Causes Of Hyperferritinemia Research Articles

Hemochromatosis - too much iron

Hemochromatosis is a disorder of genetic origin which affects iron hemostasis, resulting in an increased transferrin saturation, hyperferritinemia and parenchymal iron overload.Recently, a new system for the classification of hemochromatosis has been proposed, wherein patients are separated into 4 groups, based on the disease affected iron regulatory genes. Excess iron and increased transferrin saturation results in the formation of non-transferrin bound iron which leads to tissue damage. Hemochromatosis is a common genetic disease, but screening of the general population is not routinely recommended. In order to provide ideal care for hemochromatosis patients, it is crucial to delineate hemochromatosis from other causes of hyperferritinemia, which is a common finding in patients with metabolic disorders. This article summarizes the diagnostic algorithm for hemochromatosis. Furthermore, recommendations for optimal care - including targets for phlebotomy - are discussed.

Diagnostic Interpretation and further evaluation of Extreme Hyperferritinemia (>10,000 microg/L) with reduced % Tsat (<50%) in pediatric patients in Tertiary care Hospital

Background: Ferritin is a soluble protein which provides intracellular storage of bioavailable iron. It is found primarily in Liver, bone marrow macrophages, spleen. Ferritin is measured by ELISA, RIA and Mass spectrometry. The main aim of this study is to etiologically categorise extreme hyperferritinemia (serum ferritin > 10000 microg/L). Methodology and Results: This is 05 years retrospective study (July -2018 to June 2023), conducted in hematology section, MMCH, KSA. Out of 34 cases of extreme hyperferritinemia, viral infection was the most common cause comprising 41% of all cases. Amongst the infectious etiology, 6 cases of EBV, 3 cases of ALF of suspected viral etiology, 2 cases of PIDS with secondary infection, 1 case each of Hepatitis A virus and CMV noted. 10 cases presented as Macrophage Activating syndrome comprising 29% of total cases of which 70 were Systemic Juvenile Idiopathic arthritis and remaining 30% includes SLE and juvenile rheumatoid arthritis. Discussion: Study conducted by Dondu et al., indicate that the most common causes of hyperferritinemia are rheumatologic diseases and infections, which were identified in 59.1 and 27.3%, respectively. Present study showed infective etiology as the most common cause of extreme hyperferritinemia. Reasons for differences in results are because other studies were conducted in Adult patients and in Rheumatologic department. Conclusion: Our study formulated a systematic investigating pathway for raised serum ferritin. If the laboratory screening tests, BMA and other sophisticated tests are done in systematic way, then challenging cases can be diagnosed easily.

A form of inherited hyperferritinemia associated with bi-allelic pathogenic variants of STAB1

Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.

Hyperferritinemia in a Chilean Academic Healthcare Network: A Retrospective Study

The distribution of causes of hyperferritinemia in international series is heterogeneous. Also, the association between ferritin and prognosis is controversial. This study aims to describe the diagnosis associated with hyperferritinemia in a retrospective cohort at an academic healthcare network in Chile. A retrospective review of adult patients admitted to our academic medical center from June 2014 to February 2017 with ferritin ≥3,000 ng/mL. All patients were classified into nine diagnostic categories. Then, the association between ferritin level and disease category, as well as mortality, was evaluated. Ninety-nine patients were identified. The mean age was 50.8 ± 19.9 years, 54.5% were men. The most frequent categories were "inflammatory and autoimmune diseases" (21.2%) and "hematological malignancies" (19.2%). The average ferritin was 10,539 ± 13,016.9 ng/mL, while the higher mean was 16,707 ng/mL in the "inflammatory and autoimmune diseases" category. There was a statistically significant association between the ferritin value and age but not between ferritin and diagnostic categories. In the group over 50, hematologic neoplasms (19%) and infections (19%) were more frequent. In those under 50, inflammatory and autoimmune diseases were more frequent (26.8%). There was no association between the ferritin level and mortality at 1, 3, and 12 months. The most frequent categories were "inflammatory and autoimmune diseases" and "hematological malignancies", but ferritin level was similar in both. Further research could validate a prognostic role.

