The clinical relevance of detectable plasma iron species in iron overload states and subsequent to intravenous iron-carbohydrate administration.

Many disorders of iron homeostasis (e.g., iron overload) are associated with the dynamic kinetic profiles of multiple non-transferrin bound iron (NTBI) species, chronic exposure to which is associated with deleterious end-organ effects. Here we discuss the chemical nature of NTBI species, challenges with measuring NTBI in plasma, and the clinical relevance of NTBI exposure based on source (iron overload disorder vs. intravenous iron-carbohydrate complex administration). NTBI is not a single entity but consists of multiple, often poorly characterized species, some of which are kinetically non-exchangeable while others are relatively exchangeable. Prolonged presence of plasma NTBI is associated with excessive tissue iron accumulation in susceptible tissues, with consequences, such as endocrinopathy and heart failure. In contrast, intravenous iron-carbohydrate nanomedicines administration leads only to transient NTBI appearance and lacks evidence for association with adverse clinical outcomes. Assays to measure plasma NTBI are typically technically complex and remain chiefly a research tool. There have been two general approaches to estimating NTBI: capture assays and redox-activity assays. Early assays could not avoid capturing some iron from transferrin, thus overestimating NTBI. By contrast, some later assays may have promoted the donation of NTBI species to transferrin during the assay procedure, potentially underestimating NTBI levels. The levels of transferrin saturation at which NTBI species have been detectable have varied between different methodologies and between patient populations studied.

How I treat unexplained refractory iron deficiency anemia.

Endoscopic gastrointestinal workup fails to establish the cause of iron deficiency anemia (IDA) in a substantial proportion of patients. In patients referred for hematologic evaluation with unexplained or refractory IDA, screening for celiac disease, autoimmune gastritis, Helicobacter pylori, and hereditary forms of IDA is recommended. About 4% to 6% of patients with obscure refractory IDA have celiac disease, and autoimmune gastritis is encountered in 20% to 27% of patients. Stratification by age cohorts in autoimmune gastritis implies a disease presenting as IDA many years before the establishment of clinical cobalamin deficiency. Over 50% of patients with unexplained refractory IDA have active H pylori infection and, after excluding all other causes of IDA, 64% to 75% of such patients are permanently cured by H pylori eradication. In young patients with a history suggestive of hereditary iron deficiency with serum ferritin higher than expected for IDA, mutations involving iron trafficking and regulation should be considered. Recognition of the respective roles of H pylori, autoimmune gastritis, celiac disease, and genetic defects in the pathogenesis of iron deficiency should have a strong impact on the current diagnostic workup and management of unexplained, or refractory, IDA.

Iron overload in Asia.

In a remarkable study in this issue of Blood, Lok and colleagues describe the genotypic and phenotypic characteristics of hereditary hemochromatosis in 42 cases in 8 distinct families of Asian origin.

Vaccine efficacy and iron deficiency: an intertwined pair?

Vaccines are the most effective measure to prevent deaths and illness from infectious diseases. Nevertheless, the efficacy of several paediatric vaccines is lower in low-income and middle-income countries (LMICs), where mortality from vaccine-preventable infections remains high. Vaccine efficacy can also be decreased in adults in the context of some common comorbidities. Identifying and correcting the specific causes of impaired vaccine efficacy is of substantial value to global health. Iron deficiency is the most common micronutrient deficiency worldwide, affecting more than 2 billion people, and its prevalence in LMICs could increase as food security is threatened by the COVID-19 pandemic. In this Viewpoint, we highlight evidence showing that iron deficiency limits adaptive immunity and responses to vaccines, representing an under-appreciated additional disadvantage to iron deficient populations. We propose a framework for urgent detailed studies of iron-vaccine interactions to investigate and clarify the issue. This framework includes retrospective analysis of newly available datasets derived from trials of COVID-19 and other vaccines, and prospective testing of whether nutritional iron interventions, commonly used worldwide to combat anaemia, improve vaccine performance.

