cramp as the initial manifestation of dopa-responsive dystonia with a novel heterozygous GCH1 mutation

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 361
Author(s):  
Takafumi Hasegawa ◽  
Tatsuhiko Hosaka ◽  
Ryuhei Harada ◽  
Ichiro Kawahata ◽  
Kyoko Hoshino ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Age Of Onset ◽  
Diurnal Fluctuation ◽  
Heterozygous Mutation ◽  
Loss Of Function ◽  
Initial Manifestation ◽  
Japanese Male ◽  
Old Japanese ◽  
History Of ◽  
Classic Form

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a phenotypically and genetically heterogeneous group of neurological disorders that typically presents as early-onset lower limb dystonia with diurnal fluctuation, and exhibits a marked, persistent response to levodopa. Heterozygous loss-of-function mutations in the guanosine triphosphate cyclohydrolase 1 (GCH1) are the most common cause of DRD. In addition to the classic form of the disease, there have been a number of studies addressing atypical clinical features of GCH1 related DRD with variable age of onset. This report describes a 37-year-old Japanese male patient with a 10-year history of focal upper limb dystonia that initially emerged as task-specific, guitarist’s cramp. The dystonic symptoms responded very well to levodopa treatment, and genetic analysis identified a novel heterozygous mutation in the C-terminal catalytic domain of GCH1. Insufficient recognition of this treatable condition often leads to misdiagnosis, which causes delays in the patient receiving adequate dopamine replenishing therapy. A diagnostic trial with levodopa should be considered in all patients with relatively young-onset dystonia, whether they have classic features of DRD or not.

scholarly journals SUN-096 Incidentally Found Severe Hypercalcemia in a Pediatric Patient, Diagnostic Challenge

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Liliana Burdea ◽  
Natalia Salazar ◽  
Carla Minutti ◽  
Stelios Mantis
Keyword(s):  
Vitamin D ◽  
Pulmonary Stenosis ◽  
Laboratory Evaluation ◽  
Global Developmental Delay ◽  
Renal Ultrasound ◽  
Severe Hypercalcemia ◽  
Medullary Nephrocalcinosis ◽  
History Of ◽  
Idiopathic Infantile Hypercalcemia ◽  
Peripheral Pulmonary Stenosis

Abstract Introduction: Idiopathic infantile hypercalcemia is an intriguing feature of Williams syndrome (WS), occurring in ~15% of diagnoses and is typically not clinically severe. Symptomatic hypercalcemia usually resolves during childhood, but lifelong abnormalities of calcium(Ca) and vitamin D metabolism may persist. The cause of the abnormality in Ca metabolism is still unknown. Hypercalciuria generally accompanies hypercalcemia, but isolated hypercalciuria, especially after infancy, can also occur. Nephrocalcinosis is relatively rare, found in less than 10% of patients undergoing renal ultrasonography. We report a 13-month-old female infant with a history of peripheral pulmonary stenosis and constipation, who presented with severe hypercalcemia that led to a new diagnosis of WS. Case presentation: A 13-month-old girl with a history of peripheral pulmonary stenosis, global developmental delay, and constipation presented to the neurology clinic for evaluation of gross motor delay. She was found to have upper body part hypotonia, decreased reflexes, and on laboratory evaluation, severe hypercalcemia with Ca level of 15.0 mg/dL (8.7 - 10.7). The patient was admitted for management of severe hypercalcemia. Physical exam was also remarkable for subtle features of WS: a happy baby, very social, with prominent eyes, full cheeks, flat nasal bridge, round nasal tip, full lips, and a wide smile. Repeated Ca level on admission was 15.9 mg/dL, with normal albumin level of 4.6 g/dL (2.9-5.5), elevated ionized calcium (iCal) of 1.99 mmol/L (0.95 - 1.32), and intact parathyroid hormone (PTH) of <4.0 pg/mL (8.0 - 85.0). Further evaluation revealed a normal 25 hydroxy-vitamin D:41 ng/mL (30-80) and low 1,25-dihydroxy vitamin D:10pg/mL (31-87). Further evaluation revealed elevated urine calcium to creatinine ratio of 0.7 (normal for age <0.56) and renal ultrasound remarkable for medullary nephrocalcinosis. The patient had a complete blood count within normal limits and a PTH related protein of 26 pg/mL (14-27), ruling out malignancy. Hypercalcemia responded well to intravenous fluids and diuretics, the patient being discharged home after two days on furosemide and potassium supplements with close electrolytes monitoring. The patient required calcium reducing therapy for four months to maintain Ca levels within 9-12 range. The medication was decreased gradually based on calcium and ical levels. The patient is currently doing well, with a normal calcium level, and has being off medication for the past three months. Conclusion: This is a rare case of severe hypercalcemia, which led to the diagnosis of WS. Although idiopathic infantile hypercalcemia occurs in 15% of patients with WS, usually the presentation is mild, and the patients do not require medical interventions. Our patient presented with severe hypercalcemia and subtle physical features of WS that led to genetic testing and final diagnosis.

