Iron deficiency - Cancer Therapy Advisor
In iron deficiency without anemia, ferritin is typically in the range of ng/mL. . a hemoglobin less than 10 g/dL, or if they fail to respond to a trial of iron replacement therapy. .. "Anemia and chronic kidney disease: What's the connection?. Of note, iron reduction was targeted to reduce serum ferritin levels to . of the study were defined as follows: " to define the relationship between ferritin and iron. intravenous (IV) iron therapy, use the. lowest effective dose of ESA, and pro-. vide IV iron therapy in patients with. higher serum ferritin levels.
The decision to proceed with upper or lower gastrointestinal evaluation initially should be based on clinician judgement and consideration of the presenting symptoms if any. In patients describing dysphagia, gastritic symptoms, nausea, vomiting, or upper abdominal pain upper GI lesions should be suspected. Patients complaining of diarrhea or constipation, hematochezia, or lower abdominal pain should raise suspicion for a lower GI lesion. If no clear symptoms are evident, evaluation of the lower gastrointestinal tract should be the initial diagnostic approach.
Upper endoscopy is the evaluation of choice for the upper GI tract. Upper GI radiographic series are often initially pursued, although these may miss smaller mucosal lesions or vascular ectasia. Subtle lesions, such as mild esophagitis, should not be assumed to be the sole lesion explaining chronic blood loss, and further evaluation of the GI tract lower should follow.
Lower endoscopy colonoscopy is again favored over radiographic imaging in the evaluation of the lower GI tract given the higher sensitivity in identification of smaller mucosal lesions i. If the above evaluation is completed and has not revealed a likely etiology to explain the anemia of iron deficiency through evidence of chronic blood loss, consideration should be given to whether the diagnosis of iron deficiency is indeed accurate - with repeat evaluation for other anemic 'mimics' of iron deficiency including thallesemia, sideroblastic anemia, or the anemia of chronic disease or inflammation.
A nongastrointestinal source of blood loss should also be considered uterine, GU, pulmonaryas well as the possibility of nutritional deficits for iron either due to inadequate intake or absorption gastrectomy status, celiac diseaseor increased demands most commonly due to menstruation and pregnancy.
Evaluation of the severity of anemia, associated symptoms, and effect on comorbidities if presentin order to rapidly identify the need for blood transfusion. Establishment of cause through evaluation of the gastrointestinal tract for evidence of a lesion or lesions to explain blood loss: Initiation of appropriate therapy A. Evaluation of extent of anemia and indications if any for blood transfusion. Hb less than 7 and hemodynamic instability are clear indications for blood transfusion.
In the setting of symptomatic anemia, active and ongoing bleeding, or concurrent coronary artery disease or ACS, higher transfusion thresholds may be warranted. Physical Examination Tips to Guide Management. Evaluation of fecal occult blood or overt lower GI bleeding and or culprit rectal lesions through digital rectal examination and direct visualization of the stool for melena or hematochezia followed by fecal occult blood guaiac testing may rapidly suggest anemia of iron deficiency as well as the likely source.
Once a diagnosis of iron deficiency with or without anemia has been confirmed and appropriate iron replacement therapy initiated, evaluation of other physical examination findings during ongoing surveillance to evaluate the efficacy of therapy may include monitoring for the resolution of any associated physical examination findings that may have been referable to the iron deficiency and present on initial examination.
For example, resolution of pallor with correction of anemia, clinical resolution of glossitis, stomatitis, and angular cheilitis, if present, may be observed with appropriate and effective iron replacement therapy. A failure of this expected response to appropriate therapy should prompt the treating clinician to consider: Iron repletion should continue until hemoglobin levels have normalized. Following this, the effective iron supplementation dose should continue for a further 3 months of therapy to fully replete body iron stores.
Subsequent surveillance for recurrence of iron deficiency anemia should involve measurement of the complete blood count every 3 months for one year and then yearly thereafter. Most important, however, is the identification and appropriate management of the underlying cause of iron deficiency.
As there is no physiologic mechanism for iron excretion, clinicians must assume that the cause is blood loss, and the most likely source second to menstruation is gastrointestinal bleeding, possibly due to a gastrointestinal carcinoma.
Evaluation of the gastrointestinal tract with endoscopy lower, upper, or both, possibly including evaluation of the small bowel by enteroscopy or capsule endoscopy is warranted based on clinician judgement, presenting symptoms, and findings on step-wise endoscopic evaluation as detailed above.
