Different Types of Iron Deficiency

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Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routine, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.


Iron deficiency (ID) and iron deficiency anaemia (IDA) cause an immense disease burden worldwide. Globally, there were over 1·2 billion cases of IDA in 2016.1 IDA is among the five greatest causes of years lived with disability globally, the leading cause of years lived with disability in low-income and middle-income countries (LMICs), and is the leading cause of years lived with disability among women across 35 countries.1 Controlling anaemia is a global health priority: WHO is aiming for a 50% reduction in anaemia prevalence in women by 2025.2

When iron intake is inadequate to meet requirements or to compensate for physiological or pathological losses, body iron stores become depleted. Absolute ID occurs when iron stores are insufficient to meet the needs of the individual, and is particularly common in young children (younger than 5 years) and premenopausal (especially pregnant) women. In patients with inflammation, withholding of iron from the plasma promotes iron-deficient erythropoiesis and anaemia despite adequate body iron stores (functional iron deficiency). This process is common in patients with complex medical or surgical disorders, in people living in areas where infection prevalence is high, and in patients receiving erythropoiesis-stimulating agents.3

Iron is crucial for numerous physiological and cellular processes and ID causes diverse health consequences. Management of ID is an important and complex challenge faced by practitioners of medicine, nutrition, and public health worldwide. In this Seminar, we update the physiology, diagnosis, and clinical management of ID and identify future translational and clinical research directions.

Clinical presentation

ID can cause symptoms both in the presence and absence of anaemia or can be asymptomatic. Common symptoms and signs include fatigue and lethargy reduced concentration, dizziness, tinnitus, pallor, and headache. In susceptible individuals, ID promotes restless leg syndrome.4 Other presentations include alopecia, dry hair or skin, koilonychia, and atrophic glossitis. Symptoms in infants (aged younger than 12 months) with ID can include poor feeding and irritability.5 Patients might also present with pica: the compulsive ingestion of non-nutritive foods, such as soil or clay, ice, or raw ingredients (eg, uncooked rice).6 ID and anaemia can also exacerbate symptoms and worsen the prognosis of medical conditions, including heart failure7 and ischaemic heart disease.8 Severe IDA can cause haemodynamic instability. Preoperative anaemia increases the risk of blood transfusion and is correlated with postoperative morbidity and mortality.9 Even when asymptomatic, ID can promote suboptimal functional outcomes, including impaired physical exercise performance, child neurocognitive development, and pregnancy outcomes.10

*Epidemiology of ID

*Molecular pathology of ID

*Clinical pathophysiology of absolute ID

-Blood loss
-Inadequate iron intake and absorption
-Increased iron needs during life

*Diagnosis of ID

*Further investigation of ID

*Treatment of ID

*Oral iron supplementation

*Parenteral iron therapy

*Clinical benefits of iron therapy

*Iron interventions in patients without complex medical conditions

*Parenteral iron in patients with complex conditions

-Congestive cardiac failure
-Inflammatory bowel disease
-Perioperative optimisation
-Chronic kidney disease

*Preventing ID in LMICs


Clinicians regularly encounter ID and IDA. Understanding the pathophysiology of absolute and functional ID guides diagnosis, appropriate use of established and emerging treatments, and rational deployment of further investigations. Further research into the biology, epidemiology, diagnosis and treatment of ID (panel 2) will continue to transform approaches to this common condition.


