Iron Deficiency Anemia

Anemia is defined as hemoglobin below two standard deviations of the mean for the age and gender of the patient. Iron is an essential component of the hemoglobin molecule. The most common cause of anemia worldwide is iron deficiency, which results in microcytic and hypochromic red cells on the peripheral smear. Several causes of iron deficiency vary based on age, gender, and socioeconomic status. The patient often will have nonspecific complaints such as fatigue and dyspnea on exertion. Treatment is a reversal of the underlying condition as well as iron supplementation. Iron supplementation is most often oral, but certain cases may require intravenous iron. Patients with iron-deficient anemia have been found to have a longer hospital stay, along with a higher number of adverse events.

Other Names

  • Iron-deficiency Anemia in Athletes (IDA)
  • Iron Deficiency Nonanaemia (IDNA)
  • Iron Deficiency Without Anemia
  • Nutritional Iron Deficiency
  • Nonanemic iron deficiency

Pathophysiology

  • General
    • The spectrum of disease results in a negative iron balance
    • In other words, iron losses exceed iron intake and absorption
    • Early stages of iron deficiency can have normal hemoglobin levels
    • Athletes are considered to be more susceptible than the general population
  • Increased susceptibility
    • Hematological adaptation to training imposes greater demand on oxygen transport
    • Iron loss during exercise includes sweating, hematuria, gastrointestinal bleeding
    • These processes may seem insignificant but can accumulate over time
  • Dietary Iron
    • Difficult to replenish iron stores through diet alone
    • Partly due to bioavailability: haem (15–35%), non-haem (2–20%)
    • Some athletes may prefer a vegan or vegetarian intake
    • Low energy availability (intentional or unintentional)
  • Iron requirements
    • Athletes have higher dietary iron requirements relative to the general population
  • Hemoglobin
    • Hemoglobin is normal in the early stages of iron deficiency
    • In later or more severe stages, athletes can develop anemia and become symptomatic
  • IDA can negatively affect
    • Sports performance
    • Immune function
    • Temperature regulation
    • Cognitive abilities
    • The efficiency of energy metabolism

Physiology

  • Iron metabolism
    • Not endogenously synthesized by the human body
    • Must be replaced exogenously
    • 60-70% used for hemoglobin synthesis, 5% for myoglobin, 20-30% stored as ferritin
    • Roles: aerobic metabolism, intracellular metabolism, optimal mental function
  • Hemoglobin
    • Iron is a critical component of heme formation
    • Responsible for oxygen transport
    • Direct correlation between iron stores, arterial oxygen content, and maximal contractility of skeletal muscle
  • Ferritin
    • Reflection of total iron body stores, a reliable marker of iron deficiency
    • Acute-phase reactant can be falsely elevated following exercise
  • Evaluation of total body iron status
    • Serum iron levels do not reliably reflect the total iron status
    • A value of 1 ng/mL of ferritin corresponds to about 5 to 9 mg of stored iron
    • Other biomarkers for iron stores not routinely used:
      • Transferrin
      • Transferrin saturation
      • Soluble transferrin receptor
  • Hepcidin
    • Primary iron regulatory hormone
    • Elevated in athletes due to exercise-induced inflammation
    • When elevated, suppresses absorption of duodenal enterocytes, iron recycling by macrophages
    • Thus exercise likely impedes normal iron conservation
  • Calcium
    • Inhibits iron absorption
    • In non-heme iron, between 39-74% depending on dose
  • Ascorbic Acid/ Vitamin C
    • Shown to increase non-heme iron absorption by up to 300%

Causes

  • Sports participation
    • Being an athlete appears to contribute to iron deficiency, hypoferritinemia
    • Rowland et al: among runners, the number of ID men and women increased from the start to the end of the season
    • Among female athletes, the serum ferritin level decreased 14 to 9 ng/mL by the end of the season
    • The inverse relationship between training intensity or level and serum ferritin has mixed reports
  • Other losses
    • These processes may seem insignificant but can accumulate over time
    • Gastrointestinal bleeding among runners is reported to be between 8% and 83%
    • Hematuria has been described in up to 90% of runners following a marathon
    • Sweat can contribute significantly to iron losses
    • Hemolysis is some sports has been suggested
  • Iron deficiency specific to women
    • In part due to blood loss from menstruation
    • In part due to less iron consumption compared to men
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Dietary Intake

