Refractory Iron Deficiency Anemia Research Articles

Single-center experience of four cases with iron-refractory iron deficiency anemia (IRIDA)

Background. Iron refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive type of anemia characterized by unresponsiveness to oral iron therapy and partial response to parenteral iron therapy. In this article, we report the clinical presentation of four patients with IRIDA admitted to our clinic, including their laboratory values at admission and after oral and parenteral iron treatment, and the analysis of their mutation(s) in TMPRSS6 gene. Case. Four patients from different families, aged between 3 and 14 years, two girls and two boys, two of whom were from consanguineous marriages, who were diagnosed with iron deficiency anemia in primary health care institutions and referred to our clinic because of inadequate response to oral iron treatment were included. Patients were evaluated for the differential diagnosis of microcytic, hypochromic anemia and investigated for the etiology of IDA. Homozygous or compound heterozygous mutations causing defective matriptase-2 protein expression were detected in the TMPRSS6 gene; these mutations included four frameshift mutations-two of which were the same in two cases and causing premature terminal stop codons-and a nonsense mutation, all of which were previously demonstrated in the literature. The response to parental iron therapy ranged from complete non-response to mild to good response in hemoglobin levels, but none of the patients showed improvement in iron parameters. Conclusions. Increased awareness of IRIDA and keeping it in mind in the differential diagnosis in the presence of hypochromic microcytic anemia that does not respond to iron treatment will be crucial in improving the diagnosis and treatment of the disease and ultimately enhancing the quality of care for affected individuals.

Recombinant erythropoietin for the treatment of iron deficiency anemia in pregnancy: A systematic review.

Treatment options for severe, refractory iron deficiency anemia are limited in pregnancy. To review the available literature on the use of recombinant erythropoietin in the treatment of iron deficiency anemia in pregnancy. An electronic search of seven databases from inception to March 2022 was performed using a combination of keywords. We included all randomized controlled or observational studies of pregnant patients with iron deficiency anemia who received recombinant erythropoietin or control. The primary outcome was a change in hematologic parameters (hemoglobin or hematocrit) after treatment. Studies were appraised using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data were summarized using narrative synthesis and descriptive statistics as appropriate. This study was registered with PROSPERO, CRD42022313328. Of 234 studies screened, five studies met the inclusion criteria and had sufficient data for analysis (n = 103 recombinant erythropoietin and n = 104 controls). All patients in the intervention group received iron supplementation (intravenous or oral) in addition to recombinant erythropoietin. All patients in the control group received iron supplementation (intravenous or oral) alone. As the result of variance between studies in inclusion criteria, the timing of repeat blood draws, and data reporting, a meta-analysis could not be performed. Three studies found that serial recombinant erythropoietin combined with iron supplementation was more effective at raising hematologic laboratory parameters (hemoglobin or hematocrit) than iron alone. One study reported no difference in hemoglobin or hematocrit levels between groups at day 28. However, patients in this study only received one dose of recombinant erythropoietin, whereas those in the other studies received serial doses. Another study also found no difference in hemoglobin levels by day 28, but patients in the recombinant erythropoietin group had lower hemoglobin levels at baseline and a more rapid rise in hemoglobin than iron alone. This is demonstrated by a more significant rise in hemoglobin at day 11 in the recombinant erythropoietin group than in the control group. Serial recombinant erythropoietin administration and iron supplementation may be more effective at treating refractory iron deficiency anemia in pregnancy than iron supplementation alone.

IRIDA- An Indian perspective

Iron deficiency anemia (IDA) is the most common type of anemia globally (IDA), the treatment being iron supplementation. However, in a few individuals, there is absent to suboptimal response to iron supplementation due to iron not being taken up by the body of the individual. This condition is known as iron-refractory IDA (IRIDA). Iron refractory iron deficiency anemia is a rare genetic condition that follows an autosomal recessive inheritance due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation, and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. This condition is likely being missed or under-diagnosed in our iron deficient endemic setting due to a lack of general awareness amongst physicians in establishing the diagnosis or due to the lack of availability of proper genetic testing.

