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Flashcards in Iron Deficiency and Overload Deck (23):
1

What is the distribution of iron in the body?

  • Iron plays an essential role in the normal function and metabolism of virtually all cells; iron is particularly essential for the synthesis of heme-containing compounds, hemoglobin, and myoglobin
  • Iron distribution—The typical adult male has a total body iron content of 4 grams
    • 75% is in hemoglobin and myoglobin, and the remainder is in body stores
    • Due to menstrual loss, an adult woman has a lower iron content

2

What is the nutritional requirement for iron?

  • Iron absorption is tightly regulated, but we have no substantial mechanism for excretion
  • The typical male ingests 15-20 mg of iron each day and at steady state, this amount is often sufficient for the replacement of that iron lost in sweat, tears, urine and feces (typically 1-4 mg of elemental iron)
  • Women have increased requirements due to menstrual loss and increased demands associated with pregnancy
  • The typical dietary source of iron comes from meat-derived heme iron
    • non-heme iron (from vegetables as well as cereals) is less bioavailable, and certain compounds, such as phosphates and phytates impair absorption

3

What are the determinants of iron absorption?

  • Inorganic (non-heme) iron from food is released via action of proteolytic enzymes and HCl in the stomach
  • The acidic environment facilitates reduction of Fe3+ to Fe2+, allowing for absorption in the duodenum and upper jejunum
  • Vitamin C is a reducing agent, facilitating absorption, which is why this can be recommended along with iron supplements for some patients
  • Fe2+ binds the divalent metal ion transporter (DMT-1) at the apical membrane of the duodenal enterocyte, allowing for internalization of iron
    • DMT-1 is up-regulated in iron deficiency, and down-regulated in states of overload
    • Heme iron may be absorbed via a specific receptor on the duodenal enterocyte (HCP-1)

4

What is the role of ferroportin in iron export?

  • Iron export is regulated through ferroportin, the only known human iron exporter, expressed on the basolateral membrane of the enterocyte
  • Ferroportin allows for the iron absorbed in the duodenal enterocyte to pass through to the circulation where it's bound to transferrin and delivered either for storage or to the erythroid marrow for new red blood cell production
  • Ferroportin is also expressed on the surface of the macrophage, which allows for the recycling of iron from obtained from senescent red blood cells engulfed by macrophages

5

What is the role of hepcidin in iron export?

  • Hepcidin is an acute phase protein, synthesized by the liver, known as the “master regulator of iron”
  • When present, it results in the internalization and degradation of ferroportin
    • The consequence is:
      • an interruption of iron flow through the macrophage, or duodenal enterocyte
      • sequestration of iron in the reticuloendothelial system
      • storage as ferritin
  • Hepcidin is feedback regulated by iron
    • With iron deficiency, the goal is to maximize iron availability, and hepcidin will be suppressed, mediated by a serine protease, TMPRSS6, which preserves a constant iron flow
    • On the other hand, with iron sufficiency, to protect from the oxidative and inflammatory stress of iron, hepcidin is up-regulated, occurring largely through the function of the BMP-6/SMAD signaling pathway that includes its accessory proteins, HFE, Hemojuvelin (HJV), and Transferrin Receptor
  • Any increased drive for erythroid activity also suppresses hepcidin-this may be mediated through a recently described factor called erythroferrone
  • Inflammation is a potent up-regulator of hepcidin, especially the inflammatory cytokine IL-6, signaling through the JAK-STAT pathway
    • The inflammatory-induced iron sequestration likely reflects an evolutionary response, aiming to limit iron from the invading micro-organism, since iron is a growth factor for many microorganisms

6

What are the major diseases that result from defects in hepcidin?

  • hepcidin is appropriately suppressed in iron deficiency anemia (allowing for maximal iron flow)
  • up-regulated in anemia of inflammation (resulting in iron sequestration and lack of availability for erythropoeisis)
  • relatively deficient in hemochromatosis (resulting in varying degrees of iron overload)

7

What are the components of iron transport?

