Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger?

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.

A Japanese female with chronic mild anemia and primary iron overloading disease.

A 65-year-old woman died of congestive heart failure and diabetes mellitus. She had a history of mild anemia since adolescence, but received neither iron supplementation nor transfusion. The cirrhotic liver obtained at autopsy contained a large amount of iron. The heart and pancreas also had excess iron. Her iron overload may be due to excess iron absorption in the gut because of the absence of an iatrogenic background such as transfusion or iron supplementation.

Hyperferritinemia in the elderly can differentiate the bad from the worst: A retrospective cohort analysis.

Both total-body iron stores and inflammation influence the concentration of ferritin in the blood. Ferritin as an inflammatory marker might serve as a prognostic marker in the elderly. Therefore, we characterized the clinical circumstances and long-term outcomes of hyperferritinemia (> 1000 µg/L) in hospitalized elderly patients.A retrospective analysis of elderly (> 70 years) inpatients with ferritin levels of > 1000 µg/L in a tertiary medical center during a 3-year period. We obtained both laboratory and clinical data, assessing the potential association of high ferritin levels with long-term mortality.Overall, 242 patients (median age 79 years; median ferritin level 1436 µg/L) met the inclusion criteria and were followed for a median time of 18.6 months. Clinical outcomes were dismal for the whole cohort: the diagnosis of solid malignancy occurred in 23.5% of cases while 31% had a severe infection (ranging from sepsis to septic shock). The median survival time of the whole cohort was 4.7 months only. Within the cohort, risk stratification was feasible: higher ferritin levels differentiate between groups of patients who had a poor prognosis (with either septic shock or solid malignancy) and those who had a relatively favorable prognosis (patients diagnosed as suffering from sepsis without shock and patients with iatrogenic causes for hyperferritinemia).Hyperferritinemia in elderly inpatients is associated with high rates of mortality. Within this group of patients, differential ferritin levels enable further risk stratification. High ferritin levels in the elderly can differentiate the bad from the worst.

Cardiac T2* MR in patients with thalassemia major: a 10-year long-term follow-up.

The consequence of regular blood transfusion in patients with thalassemia major (TM) is iron overload. Herein, we report the long-term impact of chelation on liver iron concentration (LIC) and cardiac T2* MR in patients with TM. This is a retrospective cohort study over 10 years of adolescents and adults with TM aged at least 10 years who had their first cardiac T2* MR between September 2006 and February 2007. One-year chelation therapy was considered the unit of analysis. A total of 99 patients were included in this study with a median age of 18 years. The median cardiac T2* MR and LIC at baseline were 19 ms and 11.6 mg/g dw, respectively. During follow-up, 18 patients died and six underwent successful bone marrow transplantation. Factors associated with decreased survival were older age (HR 1.12, p = 0.014) and high risk cardiac T2* (HR 8.04, p = 0.004). The median cardiac T2* and LIC significantly improved over the 10-year follow-up period (p = 0.000011 and 0.00072, respectively). In conclusion, this long-term "real-life" study confirms that low cardiac T2* adversely impacts the overall survival in patients with TM. Higher baseline LIC predicts a larger reduction in LIC, and lower baseline cardiac T2* predicts a larger improvement in T2*.

Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.

The circadian clock is important for cellular and organ function. However, its function in sickle cell disease (SCD), a life-threatening hemolytic disorder, remains unknown. Here, we performed an unbiased microarray screen, which revealed significantly altered expression of circadian rhythmic genes, inflammatory response genes, and iron metabolic genes in SCD Berkeley transgenic mouse lungs compared with controls. Given the vital role of period 2 (Per2) in the core clock and the unrecognized role of Per2 in SCD, we transplanted the bone marrow (BM) of SCD mice to Per2Luciferase mice, which revealed that Per2 expression was up-regulated in SCD mouse lung. Next, we transplanted the BM of SCD mice to period 1 (Per1)/Per2 double deficient [Per1/Per2 double knockout (dKO)] and wild-type mice, respectively. We discovered that Per1/Per2 dKO mice transplanted with SCD BM (SCD → Per1/Per2 dKO) displayed severe irradiation sensitivity and were more susceptible to an early death. Although we observed an increase of peripheral inflammatory cells, we did not detect differences in erythrocyte sickling. However, there was further lung damage due to elevated pulmonary congestion, inflammatory cell infiltration, iron overload, and secretion of IL-6 in lavage fluid. Overall, we demonstrate that Per1/Per2 is beneficial to counteract elevated systemic inflammation, lung tissue inflammation, and iron overload in SCD.-Adebiyi, M. G., Zhao, Z., Ye, Y., Manalo, J., Hong, Y., Lee, C. C., Xian, W., McKeon, F., Culp-Hill, R., D' Alessandro, A., Kellems, R. E., Yoo, S.-H., Han, L., Xia, Y. Circadian period 2: a missing beneficial factor in sickle cell disease by lowering pulmonary inflammation, iron overload, and mortality.