scholarly journals Identification of New Mutations of the HFE, Hepcidin, and Transferrin Receptor 2 Genes by Denaturing HPLC Analysis of Individuals with Biochemical Indications of Iron Overload

2003 ◽  
Vol 49 (12) ◽  
pp. 1981-1988 ◽  
Author(s):  
Giorgio Biasiotto ◽  
Silvana Belloli ◽  
Giuseppina Ruggeri ◽  
Isabella Zanella ◽  
Gianmario Gerardi ◽  
...  
Keyword(s):  
Transferrin Receptor ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Organ Damage ◽  
Hfe Gene ◽  
Perfect Agreement ◽  
Exon 2 ◽  
Damage And Failure ◽  
Parenchymal Cells ◽  
Transferrin Receptor 2

Abstract Background: Hereditary hemochromatosis is a recessive disorder characterized by iron accumulation in parenchymal cells, followed by organ damage and failure. The disorder is mainly attributable to the C282Y and H63D mutations in the HFE gene, but additional mutations in the HFE, transferrin receptor 2 (TfR2), and hepcidin genes have been reported. The copresence of mutations in different genes may explain the phenotypic heterogeneity of the disorder and its variable penetrance. Methods: We used denaturing HPLC (DHPLC) for rapid DNA scanning of the HFE (exons 2, 3, and 4), hepcidin, and TfR2 (exons 2, 4 and 6) genes in a cohort of 657 individuals with altered indicators of iron status. Results: DHPLC identification of C282Y and H63D HFE alleles was in perfect agreement with the restriction endonuclease assay. Fourteen DNA samples were heterozygous for the HFE S65C mutation. In addition, we found novel mutations: two in HFE (R66C in exon 2 and R224G in exon 4), one in the hepcidin gene (G71D), and one in TfR2 (V22I), plus several intronic or silent substitutions. Six of the seven individuals with hepcidin or TfR2 coding mutations carried also HFE C282Y or S65C mutations. Conclusion: DHPLC is an efficient method for mutational screening for the genes involved in hereditary hemochromatosis and for the study of their copresence.

scholarly journals Iron and Liver Diseases

2000 ◽  
Vol 14 (suppl d) ◽  
pp. 89D-92D ◽  
Author(s):  
Silvia Fargion ◽  
Michela Mattioli ◽  
Anna Ludovica Fracanzani ◽  
Gemino Fiorelli
Keyword(s):  
Liver Diseases ◽  
Hereditary Hemochromatosis ◽  
Hfe Gene ◽  
Chronic Liver Diseases ◽  
Liver Iron ◽  
Excess Iron ◽  
Cancer Occurrence ◽  
History Of ◽  
Genetic Hemochromatosis ◽  
Severe Fibrosis

