A Population-Based and Clinical Cohort Validation of the Novel Consensus Definition of Metabolic Hyperferritinemia.

CONTEXT: There is limited data on the clinical significance of metabolic hyperferritinemia (MHF) based on the most recent consensus. OBJECTIVE: We aimed to validate the clinical outcomes of MHF in the general population and patients with biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: The NHANES database and PERSONS cohort were included. MHF was defined as elevated serum ferritin with metabolic dysfunction (MD) and stratified into different grades according to ferritin (grade 1: 200 [females]/300 [males]-550 ng/mL; grade 2: 550-1000 ng/mL; grade 3: >1000 ng/mL). The clinical outcomes, including all-cause death, comorbidities, and liver histology, were compared between non-MHF and MHF in adjusted models. RESULTS: In NHANES, compared with non-MHF with MD, MHF was related to higher risks of advanced fibrosis (P = .036), elevated albumin-creatinine ratio (UACR, P = .001), and sarcopenia (P = .013). Although the association between all grades of MHF and mortality was insignificant (P = .122), grades 2/3 was associated with increased mortality (P = .029). When comparing with non-MHF without MD, the harmful effects of MHF were more significant in mortality (P < .001), elevated UACR (P < .001), cardiovascular disease (P = .028), and sarcopenia (P < .001). In the PERSONS cohort, MHF was associated with more advanced grades of steatosis (P < .001), lobular inflammation (P < .001), advanced fibrosis (P = .017), and more severe hepatocellular iron deposition (P < .001). CONCLUSION: Both in the general population and in at-risk individuals with MAFLD, MHF was related with poorer clinical outcomes.

[Management of iron overload during pregnancy and childbirth in a patient with ferroportin disease].

An asymptomatic woman in her early 40s with a history of hyperferritinemia (5,412 ng/ml) was referred to our hospital after repeated phlebotomy for hemosiderosis. She had unexplained hyperferritinemia, low-normal transferrin saturation, and high hepcidin levels, in the absence of iron overload-induced organ injury. She was diagnosed with ferroportin disease based on detection of the SLC40A1 variant SLC40A1 c.485_487del (p.Val162del) on genetic analysis. Her ferritin levels remained stable during pregnancy, and postpartum anemia was successfully treated with 2-week oral iron therapy. Ferroportin disease is characterized by impaired iron export and preferential iron trapping in tissue macrophages. To reduce risk of anemia, a non-aggressive phlebotomy regimen is recommended in patients with ferroportin disease, which shows a milder clinical course compared with other classical hemochromatosis subtypes.

Hyperferritinemia and liver iron content determined with MRI: Reintroduction of the liver iron index.

BACKGROUND: Hyperferritinemia is found in around 12 % of the general population. Analyzing the cause can be difficult. In case of doubt about the presence of major iron overload most guidelines advice to perform a MRI as a reliable non-invasive marker to measure liver iron concentration (LIC). In general, a LIC of ≥ 36 µmol/g dw is considered the be elevated however in hyperferritinemia associated with, for example, obesity or alcohol (over)consumption the LIC can be ≥ 36 µmol/g dw in abscence of major iron overload. So, unfortunately a clear cut-off value to differentiate iron overload from normal iron content is lacking. Previously the liver iron index (LII) (LIC measured in liver biopsy (LIC-b)/age (years)), was introduced to differentiate between patients with major (LII ≥ 2) and minor or no iron overload (LII < 2). Based on the good correlation between the LIC-b and LIC determined with MRI (LIC-MRI), our goal was to investigate whether a LII_MRI ≥ 2 is a good indicator of major iron overload, reflected by a significantly higher amount of iron needed to be mobilized to reach iron depletion. METHODS: We compared the amount of mobilized iron to reach depletion and inflammation-related characteristics in two groups: LII-MRI ≥ 2 versus LII-MRI <2 in 92 hyperferritinemia patients who underwent HFE genotyping and MRI-LIC determination. RESULTS: Significantly more iron needed to be mobilized to reach iron depletion in the LII ≥ 2 group (mean 4741, SD ± 4135 mg) versus the LII-MRI <2 group (mean 1340, SD ± 533 mg), P < 0.001. Furthermore, hyperferritinemia in LII-MRI < 2 patients was more often related to components of the metabolic syndrome while hyperferritinemia in LII-MRI ≥ 2 patients was more often related to HFE mutations. ROC curve analysis showed good performance of LII =2 as cut-off value. However the calculations showed that the optimal cut-off for the LII = 3.4. CONCLUSION: The LII-MRI with a cut-off value of 2 is an effective method to differentiate major from minor iron overload in patients with hyperferritinemia. But the LII-MRI = 3.4 seems a more promising diagnostic test for major iron overload.