Beta-thalassemia: renal complications and mechanisms: a narrative review.

OBJECTIVES: Beta-thalassemias are a group of recessively autosomal inherited disorders of hemoglobin synthesis, which, due to mutations of the beta-globin gene, lead to various degrees of defective beta-chain production, an imbalance in alpha/beta-globin chain synthesis, ineffective erythropoiesis, and anemia. Improved survival in thalassemic patients has led to the emergence of previously unrecognized complications, such as renal disease. METHODS: A comprehensive literature review through PubMed was undertaken to summarize the published evidence on the epidemiology and pathophysiology of renal disease in thalassemia. Literature sources published in English since 1990 were searched, using the terms beta-thalassemia, renal disease. RESULTS: Renal disease is considered to be the 4th cause of morbidity among patients with transfusion dependent thalassemia. Chronic anemia, hypoxia and iron overload are the main mechanisms implicated in development of renal injury, whereas several studies also suggested a contributive role of iron chelators. DISCUSSION AND CONCLUSION: Kidney disease may develop through progressive renal tubular and glomerular damage; thus, its early recognition is important in order to prevent and/or reverse deterioration. This review will provide an insight on the involved mechanisms implicated in kidney disease in thalassemic patients and will discuss the updates on diagnosis and prevention of renal complications in thalassemia.

Small alarmones (p)ppGpp regulate virulence associated traits and pathogenesis of Salmonella enterica serovar Typhi.

How Salmonella enterica serovar Typhi (S. Typhi), an important human pathogen, survives the stressful microenvironments inside the gastrointestinal tract and within macrophages remains poorly understood. We report here that S. Typhi has a bonafide stringent response (SR) system, which is mediated by (p)ppGpp and regulates multiple virulence-associated traits and the pathogenicity of the S. Typhi Ty2 strain. In an iron overload mouse model of S. Typhi infection, the (p)ppGpp0 (Ty2ΔRelAΔSpoT) strain showed minimal systemic spread and no mortality, as opposed to 100% death of the mice challenged with the isogenic wild-type strain. Ty2ΔRelAΔSpoT had markedly elongated morphology with incomplete septa formation and demonstrated severely attenuated motility and chemotaxis due to the loss of flagella. Absence of the Vi-polysaccharide capsule rendered the mutant strain highly susceptible to complement-mediated lysis. The phenotypes of Ty2ΔRelAΔSpoT was contributed by transcriptional repression of several genes, including fliC, tviA, and ftsZ, as found by reverse transcriptase quantitative polymerase chain reaction and gene complementation studies. Finally, Ty2ΔRelAΔSpoT had markedly reduced invasion into intestinal epithelial cells and significantly attenuated survival within macrophages. To the best of our knowledge, this was the first study that addressed SR in S. Typhi and showed that (p)ppGpp was essential for optimal pathogenic fitness of the organism.

Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis.

Anemia of lower-risk myelodysplastic syndromes (MDSs) and primary myelofibrosis (PMF) generally becomes resistant to available treatments, leading to red blood cell (RBC) transfusions, iron overload, shortened survival, and poor quality of life. The transforming growth factor-ß superfamily, including activins and growth differentiation factors (GDFs), is aberrantly expressed in lower-risk MDSs and PMF. Luspatercept (and sotatercept), ligand traps that particularly inhibit GDF11, lead to RBC transfusion independence in 10% to 50% of lower-risk MDSs resistant to available treatments, and have started to be used in PMF.

Effectiveness and Safety of Deferasirox in Thalassemia with Iron Overload: A Meta-Analysis.