Prevalence and severity of thrombocytopenia in patients with hyperferritinemia

ABSTRACTBackgroundIn patients with tumors, inflammation, and blood disorders, hyperferritinemia has been associated with the severity of the underlying disease and is frequently accompanied by a co-occurring low platelet count or thrombocytopenia. Despite this, no established correlation has been identified between hyperferritinemia and platelet count. In this retrospective, double-center study, we sought to describe the prevalence and severity of thrombocytopenia in patients with hyperferritinemia.Study and designA total of 901 samples were enrolled in this study, all of which had significantly high ferritin levels (>2000 μg/L) between January 2019 and June 2021. We analyzed the general distribution, incidence of thrombocytopenia in patients with hyperferritinemia, and the relationship between ferritin level and platelet count. p-values < 0.05 were considered statistically significant.ResultsThe total incidence of thrombocytopenia in patients with hyperferritinemia was 64.7%. Hematological diseases were the most frequent cause of hyperferritinemia (43.1%), followed by solid tumors (29.5%) and infectious diseases (11.7%). Patients with thrombocytopenia (<150 × 109/L) had significantly higher ferritin levels than those with platelet counts exceeding 150 × 109/L, with median ferritin levels of 4011 and 3221 μg/L, respectively (P < 0.001). Additionally, the results showed that the incidence of thrombocytopenia was higher in hematological patients with chronic transfusion than in those without chronic blood transfusions (93% vs 69%).ConclusionsIn conclusion, our results suggest that hematological diseases are the most common cause of hyperferritinemia and that patients with chronic blood transfusions are more susceptible to thrombocytopenia. Elevated ferritin levels may act as a trigger for thrombocytopenia.

Hereditary Hyperferritinemia.

Ferritin is a ubiquitous protein that is present in most tissues as a cytosolic protein. The major and common role of ferritin is to bind Fe2+, oxidize it and sequester it in a safe form in the cell, and to release iron according to cellular needs. Ferritin is also present at a considerably low proportion in normal mammalian sera and is relatively iron poor compared to tissues. Serum ferritin might provide a useful and convenient method of assessing the status of iron storage, and its measurement has become a routine laboratory test. However, many additional factors, including inflammation, infection, metabolic abnormalities, and malignancy-all of which may elevate serum ferritin-complicate interpretation of this value. Despite this long history of clinical use, fundamental aspects of the biology of serum ferritin are still unclear. According to the high number of factors involved in regulation of ferritin synthesis, secretion, and uptake, and in its central role in iron metabolism, hyperferritinemia is a relatively common finding in clinical practice and is found in a large spectrum of conditions, both genetic and acquired, associated or not with iron overload. The diagnostic strategy to reveal the cause of hyperferritinemia includes family and personal medical history, biochemical and genetic tests, and evaluation of liver iron by direct or indirect methods. This review is focused on the forms of inherited hyperferritinemia with or without iron overload presenting with normal transferrin saturation, as well as a step-by-step approach to distinguish these forms to the acquired forms, common and rare, of isolated hyperferritinemia.

Extreme Hyperferritinemia: Causes and Prognosis.