  • Iron (Fe3+, converted back by hephestin) in the bloodstream is bound to transferrin, ultimately fed to developing erythroblasts in the marrow, via transferrin receptors
  • There are 2 of these receptors—TfR1 andTfR2
    • These receptors increase in the presence of iron deficiency
    • The transferrin/receptor complex is internalized with the erythroblast, and iron is released and incorporated for heme synthesis
    • The transferrin/receptor complex is then recycled as well

8

What are the components of iron storage?

  • About 25% of the body’s iron is stored in the liver, macrophage, and marrow
    • Storage iron exists principally as ferritin
  • Plasma ferritin is derived from tissue macrophages, and can be measured, reflecting a very useful measure of iron status/stores
  • Ferritin synthesis is decreased with iron deficiency, and increased in states of sufficiency
  • Inflammation also up-regulates ferritin (acute-phase reactant)

9

What are some of the more common modalities in assessing iron stores in the body?

  • Serum iron—direct measure of iron bound to transferring (50-150 mcg/dL)
  • Total Iron Binding Capacity—measure of the amount of iron that can be bound by transferrin (300-360 mcg/dL)
  • Percent saturation—Iron/TIBC-normal range is 20-50%
  • Ferritin—measure of total body iron stores—(50-200 mcg/L in normal male)
  • Bone marrow—Prussian blue stain
  • Magnetic Resonance Imaging (eg, of the liver)

10

What is iron deficiency anemia and what are the manifestations of IDA prior to overt clinical symptoms?

  • IDA is the most common anemia worldwide, and typically reflects a manifestation of another primary pathology, such as blood loss, or less commonly, malabsorption
    • Therefore, once IDA is recognized, it is important not only to replace iron, but to search for the root cause of deficiency
  • Prior to overt IDA, there are stages that can be recognized by labs.
    • Iron Store Depletion—Suggested by a ferritin below the normal reference range
      • If some iron stores are still present, the iron, IBC, and hemoglobin remain normal
    • Iron-Deficient Erythropoiesis—In this state, the serum iron falls, accompanied by a rise in the TIBC
      • Accordingly, there is a decrease in the % saturation
      • The ferritin will be reduced as well
      • In early stages of IDE, there may be only minimal anemia, and little change in red cell morphology and indices (MCV)

11

What are the findings in overt iron deficiency anemia?

  • Overt IDA can be relatively easy to recognize as:
    • serum iron is reduced
    • TIBC is increased
    • % saturation is reduced
    • ferritin is reduced below the normal reference range
  • Recalling its regulation, hepcidin would be appropriately suppressed
  • Often, moderate to severe anemia ensues, and there are distinct changes in red blood cell morphology, particularly microcytosis (decrease in MCV) and hypochromia
  • Increasingly severe IDA will subsequently result in bizarre red cell changes, including pencil or cigar-shaped cells

12

What are some of the associated conditions with iron deficiency anemia?

  • Conditions that result in increased requirements for iron are the main causes for IDA:
    • Blood loss—GI and GU tracts most common
    • Growth and Pregnancy
    • Iron loss—Occasionally seen with chronic intravascular hemolysis
  • Less common causes of IDA come from a decreased supply of iron
    • Malabsorption—Celiac disease is a common consideration here
      • Gastrectomy or gastric bypass can also affect iron absorption
      • Atrophic gastritis and H.Pylori are also on this list of causes
    • Dietary deficiency is a very rare cause of IDA in developed countries

13

What are the symptoms and consequences of iron deficiency anemia?

  • Symptoms can arise from anemia itself, which can include:
    • fatigue
    • shortness of breath with exertion
    • dizziness
    • lightheadedness
    • fast heartbeats
  • Other characteristic changes result from inability to replace rapidly turning over epithelial cells, such as:
    • nails (brittle)
    • corners of the mouth (cracked)
    • tongue (sensitive/inflamed)
    • lining of the stomach
  • A characteristic symptom includes an unusual craving for ice or starch (PICA)
  • Finally, there may be symptoms from the underlying disease leading to IDA (example: cancer or duodenal ulcer leading to blood loss)

14

What is the treatment of iron deficiency anemia?

