A case series highlighting structured hematological, biochemical and molecular approach to clinical oral iron refractoriness in children: A pressing need for a 3-tier system for classification of variants in TMPRSS6 gene.

In current study, we discuss clinical oral iron refractoriness cases and highlight need for a classification system to define TMPRSS6 gene variants. Out of 231 cases of microcytic hypochromic anemia screened (Sept 2019-Dec 2020), 17 cases (7.35%) with unexplained iron refractoriness (URIDA) phenotype were enrolled after ruling out secondary causes and compliance related issues. 11 (65%) had absent/negligible response (0-0.4 g/dl Hb rise) while 6 (35%) partial (0.5-0.9 g/dl Hb rise) response to initial iron trial at 4-8 weeks. Of these 17 cases, inappropriate hepcidin levels (normal-high) were noted in 11/15 (73%) tested. TSAT/Hepcidin ratio was low in 13/15 (87%). Genetic analysis of TMPRSS6 gene by NGS revealed variations in 15/17 (88%) cases. 10/15 cases with variations harbored a common splice site INDEL that was noted to be pathogenic SNP (MAF-0.19) on case-control association study in combination with other known missense SNPs with an odds ratio of 6.38 and relative risk 2.66 (p- < 0.01).

Parenteral iron therapy and phosphorus homeostasis: A review.

Phosphorus has an essential role in cellular and extracellular metabolism; maintenance of normal phosphorus homeostasis is critical. Phosphorus homeostasis can be affected by diet and certain medications; some intravenous iron formulations can induce renal phosphate excretion and hypophosphatemia, likely through increasing serum concentrations of intact fibroblast growth factor 23. Case studies provide insights into two types of hypophosphatemia: acute symptomatic and chronic hypophosphatemia, while considering the role of pre-existing conditions and comorbidities, medications, and intravenous iron. This review examines phosphorus homeostasis and hypophosphatemia, with emphasis on effects of iron deficiency and iron replacement using intravenous iron formulations.

Neuronopathic Gaucher disease presenting with microcytic hypochromic anemia.

Gaucher disease (GD) is caused by a hereditary deficiency of glucocerebrosidase, resulting in accumulation of glucosylceramide and potentially manifesting as hepatosplenomegaly. We report the case of a 15-month-old boy with chronic neuronopathic GD. The patient had prolonged anemia despite continued iron supplementation for 3 months. White blood count (WBC), hemoglobin (Hb), platelet count, and corrected reticulocyte count were 3,300 /µL, 8.7 g/dL, 90,000 /µL, and 0.55, respectively. The patient had microcytic hypochromic anemia with mildly elevated ferritin. Physical examination revealed hepatosplenomegaly. Bone-marrow aspiration showed sheets of Gaucher cells. Glucocerebrosidase activity in monocytes was significantly lower than normal. Genetic analysis revealed a homozygous L444P mutation of GBA, and he was diagnosed with type 1 GD. Enzyme replacement treatment (ERT) consisting of imiglucerase was initiated and was effective; WBC, Hb, and platelet count gradually normalized and the hepatosplenomegaly improved. However, when the patient entered elementary school, he showed mild impaired cognitive function, and supranuclear gaze palsy occurred the same year. He was ultimately diagnosed with type 3 GD and continued ERT. Pediatric hemato-oncologists should be aware of GD, especially when patients exhibit anemia refractory to iron therapy, radiologic bone deformity, neurologic signs or symptoms, and growth retardation.

Favourable improvement in haematological parameters in response to oral iron and vitamin C combination in children with Iron Refractory Iron Deficiency Anemia (IRIDA) phenotype.

Treatment in IRIDA focuses on use of intravenous iron preparations to circumvent oral absorptive defect resulting from high levels of hepcidin due to TMPRSS6 gene variations. However, recent case reports and recommendations on atypical microcytic hypochromic anemias advocate use of oral iron and vitamin c trial before parenteral iron, as the same results in comparable improvement in haemoglobin. We prospectively evaluated our IRIDA cohort (n = 7) with oral iron and vitamin c dose over a period of 10 weeks and noted complete response in majority (6/7 = 86%) with >2 g/dL rise in Hb along with significant improvement of other iron related indices.

How to Supplement Iron in Patients with Renal Anemia.