The significance of extreme hyperferritinemia and its association with certain diagnoses and prognoses are not well characterized. We performed a retrospective analysis of adult patients with at least one total serum ferritin (TSF) measurement ≥ 5000 µg/L over 2 years, in three university hospitals. Conditions associated with hyperferritinemia were collected, and patients were classified into 10 etiological groups. Intensive care unit (ICU) transfer and mortality rates were recorded. A total of 495 patients were identified, of which 56% had a TSF level between 5000 and 10,000 µg/L. There were multiple underlying causes in 81% of the patients. The most common causes were infections (38%), hemophagocytic lymphohistiocytosis (HLH, 18%), and acute hepatitis (14%). For TSF levels > 10,000 µg/L, there were no solid cancer or hematological malignancy without another cause of hyperferritinemia. Isolated iron-overload syndromes never exceeded TSF levels > 15,000 µg/L. Extreme hyperferritinemia (TSF levels > 25,000 µg/L) was associated with only four causes: HLH, infections, acute hepatitis and cytokine release syndromes. A total of 32% of patients were transferred to an ICU, and 28% died. Both ICU transfer rate and mortality were statistically associated with ferritin levels. An optimized threshold of 13,405 μg/L was the best predictor for the diagnosis of HLH, with a sensitivity of 76.4% and a specificity of 79.3%. Hyperferritinemia reflects a variety of conditions, but only four causes are associated with extreme hyperferritinemia, in which HLH and acute hepatitis are the most common. Extreme hyperferritinemia has a poor prognosis with increased mortality.

Iron overload disorders.

Iron overload disorders represent a variety of conditions that lead to increased total body iron stores and resultant end‐organ damage. An elevated ferritin and transferrin‐iron saturation can be commonly encountered in the evaluation of elevated liver enzymes. Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D, mutations most encountered in hereditary hemochromatosis, should be pursued in evaluation of hyperferritinemia. Magnetic resonance imaging with quantitative assessment of iron content or liver biopsy (especially if liver disease is a cause of iron overload) should be used as appropriate. A secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations. Differential diagnosis of secondary iron overload includes hematologic disorders, iatrogenic causes, or chronic liver diseases. More common hematologic disorders include thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency. If iron overload has been excluded, evaluation for causes of hyperferritinemia should be pursued. Causes of hyperferritinemia include chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions, such as adult‐onset Still's disease or hemophagocytic lymphohistiocytosis. In this review, we describe the diagnostic testing of patients with suspected hereditary hemochromatosis, the evaluation of patients with elevated serum ferritin levels, and signs of secondary overload and treatment options for those with secondary iron overload.

20-Year-Old Man With Elevated Liver Tests

20-Year-Old Man With Elevated Liver Tests

Prevalence of HFE-related haemochromatosis and secondary causes of hyperferritinaemia and their association with iron overload in 1059 French patients treated by venesection.

Venesection is the key therapy in haemochromatosis, but it remains controversial in hyperferritinaemia with moderate iron accumulation. There is substantial evidence that the results of HFE genotyping are routinely misinterpreted, while elevated serum ferritin has become more frequent in recent years in white adult populations following the increase of obesity and metabolic traits. To examine the reasons for prescribing venesection in 1,059 French patients during the period 2012-2015, determine the true prevalence of HFE-related haemochromatosis, and compare iron overload profiles between haemochromatosis and non-haemochromatosis patients. Only 258 of the 488 patients referred for haemochromatosis had the p.[Cys282Tyr];[Cys282Tyr] disease causative genotype (adjusted prevalence: 24.4%). Of the 801 remaining patients, 112 (14.0%) had the debated p.[Cys282Tyr];[His63Asp] compound heterozygote genotype, 643 (80.3%) had central obesity, 475 (59.3%) had metabolic syndrome (MetS) and 93 (11.6%) were heavy drinkers. The non-haemochromatosis patients started therapeutic venesection 9years later than haemochromatosis patients (P<0.001). Despite similar serum ferritin values, they had lower transferrin saturation (41.1% vs 74.3%; P<0.001), lower amounts of iron removed by venesection (1.7 vs 3.2g; P<0.001) and lower hepatic iron concentrations (107 vs 237µmol/g; P<0.001). Haemochromatosis is over-diagnosed and is no longer the main reason for therapeutic venesection in France. Obesity and other metabolic abnormalities are frequently associated with mild elevation of serum ferritin, the MetS is confirmed in ~50% of treated patients. There is a minimal relationship between serum ferritin and iron overload in non-p.Cys282Tyr homozygotes. Our observations raise questions about venesection indications in non-haemochromatosis patients.

INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis\u2014a protocol for a prospective open-label blinded endpoint randomised controlled trial

BackgroundThe effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturationMethodsIn a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 μg/L and ≤ 2000 μg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 μg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed.DiscussionThe INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory.Trial registrationThis trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987. Registered 29 June 2020.

From the Editor’s Desk…

From the Editor’s Desk…

Evaluation of hyperferritinemia causes in rheumatology practice: a retrospective, single-center experience.

Hyperferritinemia may develop due to various reasons such as inflammation, infection, or malignancy. The purpose of the study to explore the prevalence and to figure out the causes of general hyperferritinemia and extreme hyperferritinemia as detected through the ferritin measurements requested by the rheumatology department. Adult patients at the age of 18 years and older with at least one serum ferritin level measurement at or above 500 ng/mL as requested by the rheumatology department between January 2010 and December 2019 were evaluated retrospectively. Hyperferritinemia was detected in 4.7% of 11,498 serum ferritin tests. The mean age of 242 patients found to have hyperferritinemia was 53.7 ± 17.1 years; of the patients, 63.2% were female, and the mean serum ferritin value was 2820 ± 5080 ng/mL. The most common cause of hyperferritinemia was rheumatological diseases with a ratio of 59.1%, which was followed by infections, iron overload, and solid malignancy. Among the rheumatologic diseases, adult-onset Still’s disease (AOSD), rheumatoid arthritis, and vasculitis were the cause accounting for hyperferritinemia. Ferritin levels were significantly higher in the AOSD group compared to the other rheumatologic disease groups (p < 0.0001). While extreme hyperferritinemia (ferritin ≥ 10,000 ng/mL) rate in our cohort was 0.2%, the most common cause was AOSD (15/17). In patients with hyperferritinemia, 3 month mortality was found to be 8.7%. CRP level was identified as the only independent predictor for the 3 month mortality in all patients [OR 1.088 (95% CI 1.004–1.178), p = 0.039]. Although rheumatologic disease activation and infections are the most common causes, the other causes should also be considered for the differential diagnosis.

Hyperferritinaemia and iron overload in Asian patients: lessons from an Australian tertiary centre experience.

Iron overload is described in Asian patients but presents with a different phenotype and genotype compared to Caucasian patients. We retrospectively identified 64 Asian patients and compared them to 64 matched non-Asian patients with at least one episode of serum ferritin >500 μg/L. Of the Asian patients, one (1.6%) had proven iron overload, while other common causes of hyperferritinaemia included recent blood transfusion (47%), acute infection (11%) and haematological malignancy (8%). A greater proportion of non-Asian patients had hyperferritinaemia secondary to high alcohol intake. Iron overload is rare in Asians and unexplained hyperferritinaemia in Asian patients is more likely to be due to other factors.

Brucellosis as a cause of hyperferritinemia in systemic arthritis.

Brucellosis as a cause of hyperferritinemia in systemic arthritis.

Prolonged exposure to welding fumes as a novel cause of systemic iron overload.

Background & AimsInhalation of welding fume may cause pulmonary disease known as welder's lung. At our centre we came across a number of welders with systemic iron overload and prolonged occupational history and we aimed at characterizing this novel clinical form of iron overload.MethodsAfter exclusion of other known causes of iron overload, 20 welders were fully evaluated for working history, hepatic, metabolic and iron status. MRI iron assessment was performed in 19 patients and liver biopsy in 12. We included 40 HFE‐HH patients and 24 healthy controls for comparison.Results75% of patients showed lung HRCT alterations; 90% had s‐FERR > 1000 ng/mL and 60% had TSAT > 45%. Liver iron overload was mild in 8 and moderate‐severe in 12. The median iron removed was 7.8 g. Welders showed significantly lower TSAT and higher SIS and SIS/TIS ratio than HFE‐HH patients. Serum hepcidin was significantly higher in welders than in HFE‐HH patients and healthy controls. At liver biopsy, 50% showed liver fibrosis that was mild in four, and moderate‐severe in two. Liver staging correlated with liver iron overload.ConclusionsWelders with prolonged fume exposure can develop severe liver iron overload. The mechanism of liver iron accumulation is quite different to that of HFE‐HH suggesting that reticuloendothelial cells may be the initial site of deposition. We recommend routine measurement of serum iron indices in welders to provide adequate diagnosis and therapy, and the inclusion of prolonged welding fume exposure in the list of acquired causes of hyperferritinemia and iron overload.