  • Recommended Dietary Intake
    • Adolescents (9-13) years: 8 mg/day
    • Adult Males: 8 mg/day
    • Pre-menopausal Adult Women: 18 mg/day
  • Heme Iron
    • Sources: hemoglobin, myoglobin in animal-based food
    • Bioavailability 15-35%
    • It May represent 10% of dietary intake but 1/3 of absorbed iron
  • Non-Heme Iron
    • Sources: plants and animal-based foods
    • Bioavailability 2-20%
    • For this reason, vegetarians are at increased risk of ID
    • Absorption is inhibited by iron-binding ligands found in tea, coffee, whole grain cereals, legumes, nuts
    • In one study, up to 1/3 of elite athletes were vegetarian or exluded red meat

Effects on Performance

  • Iron deficiency non-anemia
    • Debated whether isolated ID can have deleterious effects on performance
    • In animal models, IDNA leads to diminished endurance
    • In humans, research has failed to reproduce these findings

Associated Pathology

  • Relative Energy Deficiency In Sport
  • Female Athlete Triad
  • Exercise-induced hemolysis
    • Increases recycling of iron
    • Can result in altered iron metabolism and losses
    • Inadequate iron intake. Eating too little iron over an extended amount of time can cause a shortage in your body. …
    • Pregnancy or blood loss due to menstruation.
    • Internal bleeding.
    • Inability to absorb iron.
    • Endometriosis.
    • Genetics.
  • Female Athlete
    • In part due to blood loss from menstruation
    • In part due to less iron consumption compared to men
  • Sports
    • Distance running
    • Cross country

Differential Diagnosis

  • Fatigue or decrease in exercise performance
    • Relative Energy Deficiency In Sport
    • Female Athlete Triad
    • Iron Deficiency Anemia
    • Hypothyroidism
    • Diabetes Mellitus
    • Sleep Dysfunction
    • Overtraining Syndrome
    • Toxicology
    • Psychiatric including depression, anxiety
    • Chronic Fatigue Syndrome
    • Fatigued Athlete Myopathic Syndrome
  • Microcytic Anemia
    • Iron deficiency
    • Thalassemia
    • Sideroblastic anemias
    • Anemia of chronic disease
    • Lead poisoning

Symptoms

Initially, iron deficiency anemia can be so mild that it goes unnoticed. But as the body becomes more deficient in iron and anemia worsens, the signs and symptoms intensify.

Iron deficiency anemia signs and symptoms may include:

  • Common symptoms include fatigue, paleness, shortness of breath, and dry or damaged hair and skin.
  • Extreme fatigue
  • Weakness
  • Pale skin
  • Chest pain, fast heartbeat, or shortness of breath
  • Headache, dizziness, or lightheadedness
  • Cold hands and feet
  • Inflammation or soreness of your tongue
  • Brittle nails
  • Unusual cravings for non-nutritive substances, such as ice, dirt or starch
  • Poor appetite, especially in infants and children with iron deficiency anemia

Diagnosis

  • History
    • Patients with IDNA are often asymptomatic
    • Classic symptoms of IDA: lethargy, fatigue, weakness, shortness of breath
    • Athletes may experience reduced work capacity, diminished training, and performance outcomes
    • Inability to respond to or adapt to training stress[22]
    • Especially as intensity increases
  • Physical Exam
    • The pallor of the skin, conjunctiva in mild or severe anemia
    • Much less common: koilonychia (spoon nails), glossitis, or dysphagia are rare in the developed world

Normal Laboratory Values

  • Hemoglobin (HgB)
    • Males: <13 g/dL
    • Females: <12 g/dL
  • Ferritin
    • General: >12 to 20 ng/mL
    • Males: 90 ng/mL
    • Females: 25 to 30 ng/mL
  • Others not routinely tested in athletes
    • Mean Corpuscular Volume (MCV): 80 – 100 fL
    • Serum Iron
    • Total Iron Binding Capacity (TIBC)
    • Red Cell Distribution Width (RDW)