Deferasirox (DFX) has recently been used to treat thalassemia with iron overload; however, its long-term effectiveness and safety await multi-year studies. In this study, a systematic meta-analysis was performed to assess the effectiveness and safety of DFX in the treatment of thalassemia with iron overload. We performed a systematic electronic literature search for randomized controlled studies of DFX in the Embase, Medline, Cochrane, and Chinese Biomedical Literature (CBM) databases from January 1990 to May 2018. Particular attention was paid to mortality, serum ferritin (SF), liver iron concentration (LIC), myocardial iron concentration, and adverse events (AEs). Six studies comparing DFX with deferoxamine (DFO) and placebo were enrolled. DFX was not better than DFO in lowering SF and LIC, with an exception that high DFX dose (> 30 mg/kg/day) was superior to DFO in LIC. Otherwise, AEs such as gastrointestinal problems appeared to be more common with DFX. DFX does not seem to be superior to DFO at low dose. Similar efficacy seems to be achievable depending on dose. However, the convenient oral administration of DFX has a higher compliance rate.

Deferasirox in the treatment of iron overload during myeloproliferative neoplasms in fibrotic phase: does ferritin decrement matter?

Few data are available on the treatment with DFX in patients with transfusion dependent Ph- Myeloproliferative Neoplasms in fibrotic phase. Here we report 48MPNpatients and iron overload treated with DFX. Starting DFX dose was 20 mg/Kg in 23 patients, 15 mg/Kg in 20 patientsand 10 mg/Kg in 5 patients. After a median treatment of 27.6 months, 5 patients achieved ferritin<500 ng/ml, 11 < 1000 ng/ml and 3 a reduction >50% of basal ferritin with a global response rate of 41%. As to hematological improvement, 9/47 patients (19.1%) showed a persistent rise of Hb>1.5 g/dl, with disappearance of transfusion requirement in 6 cases. The median OS from DFX initiation in patients with chelation response was 61.0 months compared to 15.8 months in patients without chelation efficacy. Treatment with DFX is feasible and effective in MPN with iron overload and a hematological improvement can occur in a sizeable rate of patients.

Clinical consequences of iron overload in patients with myelodysplastic syndromes: the case for iron chelation therapy.

INTRODUCTION: Patients with myelodysplastic syndromes (MDS) are at increased risk of iron overload due to ineffective erythropoiesis and chronic transfusion therapy. The clinical consequences of iron overload include cardiac and/or hepatic failure, endocrinopathies, and infection risk. Areas covered: Iron chelation therapy (ICT) can help remove excess iron and ultimately reduce the clinical consequences of iron overload. The authors reviewed recent (last five years) English-language articles from PubMed on the topic of iron overload-related complications and the use of ICT (primarily deferasirox) to improve outcomes in patients with MDS. Expert commentary: While a benefit of ICT has been more firmly established in other transfusion-dependent conditions, such as thalassemia, its role in reducing iron overload in MDS remains controversial due to the lack of prospective controlled data demonstrating a survival benefit. Orally administered chelation agents (e.g. deferasirox) are now available, and observational and/or retrospective data support a survival benefit of using ICT in MDS. The placebo-controlled TELESTO trial (NCT00940602) is currently examining the use of deferasirox in MDS patients with iron overload, and is evaluating specifically whether use of ICT to alleviate iron overload can also reduce iron overload-related complications in MDS and improve survival.

Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron.

The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus Hepcidin analogs may be useful for treatment of siderophilic infections.

Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation.

Iron overload is an adverse prognostic factor for patients undergoing hematopoietic stem cell transplantation (HSCT). In the HSCT setting, pretransplant and early posttransplant ferritin and transferrin saturation were found to be highly elevated due to high transfusion requirements. In addition to that, post-HSCT iron overload was shown to be related to infections, hepatic sinusoidal obstruction syndrome, mucositis, liver dysfunction, and acute graft-versus-host disease. Hyperferritinemia causes decreased survival rates in both pre- and posttransplant settings. Serum ferritin levels, magnetic resonance imaging, and liver biopsy are diagnostic tools for iron overload. Organ dysfunction due to iron overload may cause high mortality rates and therefore sufficient iron chelation therapy is recommended in this setting. In this review the management of iron overload in adult HSCT is discussed.

Increased Bone Marrow Iron Scores Are Strongly Correlated With Elevated Serum Ferritin Levels and Poorer Survival in Patients With Iron Overload That Underwent Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Experience.