Novel TMPRSS6 variants and their impact on iron-refractory iron deficiency anaemia in pregnancy: A North Indian genotype phenotype study.

Iron-refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness. It identified a final cohort of 10 (2.15% prevalence) individuals with IRIDA phenotype. Haematological and biochemical analysis revealed significant differences between iron responders and iron non-responders, with iron non-responders showing lower haemoglobin, red blood cell count, serum iron and serum ferritin levels, along with elevated HEPC (9.47 ± 2.75 ng/mL, p = 0.0009) and erythropoietin (4.58 ± 4.07 µ/mL, p = 0.0196) levels. Genetic sequencing of the TMPRSS6 gene in this final cohort identified 10 novel variants, including seven missense and three frame-shift mutations, with four missense variants showing high functional impact defining the IRIDA phenotype. Structural analysis revealed significant damage caused by two variants (p.L83R and p.S235R). This study provides valuable insights into IRIDA among pregnant women in the Indian subcontinent, unveiling its underlying causes of unresponsiveness, genetic mechanisms and prevalence. Furthermore, research collaboration is essential to validate these findings and develop effective treatments.

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.

Diagnosis and treatment of iron deficiency anemia

The causes of iron deficiency anemia include blood loss, increased demand, insufficient dietary intake, and disorders affecting iron absorption. In certain circumstances, atrophic gastritis, either autoimmune or due to Helicobacter pylori infection, may contribute. On very rare occasions, iron-refractory iron deficiency anemia can develop as a consequence of TMPRSS6 mutations. Iron deficiency anemia is diagnosed by identification of microcytic hypochromic anemia with low serum ferritin levels. In cases of chronic disorders such as chronic kidney disease, chronic heart failure, and chronic inflammatory disorders, the diagnosis may also incorporate transferrin saturation. Treatment of underlying diseases is recommended along with iron supplementation. While oral iron supplements are the first choice, intravenous iron may be considered when oral administration is impractical, iron absorption is impaired, or rapid iron replenishment is necessary. Recently, high-dose intravenous iron formulations became available in Japan, but their use requires caution due to potential risks of allergic reactions, hypophosphatemia/osteomalacia, iron overload, and vascular leakage. Notably, the benefits of high-dose intravenous iron for patients with heart failure and iron deficiency are recognized in the field of cardiology. This article provides an overview, incorporating recent developments in the field of iron deficiency anemia.

Rker-216 Reversed Microcytic Anemia in a Mouse Model of Iron Refractory Iron Deficiency Anemia