[Treatment of hemophagocytic lymphohistiocytosis in patients in the intensive care unit]. / Behandlung der hämophagozytischen Lymphohistiozytose bei Patienten auf der Intensivstation.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by hyperferritinemia. A differentiation is made between hereditary and acquired forms. In contrast to children, almost all cases in adult patients consist of acquired secondary HLH. Infections, malignancies and autoimmune diseases are frequent triggers of secondary HLH. More recently, cases of HLH have also been described in association with immunotherapy, e.g., when using chimeric antigen receptor (CAR) T­cell treatment. In critically ill patients in the intensive care unit (ICU), sepsis represents the major differential diagnosis of HLH due to the frequently similar clinical presentation. Sometimes both sepsis and HLH are present at the same time. An early diagnosis and timely initiation of immunosuppressive treatment are essential for the further course and prognosis of HLH. Therefore, HLH should be considered as a possible diagnosis in critically ill patients with persistent fever and additional compatible symptoms (e.g., splenomegaly, neurological symptoms) or laboratory parameters (e.g., hyperferritinemia, cytopenia of two or three cell lines, increased transaminases). The diagnosis of HLH is made on the basis of the HLH-2004 criteria. The HScore can be used to estimate the probability of the presence of HLH. Corticosteroids given at high doses are the cornerstone of HLH treatment. Furthermore, immunoglobulins, etoposide, anakinra or ruxolitinib can complement treatment depending on the HLH trigger. The course of HLH depends on the timely initiation of treatment, the underlying trigger and the response to treatment. Despite progress in terms of diagnostics and targeted treatment, the prognosis of critically ill HLH patients is still poor.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

[Diagnosis and treatment of iron overload]. / Diagnostic et traitement d'une surcharge en fer.

Etiological investigation of hyperferritinemia includes a full clinical examination, with the measurement of waist circumference, and simple biological tests including transferrin saturation. The classification between hyperferritinemia without iron overload (inflammation, excessive alcohol intake, cytolysis, L-ferritin mutation) or with iron overload is then relatively easy. Dysmetabolic iron overload syndrome is the most common iron overload disease and is defined by an unexplained serum ferritin level elevation associated with various metabolic syndrome criteria and mild hepatic iron content increase assessed by magnetic resonance imaging. Bloodlettings are often poorly tolerated without clear benefit. Type 1 genetic hemochromatosis (homozygous C282Y mutation on the HFE gene) leads to iron accumulation through an increase of dietary iron absorption due to hypohepcidinemia. More than 95% of hemochromatosis are type 1 hemochromatosis but the phenotypic expression is highly variable. Elastography is recommended to identify advanced hepatic fibrosis when serum ferritin exceeds 1000µg/L. Life expectancy is normal when bloodlettings are started early. Ferroportin gene mutation is an autosomal dominant disease with generally moderate iron overload. Chelators are used in iron overload associated with anaemia (myelodysplastic syndromes or transfusion-dependent thalassemia). Chelation is initiated when hepatic iron content exceeds 120µmol/g. Deferasirox is often used as first-line therapy, but deferiprone may be of interest despite haematological toxicity (neutropenia). Deferoxamine (parenteral route) is the treatment of choice for severe iron overload or emergency conditions.

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.

Prevalence and severity of thrombocytopenia in patients with hyperferritinemia.

BACKGROUND: In 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 DESIGN: A 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. RESULTS: The 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%). CONCLUSIONS: In 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.

Hypocomplementemic urticarial vasculitis case with hemophagocytic lymphohistiocytosis following SARS-CoV-2 mRNA vaccination.

A 61-year-old man with no previous record of autoimmune disease developed fever, polyarthralgia, purpura, and urticaria-like rash 2 weeks after the first dose of the Moderna mRNA-1273 vaccine, and symptoms deteriorated following the second dose. He presented reduced erythrocyte and platelet counts, hyperferritinemia, high sIL-2R levels, and severe hypocomplementemia. We diagnosed hypocomplementemic urticarial vasculitis (HUVS), and his symptoms as well as laboratory findings improved following treatment with mPSL 1000 mg/day for 3 days and PSL 40 mg/day. Twelve weeks following treatment initiation, the patient relapsed with fever, sore throat, pancytopenia, and hyperferritinemia when the PSL dose was reduced to 12.5 mg/day. Bone marrow biopsy and MRI presented fatty marrow and hemophagocytosis. The patient's blood cells started recovering using ATG + CsA + EPAG therapy for hemophagocytic lymphohistiocytosis (HLH). This is the first case report of HUVS and HLH following SARS-CoV-2 mRNA vaccination. It is presumed that SARS-CoV-2 mRNA vaccine can induce the excessive production of certain types of cytokines, such as TNF-α, IL-1, IL-4, IL-5, IL-6, and IL-17 as a consequence of IL-6 Amplification (IL-6 Amp). SARS-CoV-2 mRNA-vaccines can cause disruption of immune homeostasis in healthy individuals. An extremely rare disease of HUVS complicated by HLH can be developed as a consequence.