BACKGROUND: Iron overload is one of the most significant problems as a leading cause of death in patients with leukemia and those who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). METHODS: In the current study, we retrospectively evaluated the bone marrow iron scores (BMIS) in patients who underwent alloHSCT (n = 125). The first available bone marrow biopsy specimens prior to the alloHSCT procedure or date of hospitalization (control group) were assessed in a blinded fashion using a standardized scoring system. RESULTS: A total of 125 patients were enrolled in the study. Seventy-six (60.8%) of the patients were male, and 49 (39.2%) were female. The median level of pre-transplant serum ferritin was 1023.00 ng/mL (range, 393.80-1627.50 ng/mL). The majority of the patients were diagnosed with acute leukemia (83; 66.4%) and lymphomas (20; 16.0%). The median time for neutrophil engraftment was 14.00 days (range, 13.00-16.00 days) and 11.00 days (range, 10.00-14.00 days) for platelet engraftment. The peri-transplant mortality was similar to international mortality rates (3; 2.4%). The overall survival and disease-free survival were strongly correlated with the degree of BMIS, and both were significantly poorer in patients with high bone marrow iron content (P < .001 and P = .012, respectively). CONCLUSION: The validation of BMIS for risk stratification in patients who undergo alloHSCT may predict posttransplant outcomes.

Increased Hepatic Iron Content Predicts Poor Survival in Patients With Iron Overload Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation.

AIM: Iron overload results in increased infection, venous-oclusive disease and hepatic dysfunction in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients. Liver is one of the most common sites of iron overload. PATIENTS AND METHODS: A total of 50 alloHSCT recipients that underwent liver biopsy in Erciyes Stem Cell Transplantation Hospital, Erciyes University, between 2004 and 2011 were enrolled in the study. The liver biopsy specimens have been obtained from the archives of Erciyes University, Department of Pathology and stainned for iron content. RESULTS: The mean age was found 34 ± 11 years. For median overall survival (OS); 53 months (min-max: 41-65) in patients with grade 0, 55 months (min-max: 47-64) in patients with grade 1, in patients with grade 2 patients 25.4 months (11.5-39.4 ), grade 3 patients 29.3 months (min-max: 12.3-46.3) and grade 4 patients 2.6 months (min-max: 2.0-3.3). Overall survival was correlated with the degree of liver iron content and it was statistically significant in Kaplan-Meier analysis (P < .001). Disease-free survival was found (DFS); grade 0 patients 47.1 months (min-max: 32.0-62.0), grade 1 patients 36.9 months (min-max: 21.0-65.0), grade 2 patients 23.5 months (min-max: 12.0-59.0), grade 3 patients 27.4 months (min-max: 5.3-59.3) and grade 4 patients 2.6 months (min-max: 2.0-3.0). For DFS; it was negatively correlated with the degree of liver iron content nevertheless; it was not was statistically significant in Kaplan-Meier analysis (P = .093).Hepatic iron overload might be associated with poor survival in patients with transfusional iron overload that underwent alloHSCT. CONCLUSION: Hepatic iron content might be associated with poorer prognosis in patients with iron overload that underwent alloHSCT.

SF3B1-mutated myelodysplastic syndrome with ring sideroblasts harbors more severe iron overload and corresponding over-erythropoiesis.

OBJECTIVE: To clarify the possible biological differences and implication of the SF3B1 gene for patients with MDS-RS (myelodysplastic syndromes with ring sideroblasts). METHODS: Sanger sequencing was performed on mutation hotspots of the SF3B1 gene in MDS-RS patients. The differences between the SF3B1 mutated and wild-type subsets, including the ultrastructure of erythroid precursors, iron profile parameters, erythropoiesis-related measurements, as well as clinical features, were analyzed. RESULTS: SF3B1 mutations were detected in 33 out of fifty-two MDS-RS patients (63%). The vast majority of patients with mutations (94%) were categorized in the lower risk group according to the IPSS (International Prognostic Scoring System), in contrast to only fifty-eight percent of the wild-type cases. In addition to the notably higher percentages of erythroblasts and ring sideroblasts in patients with mutations, abundant electron-dense granules in the mitochondria of the erythroid precursors were clearly observed. Moreover, patients with mutations presented both improper iron uptake and distribution (lower serum hepcidin-25 concentration, P=0.028) and enhanced erythropoietic activity (higher soluble transferrin receptor level, P=0.132; higher growth differentiation factor 15 concentration, P<0.001). Finally, MDS-RS patients carrying SF3B1 mutations had a better overall survival (median 38 vs. 18 months, P=0.001) compared to those without mutations. By multivariable analysis, the prognostic significance of the SF3B1 mutation was primarily accounted for by IPSS risk categorization. CONCLUSION: MDS-RS patients carrying SF3B1 mutations harbored a more severe iron overload and corresponding over-erythropoiesis. The better overall survival of SF3B1-mutated MDS-RS patients may be mainly due to the clustering of patients with lower risk disease in this group.