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.

Lactoferrin efficacy in treating hyperferritinemia in patients suffering from pathologies unrelated to hereditary hemochromatosis.

Ferritin (Ftn), a globular protein, sequesters 4500 atoms of iron per molecule. Elevated serum Ftn levels (hyperferritinemia) is an indicator of iron homeostasis disorders. We present the results of an observational study involving 17 patients with hyperferritinemia unrelated to hereditary hemochromatosis (HH). All participants received treatment with 200 mg of bovine lactoferrin (bLf) once (n = 14) or twice (n = 3) a day before meals. The patients, treated with 200 mg/day of bLf, exhibited a significant increase in red blood cells (+10%, p < 0.001), hemoglobin (+4%, p < 0.001), and hematocrit (+15%, p = 0.004), accompanied by a significant reduction in serum Ftn levels (-52%, p < 0.001), C-reactive protein (CRP) (-85.0%, p < 0.001), and D-dimers (-19%, p < 0.001). Among the three patients treated with 400 mg/day of bLf, two had effects similar to those of patients bLf-treated with 200 mg/day and one experienced a strong reduction of Ftn, CRP, and erythrocyte sedimentation rate (from -97% to -75%). The decrease in serum Ftn levels due to bLf treatment was largely independent of gender (p = 0.78), age (p = 0.66), baseline symptoms (p = 0.20), and concomitant acute (p = 0.34) and chronic (p = 0.53) infections. Although this observational pilot study yields positive effects in patients with hyperferritinemia unrelated to HH treated with bLf, a larger sample size is needed for conclusive results.

Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.

High ferritin is an important and sensitive biomarker for the various forms of hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system at UPMC Children's Hospital where serum ferritin > 1000 ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Diagnosing aceruloplasminemia: navigating through red herrings.

A 58-year-old female was found to have hyperferritinemia (Serum ferritin:1683 ng/mL) during work-up for mild normocytic anemia. Transferrin saturation(TSAT) was low-normal. Magnetic resonance imaging (MRI) abdomen showed evidence of hepatic iron deposition. Liver biopsy showed 4 + hepatic iron deposition without any evidence of steatosis or fibrosis. Quantitative liver iron was elevated at 348.3 µmol/g dry liver weight [Reference range(RR): 3-33 µmol/g dry liver weight]. She was presumptively diagnosed with tissue iron overload, cause uncertain. A diagnosis of ferroportin disease (FD) was considered, but the pattern of iron distribution in the liver, mainly within the hepatic parenchyma (rather than in the hepatic Kupffer cells seen in FD), and the presence of anemia (uncommon in FD) made this less likely. She was treated with intermittent phlebotomy for over a decade with poor tolerance due to worsening normocytic to microcytic anemia. A trial of deferasirox was done but it was discontinued after a month due to significant side effects. During the course of treatment, her ferritin level decreased. Over the past 1.5 years, she developed progressively worsening neurocognitive decline. MRI brain showed areas of susceptibility involving basal ganglia, midbrain and cerebellum raising suspicion for metabolic deposition disease. Neuroimaging findings led to testing for serum copper and ceruloplasmin levels which were both found to be severely low. Low serum copper, ceruloplasmin levels and neuroimaging findings led us to consider Wilson disease however prior liver biopsy showing elevated hepatic iron rather than hepatic copper excluded the diagnosis of Wilson disease. After shared decision making, ceruloplasmin gene analysis was not pursued due to patient's preference and prohibitive cost of testing. The diagnosis of aceruloplasminemia was ultimately made. The biochemical triad of hyperferritinemia, low-normal TSAT and microcytic anemia should raise the possibility of aceruloplasminemia. Since neurological manifestations are rare in most inherited iron overload syndromes, neurological symptoms in a patient with tissue iron overload should prompt consideration of aceruloplasminemia as a differential diagnosis.

Enzyme replacement therapy improves erythropoiesis and iron dysregulation in Gaucher disease.