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Figure 1: Coordinated homoeostatic response to absolute and functional iron deficiency Red arrows refer to physiological stimuli (eg, absolute iron deficiency or increased erythropoiesis) that suppress hepcidin expression. During absolute iron deficiency, decreased circulating transferrin saturation and liver iron storage suppress hepcidin transcription via reduced BMP-SMAD signalling (yellow pathway). As a consequence, duodenal and macrophage FPN proteins are stabilised, facilitating dietary iron absorption in duodenal enterocytes and release of iron from macrophages of the reticuloendothelial system, thereby increasing iron concentrations in the plasma. Additionally, reduced iron concentration in duodenal enterocytes is sensed by the iron-dependent prolyl hydroxylase domain enzymes that increase the stability of the transcription factor HIF-2, which regulates transcription of apical (CYBRD1 and DMT1) and basolateral (FPN) iron transport machinery. During iron deficiency, in most cell types the IRP/IRE system stabilises mRNAs of proteins crucial for iron uptake (eg, TfR1 and DMT1) and suppresses the synthesis of proteins involved in the storage (ferritin), utilisation (cytoplasmic and mitochondrial iron-containing proteins), and export (FPN) of iron. In functional iron deficiency, inflammation increases hepatic hepcidin expression via IL6-JAK2-STAT3 signalling (green pathway), causing reduced FPN abundance and function on cells, depriving the plasma of iron. In response to iron deficiency anaemia, the kidney produces erythropoietin, which stimulates erythropoiesis. Erythroblast erythropoietin sensitivity can be modulated by TfR2. In absolute iron deficiency, erythroblasts and erythrocytes donate iron through FPN-mediated iron export. Increased erythropoiesis (eg, during recovery from anaemia) causes secretion of erythroferrone, which suppresses hepatic hepcidin expression via inhibition of BMP-SMAD signalling (red pathway). LSEC=liver sinusoidal endothelial cell. P=phosphorylated. TSAT=transferrin saturation.
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Figure 2: Absolute and functional iron deficiency In absolute iron deficiency, total body iron concentrations are reduced due to uncompensated negative iron balance. Patients with absolute iron deficiency have low tissue iron stores, low bone marrow iron stores, and low plasma iron (transferrin saturation), and in the absence of other signals, hepcidin is suppressed homoeostatically upregulating iron absorption. Anaemia of inflammation is common in patients with conditions including acute and chronic infection, autoimmune conditions, cancer, recent surgery, and heart failure. The predominant mechanism of anaemia of inflammation is functional iron deficiency, in which inflammation-mediated increases in hepcidin prevent cellular iron export (especially from macrophages) to the plasma, resulting in reduced transferrin saturation, iron-deficient erythropoiesis, and anaemia, even with sufficient body iron stores. Functional iron deficiency is the predominant mechanism of anaemia of inflammation, but other causes (eg, direct bone marrow suppression, reduced erythropoietin production and marrow responsiveness, and reduced red blood cell survival) can also contribute. Functional and absolute iron deficiency can coexist, and functional iron deficiency might promote absolute iron deficiency through sustained impairment of iron uptake. Therapy for absolute iron deficiency focuses on improving iron stores, ameliorating blood losses, and optimising iron absorption. Therapy for functional iron deficiency focuses on controlling the underlying conditions. Parenteral iron therapy can be used if the patient is symptomatically anaemic.
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Figure 3: Biomarkers for diagnosis of iron deficiency A suggested interpretation of both widely available and emerging biomarkers to diagnose different iron deficiency syndromes. Concomitant measurement of an inflammatory biomarker (eg, C-reactive protein) is recommended to enable interpretation of ferritin in patients at risk of inflammation. *Diagnostic thresholds for reticulocyte hemoglobin content vary between the type of analyzer, and for non-standardized hepcidin and soluble transferrin receptor assays, between manufacturers.
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Panel 2: Future research and clinical directions


• Improved data on the prevalence of iron deficiency across low-income, middle-income, and high-income countries through routine incorporation of iron biomarkers in population surveys will enable appropriate targeting of public health and clinical interventions


• Rational, evidence-based thresholds for defining iron deficiency using existing biomarkers, such as ferritin and standardised soluble transferrin receptor, and available but underused biomarkers, such as reticulocyte haemoglobin content

• Identification and validation of functional markers of iron deficiency beyond haemoglobin

• Introduction of standardised hepcidin measurement into routine clinical diagnosis through availability on automated laboratory platforms

• Non-invasive faecal and blood-based tools and improved imaging technology to detect luminal pathologies, such as malignancy and coeliac disease


• Further characterisation of the clinical role and safety of parenteral iron across the range of iron deficiency syndromes, clinical disease groups, and demographic populations

• Development of personalised iron supplementation strategies based on genetic loci that are associated with treatment outcomes of iron supplementation

• Clarification of clinical implications and role for screening and treatment of parenteral iron-induced hypophosphataemia

• Characterisation of possible long-term adverse effects of sustained parenteral iron therapy in patients with functional iron deficiency (including chronic kidney disease)

• Introduction of novel therapies for functional iron deficiency that inhibits hepcidin production, directly target hepcidin itself, or prevent its action on ferroportin; or promote erythropoietin production and iron transport

• Improved understanding of the benefits, risks, and optimal approaches for delivering iron to prevent and treat anaemia in children, adolescents, and women in low-income countries
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