Abnormal Laboratory Values

  • Iron Deficiency Non-Anemia (IDNA)
    • HgB: >12 g/dL females, >13 g/dL males
    • Ferritin: <12 to 20 ng/mL<12 to 20 ng/mL[23]
  • Iron Deficiency Anemia (IDA)
    • HgB: <12 g/dL females, <13 g/dL males
    • Ferritin: <12 to 20 ng/mL

Dietician

  • Athletes will benefit from evaluation by an accredited sports dietician
    • They can perform nutritional analysis and counseling
    • May recognize other risk factors such as low energy availability

Screening & Testing

  • General
    • Hemoglobin and ferritin levels are appropriate screening tests
    • Note that ferritin is an acute phase reactant and is elevated following vigorous exercise or inflammatory conditions
  • Recommendations for screening[24]
    • Female athletes
    • Males in endurance sports
    • Competition level: typically elite or highly competitive athletes
  • Indications for testing
    • Athletes experiencing an unexplained decrease in performance
    • Individuals consuming a vegetarian diet
    • Athletes with a previous history of iron deficiency
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Treatment

If you have iron-deficiency anemia, taking iron orally or getting iron administered intravenously along with vitamin C is often the fastest way to raise your iron levels. Iron is necessary to produce hemoglobin in red blood cells, which helps the RBCs carry oxygen to organs and other tissues of the body.

Oral Iron Supplementation

  • Indications for treatment
    • Ferritin levels below normal cut off (<12 to 20 ng/mL)
    • Any evidence of anemia (clinical or laboratory)
  • Compliance issues
    • Adherence is low, ranging from 40-60% in the general population, but >80% in athletes
    • Ferrous Sulfate has a 2.6 OR of GI distress[25] which discourages compliance
    • This may be related to greater doses resulting in uninsured iron in the intestinal lumen
    • Often resulting in suboptimal treatment efficacy
  • Timing
    • Iron supplementation within 30 minutes of exercise in the morning may potentiate iron absorption
    • McCormick et al: more iron absorbed following morning exercise, compared to breakfast or an evening meal without exercise
    • Hepcidin increases following exercise and diurnal increases during the day may limit absorption in the evening

Oral Preparations

  • General
    • Ferrous sulfate, gluconate, and fumarate are most extensively used and studied
    • Cost-effective, good bioavailability (10-15%), 3-4x more bioavailable than ferric iron
    • Most frequently prescribed because it is effective, inexpensive, and low risk
  • Ferrous Sulfate (FeSO4)
    • Most frequently prescribed iron supplement
    • 100 mg per day can increase athletes’ iron stores 30-50% over 6-8 weeks
    • 60-120 mg are commonly prescribed doses, varied based on severity and degree of GI distress
  • Ferrous Gluconate (C12H24FeO14)
  • Ferrous Fumarate (C4H2FeO4)
    • Positive outcomes on iron stores in athletes
    • Similar absorption kinetics to ferrous sulfate
  • Other formulations
    • Iron amino acid chelates iron, preventing it from binding to dietary inhibitors
    • Lipophilic chelate is absorbed before hydrolysis which may protect against GI side effects
  • Ferrous bisglycinate chelate
    • may reduce GI distress, and increase GI absorption by 4-5x compared to ferrous sulfate
    • Currently limited by cost
  • Controlled release iron preps
    • E.g.: carbonyl iron and polysaccharide-iron complexes (IPC)
    • The goal is to minimize GI upset by delaying the iron release in the intestine
    • Studies report better tolerability
    • Therapeutic efficacy is debated, however, a meta-analysis showed benefit
  • Ferric Iron
    • Not commonly used, must be reduced to ferrous iron in the gut to be absorbed
  • Vitamin C
    • Some oral iron supplements contain vitamin C
    • It is a powerful promotor of non-heme iron absorption and acts to maximize iron bioavailability

