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.

Αlpha-thalassemia: A practical overview.

α-Thalassemia is an inherited blood disorder characterized by decreased synthesis of α-globin chains that results in an imbalance of α and ß globin and thus varying degrees of ineffective erythropoiesis, decreased red blood cell (RBC) survival, chronic hemolytic anemia, and subsequent comorbidities. Clinical presentation varies depending on the genotype, ranging from a silent or mild carrier state to severe, transfusion-dependent or lethal disease. Management of patients with α-thalassemia is primarily supportive, addressing either symptoms (eg, RBC transfusions for anemia), complications of the disease, or its transfusion-dependence (eg, chelation therapy for iron overload). Several novel therapies are also in development, including curative gene manipulation techniques and disease modifying agents that target ineffective erythropoiesis and chronic hemolytic anemia. This review of α-thalassemia and its various manifestations provides practical information for clinicians who practice beyond those regions where it is found with high frequency.

Hereditary hemochromatosis with homozygous C282Y HFE mutation: possible clinical model to assess effects of elevated reactive oxygen species on the development of cardiovascular disease.

Hereditary hemochromatosis with the homozygous C282Y HFE mutation (HH-282H) is a genetic condition which causes iron overload (IO) and elevated reactive oxygen species (ROS) secondary to the IO. Interestingly, even after successful iron removal therapy, HH-282H subjects demonstrate chronically elevated ROS. Raised ROS are also associated with the development of multiple cardiovascular diseases and HH-282H subjects may be at risk to develop these complications. In this narrative review, we consider HH-282H subjects as a clinical model for assessing the contribution of elevated ROS to the development of cardiovascular diseases in subjects with fewer confounding clinical risk factors as compared to other disease conditions with high ROS. We identify HH-282H subjects as a potentially unique clinical model to assess the impact of chronically elevated ROS on the development of cardiovascular disease and to serve as a clinical model to detect effective interventions for anti-ROS therapy.

Research on the clinical factors of cardiac iron deposition in children with beta-thalassemia major.

Magnetic resonance imaging (MRI) T2* is the gold standard for detecting iron deposition in cardiac tissue, but the technique has limitations and cannot be fully performed in paediatric thalassemia patients. The aim of this study was to analyse clinical data to identify other predictors of cardiac iron deposition. A retrospective analysis was performed on 370 children with ß-TM. According to the cardiac MRI results, patients were allocated to a cardiac deposition group and noncardiac deposition group. Multivariate analysis revealed that genotype and corrected QT interval were associated with cardiac iron deposition, indicating that the-ß0/ß0 genotype conferred greater susceptibility to cardiac iron deposition. Receiver operating characteristic curve (ROC) analysis was performed, and the area under the curve (AUC) of genotype was 0.651. The AUC for the corrected QT interval was 0.711, at a cut-off value of 418.5 ms. ROC analysis of the combined genotype and corrected QT interval showed an AUC of 0.762 with 81.3% sensitivity and 64.7% specificity. Compared to patients with the ß+/ß+ and ß0ß+ genotypes, ß0ß0 children with ß-TM were more likely to have cardiac iron deposition.  Conclusion: The genotype and QTc interval can be used to predict cardiac iron deposition in children with ß-TM who are unable to undergo MRI T2 testing.

Iron Overload in Children With Leukemia; Identification of a Cutoff Value for Serum Ferritin Level.

OBJECTIVE: To determine the prevalence of iron overload in children with acute lymphoblastic leukemia (ALL) after treatment cessation and establish a cutoff value for serum ferritin level as an indicator of iron overload. BACKGROUND: Early detection and monitoring of iron overload in patients with leukemia is crucial. METHODS: In this prospective cohort study, 66 pediatric patients with ALL who were treated at a tertiary referral center affiliated with Shiraz University of Medical Sciences in Shiraz, Southern Iran, were investigated from July 2020 to December 2022. Serum ferritin levels were measured 6 months after treatment completion. T2* magnetic resonance imaging of the liver and heart was done for all patients. The receiver operating characteristic curve was used to illustrate the area under the receiver operating characteristic curve to assess the diagnostic value of serum ferritin level and total transfusion volume. RESULTS: A total of 24 patients (36.4%) had iron overload in the heart or liver based on T2 magnetic resonance imaging findings. Serum ferritin level was a highly accurate diagnostic marker for iron overload in pediatric patients with ALL, with a sensitivity of 95.8%, and specificity of 85.7% for a cutoff value of 238.5 ng/mL. Also, blood transfusion was a good predictor of iron overload a sensitivity of 75% and specificity of 81% for a cutoff value of 28.3 mL/kg. CONCLUSION: We identified specific cutoff values for serum ferritin and blood transfusion volume to predict iron overload with high sensitivity and specificity. These markers offer a cost-effective and accessible approach for periodic screening of iron deposition, particularly in resource-constrained settings.