Magnetic Resonance Liver Iron Concentration Can Guide Venesection Decision-Making in Hyperferritinemia.

BACKGROUND: The clinical benefit of venesection in suspected iron overload can be unclear and serum ferritin may overestimate the degree of iron overload. AIMS: To help inform practice, we examined magnetic resonance liver iron concentration (MRLIC) in a cohort investigated for haemochromatosis. METHODS: One hundred and six subjects with suspected haemochromatosis underwent HFE genotyping and MRLIC with time-matched serum ferritin and transferrin saturation values. For those treated with venesection, volume of blood removed was calculated as a measure of iron overload. RESULTS: Forty-seven C282Y homozygotes had median ferritin 937 µg/l and MRLIC 4.83 mg/g; MRLIC was significantly higher vs non-homozygotes for any given ferritin concentration. No significant difference in MRLIC was observed between homozygotes with and without additional risk factors for hyperferritinemia. Thirty-three compound heterozygotes (C282Y/H63D) had median ferritin 767 µg/l and MRLIC 2.58 mg/g; ferritin < 750 µg/l showed 100% specificity for lack of significant iron overload (< 3.2 mg/g). 79% of C282Y/H63D had additional risk factors-mean MRLIC was significantly lower in this sub-group (2.4 mg/g vs 3.23 mg/g). 26 C282Y heterozygous or wild-type had median ferritin 1226 µg/l and MRLIC 2.13 mg/g; 69% with additional risk factors had significantly higher ferritin concentrations (with comparable MRLIC) and ferritin < 1000 µg/l showed 100% specificity for lack of significant iron overload. In 31 patients (26 homozygotes, 5 C282Y/H63D) venesected to ferritin < 100 µg/l, MRLIC and total venesection volume correlated strongly (r = 0.749), unlike MRLIC and serum ferritin. CONCLUSION: MRLIC is an accurate marker of iron overload in haemochromatosis. We propose serum ferritin thresholds in non-homozygotes which, if validated, could tailor cost-effective use of MRLIC in venesection decision-making.

Perioperative Management of Recurrent Hemophagocytic Syndrome in a Pregnant Woman: A Case Report.

BACKGROUND Hemophagocytic syndrome (HPS) is a rare syndrome characterized by abnormal activation of histiocytes and hemophagocytosis. We report the clinical management of recurrent HPS following 2 cesarean sections in the same patient. CASE REPORT A 33-year-old primiparous mother presented during her second trimester of pregnancy, and HPS was diagnosed based on pancytopenia, hyperferritinemia (13 170 ng/ml), and hemophagocytosis in bone marrow examination. Despite steroid therapy, her HPS did not improve. Following the delivery of a healthy premature infant, there was no improvement in HPS, and immunochemotherapy was started 4 days postoperatively. Thrombocytopenia and hyperferritinemia persisted but normalized over the next 2 months, and immunochemotherapy was discontinued after 6 months. About 1 year after chemotherapy, the patient became pregnant with her second child. At 35 weeks of gestation, recurrence of HPS was suspected, and a C-section was performed at 36 weeks of gestation. The surgery was complicated by placenta previa, and general anesthesia was initiated after successful delivery of the infant. Epidural anesthesia was not performed due to concerns for postoperative thrombocytopenia. CONCLUSIONS Interestingly, HPS was likely triggered twice by pregnancy in this patient. Although reports of HPS during pregnancy are rare, there have been reports of rapid deterioration and death. Early diagnosis and therapeutic intervention are essential.

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.

Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/µL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.

Relation of Liver Siderosis to Liver Fibrosis in Hemodialysis Patients With Severe Hyperferritinemia Secondary to High Doses of Intravenous Iron Supplementation.