Background Iron refractory iron deficiency anemia (IRIDA) is an inherited disease caused by TMPRSS6 mutations that increase serum hepcidin and result in microcytic anemia from iron malabsorption. As hepcidin promotes ferroportin (Fpn) degradation to limit iron absorption, its production in anemia should be decreased to make up body iron deficits. In contrast to typical iron deficiency anemia that can be improved by oral iron supplementation or intravenous (IV) iron infusion, IRIDA patients tend to have no response to iron supplements and only transiently respond to iron infusion, resulting in lifelong anemia. Hepcidin is mainly regulated by the bone morphogenetic protein (BMP) pathway, in which BMP ligands activate transcription factors SMAD1/5/9 by binding to the BMP receptors, including ALK2. We previously showed that RKER-216 (m216), a research ALK2 neutralizing antibody, improved iron availability in mice with anemia of inflammation resulting from high hepcidin. Here, we explored m216 pharmacology in an IRIDA mouse model. Aim To examine 1) mechanism of action (MOA), 2) efficacy of IV iron infusion and m216-mediated iron absorption, and 3) dose response of m216 in resolving microcytic anemia in Tmprss6 knockout (KO) mice. Methods TMPRSS6 KO mice at 8-11 weeks (wk) were subcutaneously dosed with isotype control or m216 at 1 or 3 mg/kg in all studies. Mice were given a single dose for 6, 24 or 96 h in MOA and twice weekly for 9 or 21 d for efficacy studies. For IV iron, KO mice were given a single dose of iron dextran at 100 mg/kg and evaluated on day 9. Results TMPRSS6 KO mice at 8 wk had high serum hepcidin, low transferrin saturation (TSAT), and microcytic anemia as indicated by low mean corpuscular volume (MCV) and hemoglobin (Hb), key features in IRIDA. Liver SMAD1/5/9 phosphorylation, hepcidin ( Hamp) mRNA, and serum hepcidin levels were decreased similarly in KO mice dosed with 1 or 3 mg/kg of m216 for 6 h, compared to isotype controls. KO mice given both dose levels for 24 h decreased serum hepcidin by 88% and increased TSAT by 4-fold, compared to isotype mice, but only mice receiving 3 mg/kg had sustained effects by 96 h. These data suggest that m216 inhibited SMAD signaling to lower serum hepcidin, allowing more iron absorption to increase TSAT. To explore the relevance of m216 to current therapy, we compared the result of IV iron or 1 mg/kg of m216 in KO mice for 9 d. Compared to controls, liver iron, serum hepcidin, and TSAT were increased in mice given IV iron whereas mice receiving m216 exhibited reduced hepcidin with increased duodenal Fpn and TSAT, confirming target engagement. Although TSAT was higher in mice dosed with m216 compared to IV iron, anemia improved similarly (1-2 g/dl in Hb; 2 fl in MCV) in these two groups. These data suggest that despite high hepcidin, IV iron improved anemia via increased TSAT; however, the relationship between TSAT and anemia recovery is not always linear. We next examined KO mice dosed with m216 at 1 or 3 mg/kg for 3 wk. Hb and MCV improved from 9.2 g/dl and 26.2 fl in isotype controls to 11.5 g/dl and 33.7 fl in 1 mg/kg-m216 mice and further improved to 14.1 g/dl and 39.8 fl in the 3 mg/kg-m216 cohort, respectively, showing a dose proportional mitigation in improving microcytic anemia compared to isotype controls. In fact, Hb and MCV of the 3 mg/kg-m216 cohort were restored to the levels of WT mice, indicating that microcytic anemia was fully resolved in this group. Conclusion These data suggest that m216 inhibited the BMP pathway to increase iron absorption via hepcidin suppression and was able to provide similar effects as iron infusion in reversing microcytic anemia in a mouse model of IRIDA.

The Role of Hepcidin and an Oral Iron Absorption Test in Identifying the Root Cause of Iron-Restricted Anemia (Enter-Iron)

Introduction: Traditional iron parameters often fail to distinguish the cause of iron-restricted anemia in patients without an obvious underlying cause. We evaluated whether an oral iron absorption test (OIAT) and hepcidin measurement could be useful diagnostic tests in these patients. Methods: We retrospectively analyzed data extracted from medical records of all patients who underwent an OIAT and hepcidin measurement, noting subsequent clinical diagnosis. Δ Iron >15 µmol/L during the OIAT and a hepcidin level below the median (or suppressed ≤0.5 nm) were considered appropriate. Results: Thirty-nine adult patients were included in the study. Sixteen patients with adequate OIAT had suppressed hepcidin levels indicative of classical iron-deficiency anemia (IDA); 59% of patients had abnormal OIAT. In this group, most patients with low hepcidin levels had anemia associated with abnormalities in the gastrointestinal tract, whereas 83.3% patients with high hepcidin levels had iron-refractory iron-deficiency anemia (IRIDA), confirmed by genetic testing. Finally, transferrin/log ferritin ratio accurately identified patients with suppressed hepcidin: AUC 0.98 [95% CI: 0.95–1.02], p < 0.001. Conclusion: OIAT differentiates between classical IDA and other types of anemia caused by abnormalities in iron absorption or systemic iron availability. Additionally, elevated hepcidin in patients with oral iron malabsorption could indicate IRIDA.