Iron deficiency is a major cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) and is often observed in chronic kidney disease (CKD) patients with anemia. With iron supplementation, ESA doses can be decreased, resulting in lower treatment costs and possibly lower cardiovascular risks that are associated with high-dose ESA therapy. The 2012 Kidney Disease: Improving Global Outcomes Guideline specified ferritin ≤ 500 ng/ml and transferrin saturation (TSAT) ≤ 30% as thresholds of iron parameters for CKD patients. However, long-term safety (in terms of mortality, cardiovascular/infection risk and tissue deposition) of high-dose intravenous iron supplementation with such high target levels of ferritin/TSAT has not been confirmed. Recently, there has been increase in the use of intravenous iron and average ferritin levels in dialysis patients in the United States. Clinical trials conducted so far have been underpowered to conclusively establish the long-term safety of intravenous iron supplementation. Results from observational studies are conflicting, and many experimental studies have even shown negative effects of intravenous iron. Clearly, randomized clinical trials are urgently needed, studying various doses of intravenous iron, with sufficient patient numbers and longer observation periods, to investigate mortality, cardiovascular effects and infection risks of this treatment. Until the long-term safety of iron supplementation at high doses is established, a more prudent decision on iron supplementation with lower target levels of ferritin/TSAT seems reasonable, in light of the decades of experience with ESA that has shown that definitive clinical outcomes have been dissociated from surrogate outcomes (especially hemoglobin concentration).

Cerebral dural sinus thrombosis associated with adenomyosis: a case report.

We report a case of cerebral venous thrombosis (CVT) associated with a giant adenomyosis. At admission, the patient demonstrated generalized seizures and consciousness disturbance. Brain fluid-attenuated inversion recovery magnetic resonance imaging revealed a localized, high-intensity region in the left frontal lobe. Subsequent brain angiography showed that right internal carotid angiograms display abrupt termination of the anterior half of the superior sagittal sinus and a filling defect in the lateral part of the left transverse sinus. The patient complicated with iron deficiency anemia (IDA) and adenomyosis with higher levels of serum carbohydrate antigen 125 (CA125) and d-dimer. After 1 year from onset, intermittent severe menalgia and headache persisted, and blood examination revealed abnormal values; the patient was receiving oral medications. Finally, adenomyosis resection was performed with a favorable outcome, and no recurrence was observed during the 2-year follow-up period. We conclude that IDA and increased CA125 levels may have promoted hypercoagulability and CVT. This report emphasizes the possible relationship between CVT and adenomyosis.

Cutaneous siderosis after intramuscular iron injections: a case report.

Skin reactions against injected or implanted foreign materials are not rare. Siderosis is a disease characterized by the accumulation of iron in various tissues. Brownish-gray discoloration of the skin can be seen as a side-effect on the injection area after the parenteral iron treatment. Here, we present cutaneous siderosis case developed after multiple intramuscular iron injection on the gluteal region for iron-deficiency anemia. Development of cutaneous siderosis after intramuscular iron injection rarely has been reported in the literature before.

Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy.

Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis. Clinical and biological presentation did not fit any previously described genetic iron-deficiency anemia. Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA, and no additional mutations in known iron-regulatory genes. Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued oral iron therapy. Our results have implications for genetic testing in early childhood iron deficiency anemia. Importantly, they emphasize that whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations, including hypomorphic mutations or compound heterozygosity leading to different phenotypes in known Mendelian diseases.

[Whipple's disease--a rare and severe systemic infection]. / Whipplen tauti--harvinainen ja vakava systeemi-infektio.

Whipple's disease is a very rare systemic infection caused by the bacterium Tropheryma whipplei. If untreated it can be fatal. Approximately one thousand infections caused by this microorganism have been reported globally. Our two patients with Whipple's disease suffered from weight loss, diarrhea and abdominal pain and distention, and were diagnosed with microcytic anemia and significant hypoalbuminemia. In the third patient the manifestation was blood culture negative endocarditis causing aortic insufficiency, atrial fibrillation and coronary embolisation. Antimicrobial drug therapy was effective for all three patients.

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts.

BACKGROUND: Hypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in samples from a DMT1-mutant patient before and after treatment with erythropoietin, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. DESIGN AND METHODS: Colony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To enable a comparison with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. RESULTS: Erythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration increased activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in having increased plasma iron but differed by having functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. CONCLUSIONS: Erythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.

[A case of posterior reversible encephalopathy syndrome occurring after anemia correction].