Autoimmune gastritis.

Autoimmune gastritis (AIG) is an increasingly prevalent, organ-specific, immune-mediated disorder characterized by the destruction of gastric parietal cells, leading to the loss of intrinsic factor and reduced acid output. These alterations result in malabsorption of iron, vitamin B12 (pernicious anaemia) and potentially other micronutrients. For several years, most studies have focused on pernicious anaemia only, generating confusion between the two entities. In AIG, the gastric proton pump, H+/K+ ATPase, is the major autoantigen recognized by autoreactive T cells. The T cell-dependent activation of B cells stimulates the production of anti-parietal cell antibodies, the serological hallmark of AIG. The role of Helicobacter pylori infection in activating or favouring the autoimmune process is still uncertain. Early histopathological alterations allowing a more precise and prompt recognition have recently been described. AIG is burdened by a substantial diagnostic delay as it can present with varied clinical signs including, among others, gastrointestinal symptoms and neuropsychiatric manifestations. In advanced stages, AIG might progress to neuroendocrine tumours and gastric adenocarcinoma. Management includes early detection through a proactive case-finding strategy, micronutrient supplementation and endoscopic surveillance. This Primer comprehensively describes the most important insights regarding the epidemiology, pathophysiology, diagnosis and management of AIG, focusing on the most controversial, outstanding issues and future directions.

Pathogenesis and management of iron deficiency anemia: emerging role of celiac disease, helicobacter pylori, and autoimmune gastritis.

The causes of iron deficiency vary significantly during different stages of life, and according to gender and socioeconomic circumstances. Although dietary iron is important, iron deficiency anemia (IDA) is mostly attributed to blood loss and may be the presenting clinical feature of occult bleeding from the gastrointestinal (GI) tract heralding underlying malignancy. Conventional GI diagnostic workup fails to establish the cause of iron deficiency in about one third of patients. However, abnormal iron absorption caused by hereditary iron-refractory iron deficiency anemia (IRIDA) or acquired disease is increasingly recognized as an important cause of unexplained iron deficiency. The recent availability of convenient, non-invasive screening methods to identify celiac disease, autoimmune atrophic gastritis and Helicobacter pylori infection has greatly facilitated the recognition of patients with these entities. Cure of previously refractory IDA by H pylori eradication provides strong evidence supporting a cause-and-effect relation. The intriguing recent observations of H pylori antibodies directed against epitopes on gastric mucosal cells in atrophic gastritis imply an autoimmune mechanism triggered by H pylori and directed against gastric parietal cells by means of antigenic mimicry. Improved understanding of the role of abnormal iron absorption in IDA has important implications for current concepts related to the pathogenesis and management of IDA.

Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies.

Thalassaemia intermedia (TI) is a syndrome marked by its diverse underlying genetic basis although its pathophysiology remains unclear, particularly regarding the nature of iron loading and toxicity. It is, however, evident that there are key differences from the extensively studied thalassaemia major (TM) population and caution is required when assessing iron load based on serum ferritin values, as this approach is known to underestimate the true extent of iron loading in patients with TI. Although effective iron chelation therapy has been available for many years, studies in TI-specific populations are rare and evidence suggests that management of iron levels may be less rigorous than in patients with TM and other chronic anaemias. Better understanding of the need to assess and treat iron overload in both transfused and non-transfused TI patients is clearly required.

High nontransferrin bound iron levels and heart disease in thalassemia major.