Genomics of iron refractory iron deficiency anemia phenotype reveals a spectrum of novel pathogenic biallelic and monoallelic TMPRSS6 variants and rare overlapping disorders

The study highlights genomic findings in a series of 13 IRIDA phenotype cases. All had microcytic hypochromic anemia with suboptimal oral iron response to two different oral iron preparations at 4–6 weeks and low-normal ferritin, low transferrin saturation, and inappropriately high hepcidin. Targeted NGS on a 26-gene iron panel revealed pathogenic TMPRSS6 variants in 5/13 (38 %) cases. In addition, 2 (15 %) cases revealed rare SMAD4 and TBXAS1 gene variants that can present with refractory anemia but were consistent with diagnosis of hereditary hemorrhagic telangiectasia and Ghosal hematodiaphyseal dysplasia respectively.

Matriptase-2 regulates iron homeostasis primarily by setting the basal levels of hepatic hepcidin expression through a nonproteolytic mechanism

Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease. It plays a key role in iron homeostasis by suppressing the iron-regulatory hormone, hepcidin. Lack of functional MT2 results in an inappropriately high hepcidin and iron-refractory iron-deficiency anemia. Mt2 cleaves multiple components of the hepcidin-induction pathway in vitro. It is inhibited by the membrane-anchored serine protease inhibitor, Hai-2. Earlier in vivo studies show that Mt2 can suppress hepcidin expression independently of its proteolytic activity. In this study, our data indicate that hepatic Mt2 was a limiting factor in suppressing hepcidin. Studies in Tmprss6-/- mice revealed that increases in the dietary iron to ∼0.5% were sufficient to overcome the high hepcidin barrier and to correct the iron-deficiency anemia. Interestingly, the increased iron in Tmprss6-/- mice was able to further upregulate hepcidin expression to a similar magnitude as in wild-type mice. These results suggest that lack of Mt2 does not impact the iron induction of hepcidin. Additional studies of wild-type Mt2 and the proteolytic-dead form, fMt2S762A, indicated that the function of Mt2 is to lower the basal levels of hepcidin expression in a manner that primarily relies on its nonproteolytic role. This idea is supported by the studies in mice with the hepatocyte-specific ablation of Hai-2, which showed a marginal impact on iron homeostasis and no significant effects on iron regulation of hepcidin. Together, these observations suggest that the function of Mt2 is to set the basal levels of hepcidin expression and that this process is primarily accomplished through a nonproteolytic mechanism.

Myelin oligodendrocyte glycoprotein antibody-associated disease as a novel presentation of central nervous system autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome

BackgroundWiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon.Case PresentationWe describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS.ConclusionsThis case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.

A stepwise diagnostic approach for undiagnosed Anemia in children: A model for low-middle income country