Anemia and hyperferritinemia are frequent findings at diagnosis of Gaucher disease (GD). Macrophage-independent dyserythropoiesis and abnormal iron metabolism have been shown. We evaluated hematological and iron status at diagnosis (T0) and the effect of enzyme replacement therapy (ERT) on erythropoiesis and iron utilization over 5-year follow-up in type 1 GD patients and in an ex vivo model of erythropoiesis from CD34 + peripheral blood cells. At T0, 41% of patients had anemia and 51% hyperferritinemia. Hemoglobin increased from 12.6 (T0) to 13.9 g/dL (T6), GFD15, a marker of ineffective erythropoiesis, decreased from 5401 to 710 pg/ml, and serum ferritin decreased from 614 to 140 mcg/L (p < 0.001). In parallel, transferrin saturation (TSAT) increased. Hepcidin, although in the normal range, decreased from T0 to T6. Ex vivo studies showed that ERT restores the erythroid cells derived from CD34 + impaired ability to differentiate. During ERT, an increase in TFRC expression, consistent with the ability of erythroid precursors to uptake iron, and a reduction in HAMP and concomitant increase in SLC40A1 were observed. This is the largest study with a longitudinal follow-up evaluating erythropoiesis and iron metabolism, combining clinical and ex vivo data in GD. Iron dysregulation likely contributes to anemia, and ERT, by improving iron distribution, improves erythropoiesis.

Marked hyperferritinemia in critically ill cancer patients.

OBJECTIVES: To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS: A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 µg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS: A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 µg/L (range: 10.300-426.073 µg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION: Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.

Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population.

BACKGROUND & AIMS: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. METHODS: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. RESULTS: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. CONCLUSION: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

Prognostic Factors of Adult Hemophagocytic Lymphohistiocytosis and Clinical Utility of HLH-2004 Diagnostic Criteria and HScore: A Real-World Multicenter Study from Thailand.

INTRODUCTION: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. METHODS: This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. RESULTS: A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 µg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio [HR] 2.47; 95% confidence interval [CI] 1.39-4.37, HR 4.69; 95% CI 1.38-15.92, HR 6.09; 95% CI 1.84-20.14, and HR 6.02; 95% CI 1.64-22.05, respectively). CONCLUSION: Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease-triggered HLH has favorable outcomes. Future prospective study is required to verify the use of the adapted HLH-2004 criteria.

Clinical Features of Cytokine Storm Syndrome.

Cytokine storm syndrome (CSS) is a severe life-threatening condition characterized by a clinical phenotype of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, and multiple organ failure (MOF), and, if untreated, it can potentially lead to death. The hallmark of CSS is an uncontrolled and dysfunctional immune response involving the continual activation and expansion of lymphocytes and macrophages, which secrete large amounts of cytokines, causing a cytokine storm. Many clinical features of CSS can be explained by the effects of pro-inflammatory cytokines, such as interferon (IFN)-γ, tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and IL-18 [1-7]. These cytokines are elevated in most patients with CSS as well as in animal models of CSS [8, 9]. A constellation of symptoms, signs, and laboratory abnormalities occurs that depends on the severity of the syndrome, the underlying predisposing conditions, and the triggering agent.

The History of Macrophage Activation Syndrome in Autoimmune Diseases.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

Effects of Hyperferritinemia on Functional Outcome in Acute Ischemic Stroke Patients with Admission Hyperglycemia.

INTRODUCTION: Hyperferritinemia, presented as elevated serum ferritin level, is an indicator of high iron status which plays roles in secondary brain injury after acute ischemic stroke (AIS). However, the effects of hyperferritinemia and poor outcomes remain uncertain. Additionally, admission hyperglycemia quite frequently accompanies AIS patients, which is associated with unfavorable outcome. Thus, we aimed to investigate the effects of hyperferritinemia on 3-month and 1-year functional outcomes in AIS patients and especially those with admission hyperglycemia. METHODS: AIS patients within 24 h of onset were enrolled at West China Hospital from October 2016 to December 2019. Serum ferritin and blood glucose levels were tested on admission. Poor functional outcome at 3 months and 1 year was defined as modified Rankin Scale score ≥3. Multivariable analysis was used to investigate the associations between hyperferritinemia and 3-month and 1-year outcomes. Subgroup analysis was performed in patients with and without hyperglycemia. RESULTS: Of 723 patients (mean age 68.11 years, 60.6% males) finally included, 347 (48.0%) had hyperferritinemia. The incidence of poor outcome was 45.2% at 3 months and 41.2% at 1 year. Patients with hyperferritinemia had a higher frequency of poor 3-month outcome (51.8% vs. 39.2%, p = 0.001) and poor 1-year outcome (46.8% vs. 36.1%, p = 0.004). In all AIS patients, hyperferritinemia was not independently associated with poor functional outcome at 3 months or 1 year after adjusting for confounders (all p > 0.05). In AIS patients with hyperglycemia, hyperferritinemia was an independent factor correlated with poor 3-month outcome (OR = 1.711, 95% CI 1.093-2.681, p = 0.019) but not with poor 1-year outcome (p > 0.05). CONCLUSIONS: High iron status, presented as hyperferritinemia, is associated with poor 3-month functional outcome in AIS patients with hyperglycemia. Evaluating serum ferritin level may be conducive to assess the risk of short-term poor outcome in AIS patients with hyperglycemia. Further studies will be required to confirm our findings.