Although the presence of nontransferrin bound plasma iron (NTBI) in transfusional iron overload is well documented, knowledge about its clinical significance is limited. We assessed NTBI levels in a large and homogeneous series of thalassemia patients on regular transfusion and chelation and explored the hypothesis that NTBI levels may be associated with relevant clinical outcomes: in particular, heart disease. Among 174 patients with thalassemia major and intermedia, we showed the presence NTBI in 145 of 174 or 83.3% of cases. NTBI levels correlated with transferrin saturation, age, and ALT, and not with serum ferritin or liver iron concentrations. At a multiple regression analysis, transferrin saturation and heart disease but not age was independent predictors of NTBI. Patients with heart disease had NTBI levels significantly higher than those without. All patients with heart disease had transferrin saturation above 70%, and all were NTBI positive. Conversely, none of the patients without NTBI and/or with transferrin saturation less than 70% had preclinical or clinical heart disease. To our knowledge, this is the first documentation of a link between the presence of NTBI in thalassemic patients with transfusional iron overload and heart disease. Further investigation from these preliminary findings may clarify whether NTBI assessment may have a role in evaluating the risks and optimizing treatment for transfusion-dependent patients.

Iron deficiency, Helicobacter infection and gastritis.

Despite elegant regulatory mechanisms, iron deficiency anemia (IDA) remains one of the most common nutritional deficiencies of mankind. Iron deficiency is the result of an interplay between increased host requirements, limited external supply, and increased blood loss. When related to increased physiologic needs associated with normal development, iron deficiency is designated physiologic or nutritional. By contrast, pathological iron deficiency, with the exception of gross menorrhagia, is most often the result of gastrointestinal disease associated with abnormal blood loss or malabsorption. If gastroenterologic evaluation fails to disclose a likely cause of IDA, or in patients refractory to oral iron treatment, screening for celiac disease (anti-tissue transglutaminase antibodies), autoimmune gastritis (gastrin, anti-parietal or anti-intrinsic factor antibodies), and Helicobacter pylori (IgG antibodies and urease breath test) is recommended. Recent studies indicate that 20-27% of patients with unexplained IDA have autoimmune gastritis, about 50% have evidence of active H. pylori infection, and 4-6% have celiac disease. The implications for abnormal iron absorption of celiac disease or autoimmune gastritis are obvious. In patients with unexplained IDA and H. pylori infection, cure of refractory IDA by H. pylori eradication offers strong evidence for a cause-and-effect relation between H. pylori infection and unexplained IDA. Stratification by age cohorts in autoimmune gastritis implies a disease presenting as IDA many years before the establishment of clinical cobalamin deficiency. It is likely caused by an autoimmune process triggered by antigenic mimicry between H. pylori epitopes and major autoantigens of the gastric mucosa. Recognition of the respective roles of H. pylori and autoimmune gastritis in the pathogenesis of iron deficiency may have a strong impact on the diagnostic workup and management of unexplained, or refractory IDA.

Decreased treatment failure rates following duodenal release ferrous glycine sulfate in iron deficiency anemia associated with autoimmune gastritis and Helicobacter pylori gastritis.

BACKGROUND AND OBJECTIVES: Since gastric acidity and ascorbate play a critical role in the solubilization and reduction of iron for subsequent absorption, the achlorhydria associated with autoimmune and Helicobacter pylori gastritis may explain the poor response of such patients to oral iron treatment. In order to circumvent this problem, we explored the therapeutic potential of a duodenal formulation of ferrous glycine sulfate consisting of micropellets that do not dissolve at the acid environment of the stomach but, owing to their solubility at a higher pH, discharge their content directly into the duodenum. DESIGN AND METHODS: In a case-control study, the treatment results of 39 patients with iron deficiency anemia receiving a duodenal formulation of ferrous glycine sulfate (group A) were compared with the results of 39 patients receiving other oral iron compounds (group B). Autoimmune gastritis, H. pylori gastritis or both were present in over 75% of patients in each group. RESULTS: After 1 and 3 months of treatment, mean hemoglobin in group A increased from 9.5 +/- 1.2 to 11.2 +/- 1.3 and 12.8 +/- 1.3 g/dl, respectively. By comparison, in group B, the corresponding values increased from 9.3 +/- 1.3 to 10.2 +/- 1.5 (p = 0.019) and 11.1 +/- 1.7 g/dl (p = 0.022). A favorable response, defined as a more than 2 g/dl increase in basal hemoglobin or hemoglobin exceeding 12 g/dl, was obtained in 33 of 39 patients in group A compared with only 18 of 39 in group B (p = 0.009). Because of treatment failure, 14 patients in group B were subsequently referred for intravenous ferric sucrose therapy versus only 3 in group A (p < 0.0001). Conversely, of 5 patients in group A managed by intravenous iron prior to referral, 4 became independent of parenteral iron after starting the duodenal formulation of ferrous glycine sulfate. INTERPRETATION AND CONCLUSIONS: In patients with iron deficiency anemia associated with autoimmune and H. pylori gastritis with a high rate of refractoriness to oral iron treatment, satisfactory response to a duodenal formulation of ferrous glycine sulfate can be elicited in the vast majority of cases, obviating the need for expensive, inconvenient and occasionally risky intravenous iron administration.