OBJECTIVE: Aggressive iron substitution in hemodialysis (HD) patients leads to iron overload. The association between liver siderosis and fibrosis is still debatable. We studied the association of liver siderosis with liver fibrosis in HD patients. Furthermore, we studied the performance of liver stiffness measurements (LSMs) in identifying advanced liver fibrosis. We investigated the performance of biochemical indicators of iron status in identifying advanced liver fibrosis. METHODS: Fifty-five HD patients (average HD duration 6 ± 2 years) with hyperferritinemia secondary to intravenous iron supplementation (weakly iron dose 252.7 ± 63 mg; median blood transfusions 3 [2-5]) were recruited. The liver fibrosis grade was determined with Fibroscan, aminotransferase-to-platelet ratio index (APRI), and Fib-4 index. Liver iron concentration (LIC) was estimated with magnetic resonance imaging (MRI). Iron parameters and liver function biochemical indicators were also assessed. RESULTS: The median serum ferritin and transferrin saturation (TSAT) were 3531 µg/L and 77%, respectively. 34.5%, 20%, and 45.5% of the patients showed mild, moderate, or severe liver siderosis, respectively. All patients with severe liver siderosis showed advanced liver fibrosis. Patients with severe liver siderosis and advanced liver stiffness showed higher serum iron, TSAT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, APRI, and Fib-4 index scores than those with mild liver siderosis. Serum iron and TSAT showed good utility in identifying advanced liver fibrosis determined with Fibroscan, APRI, and Fib-4 index. Liver stiffness exhibited good utility in identifying advanced liver fibrosis diagnosed with APRI and Fib-4 index. CONCLUSIONS: High weekly intravenous iron dose associated with severe hyperferritinemia, high serum iron, and TSAT might lead to severe liver siderosis and concomitant liver fibrosis in HD patients. Serum iron, TSAT, Fibroscan, Fib-4, and APRI scores might offer noninvasive tools for identifying advanced liver fibrosis in those patients.

Hyperferritinemia with iron deposition in the basal ganglia and tremor as the initial manifestation of follicular lymphoma.

Iron is an essential element for brain cells that is required for the transport of oxygen, energy generation, myelin synthesis, and production of neurotransmitters. Disturbances in the homeostatic mechanisms of iron metabolism may cause iron accumulation with subsequent oxidative stress and cellular damage. It is important to consider the possibility of both a genetic and acquired iron overload syndrome in patients with neurological symptoms and hyperferritinemia. In this article, we are reporting a unique case characterized by hyperferritinemia with widespread deposition of iron in more than one bodily organ, movement disorder, and hidden malignancy. We stress on the importance of early diagnosis using a systematic approach since early treatment with iron chelators is warranted to prevent the progression of neurological symptoms. Even those patients who have no neurological symptoms with high iron should be monitored closely and treated early to avoid the deposition of iron in the brain. Whether brain damage and MRI changes are reversible completely or partially is a subject for further research.

[Hyperferritinemia in a Chilean Academic Healthcare Network: A Retrospective Study]. / Hiperferritinemia: Experiencia de un Centro Universitario en Chile.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Hiperferritinemia y sospecha de sobrecarga de hierro en pacientes del Hospital Pablo Tobón Uribe, entre los años 2010 a 2020 / Hyperferritinemia and suspected iron overload in patients at the Pablo Tobón Uribe Hospital, between 2010 and 2020

Introducción. El objetivo de esta investigación fue comparar el perfil bioquímico y clínico de los pacientes con hiperferritinemia secundaria a hemocromatosis hereditaria (HH), frente a aquellos con hiperferritinemia por causas sospechosas de sobrecarga de hierro (Fe) diferentes a la HH. Metodología. Se estudiaron 92 pacientes (61 hombres y 31 mujeres), remitidos tras la detección de valores de ferritina >300 µg/L en hombres y >200 µg/L en mujeres. En todos se analizaron datos demográficos generales, comorbilidades, motivo de remisión para estudios de hiperferritinemia, manifestaciones clínicas, antecedente familiar de HH y tratamiento reci-bido. Los resultados de las pruebas de laboratorio, imagenología, hallazgos histopatológicos y estudios genéticos, se describieron según la disponibilidad. Resultados. El 96,74 % de los pacientes fueron evaluados en consulta externa, 86,96 % procedían de Medellín o de otros municipios de Antioquia, Colombia. La edad promedio de los participantes fue de 52 años, la principal razón para ser derivados para estudios fue la elevación de los marcadores de Fe sérico, la causa más frecuente de hiperferritinemia fueron los diagnósticos diferentes a la HH (64,13 %) y entre quienes no tenían HH, la etiología metabólica fue la más común (59,32 %). Los pacientes con HH tuvieron niveles más elevados de ferritina y Fe sérico, mientras que en el grupo sin HH se presentaron mayores elevaciones en la saturación de transferrina, transfe-rrina y transaminasas. En pacientes con sobrecarga de Fe, la mutación más frecuentemente encontrada fue la homocigota H63D (36,67 %). Finalmente, 93,94 % de los pacientes con HH recibieron tratamiento con flebotomías, mientras que los cambios en el estilo de vida fueron indicados en el 55,93 % de los pacientes sin HH. Conclusiones. La hiperferritinemia es una presentación clínica frecuente y es importante hacer un abordaje sistemático para identificar sus causas. Aunque la HH es una causa importante de elevación persistente de ferritina, en el enfoque de los pacientes con esta condición, se deben descartar etiologías más frecuentes como la hiperferritinemia de etiología metabólica.