  • Iron supplementation is the treatment of choice
    • Depending on the clinical situation, some patients will also need blood transfusion
    • Typically, oral preparations (many different formulations are available) are recommended, unless a patient has a known malabsorptive state that will hinder effectiveness
  • Typically, with adequate supplementation, the hemoglobin may rise as much as 2-3 g/dL over a 1 month period
  • Ideally, patients are treated with 200mg of elemental iron per day (3 tablets), ideally for a 6 month period to fully replenish stores
  • As many as 25% of patients will have side effects (GI upset, constipation, diarrhea) that prevent them from tolerating the dose required to replenish stores
    • In states of severe intolerance or malabsorption, intravenous iron can be prescribed

15

What is anemia of inflammation and what is the pathophysiology?

  • AI is among the most common causes of anemia that will be seen in hospitalized patients
  • In the case of AI, iron is available, but is sequestered, and cannot be delivered to the erythroid marrow for adequate erythropoiesis
  • The hallmark pathophysiological abnormality is an increase in hepcidin, driven by inflammation
  • As a result of hepcidin’s presence, ferroportin is internalized and degraded and iron export halts
  • Iron is then relegated to storage sites, accounting for one mechanism of ferritin increase (the other is an inflammatory increase)

16

What are the typical associated disease with anemia of inflammation?

  • Typical associated diseases include:
    • inflammatory conditions (Rheumatoid arthritis)
    • infection
    • malignancy
  • The presence of such a condition along with anemia may suggest the presence of AI
  • AI is typically a normochromic, normocytic anemia, but microcytosis can be seen in severe cases, those of a longstanding duration, and when there is concurrent iron deficiency
  • The appearance of increased inflammatory markers is also supportive, including increases in:
    • sedimentation rate
    • C-reactive protein
    • fibrinogen
    • platelet count

17

What are the laboratory findings involved in the diagnosis of anemia of inflammation?

  • Since iron studies best characterize AI, it is important to distinguish this entity from IDA:
    • Serum iron - low (ID also low)
    • Transferrin - low (ID is high)
    • Tf receptor - normal or low (ID is high)
    • Ferritin - normal or high (ID is low)
    • Erythropoietin - not appropriately increased (ID is high)
  • A potentially useful test is the soluble transferring receptor assay (sTfR)
  • In IDA, the transferrin receptor is up-regulated and becomes soluble
    • Therefore, the soluble transferrin receptor increases in IDA, but is typically normal in isolated AI
    • When combined with the ferritin as a ratio, this may be one test to help distinguish IDA from AI (example: IDA—increased sTfR/log ferritin—therefore, an increased ratio supports a diagnosis of IDA)

18

What are the symptoms and consequences of anemia of inflammation?

Patients may have symptoms from anemia in addition to symptoms from an underlying disease, which is by definition, present (such as joint swelling from rheumatoid arthritis)

19

What is the treatment of anemia of inflammation?

  • With AI, the optimal strategy is to treat the underlying disease, but this can absolutely be challenging—in many cases, the disease underlying AI is unknown
    • Alternatively, the underlying disease in many cases is incurable, such as chronic kidney disease (without transplantation) or certain malignancies
  • Further, definitive therapies can be poorly tolerated
    • Therefore, complimentary strategies to treat anemia are required
    • The most widely used strategy is iron supplementation, but this is not always appropriate
  • AI is a disease of iron sequestration—iron is present in storage sites, but not available for use
    • Iron is recommended only for patients with a strong suspicion of or proven concurrent IDA
  • The oral route is the easiest and cheapest, but the ideal dose is often poorly tolerated or poorly complied with
    • Additionally, if hepcidin levels are increased due to inflammatory stress, transport across the duodenal enterocyte is blocked, and oral supplementation is destined to fail
    • In this situation, intravenous (IV) iron is recommended if IDA is strongly suspected or confirmed

20

What is the pathophysiology and genetics of hemachromatosis?