BackgroundReaching a precise diagnosis in rare inherited anemia is extremely difficult and challenging, especially in areas with limited use of genetic studies, which makes undiagnosed anemia a unique clinical entity in tertiary hematology centers. In this study, we aim at plotting a stepwise diagnostic approach in children with undiagnosed anemia while identifying indications for genetic testing. Patients and methodsA one-year cross-sectional study involved 44 children and adolescents with undiagnosed anemia after undergoing an initial routine panel of investigations. They were classified based on mean corpuscular volume (MCV) into 3 groups: microcytic (n = 19), normocytic (n = 14) and macrocytic (n = 11). An algorithm that included four levels of investigations was devised for each category. ResultsAfter applying a systematic diagnostic approach, 33 patients (75 %) were diagnosed of whom 7 (15 %) had combined diagnoses, while 11 (25 %) patients remained undiagnosed. Based on the first, second, third and fourth levels of investigations, patients were diagnosed, respectively, as follows: of the 11 patients, 7 were microcytic, 3 normocytic and 1 macrocytic; of the 7 patients, 2 were microcytic, 2 normocytic, and 3 macrocytic; of 10 patients, 5 were microcytic, 4 normocytic and 1 macrocytic; finally, of the 16 patients, 8 were microcytic, 6 normocytic and 2 macrocytic. Numbers recorded appear higher than the actual number of the patients because some of them were diagnosed by more than one level of investigation. The diagnoses obtained in the microcytic group showed hemoglobinopathies, iron refractory iron deficiency anemia (IRIDA), membrane defects, sideroblastic anemia, hypo-transferrinemia, a combined diagnosis of sickle cell trait and pyropoikilocytosis. The diagnoses also showed a combined diagnosis of hereditary spherocytosis (HS) and alpha thalassemia minor, and a combined diagnosis of iron deficiency anemia and beta thalassemia minor, while 15 % remained undiagnosed. In the normocytic group, the diagnosis revealed autosomal recessive (AR) HS, vitamin B12 deficiency, pyruvate kinase deficiency (PKD), congenital dyserythropoietic anemia (CDA) type I, Diamond Blackfan anemia and beta thalassemia major. In addition, it showed a combined diagnosis of AR HS and CDA type II, a combined diagnosis of AR HS and PKD, and a combined diagnosis of dehydrated stomatocytosis (DHS) and G6PD carrier, meanwhile 20 % remained undiagnosed. Finally, the macrocytic group was diagnosed by vitamin B12 deficiency, sideroblastic anemia, PKD, a combined diagnosis of PKD and G6PD deficiency carrier, while 45 % remained undiagnosed. ConclusionConducting a stepwise approach with different levels of investigations may help reach the diagnosis of difficult anemia without having to resort to unnecessary investigations. Combined diagnosis is an important cause of undiagnosed anemia, especially in countries with high frequency of consanguinity. The remaining 25 % of the patients continued to be undiagnosed, requiring more sophisticated investigations.

Anastomotic Ulcers: Current Understanding of the Pathogenesis and Management.

Anastomotic ulceration following intestinal resection is an under- recognized problem in pediatrics. We discuss the relevant literature regarding this condition. Anastomotic Ulceration following intestinal resection is a potentially life threatening cause of refractory anemia. Evaluation should include correction of micronutrient deficiencies and endoscopic evaluation by upper and lower endoscopy and small intestinal endoscopy if necessary. Initial treatment by medical therapy may consist of anti-inflammatory agents as well as antibiotics to treat small intestinal bacterial overgrowth. Surgical resection should be considered if refractory to treatment. Anastomotic ulcers in pediatric patients with small bowel resection should be considered as a cause of refractory iron deficiency anemia. Endoscopic evaluation should be undertaken to look for evidence of anastomotic ulcers. Surgical resection should be considered if medical therapy fails.

Refractory Iron Deficiency Anemia Secondary to Angiodysplasia-Related Gastrointestinal Bleeding Successfully Treated With Bevacizumab

Refractory Iron Deficiency Anemia Secondary to Angiodysplasia-Related Gastrointestinal Bleeding Successfully Treated With Bevacizumab

A Rationally Designed Complex Replenishes the Transferrin Iron Pool Directly and with High Specificity.

Many forms of anemia are caused or complicated by pathologic restriction of iron (Fe). Chronic inflammation and certain genetic mutations decrease the activity of ferroportin, the only Fe-exporter protein, so that endogenously recycled or nutritionally absorbed Fe cannot be exported to the extracellular Fe carrier protein transferrin for delivery to the bone marrow. Diminished ferroportin activity renders anemia correction challenging as Fe administered intravenously or through nutritional supplementation is trafficked through the ferroportin-transferrin axis. Utilizing judicious application of coordination chemistry principles, we designed an Fe complex (Fe-BBG) with solution thermodynamics and Fe dissociation kinetics optimized to replenish the transferrin-Fe pool rapidly, directly, and with precision. Fe-BBG is unreactive under conditions designed to force redox cycling and production of reactive oxygen species. The BBG ligand has a low affinity for divalent metal ions and does not compete for binding of other endogenously present ions including Cu and Zn. Treatment with Fe-BBG confers anemia correction in a mouse model of iron-refractory iron-deficiency anemia. Repeated exposure to Fe-BBG did not cause adverse clinical chemistry changes or trigger the expression of genes related to oxidative stress or inflammation. Fe-BBG represents the first entry in a promising new class of transferrin-targeted Fe replacement drugs.