Introduction. The aim of this investigation was to compare the biochemical and clinical profile of patients with secondary hyperferritinemia caused by hereditary hemochromatosis (HH), versus those with hyperferritinemia due to suspected causes of iron (Fe) overload other than HH. Methodology. A total of 92 patients (61 men and 31 women) referred after the detection of ferritin values >300 µg/L in men and >200 µg/L in women were studied. General demographic data, comorbidities, referral reasons for hyperferritinemia studies, clinical manifestations, family history of HH, and treatment received were analyzed in all patients. The results of laboratory tests, medical imaging, histopatho-logical findings, and genetic studies were described based on availability. Results. Of all patients, 96.74% were evaluated as outpatients, 86,96% from the municipality of Medellin in Antioquia, Colombia. The average age of the participants was 52 years, the main reason for being referred for studies was the elevation of serum Fe markers, the most frequent cause of hyperferritinemia in the population studied were conditions other than HH (64.13%), and among those who did not have HH, the metabolic etiology was the most common cause (60%). Patients with HH had higher levels of ferritin and serum Fe, while in the group without HH there were greater elevations of transferrin saturation, transferrin and transaminases. In patients with iron overload, the most frequently found mutation was the homozygous H63D (36.67%). Finally, 93.94% of the patients with HH received phlebotomy treatment, while changes in lifestyle were indicated in 55.93% of patients without HH. Conclusions. Hyperferritinemia is a frequent clinical presentation and it is important to make a systematic approach to identify its causes. Although HH is an important cause of persistent ferritin elevation, in the approach to patients with this condition, more frequent etiologies such as hyperfe-rritinemia of metabolic etiology should be ruled out.

Hemophagocytic lymphohistiocytosis: presentation and outcome of twenty-one patients at a single institution

ABSTRACT Introduction: Hemophagocytic lymphohistiocytosis comprises a systemic hyperactivation of macrophages that requires prompt recognition of symptoms and early treatment. Objective and Method: In this context, we described clinical and laboratory characteristics, therapeutic modality and outcome of 21 patients with HLH treated at a pediatric oncology hospital between January 2000 and February 2019. Results: HLH mainly affected females, fever was the most frequent clinical sign and hyperferritinemia was the most prevalent laboratory abnormality. All patients were admitted to the intensive care unit (ICU) at some point. Fifteen (71.4%) patients presented resolution criteria and eight (53.3%) of them presented reactivation. The mortality rate was 57.1% and the mean time between diagnosis and death was 9.98 months. The 5-year overall survival (OS) was 36.7%. We observed a significant difference in prognosis associated with reactivation of HLH. These patients demonstrated an estimated 5-year OS of 25%, while all patients that did not reactivate were alive until the end of the follow-up. Conclusion: In conclusion, HLH is a rare disease with a high mortality rate, especially in patients with disease reactivation and those with familial- or immunodeficiency-associated forms, which makes early recognition and genetic testing crucial for appropriate management and prompt SCT indication.

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.

Severe hyperferremia and hyperferritinemia in a dog with precursor-directed immune-mediated anemia.

A 4-year-old dog was evaluated at the Colorado State University Veterinary Teaching Hospital for lethargy and hyporexia of 24 hours duration. On presentation, she had a marked normocytic, normochromic, nonregenerative anemia (HCT 14%; RI 40-55). Her serum iron concentration (1651 µg/dL; RI 73-245) and serum ferritin concentration (1337 ng/mL; RI 89-489) were markedly elevated. Bone marrow aspirate and core biopsy were consistent with a diagnosis of precursor-directed immune-mediate anemia. To the authors' knowledge, these are the highest reported serum iron and ferritin concentrations in a patient with precursor-directed immune-mediate anemia. The iron concentration improved significantly after treatment, supporting the theory that the hyperferremia was due to hemolysis and ineffective erythropoiesis.