New Perspectives on Circulating Ferritin: Its Role in Health and Disease.

The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin saturation-the ratio between the serum iron concentration and serum transferrin-usually reflects iron availability. Additionally, serum ferritin is commonly used as a surrogate of tissue iron levels. Low serum ferritin values are interpreted as a sign of iron deficiency, and high values are the main indicator of pathological iron overload. However, in situations of inflammation, serum ferritin levels may be very high, independently of tissue iron levels. This presents a particularly puzzling challenge for the clinician evaluating the overall iron status of the patient in the presence of an inflammatory condition. The increase in serum ferritin during inflammation is one of the enigmas regarding iron metabolism. Neither the origin, the mechanism of release, nor the effects of serum ferritin are known. The use of serum ferritin as a biomarker of disease has been rising, and it has become increasingly diverse, but whether or not it contributes to controlling the disease or host pathology, and how it would do it, are important, open questions. These will be discussed here, where we spotlight circulating ferritin and revise the recent clinical and preclinical data regarding its role in health and disease.

Testing and Management of Iron Overload After Genetic Screening-Identified Hemochromatosis.

Importance: HFE gene-associated hereditary hemochromatosis type 1 (HH1) is underdiagnosed, resulting in missed opportunities for preventing morbidity and mortality. Objective: To assess whether screening for p.Cys282Tyr homozygosity is associated with recognition and management of asymptomatic iron overload. Design, Setting, and Participants: This cross-sectional study obtained data from the Geisinger MyCode Community Health Initiative, a biobank of biological samples and linked electronic health record data from a rural, integrated health care system. Participants included those who received a p.Cys282Tyr homozygous result via genomic screening (MyCode identified), had previously diagnosed HH1 (clinically identified), and those negative for p.Cys282Tyr homozygosity between 2017 and 2018. Data were analyzed from April 2020 to August 2023. Exposure: Disclosure of a p.Cys282Tyr homozygous result. Main Outcomes and Measures: Postdisclosure management and HFE-associated phenotypes in MyCode-identified participants were analyzed. Rates of HFE-associated phenotypes in MyCode-identified participants were compared with those of clinically identified participants. Relevant laboratory values and rates of laboratory iron overload among participants negative for p.Cys282Tyr homozygosity were compared with those of MyCode-identified participants. Results: A total of 86 601 participants had available exome sequences at the time of analysis, of whom 52 994 (61.4%) were assigned female at birth, and the median (IQR) age was 62.0 (47.0-73.0) years. HFE p.Cys282Tyr homozygosity was disclosed to 201 participants, of whom 57 (28.4%) had a prior clinical HH1 diagnosis, leaving 144 participants who learned of their status through screening. There were 86 300 individuals negative for p.Cys282Tyr homozygosity. After result disclosure, among MyCode-identified participants, 99 (68.8%) had a recommended laboratory test and 36 (69.2%) with laboratory or liver biopsy evidence of iron overload began phlebotomy or chelation. Fifty-three (36.8%) had iron overload; rates of laboratory iron overload were higher in MyCode-identified participants than participants negative for p.Cys282Tyr homozygosity (females: 34.1% vs 2.1%, P < .001; males: 39.0% vs 2.9%, P < .001). Iron overload (females: 34.1% vs 79.3%, P < .001; males: 40.7% vs 67.9%, P = .02) and some liver-associated phenotypes were observed at lower frequencies in MyCode-identified participants compared with clinically identified individuals. Conclusions and Relevance: Results of this cross-sectional study showed the ability of genomic screening to identify undiagnosed iron overload and encourage relevant management, suggesting the potential benefit of population screening for HFE p.Cys282Tyr homozygosity. Further studies are needed to examine the implications of genomic screening for health outcomes and cost-effectiveness.