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.

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.

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.

Genotypic-Phenotypic Correlations of Hereditary Hyperferritinemia-Cataract Syndrome: Case Series of Three Brazilian Families.

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare, frequently misdiagnosed, autosomal dominant disease caused by mutations in the FTL gene. It causes bilateral pediatric cataract and hyperferritinemia without iron overload. The objective of this case series, describing three Brazilian families, is to increase awareness of HHCS, as well as to discuss possible phenotypic interactions with concurrent mutations in HFE, the gene associated with autosomal recessive inheritance hereditary hemochromatosis. Whole-exome sequencing was performed in eight individuals with HHCS from three different families, as well as one unaffected member from each family for trio analysis-a total of eleven individuals. Ophthalmological and clinical genetic evaluations were conducted. The likely pathogenic variant c.-157G>A in FTL was found in all affected individuals. They presented slowly progressing bilateral cataract symptoms before the age of 14, with a phenotype of varied bilateral diffuse opacities. Hyperferritinemia was present in all affected members, varying from 971 ng/mL to 4899 ng/mL. There were two affected individuals with one concurrent pathogenic variant in HFE (c.187C>G, p.H63D), who were also the ones with the highest values of serum ferritin in our cohort. Few publications describe individuals with pathogenic mutations in both FTL and HFE genes, and further studies are needed to assess possible phenotypic interactions causing higher values of hyperferritinemia.

SARS-CoV-2-induced hypomethylation of the ferritin heavy chain (FTH1) gene underlies serum hyperferritinemia in severe COVID-19 patients.

High serum ferritin (hyperferritinemia), a reliable hallmark of severe COVID-19 often associates with a moderate decrease in serum iron (hypoferremia) and a moderate increase in serum hepcidin. This suggests that hyperferritinemia in severe COVID-19 is reflective of inflammation rather than iron overload. To test this possibility, the expression status of ferritin heavy chain (FTH1), transferrin receptor 1 (TFRC), hepcidin (HAMP), and ferroportin (SLC40A1) genes and promoter methylation status of FTH1 and TFRC genes were examined in blood samples obtained from COVID-19 patients showing no, mild or severe symptoms and in healthy-donor monocytes stimulated with SARS-CoV-2-derived peptides. Severe COVID-19 samples showed a significant increase in FTH1 expression and hypomethylation relative to mild or asymptomatic COVID-19 samples. S-peptide treated monocytes also showed a significant increase in FTH1 expression and hypomethylation relative to that in controls; treatment with ECD or NP did not change FTH1 expression nor its methylation status. In silico and in vitro analysis showed a significant increase in the expression of the TET3 demethylase in S peptide-treated monocytes. Findings presented here suggest that S peptide-driven hypomethylation of the FTH1 gene promoter underlies hyperferritinemia in severe COVID-19 disease.

Ferritin - from iron, through inflammation and autoimmunity, to COVID-19.

While it took decades to arrive to a conclusion that ferritin is more than an indicator of iron storage level, it took a short period of time through the COVID-19 pandemic to wonder what the reason behind high levels of ferritin in patients with severe COVID-19 might be. Unsurprisingly, acute phase reactant was not a satisfactory explanation. Moreover, the behavior of ferritin in patients with severe COVID-19 and the subsequent high mortality rates in patients with high ferritin levels necessitated further investigations to understand the role of ferritin in the diseases. Ferritin was initially described to accompany various acute infections, both viral and bacterial, indicating an acute response to inflammation. However, with the introduction of the hyperferritinemic syndrome connecting four severe pathological conditions such as adult-onset Still's disease, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and septic shock added another aspect of ferritin where it could have a pathogenetic role rather than an extremely elevated protein only. In fact, suggesting that COVID-19 is a new member in the spectrum of hyperferritinemic syndrome besides the four mentioned conditions could hopefully direct further search on the pathogenetic role of ferritin. Doubtlessly, improving our understanding of those aspects of ferritin would enormously contribute to better coping with severe diseases in terms of treatment and prevention of complications. The origin, history, importance, and the advances of searching the role of ferritin in various pathological and clinical processes are presented hereby in our article. In addition, the implications of ferritin in COVID-19 are addressed.