EP19 Hyperferritinaemia causes in a UK district general hospital

Abstract Background Hyperferritinaemia has multiple causes including iron overload, liver disease, and systemic inflammation either in the context of infection, autoimmunity, or malignancy. Marked hyperferritinaemia has been used to aid diagnosis of rare autoimmune conditions such as adult onset Still’s disease. Methods Patients with plasma ferritin concentrations over 3000 μg/L from 7 April 2014 until 30 August 2019 (just over 5 years) in a district general hospital were identified. Those without sufficient documentation to identify the likely causes of hyperferritinaemia were excluded. Included patients (n = 283) were grouped according to maximum ferritin concentration, and likely causes of hyperferritinaemia from the following list were classified as follows: Infection; solid organ malignancy; haematological malignancy, autoimmune disease; transfusion dependence; liver disease, renal failure, haemolytic anaemia. Results The most common causes of hyperferritinaemia were infection (31%), solid organ malignancy, (28%), haematological malignancy (23%), and liver disease (22%). Peak ferritin concentration did not appear to be strongly associated with the factors that caused it. To explore the diagnostic utility of ferritin to distinguish autoimmune processes, infection, malignancy, and liver disease, an association between these factors and maximum ferritin concentration was tested for using Fisher’s exact test. No statistically significant association was found (p = 0.8967). Conclusion We found no association between maximum ferritin concentration and the causes thereof, however this study does not elucidate the diagnostic utility of hyperferritinaemia since most of the patients studied had established diagnoses before their hyperferritinaemia was identified. Hyperferritinaemia appears to be a marker of severe disease, in that most of the patients studied had died by the time of data collection. Disclosures T. Fieldman None. L. Stimson None. S. Zeb None. S. Alderson None. M. Lloyd None.

Hyperferritinemia in Critically Ill Patients.

Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. Retrospective observational study. Adult surgical, anesthesiologic, and medical ICUs of a university hospital. Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). None. Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949-0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384-1.665 per log µg/L]; p < 0.001). This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted.

Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation?

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.

The SLC40A1 R178Q mutation is a recurrent cause of hemochromatosis and is associated with a novel pathogenic mechanism.

Hemochromatosis type 4 is one of the most common causes of primary iron overload, after HFE-related hemochromatosis. It is an autosomal dominant disorder, primarily due to missense mutations in SLC40A1. This gene encodes ferroportin 1 (FPN1), which is the sole iron export protein reported in mammals. Not all heterozygous missense mutations in SLC40A1 are disease-causing. Due to phenocopies and an increased demand for genetic testing, rare SLC40A1 variations are fortuitously observed in patients with a secondary cause of hyperferritinemia. Structure/function analysis is the most effective way of establishing causality when clinical and segregation data are lacking. It can also provide important insights into the mechanism of iron egress and FPN1 regulation by hepcidin. The present study aimed to determine the pathogenicity of the previously reported p.Arg178Gln variant. We present the biological, clinical, histological and radiological findings of 22 patients from six independent families of French, Belgian or Iraqi decent. Despite phenotypic variability, all patients with p.Arg178Gln had elevated serum ferritin concentrations and normal to low transferrin saturation levels. In vitro experiments demonstrated that the p.Arg178Gln mutant reduces the ability of FPN1 to export iron without causing protein mislocalization. Based on a comparative model of the 3D structure of human FPN1 in an outward facing conformation, we argue that p.Arg178 is part of an interaction network modulating the conformational changes required for iron transport. We conclude that p.Arg178Gln represents a new category of loss-of-function mutations and that the study of “gating residues” is necessary in order to fully understand the action mechanism of FPN1.