Common Pitfalls and Side-Effects of Management. The differentiation of iron deficiency anemia from other anemias, particularly the anemia of chronic disease or inflammation, can be challenging as both conditions are common, with the anemia of chronic disease being the most common anemia in hospitalized patients.
Iron deficiency anemia and the anemia of chronic disease and inflammation may also occur together. Anemia of chronic disease and inflammation is most commonly associated with connective tissue diseases, chronic infections, malignancies, chronic liver disease, and endocrinologic disorders most commonly thyroidal.
Laboratory findings that may help to differentiate between these conditions include: Despite this, ferritin levels of greater than suggest there is no iron deficiency even in states of inflammation. Initial therapy Initial treatment of the markedly anemic and symptomatic hospitalized patient suffering from a Hb of less than 7 should prompt consideration of blood transfusion - and higher hemoglobin thresholds for appropriate transfusion may be warranted in hospitalized patients with significant and symptomatic comorbidities i.
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The initial management of iron deficiency anemia involves not only repletion of the iron stores, but also the identification of the cause of iron deficiency, which is most commonly due to bleeding. Evaluation for the etiology of bleeding is paramount, most notably including evaluation of the gastrointestinal tract for culprit lesion swhich may include carcinoma as outlined above.
Iron replacement therapy should be initiated with oral iron supplementation. Ferrous iron salts are preferable due to their solubility and bioavailability at the pH of the duodenum where iron is absorbed. Standard therapy for adults involves administration of mg of ferrous sulfate which contains 60 mg of elemental iron three to four times daily. Lower doses may be as effective and better tolerated. Gastritic symptoms, heartburn, nausea, vomiting, and diarrhea may occur with oral iron repletion.
If this is encountered, taking the tablets with meals, lowering the dose, or changing to a formulation to a preparation containing less elemental iron i. Ideally, the daily intake of elemental iron provided should amount to mg in iron deficient adults.
Parenteral iron therapy may be appropriate for patients who have demonstrated intolerance to oral iron preparations despite the above modifications in oral dosage and formulation, patients with known poor absorption of oral iron due to gastrectomy status, celiac disease, inflammatory bowel disesepatients with severe anemia with ongoing blood loss resulting in iron deficits that cannot be overcome adequately through the enteral route, patients with chronic kidney disease or anemia associated with chemotherapy who are receiving erythropoeitin to manage their anemia see below.
Parenteral therapy involves significantly greater cost and potential toxicities and adverse drug events depending on the formulationand as such the choice of this route of therapy must be considered carefully. Intravenous ferric gluconate has been demonstrated to be safe and effective in the treatment of iron deficiency anemia in non-hemodialysis patients. In a study of a total of infusions in 74 adult, non-hemodialysis patients by Miller et al in involving mg of ferric gluconate infused over a 10 minute IV push or diluted in mL of isotonic saline and infused over intervals ranging from 30 to 60 minutes, no significant adverse reactions requiring hospitalization or categorized as severe or anaphylactic were reported.
Only 9 infusions resulted in mild symptoms such as pruritis, nausea, or headache for which the infusion was stopped only temporarily and then completed without incident, and 2 reactions involving dyspnea and urticaria required cessation of the infusion, yet did not require further observation or hospitalization. The treatment of anemia in chronic kidney disease using erythropoietin has been shown to improve quality of life, and for reasons that are poorly understood, patients with chronic kidney disease being treated with erythropoietin often do not respond adequately to oral iron replacement and therefore require parenteral iron therapy to treat the iron deficiency that frequently accompanies chronic kidney disease, and to ensure adequate iron stores for optimal hematopoiesis during erthyropoietin therapy.
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No change in standard management. Systolic and Diastolic Heart Failure. Hb level for consideration of blood transfusion may be higher than 7. Diabetes or other Endocrine issues. The standard of treatment for anemia associated with chemotherapy involves the administration of erythropoietin, and the magnitude of hemoglobin increase as well as improvements in quality of life are significantly greater in this therapy if intravenous iron administration is added to the regimen of treatment.
Immunosuppression HIV, chronic steroids, etc. Gastrointestinal or Nutrition Issues. Patients with celiac sprue may develop iron deficiency as a result of limited ability to absorb dietary iron. Given this limitation in absorption, the treatment of iron deficiency in these individuals may require parenteral iron repletion.