Hemophagocytosis, hyper-inflammatory responses, and multiple organ damages in COVID-19-associated hyperferritinemia.

Hyperferritinemia comes to light frequently in general practice. However, the characteristics of COVID-19-associated hyperferritinemia and the relationship with the prognosis were not well described. The retrospective study included 268 documented COVID-19 patients. They were divided into the hyperferritinemia group (≥ 500 µg/L) and the non-hyperferritinemia group (< 500 µg/L). The prevalence of fever and thrombocytopenia and the proportion of patients with mechanical ventilator support and in-hospital death were much higher in the hyperferritinemia group (P < 0.001). The hyperferritinemia patients showed higher median IL-6, D-dimer, and hsCRP (P < 0.001) and lowered FIB level (P = 0.036). The hyperferritinemia group had a higher proportion of patients with AKI, ARDS, and CSAC (P < 0.001). According to the multivariate analysis, age, chronic pulmonary disease, and hyperferritinemia were found to be significant independent predictors for in-hospital mortality [HR 1.041 (95% CI 1.015-1.068), P = 0.002; HR 0.427 (95% CI 0.206-0.882), P = 0.022; HR 6.176 (95% CI 2.447-15.587), P < 0.001, respectively]. The AUROC curve was 0.88, with a cut-off value of ≥ 971 µg/L. COVID-19 patients with hyperferritinemia had a high proportion of organ dysfunction, were more likely to show hyper-inflammation, progressed to hemophagocytic lymphohistiocytosis, and indicated a higher proportion of death.

Hemophagocytic lymphohistiocytosis after SARS-CoV-2 vaccination.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has led to the approval of novel vaccines with different mechanisms of action. Until now, more than 4.7 billion persons have been vaccinated around the world, and adverse effects not observed in pre-authorization trials are being reported at low frequency. METHODS: We report a case of severe hemophagocytic lymphohistiocytosis (HLH) after SARS-CoV-2 immunization and performed a literature search for all reported cases of COVID-19 vaccine-associated HLH. RESULTS: A 24-year-old female developed HLH after immunization with the mRNA COVID-19 vaccine Comirnaty. Diagnosis was made according to HLH-2004 criteria; the HScore was 259 (> 99% HLH probability) with maximum ferritin of 138.244 µg/L. The patient was initially treated with intravenous immunoglobulins (IVIGs) and dexamethasone without response. The addition of the human interleukin 1 receptor antagonist Anakinra resulted in full recovery within 6 weeks after vaccination. A literature search revealed 15 additional cases of HLH after SARS-CoV-2 vaccination, the majority after immunization with Comirnaty (n = 7) or the viral vector vaccine Vaxzevria (n = 6). Treatment modalities included corticosteroids (n = 13), Anakinra (n = 5), IVIGs (n = 5), and etoposide (n = 2). Eight patients underwent combination treatment. Three of 16 patients died. CONCLUSION: COVID-19 vaccines may occasionally trigger HLH, and Anakinra may be an efficacious treatment option for this condition.

COVID-19-associated-mucormycosis: possible role of free iron uptake and immunosuppression.

COVID-19-associated-mucormycosis, commonly referred to as the "Black Fungus," is a rare secondary fungal infection in COVID-19 patients prompted by a group of mucor molds. Association of this rare fungal infection with SARS-CoV-2 infection has been declared as an endemic in India, with minor cases in several other countries around the globe. Although the fungal infection is not contagious like the viral infection, the causative fungal agent is omnipresent. Infection displays an overall mortality rate of around 50%, with many other secondary side effects posing a potential threat in exacerbating COVID-19 mortality rates. In this review, we have accessed the role of free iron availability in COVID-19 patients that might correlate to the pathogenesis of the causative fungal agent. Besides, we have analyzed the negative consequences of using immunosuppressive drugs in encouraging this opportunistic fungal infection.