A mild to moderate iron excess is found in patients with liver diseases apparently unrelated to genetic hemochromatosis. Iron appears to affect the natural history of hepatitis C virus-related chronic liver diseases, alcoholic liver disease and nonalcoholic steatohepatitis by leading to a more severe fibrosis and thus aiding the evolution to cirrhosis.Ahigher frequency of mutations of the HFE gene, the gene responsible for hereditary hemochromatosis, is found in patients with liver diseases and increased liver iron than in normal patients. Patients with excess iron are potentially at a higher risk of developing hepatocellular carcinoma. Iron depletion therapy could interfere with fibrosis development and possibly reduce the risk of liver cancer occurrence.

scholarly journals HEREDITARY HEMOCHROMATOSIS AND JAK2-POSITIVE POLYCYTHEMIA VERA

2021 ◽  
Author(s):  
Ahmed Radwan ◽  
Ibraheem Othman
Keyword(s):  
Genetic Testing ◽  
Polycythemia Vera ◽  
Gene Mutation ◽  
Hereditary Hemochromatosis ◽  
Hfe Gene ◽  
C282y Mutation ◽  
Iron Saturation ◽  
Mutation Screen ◽  
Hfe Gene Mutation

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.

scholarly journals Clinical case of hereditary hemochromatosis

2018 ◽  
Vol 99 (6) ◽  
pp. 998-1003
Author(s):  
A V Solov’eva ◽  
O V Kodyakova ◽  
I N Nikitina ◽  
N P Fomenko ◽  
D R Rakita
Keyword(s):  
Serum Iron ◽  
Clinical Case ◽  
Ferritin Level ◽  
Abdominal Cavity ◽  
Hereditary Hemochromatosis ◽  
Hfe Gene ◽  
Iron Level ◽  
Homozygous Mutation ◽  
Serum Iron Level ◽  
Twin Brother

The article presents a clinical case demonstrating the difficulties of timely diagnosis of hereditary hemochromatosis, presents data on modern diagnosis and approaches to the treatment of the disease according to existing clinical guidelines. The described clinical case of hereditary hemochromatosis is associated with a homozygous mutation of C282Y in HFE gene in a 58-year-old patient and his twin brother. Initially, signs of iron deposition in the liver were found on MRI of the abdominal cavity. In laboratory analyses, the patient was found to have an increased level of serum iron - 40 µmol/l and ferritin - 1340 ng/ml. Subsequently, the investigation of HFE gene mutations was carried out and a mutation of C282Y in homozygous form (genotype A/A) was found, which is a molecular genetic confirmation of hereditary hemochromatosis of type 1. At the same time, the patient's twin brother at the targeted examination had the serum iron level of 36 µmol/l, the ferritin level of 600 ng/ml, and also the mutation of HFE gene, the allelic variant of A/A. The results of liver fibroelastometry of the patient correlate with the degree of fibrosis F1 by Metavir scale. Timely started therapeutic phlebotomies led to improved clinical and laboratory parameters of iron metabolism while maintaining normal levels of red blood cells and hemoglobin.

scholarly journals Altered Iron Parameters and Hepcidin Levels in a General Population: Lessons from the CHRIS Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2239-2239
Author(s):  
Fabiana Busti ◽  
Annalisa Castagna ◽  
Giacomo Marchi ◽  
Oliviero Olivieri ◽  
Peter Pramstaller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Organ Damage ◽  
Hfe Gene ◽  
Sequencing Data ◽  
Advisory Committees ◽  
South Tyrol ◽  
Iron Parameters