Mechanism of iron toxicity.

The subtle balance between proinflammatory and antiinflammatory cytokines plays an important role in determining the severity of the inflammatory reaction and in the anomalous iron handling associated with infection. Conversely, iron deficiency per se appears to limit the severity of the inflammatory response. All of these considerations are at present highly speculative and in need of further experimental and epidemiologic support. If confirmed, the beneficial biological effects of iron depletion may have a defensive role in inflammation and may be perturbed by the nonselective administration of iron to iron-replete patients who would not benefit from such treatment in the first place. In view of the importance of non-transferrin-bound plasma iron (NTBI) in iron toxicity and its rapid cellular uptake, it may play an important role in the harmful effects of iron in infection, and this is illustrated by the infectious complications of parenteral iron therapy in tropical countries.

Gastropathic sideropenia.

There has been an increasing awareness recently of subtle, non-bleeding gastrointestinal conditions that may result in abnormal iron absorption leading to iron-deficiency anaemia (IDA) in the absence of gastrointestinal symptoms. Thus, the importance of coeliac disease as a possible cause of IDA refractory to oral iron treatment, without other manifestations of malabsorption syndrome, is increasingly being recognized. In addition, Helicobacter pylori has been implicated in several recent studies as a cause of IDA refractory to oral iron treatment, and the anaemia responds favourably to H. pylori eradication. Likewise, achlorhydric gastric atrophy or atrophic body gastritis (ABG), a condition associated with chronic idiopathic iron deficiency, has been shown to be responsible for refractory IDA in over 20% of patients with no evidence of gastrointestinal blood loss. It has also been suggested that H. pylori gastritis may represent an early phase of ABG in which infection may trigger an autoimmune process directed against gastric parietal cells by means of antigenic mimicry. In this review we examine in a critical manner the role of H. pylori gastritis in the causation of IDA, the role of ABG in the pathogenesis of iron malabsorption, the evidence supporting a possible cause-and-effect relationship between H. pylori gastritis and ABG, and the implications of these findings for the diagnostic work-up and management of IDA.

Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia.

BACKGROUND AND OBJECTIVES: Conventional endoscopic and radiographic methods fail to identify a probable source of gastrointestinal blood loss in about one third of males and post-menopausal females and in most women of reproductive age with iron deficiency anemia (IDA). Such patients, as well as subjects refractory to oral iron treatment, are often referred for hematologic evaluation. DESIGN AND METHODS: Patient clinic, screened for non-bleeding gastrointestinal conditions including celiac disease (antiendomysial antibodies), autoimmune atrophic gastritis (hypergastrinemia with strongly positive antiparietal cell antibodies) and H. pylori infection (IgG antibodies confirmed by urease breath test). RESULTS: The mean age of all subjects was 39+/-18 years, and 119 of 150 were females. We identified 8 new cases of adult celiac disease (5%). Forty IDA patients (27%) had autoimmune atrophic gastritis of whom 22 had low serum vitamin B12 levels. H. pylori infection was the only finding in 29 patients (19%), but was a common co-existing finding in 77 (51%) of the entire group. Refractoriness to oral iron treatment was found in 100% of patients with celiac disease, 71% with autoimmune atrophic gastritis, 68% with H. pylori infection, but only 11% of subjects with no detected underlying abnormality. H. pylori eradication in previously refractory IDA patients in combination with continued oral iron therapy resulted in a significant increase in hemoglobin from 9.4+/-1.5 (mean +/- 1SD) before, to 13.5+/-1.2 g/ dL (p<0.001 by paired t test) within 3 to 6 months. INTERPRETATION AND CONCLUSIONS: The recognition that autoimmune atrophic gastritis and H. pylori infection may have a significant role in the development of unexplained or refractory IDA in a high proportion of patients should have a strong impact on our daily practice of diagnosing and managing IDA.