Other gastrointestinal diseases in which dietary and oral iron supplement absorption may be impaired include: Hematologic or Coagulation Issues. Iron deficiency commonly results from bleeding.
Identification of the source of bleeding which frequently involves evaluation of the gastrointestinal tract through endoscopy is fundamental to the management of iron deficiency and iron deficiency anemia. If chronic blood loss cannot be controlled, iron repletion, particularly through enteral routes, may not overcome the daily iron deficit due to ongoing losses - parenteral iron repletion may be required in these circumstances.
The correction of coagulopathies or bleeding diatheses is possible in the setting of iron deficiency and ongoing bleeding may be required in order to effectively manage this condition. Sign-out considerations While Hospitalized. Proper identification of underlying malignancy and potential ongoing bleeding must not be lost in care transitions between inpatient providers as well as in the transition to outpatient management.
Anticipated Length of Stay. Highly variable, but likely days depending on the degree of anemia, the presence or absence of ongoing bleeding and its rate and significance, the need for ongoing inpatient evaluation and management. When is the Patient Ready for Discharge.
Relationship between serum ferritin and total body iron stores in idiopathic haemochromatosis.
A patient is ready for discharge if: Arranging for Clinic Follow-up. When should clinic follow up be arranged and with whom. A patient identified as having iron deficiency with or without anemia in whom oral iron repletion is initiated should follow up with their primary provider within days to assess the tolerance of and response to therapy by symptoms, side effects, and possibly, measurement of the reticulocyte count as an index of appropriate and anticipated resonse to iron repletion therapy.
What tests should be conducted prior to discharge to enable best clinic first visit. CBC including reticulocyte count, red cell indices, iron indices, fecal occult blood testing to identify occult GI bleeding.
Other evaluative tests to identify the source of blood loss as indicated by inpatient clinical scenario. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit. CBC with reticulocyte count.
Table 2 from this study appears below] Iron in fatty liver and in the metabolic syndrome: In this review, the authors state the following: Furthermore, DIOS may facilitate the evolution to type 2 diabetes by altering beta-cell function, the progression of cardiovascular disease by contributing to the recruitment and activation of macrophages within arterial lesions, and the natural history of liver disease by inducing oxidative stress in hepatocytes, activation of hepatic stellate cells, and malignant transformation by promotion of cell growth and DNA damage.
The researchers conclude, "iron depletion, most frequently achieved by phlebotomy, has been shown to decrease metabolic alterations and liver enzymes in controlled studies in NAFLD. Figure 2 from the above paper appears below] Fig.
Proposed mechanisms explaining iron induced liver damage associated with steatosis and DIOS in hepatocytes brownmacrophages grayand hepatic stellate cells yellow.
The role of oxidative stress in the metabolic syndrome 9 In a second review of metabolic syndrome, iron and oxidative stress, researchers at the Harry S.
Truman VA Medical Center in Columbia, Missouri state, "Loss of reduction-oxidation redox homeostasis and generation of excess free oxygen radicals play an important role in the pathogenesis of diabetes, hypertension, and consequent cardiovascular disease.
Reactive oxygen species are integral in routine in physiologic mechanisms. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways that promote impairments in insulin metabolic signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular and renal structural and functional abnormalities. Redox control of metabolic function is a dynamic process with reversible pro- and anti-free radical processes. Labile iron is necessary for the catalysis of superoxide anion, hydrogen peroxide, and the generation of the damaging hydroxyl radical.
Acute hypoxia and cellular damage in cardiovascular tissue liberate larger amounts of cytosolic and extracellular iron that is poorly liganded; thus, large increases in the generation of oxygen free radicals are possible, causing tissue damage.
The understanding of iron and the imbalance of redox homeostasis within the vasculature is integral in hypertension and progression of metabolic dysregulation that contributes to insulin resistance, endothelial dysfunction, and cardiovascular and kidney disease.
The role of iron in the pathophysiology and treatment of chronic hepatitis C 10 Free full text This article "reviews the prevalence and risk factors for hepatic iron overload in chronic hepatitis C, with emphasis on the available data regarding the efficacy of iron depletion in the treatment of this common liver disease.