Introduction Environmental and genetic factors may lead to iron accumulation, causing irreversible organ damage. Homozygosity for the C282Y (C282Y +/+) and compound heterozygosity for the C282Y and H63D (C282Y-H63D) mutations of the HFE gene are associated with susceptibility to iron overload (IO). However, their clinical and biochemical expression is heterogeneous, with some patients showing only an increase of transferrin saturation (TSAT) for life, and others developing severe liver disease at a young age. Rarely, IO occurs in subjects without HFE-mutations or other acquired factors (e.g. alcohol intake, hemolysis, etc.). In these cases, non-HFE hemochromatosis is suspected, but the diagnosis is challenging, based on invasive (i.e., liver biopsy) or poorly available (i.e., Next-Generation Sequencing) approaches. A defective production of the iron regulatory hormone hepcidin is the key pathogenetic factor in hereditary hemochromatosis, irrespective of the gene involved, but extensive studies evaluating its potential diagnostic role are still lacking. This project evaluated hepcidin levels in a large subpopulation from the Cooperative Health Research In South Tyrol (CHRIS) study. Here we explored in particular hepcidin levels in subjects with altered iron status parameters, and their role in the identification of subjects at major risk of developing IO. Patients and Methods Study Population. The CHRIS study is a population-based study carried out in South Tyrol (Northern Italy), whose general aims are reported in detail elsewhere (Pattaro C, J Transl Med 2015). Blood samples were tested for several biochemical and genetic parameters, including those related to iron status, such as TSAT, ferritin, and C282Y and H63D mutations. Hepcidin was measured in stored aliquots by a recently updated and validated mass spectrometry-based method in tandem with liquid chromatography (LC-MS/MS), able to distinguish the active hepcidin-25 isoform (Diepeveen LE, Clin Chem Lab Med 2019). Results Among 4,642 participants, 6 were C282Y +/+ and 30 were C282Y-H63D (hereinafter defined as "HFE-H subjects"). HFE-H subjects showed ferritin levels only slightly higher than those with apparent wild-type HFE-H genotype (92.7 vs. 76.0 ng/ml, p=0.29), significantly higher TSAT (46.6 vs. 28.9%, p<0.0001) and lower hepcidin levels (1.41 vs. 2.30 nmol/l, p=0.016) (Table 1). Defective production of hepcidin was suggested by the reduced hepcidin:ferritin ratio (1.53 vs. 3.02 pmol/ng, p<0.0001), which was particularly low in C282Y +/+ (0.65 pmol/ng). Table 2 shows the prevalence of subjects with altered iron parameters (hyperferritinemia and/or increased TSAT), according to the HFE genotype. As concern HFE-H subjects, hyperferritinemia (i.e. >200 or >300 ng/ml in females and males, respectively) was detected in 16.7%, increased TSAT (>45%) in 52.8% and both in 11.1%. A biochemical pattern suggestive of IO (ferritin>500 ng/ml and TSAT>50%) was seen only in 33.3% of C282Y +/+ and in 6.7% of C282Y-H63D, while 41.7% neither had hyperferritinemia nor increased TSAT, confirming the low penetrance of such genotype. Although HFE-H subjects displayed a tendency to increase hepcidin production according to iron deposits (mean level of 1.10 nmol/l in subjects without hyperferritinemia/increased TSAT vs. 3.5 nmol/l of subjects with IO), the hepcidin:ferritin ratio was significantly lower in phenotypically expressed HFE-H subjects (0.49 vs. 2.04 pmol/ng, p=0.014) (Table 3). On the other hand, 540 participants (11.7 percent) without HFE-H genotype had hyperferritinemia, 64 (1.4%) had both hyperferritinemia and increased TSAT, and 12 (0.3 percent) had biochemical signs strongly suggestive of IO (ferritin>500 ng/ml and TSAT>50%). The latters had reduced hepcidin:ferritin ratio (0.92 pmol/ng), a value comparable to that of HFE-H iron loaded subjects (p=0.048). Whole Exome Sequencing data are available for the majority of CHRIS subjects included in this project and will be analyzed in detail in these subpopulations. Conclusions Our data suggest that the hepcidin:ferritin ratio may actually represent a useful indicator of hemochromatosis irrespective of the HFE genotype, possibly driving an optimal use of second level genetic test. Disclosures Girelli: Vifor Pharma: Other: honoraria for lectures; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; La Jolla Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

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