A 53-year-old woman was admitted to our hospital with headache and convulsion. Advanced anemia with a Hb level of 3.5 g/dl had been detected about a month earlier, and it had been treated by iron administration to achieve a Hb level of 8.9 g/dl. The patient developed status epilepticus on admission. The blood pressure was elevated, and brain diffusion weighted imaging and fluid attenuated inversion recovery imaging revealed high intensity areas in the bilateral posterior and parietal lobes, right frontal lobe, and right basal ganglia. The cerebrospinal fluid protein was elevated. The convulsions settled after continuous infusion of thiamylal under mechanical ventilation. Subsequently, the patient became conscious, and the brain MRI abnormalities gradually disappeared. While a number of factors such as hypertension, medication and others have been reported as causes of posterior reversible encephalopathy syndrome (PRES), comparatively rapid anemia correction could also possibly precipitate PRES as like as this case. Thus anemia correction needs to be undertaken carefully.

Clinical efficacy of two forms of intravenous iron--saccharated ferric oxide and cideferron--for iron deficiency anemia.

Over 90% of iron deficiency anemia cases are due to iron deficiency associated with depletion of stored iron or inadequate intake. Parenteral iron supplementation is an important part of the management of anemia, and some kinds of intravenous iron are used. However, few studies have evaluated the clinical efficacy of these drugs. The purpose of this study was to compare and assess the clinical efficacy of two types of intravenous iron injection, saccharated ferric oxide (SFO) and cideferron (CF). Medical records were obtained for 91 unrelated Japanese anemia patients treated with SFO (n = 37) or CF (n = 54) from May 2005 to May 2010 at Gunma University Hospital. Patients treated with blood transfusion, erythropoietin or oral iron were excluded. Hemoglobin (Hb) values measured on day 0, 7 and 14 were used to assess the efficacy of intravenous irons. A significant increase was observed in the mean Hb value by day 14 of administration in both the CF group and SFO group, and the mean Hb increase due to administration of CF for 7 days was comparable to that of SFO for 14 days. Age and sex did not affect improvement of Hb value. CF is fast acting and highly effective compared with SFO for the treatment of iron deficiency anemia. The use of CF may shorten a therapeutic period for iron deficiency anemia, and CF may be feasible for reducing the hospitalization period.

[Treatment with beta-erythropoietin in lung cancer--effectiveness and quality of life improvement in clinical practice]. / Eritropoetin-béta-kezelés tüdôrákban--hatékonyság és életminôség-javulás a klinikai gyakorlatban.

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases patient's quality of life, and worsens the dose-intensity of chemotherapy. The aim of this retrospective data-analysis was to evaluate quality of life and hemoglobin levels in 19 consecutive lung cancer patients receiving beta-erythropoietin, due to chemotherapy induced anemia. A self developed, patient source data based quality of life questionnaire was used. The mean pre-erythropoietin hemoglobin concentration of the patients was 96.31±6.72 g/L (mean±SD), the post-treatment hemoglobin concentration 111.63±14.05 g/L (p<0.05). During the chemotherapy of the 19 patients with lung cancer, transfusion was given only four times. The mean quality of life total score of the patients increased significantly during erythropoietin treatment that was resulted by the improvements of scores determining dizziness, tachycardia, and fatigue. Main limitations of this real life data analysis are low patient number and the lack of validation in the used questionnaire. In summary, according to our experiences, the use of beta-erythropoietin in patients with lung cancer results improved quality of life and a low rate of transfusions.

Epoetin alpha improves the response to antiviral treatment in HCV-related chronic hepatitis.

BACKGROUND: The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop treatment, thus reducing the rate of sustained virological response. AIM: We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response. METHODS: Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 µg once weekly and ribavirin 1,000-1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only. RESULTS: Patients in group 1 achieved better control of hemoglobin levels (13.8 ± 1.2 g/dl at the end of therapy) than those in group 2 (11.5 ± 0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p<0.01). CONCLUSIONS: In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.

Severe hypochromic microcytic anemia in a patient with congenital atransferrinemia.

Congenital atransferrinemia or hypotransferrinemia is a very rare autosomal recessive disorder, characterized by a deficiency of transferrin, resulting in hypochromic, microcytic anemia and hemosiderosis. The authors describe a 10-year-old Iranian girl with hypochromic microcytic anemia. The age presentation of anemia was 3 months. Further evaluations indicate severe hypochromic microcytic anemia with decreased serum levels of iron, TIBC, and increased serum level of ferritin in this patient. The serum level of transferrin was decreased. The diagnosis of atransferrinemia was confirmed. Although atransferrinemia is a rare condition, it should be considered in the cases with hypochromic microcytic anemia, decreased serum levels of iron, TIBC, and increased serum level of ferritin.