Objectives and mechanism of iron chelation therapy.

Prevention of cardiac mortality is the most important beneficial effect of iron chelation therapy. Unfortunately, compliance with the rigorous requirements of daily subcutaneous deferoxamine (DFO) infusions is still a serious limiting factor in treatment success. The development of orally effective iron chelators such as deferiprone and ICL670 is intended to improve compliance. Although total iron excretion with deferiprone is somewhat less than with DFO, deferiprone may have a better cardioprotective effect than DFO due to deferiprone's ability to penetrate cell membranes. Recent clinical studies indicate that oral ICL670 treatment is well tolerated and is as effective as parenteral DFO used at the standard dose of 40 mg/kg of body weight/day. Thus, for the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available to avoid serious organ damage. Finally, combined chelation treatment is emerging as a reasonable alternative to chelator monotherapy. Combining a weak chelator that has a better ability to penetrate cells with a stronger chelator that penetrates cells poorly but has a more efficient urinary excretion may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.

Iron chelation therapy.

Although iron chelation therapy with deferoxamine (DFO) has changed life expectancy in thalassemic patients, compliance with the rigorous requirements of long-term subcutaneous DFO infusions is unsatisfactory. This problem underlines the current efforts for developing alternative, orally effective chelators to improve compliance and treatment results. For the patient with transfusional iron overload in whom results of DFO treatment are unsatisfactory, several orally effective agents are now available. The most important of the new generation of oral chelators are deferiprone and ICL670. Total iron excretion with deferiprone is less than with DFO, but deferiprone has a better ability to penetrate cell membranes and may have a better cardioprotective effect than DFO. Current studies of the clinical efficacy and tolerability of ICL670 indicate that at a single oral dose of 20 mg/kg daily, it may be as effective as parenteral DFO used at the standard dose of 40 mg/kg daily. Combined chelation treatment, employing a weak chelator that penetrates cells better, and a stronger chelator with efficient urinary excretion, may result in improved therapeutic effect through iron shuttling between the two compounds. The efficacy of combined chelation treatment is additive and offers an increased likelihood of success in patients previously failing DFO or deferiprone monotherapy.

Non-transferrin-bound serum iron (NTBI) in megaloblastic anemia: effect of vitamin B(12) treatment.

INTRODUCTION: The abnormalities in iron metabolism associated with megaloblastic anemia are rapidly reversed by B(12) therapy in pernicious anemia (PA). Although non-tranferrin-bound plasma iron (NTBI) was previously shown to be associated with severe iron overload, its origin is unknown. METHODS AND RESULTS: Four patients with PA were studied before and after B(12) treatment. NTBI was measured by a fluorescence-based one-step assay. All patients had very high transferrin saturation, NTBI values ranging from 1.1 to 2.6 micromol/l and normal serum ferritins. B(12) treatment resulted in the disappearance of NTBI and normalization of transferrin saturation within 22-42 h. CONCLUSIONS: The prompt disappearance of NTBI following B(12) therapy implicates catabolic iron derived from ineffective erythropoiesis as the major source of NTBI in untreated PA and possibly in thalassemia major and sideroblastic anemia. Our findings offer further insight into the pathogenesis of NTBI in diseases associated with abnormal erythropoiesis.