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.

Cytokine storm in severe COVID-19 pneumonia.

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy.

Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disorder resulting from genetic and environmental factors. Hyperferritinemia has been associated with increased hepatic iron stores and worse outcomes in patients with NAFLD. The aim of this study was to evaluate the prevalence of variants of iron-related genes and their association with hyperferritinemia, hepatic iron stores and liver disease severity in patients with NAFLD. METHODS: From a cohort of 328 individuals with histological NAFLD, 23 patients with ferritin >750 ng/ml and positive iron staining, and 25 controls with normal ferritin and negative iron staining, were selected. Patients with increased transferrin saturation, anemia, inflammation, ß-thalassemia trait, HFE genotype at risk of iron overload and ferroportin mutations were excluded. A panel of 32 iron genes was re-sequenced. Literature and in silico predictions were employed for prioritization of pathogenic mutations. RESULTS: Patients with hyperferritinemia had a higher prevalence of potentially pathogenic rare variants (73.9% vs. 20%, p = 0.0002) associated with higher iron stores and more severe liver fibrosis (p <0.05). Ceruloplasmin was the most mutated gene and its variants were independently associated with hyperferritinemia, hepatic siderosis, and more severe liver fibrosis (p <0.05). In the overall cohort, ceruloplasmin variants were independently associated with hyperferritinemia (adjusted odds ratio 5.99; 95% CI 1.83-19.60; p = 0.0009). CONCLUSIONS: Variants in non-HFE iron genes, particularly ceruloplasmin, are associated with hyperferritinemia and increased hepatic iron stores in patients with NAFLD. Carriers of such variants have more severe liver fibrosis, suggesting that genetic predisposition to hepatic iron deposition may translate into liver disease. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is a common disease which can progress to cirrhosis and liver cancer. Increased levels of serum ferritin are often detected in patients with NAFLD and have been associated with altered iron metabolism and worse patient outcomes. We found that variants of genes related to iron metabolism, particularly ceruloplasmin, are associated with high ferritin levels, hepatic iron deposition and more severe liver disease in an Italian cohort of patients with NAFLD.

Conservative Management of Hyperferritinemia in Hemolytic Disease of the Fetus and Newborn: A Case Report and Review of the Literature.

We report a newborn with hemolytic disease of the fetus and newborn (HDFN) with rapid resolution of extreme hyperferritinemia without chelation. An infant born at 35+3 weeks with HDFN and a history of 3 intrauterine transfusions developed severe hyperferritinemia (maximum, 8258 mcg/L) without evidence of toxic iron deposition on liver biopsy. Her hyperferritinemia was managed with observation alone, and ferritin levels normalized rapidly. This case supports observation as being the preferred alternative to chelation therapy for significant hyperferritinemia in newborns with HDFN in the absence of demonstrated toxic end-organ iron deposition. We also include a review of the related available literature.