Using artificial intelligence to improve body iron quantification: A scoping review.

This scoping review explores the potential of artificial intelligence (AI) in enhancing the screening, diagnosis, and monitoring of disorders related to body iron levels. A systematic search was performed to identify studies that utilize machine learning in iron-related disorders. The search revealed a wide range of machine learning algorithms used by different studies. Notably, most studies used a single data type. The studies varied in terms of sample sizes, participant ages, and geographical locations. AI's role in quantifying iron concentration is still in its early stages, yet its potential is significant. The question is whether AI-based diagnostic biomarkers can offer innovative approaches for screening, diagnosing, and monitoring of iron overload and anemia.

[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.

How I treat non-transfusion-dependent ß-thalassemia.

The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent ß-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.

Autoimmune Hepatitis Disguised as Iron Overload Syndrome: Diagnostic Dilemma in a Nigerian Man.

Autoimmune hepatitis (AIH) is an extremely rare cause of chronic liver disease (CLD) in sub-Saharan Africa-there have only been 3 reported cases of AIH in Nigeria, a country of about 200 million people. We report the first case of AIH in a male patient in Nigeria and highlight its unusual presentation. A 41-year-old man with jaundice and malaise for 3 months was referred for evaluation after investigations revealed deranged liver enzymes and a cirrhotic liver. Laboratory evaluation revealed high serum immunoglobulin G, but there was also marked elevation of serum ferritin and transferrin saturation, resulting in a diagnostic dilemma between AIH and an iron overload condition such as hemochromatosis. A liver biopsy was crucial in providing a definitive diagnosis of AIH. Despite its rarity, clinicians should maintain a high index of suspicion for AIH in sub-Saharan Africa and should proceed to a liver biopsy when the cause of CLD is unclear.

Noninvasive liver iron quantification by MRI using refocused gradient-echo (bSSFP): preliminary results.

PURPOSE: To evaluate the feasibility of using a balanced steady-state free precession sequence (bSSFP) to determine liver iron content (LIC). METHOD: Thirty-five consecutive patients with liver iron overload were examined with bSSFP. Signal intensity ratios of liver parenchyma to paraspinal muscles were retrospectively correlated with LIC values obtained by FerriScan, which was used as the reference method. Combinations of bSSFP protocols were also evaluated. The best combination was utilized to calculate LIC from bSSFP data. The sensitivity and specificity for the therapeutically relevant LIC threshold of 80 µmol/g (4.5 mg/g) were determined. RESULTS: LIC values ranged from 24 to 756 µmol/g. The best SIR-to-LIC correlation of a single protocol was obtained with a 3.5-ms repetition time (TR) and 17° excitation flip angle (FA). A combination of protocols with TRs of 3.5, 5, and 6.5 ms, each at 17° FA, yielded a superior correlation. LIC values calculated using this combination resulted in a sensitivity/specificity of 0.91/0.85. CONCLUSION: bSSFP is basically suitable to determine LIC. Its advantages are high SNR efficiency and the ability to acquire the entire liver in a breath hold without acceleration techniques. KEY POINTS: · The bSSFP sequence is suited to quantify liver iron overload.. · bSSFP has a high scanning efficiency and potential for LIC screening.. · Despite susceptibility artifacts, the LIC determined from bSSFP data showed high accuracy.. CITATION FORMAT: · Wunderlich AP, Cario H, Götz M et al. Noninvasive liver iron quantification by MRI using refocused gradient-echo (bSSFP): preliminary results. Fortschr Röntgenstr 2023; 195: 804 - 808.

Haemochromatosis.

Haemochromatosis is one of the most common genetic diseases affecting patients of northern European ancestry. It is overdiagnosed in patients without iron overload and is underdiagnosed in many patients. Early diagnosis by genetic testing and therapy by periodic phlebotomy can prevent the most serious complications, which include liver cirrhosis, liver cancer, and death. This Seminar includes an update on the origins of haemochromatosis; and an overview pathophysiology, genetics, natural history, signs and symptoms, differential diagnoses, treatment with phlebotomy, outcomes, and future directions.