Hepatic iron depletion has been postulated to decrease the risk of hepatocellular carcinoma in patients with cirrhosis due to chronic hepatitis C. It is possible that iron depletion stabilizes or improves liver histology and slows disease progression in these individuals. Based on initial study biopsies of patients in each groups, liver damage assessments were compared both prior to phlebotomy treatments and approximately years later.
Only males responded to phlebotomy. Two groups CHC patients and controls were studied. CHC patients presented significantly higher values than the control group in some parameters: This greater oxidative activity could play an important role in pathogenesis and evolution of hepatitis C and thus further investigations.
Known as iron reduction therapy, phlebotomy reduces serum ALT activity. This effect might continue with maintenance phlebotomy and result in slower progression of liver fibrosis. For histological evaluation, liver biopsies were performed before and after the study period in 13 of the patients.
Thirteen patients who were virological nonresponders to interferon alone and had undergone second liver biopsies after more than 3 yr served as histological controls. The investigators concluded, "These results suggest that phlebotomy with maintenance lowers serum aminotransferase levels, improves liver inflammation, and suppresses the progression of liver fibrosis in chronic hepatitis C. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy.
To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFE-hemochromatosis. Serum iron indices and liver function tests were measured in pre- and post treatment blood samples from each patient.
Body iron stores were calculated using the removed blood volume. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. These differences are depicted below in Figures 2 and 3 from this article.
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In a step up model in which baseline concentrations of serum triglycerides and glycosylated proteins were adjusted for as continuous variables, the odds ratio for developing diabetes was 2. Insulin secretion and sensitivity were tested at baseline and 4 and 12 months thereafter. In parallel to this changes, blood HbA1c decreased significantly only in group 1 subjects, Table 2 and Figures 1 and 2 from this study appear below.
Note also that phlebotomy treatment was limited to the first month of the study only. We tested the hypothesis that decreasing circulating iron stores might improve vascular dysfunction in patients with type 2 diabetes and increased serum ferritin concentration. These changes occurred in parallel to decreases in transferrin saturation index and HbA 1c levels The best predictor of the modifications in endothelium-independent vasodilation was the change in HbA 1c levels.
At 12 months, transferrin saturation index and GTN-induced vasodilation returned to values similar to those at baseline in both groups of subjects. The mechanisms by which these changes occur should be further investigated. Table 1 from this study appears below] Association of High Serum Ferritin Concentration with Glucose Intolerance and Insulin Resistance in Healthy People 19 Free full text The objection of this letter that comments on the study described directly above was "to analyze the relationship between iron variables and glucose tolerance, insulin sensitivity, and Beta-cell function in non-diabetic persons.
These associations remained statistically significant There was no significant correlation between serum ferritin concentration and either estimated from the oral glucose tolerance test or measured Beta-cell function If prospective and interventional studies confirm an etiologic role of iron overload in the pathogenesis of insulin resistance and type 2 diabetes, reduced dietary iron intake, especially in men and postmenopausal women 9 with additional risk factors for type 2 diabetes, would appear to be a logical consequence.
In the future, actively lowering body iron stores may become a tool in preventing type 2 diabetes in selected subgroups. The Figure from this study appears below] Association Between Blood Donation Frequency, Antioxidant Enzymes and Lipid Peroxidation no abstract 20 Free full text This Iranian research was based on reported findings that linked iron as a pro-oxidant cofactor to atherosclerosis progression and the hypothesis that, "Reduction of body iron stores secondary to blood donation has been hypothesized to reduce lipid peroxidation" The researchers divided male volunteer blood donor subjects between 30 and 60 years of age into five groups according to annual frequency of blood donations.
The researchers concluded, "The current findings demonstrate evidence of greater reduction of body iron stores, increase activity of SOD, decreased oxidative stress, and decrease lipid peroxidation in high frequency blood donors when compared with low frequency blood donors.Are You Iron Deficient?
In men, insulin sensitivity and insulin secretion were evaluated through frequently sampled intravenous glucose tolerance tests with minimal model analysis.
This result was mainly attributable to the men who had given at least 2 blood donations in the previous 6 months to 5 years. Stored iron seems to impact negatively on insulin action even in healthy people, and not just in classic pathologic conditions associated with iron overload hemochromatosis and hemosiderosis.
According to these observations, it is imperative that a definition of excessive iron stores in healthy people be formulated. Figures 1 and 2 and Table 1 from this study appear below].