GUT-BIOME MODULATION WITH HUMAN MILK OLIGOSACCHARIDE (HMO) BASED SYNBIOTIC FOR A COMPLETE AND DEEP REMISSION IN CROHN’S DISEASE: A CASE STUDY

Abstract BACKGROUND Gut microbiome plays a crucial role in modulation of inflammatory and immune pathways. Diverse bacterial species from gut microbiota feed on specific prebiotics (non-digestible dietary fibers) producing metabolites, such as short chain fatty acids (SCFA). These metabolites beneficially affect the intestinal mucosa with their role in metabolic and immunologic homeostasis, and gut barrier integrity. Recently gut-biome modulation and use of metabolites gained interest as potential targets for therapeutic development, for instance in Inflammatory Bowel Disease (IBD) which includes Crohn’s disease (CD) and ulcerative colitis (UC). HYPOTHESIS Nourishing the gut-biome thru synbiotic formulation can enhance the interspecies synergy with production of metabolites and improved gut barrier integrity more naturally. This is a superior and holistic approach to reduce gut-inflammation. METHODS (CLINICAL CASE) An 11 year old male with refractory iron deficiency anemia, fecal calprotectin at 1375 µg/g, on video capsule endoscopy showed discrete linear and serpiginous ulcers with surrounding erythema in duodenum and proximal jejunum. Biopsy of colon showed multiple granulomas in terminal ileum and entire colon suggesting CD (Inflammatory phenotype). Exclusive Enteral Nutrition (EEN) with polymeric formula proved unsustainable. To nourish the gut-biome and its ecosystem a synbiotic formulation (Gastrosyn) that has a blend of specific prebiotics with HMO and complimentary probiotic blend with strains of Lactobacilli and Bifidobacterium was administered and followed for 20 weeks. Formulation also contained powerful antioxidant for synergistic effect in reducing inflammation. RESULTS After 4 weeks on synbiotic, fecal calprotectin dropped to 665ug/g which further dropped to 110 ug/g by week 12. Complete and deep remission was observed by 15 weeks as analyzed by endoscopy/colonoscopy (images), histology and lab tests results repeated several times (Calprotectin 65ug/g by week 15). Anemia also improved significantly, and patient continued to tolerate solid foods with no relapse even after 1year. CONCLUSIONS Synbiotics utilizing prebiotics that are specific to probiotic strains used is crucial for successful engraftment and biome modulation as established in recent literature. HMO based Synbiotic formulation has proven to nurture the ecosystem, and foster interspecies interactions, cross feeding, and generation of metabolites (SCFAs), providing a holistic and superior approach for remission in IBD.

TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis.

TMPRSS6 is a serine protease highly expressed in the liver. Its role in iron regulation was first reported in 2008 when mutations in TMPRSS6 were shown to be the cause of iron-refractory iron deficiency anemia (IRIDA) in humans and in mouse models. TMPRSS6 functions as a negative regulator of the expression of the systemic iron-regulatory hormone hepcidin. Over the last decade and a half, growing understanding of TMPRSS6 biology and mechanism of action has enabled development of new therapeutic approaches for patients with diseases of erythropoiesis and iron homeostasis.ClinicalTrials.gov identifier NCT03165864.