  • Hemochromatosis reflects excess iron loading of tissues, and can reflect a hereditary (primary) cause, or can be transfusion-associated (secondary)
    • In addition, some anemias are characterized by iron loading—in particular, hemoglobinopathy such as thalassemia
  • We will focus on hereditary hemochromatosis as the hallmark disorder of iron overload
  • Genetics:
    • 5 genes are involved in iron transport and when mutated, iron overload
    • The first to be identified was the HFE gene, which is essential for producing hepcidin
    • Inherited mutations of HFE are the most commonly identified in patients with hereditary hemochromatosis
    • Hemojuvelin (HJV), transferrin receptor 2, and the gene that enables ferroportin production can also be mutated, accounting for the spectrum of mutations identified in hemochromatosis

21

What is involved in the diagnosis of hemachromatosis?

  • Serum iron—increased (> 150 mcg/dL)
  • Transferrin saturation—increased (typically > 50%)
  • Serum ferritin—increased (often > 1000 mcg/L, reflecting an iron load of > 10-20 grams)
  • Liver biopsy—increased iron deposition
  • MRI—now more frequently utilized to quantify iron deposition in various end organs (liver and heart)
  • Hereditary hemochromatosis genetic screening:
    • HFE mutations are responsible for 85% of cases in the United States, commonly C282Y homozygosity (80% of cases)
    • Compound heterozygotes (C282Y/H63D) are less frequent (3-5%)
    • Homozygous H63D patients may have iron overload but less severe clinical manifestations
    • HJM, TFR2, and other mutations may account for the remainder of cases

22

What are the symptoms and consequences of hemachromatosis?

  • The first symptom of the disease is often chronic fatigue
    • Other symptoms are attributed to abnormal iron deposition
    • The liver, pancreas, anterior pituitary, joints, and heart are all sensitive to iron overload
  • Therefore, consequences (and associated symptoms) can include:
    • Liver function test abnormalities, cirrhosis, and later risk of hepatocellular cancer
    • Diabetes Mellitus
    • Hypogonadism (Loss of libido, testicular atrophy, amenorrhea)
    • Arthritis, typically involving MCP joints
    • Cardiomyopathy and arrhythmia
    • Skin changes—“bronzing”
    • Susceptibiilty to infection:
      • Listeria
      • Yersinia Enterocolitica
      • Vibrio vulnificus
    • Perhaps due to increased growth of these organisms in the setting of an iron rich environment

23

What is the treatment of hemachromatosis?

  • The treatment of choice is preventative phlebotomy as iron removal may reverse some forms of organ damage
    • Cardiac arrhythmia and heart failure may respond to iron removal, and if a patient has esophageal varices, these may improve as well
    • Liver fibrosis can improve, but cirrhosis is not reversible
    • Diabetes, gonadal failure and joint destruction are typically not reversible
  • The mainstay of therapy is phlebotomy:
    • Typically, removal of 500ml of whole blood will remove about 200mg of iron
    • Therefore, if a patient has an estimated 10 grams of iron overload, about 50 phlebotomies are needed to normalize levels
    • Typically, phlebotomies can be scheduled weekly, often with a goal of obtaining a ferritin of < 50 mcg/L and a % saturation of < 50%
    • An alternative is iron chelation therapy
      • there are subcutaneous/IV (deferoxamine) and oral options (deferasirox or deferiprone)
      • These options are typically recommended for those with iron loading anemia or transfusional iron overload, in whom phlebotomy is not an option
  • Patients should avoid iron supplementation, but typically, we do not recommend additional dietary restrictions
  • Moderation of alcohol intake is another important aspect of patient counseling