Consensus Statement on the definition and classification of metabolic hyperferritinaemia.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.

Can biomarkers predict myocardial iron overload in children with thalassemia major?

AIM: Beta-thalassemia major requires regular blood transfusions throughout life, which in turn leads to iron accumulation in the body. While cardiac T2* MRI is the gold standard in determining cardiac iron accumulation, it is not always feasible, which has led to the search for new biomarkers. Herein, the value of growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide in predicting cardiac iron accumulation is investigated in asymptomatic children with beta-thalassemia major. MATERIALS AND METHOD: Forty-one patients aged 11-21 years and 41 age-, gender-, body mass index-matched healthy controls were included. Serum growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide levels were compared between the patients and controls. Additionally, the relations of these biomarkers with cardiac and liver T2 * MRI were investigated in the patients. RESULTS: In the patients, growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide levels were higher than healthy controls (p < 0.001, p = 0.025, p < 0.001, respectively). There were no significant correlations of growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide levels with both cardiac and liver T2 * MRI measurements. While there was no significant correlation of serum galectin-3 with cardiac T2 * MRI measurements, a negative correlation was found with liver T2 * MRI measurements (p = 0.040, rho = -0.325). CONCLUSION: All three biomarkers investigated in this study failed to predict myocardial iron accumulation in asymptomatic children with beta-thalassemia major. However, a weak relation between serum galectin-3 level and hepatic iron accumulation was demonstrated.

Electrophysiological properties and heart rate variability of patients with thalassemia major in Jakarta, Indonesia.

Beta thalassemia major (TM) is a common hereditary disease in Indonesia. Iron overload due to regular transfusion may induce myocardial iron deposition leading to electrophysiological dysfunction and functional disorders of the heart. Ventricular arrhythmia is one of the most common causes of sudden cardiac death in thalassemia patients. This cross-sectional study of 62 TM patients aged 10-32 years in Cipto Mangunkusumo General Hospital was done to assess their electrophysiological properties and heart rate variability, including 24- hour Holter monitoring, signal averaged electrocardiogram (SAECG) for detection of ventricular late potential (VLP), and determination of heart rate variability (HRV). We also assessed their 12-lead ECG parameters, such as P wave, QRS complex, QT/ QTc interval, QRS dispersion, and QT/ QTc dispersion. Iron overload was defined by T2-star magnetic resonance (MR-T2*) values of less than 20 ms or ferritin level greater than 2500 ng/mL. Subjects were grouped accordingly. There were significant differences of QTc dispersion (p = 0.026) and deceleration capacity (p = 0.007) between MR-T2* groups. Multivariate analysis showed an inverse correlation between QTc dispersion and MR-T2* values. There was a proportional correlation between heart rate deceleration capacity in the low MR-T2* group (p = 0.058) and the high ferritin group (p = 0.007). No VLPs were detectable in any patients. In conclusion, prolonged QTc dispersion and decreased heart rate deceleration capacity were significantly correlated with greater odds of iron overload among patients with Thalassemia major.

Iron chelation therapy.

Iron overload is a pathological condition resulting from a congenital impairment of its regulation, increased intestinal iron absorption secondary to bone marrow erythroid hyperplasia, or a chronic transfusional regimen. In normal conditions, intracellular and systemic mechanisms contribute to maintaining iron balance. When this complex homeostatic mechanism fails, an iron overload could be present. Detecting an iron overload is not easy. The gold standard remains the liver biopsy, even if it is invasive and dangerous. Identifying iron using noninvasive techniques allowed a better understanding of the rate of iron overload in different organs, with a low risk for the patient. Estimating serum ferritin (mg/L) is the easiest and, consequently, the most employed diagnostic tool for assessing body iron stores, even if it could be a not specific method. The most common hematological causes of iron overload are myelodysplastic syndromes, sickle cell disease, and thalassemia. In all of these conditions, three drugs have been approved for the treatment of iron overload: deferiprone, deferoxamine, and deferasirox. These chelators have been demonstrated to help lower tissue iron levels and prevent iron overload complications, improving event-free survival (EFS). Nowadays, the decision to start chelation and which chelator to choose remains the joint decision of the clinician and patient.