Helicobacter pylori eradication rates using clarithromycin and levofloxacin-based regimens in patients with previous COVID-19 treatment: a randomized clinical trial

BackgroundHelicobacter pylori (H. pylori) is affecting half of the globe. It is considered a main causative organism of chronic gastritis, peptic ulcer disease, and different gastric maliganacies. It has been also correlated to extraintestinal diseases, including refractory iron deficiency anaemia, vitamin B12 deficiency, and immune thrombocytopenic purpura. The misuse of antibiotics during the coronavirus diseases 2019 (COVID-19) pandemic time can affect H. pylori eradication rates. Our aim was to compare the efficacy of clarithromycin versus levofloxacin-based regimens for H. pylori treatment in naïve patients after the COVID-19 pandemic misuse of antibiotics.MethodsA total of 270 naïve H. pylori infected patients with previous treatment for COVID-19 more than 3 months before enrolment were recruited. Patients were randomized to receive either clarithromycin, esomeprazole, and amoxicillin, or levofloxacin, esomeprazole, and amoxicillin.ResultsA total of 270 naïve H. pylori infected patients with previous treatment for COVID-19 more than 3 months before enrolment were included, 135 in each arm. In total, 19 patients in the clarithromycin group and 18 patients in the levofloxacin group stopped treatment after 2–4 days because of side effects or were lost for follow-up. Finally, 116 subjects in the clarithromycin group and 117 in the levofloxacin group were assessed. The eradication rates in intention to treat (ITT) and per protocol (PP) analyses were: group I, 55.56% and 64.66%; and Group II, 64.44% and 74.36% respectively (p = 0.11).ConclusionAs COVID-19 pandemic has moved forward fast, high resistance rates of H. pylori to both clarithromycin and levofloxacin were developed after less than two years from the start of the pandemic. Molecular & genetic testing is highly recommended to identify antimicrobial resistance patterns. Strategies to prevent antibiotic misuse in the treatment of COVID-19 are needed to prevent more antibiotic resistance.Trial Registration: The trial was registered on Clinicaltrials.gov NCT05035186. Date of registration is 2-09-2021.

The global prevalence and ethnic heterogeneity of iron-refractory iron deficiency anaemia

BackgroundIron-refractory iron deficiency anaemia (IRIDA) is an autosomal recessive iron deficiency anaemia caused by mutations in the TMPRSS6 gene. Iron deficiency anaemia is common, whereas IRIDA is rare. The prevalence of IRIDA is unclear. This study aimed to estimate the carrier frequency and genetic prevalence of IRIDA using Genome Aggregation Database (gnomAD) data.MethodsThe pathogenicity of TMPRSS6 variants was interpreted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) standards and guidelines. The minor allele frequency (MAF) of TMPRSS6 gene disease-causing variants in 141,456 unique individuals was examined to estimate the global prevalence of IRIDA in seven ethnicities: African/African American (afr), American Admixed/Latino (amr), Ashkenazi Jewish (asj), East Asian (eas), Finnish (fin), Non-Finnish European (nfe) and South Asian (sas). The global and population-specific carrier frequencies and genetic prevalence of IRIDA were calculated using the Hardy–Weinberg equation.ResultsIn total, 86 pathogenic/likely pathogenic variants (PV/LPV) were identified according to ACMG/AMP guideline. The global carrier frequency and genetic prevalence of IRIDA were 2.02 per thousand and 1.02 per million, respectively.ConclusionsThe prevalence of IRIDA is greater than previous estimates.

Diagnosis and treatment of anemia by malnutrition in the elderly

Recently, nutritional anemia has been increasing, particularly refractory iron-deficiency anemia, which has become more common not only among older adults but also among relatively young people. Coexisting conditions such as chronic inflammatory disease, gastrointestinal disease, and chronic kidney disease can all complicate diagnosis and treatment. In many cases, appropriate treatment can improve anemia. Same as iron, copper, and zinc are proven to be absorbed from the transporter in the upper gastrointestinal mucosa, but potential zinc and copper deficiencies are increasingly being reported in cases of iron deficiency. Serum zinc deficiency is more common in cases of severe iron-deficiency anemia. This paper provides an overview of refractory iron-deficiency anemia and discusses the molecular groups involved in iron dynamics, zinc, and copper metabolism.