Optimal Treatment Protocol

  • Daily Dosing
    • The most commonly employed method
  • 24 hours following an oral dose of iron > 40 mg
    • Iron absorption is suppressed for 24 hours, likely as a result of mucosal block mechanism and hepcidin
    • Any further iron ingestion during this period is likely limited, and may also increase GI distress
  • Split Dosing
    • Stoffel et al: No more effective than supplementing once daily
    • Among athletes, a single dose was superior to a split dose for rising in hemoglobin
  • Alternate Day Dosing
    • Emerging body of research: effectively replete iron stores, increase fractional absorption, reduce gastric distress compared to daily
    • Rationale: circumvent the local suppression of iron uptake by the epithelial cells 24 h following the consumption of a dose of iron
    • Stoffel et al: alternate daily iron may also increase iron absorption
    • McCormick et al: serum ferritin response similar to daily despite 50% lower total dosage over 8 weeks

Parenteral Iron

  • General
    • Can be administered IM (intramuscular) or IV (intravenous), although IV is far more commonly used
    • Effective because it bypasses the gut, circumvents side effects and absorption issues
    • The degree of increase in serum ferritin is greater in a shorter period of time compared to oral
    • Can provide a significant increase within 7-15 days (compared to 4-12 orally)
  • Indications
    • Reserved for athletes with severe stages of ID or IDA
    • Consider athletes where rapid improvement in iron stores is required
    • When gastrointestinal complications render oral iron therapy impractical
    • When the iron status is unresponsive to oral treatment and has progressed anemia
  • Dosing
    • Ranges from 300-550 mg per infusion
    • Delivered in 2-5 doses over a 10-42 day period
  • Performance benefits
    • Despite the rapid increase in iron stores
    • The overwhelming majority of athlete studies report no significant changes in endurance capacity or performance
    • Implies despite ID, there is no limitation in erythropoiesis or aerobic capacity as would be seen in IDA
  • Downsides
    • risk of anaphylactoid reaction, iron overload, more expensive
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Transdermal Iron Supplementation

  • General
    • A novel approach with the goal of bypassing the gut and avoiding the invasiveness of IV admin
    • Not currently recommended yet but may have utility in the future with more conclusive evidence of efficacy
  • Ferric Pyrophosphate (FPP)
    • It May represent one iron formulation that works transdermally
    • Enhanced by iontophoresis, microneedle systems
  • McCormick et al: use of commercial iron patch did not significantly increase iron stores in 14 endurance runners

Choose iron-rich foods

  1. Good food sources of nonheme iron include fortified cereals, beans, lentils, tofu, spinach, dried fruits (apricots, prunes, raisins), prune juice, and enriched pieces of bread, broccoli, and nuts.
  2. These foods include carrots, sweet potatoes, spinach, kale, squash, red peppers, cantaloupe, apricots, oranges, and peaches.
  3. Fruits and vegetables high in iron include dried fruits, dark leafy greens, podded peas, asparagus, button mushrooms, acorn squash, leeks, dried coconut, green beans, and raspberries. The current daily value (DV) for iron is 18 milligrams (mg).
  4. Red meat, pork, and poultry.
  5. Taro leaf, yam, owl
  6. Coconut water
  7. Sweet potato
  8. Pomegranate
  9. Seafood.
  10. Beans.
  11. Dark green leafy vegetables, such as spinach.
  12. Dried fruit, such as raisins and apricots.
  13. Iron-fortified cereals, pieces of bread, and kinds of pasta.
  14. Peas.
  15. Tofu.
  16. Baked potatoes.
  17. Cashews.
  18. Dark green leafy vegetables such as spinach.
  19. Fortified breakfast cereals.
  20. Whole-grain and enriched bread.
  21. Durk, green leafy vegetable
  22. Juices like prune juice, beetroot juice, pumpkin juice, and spinach juice are rich plant-based iron sources.
  23. peanuts, pecans, walnuts, pistachios, roasted almonds, roasted cashews, or sunflower seeds. One-half cup of dried seedless raisins, peaches, or prunes. One medium stalk of broccoli.
  24. Choosing a drink that contains vitamin C — such as orange, tomato, or grapefruit juice — around the time of your meal will increase the amount of the non-haem iron you can absorb. In one study, 100mg of vitamin C increased iron absorption four-fold.

Foods to avoid

  • tea and coffee.
  • milk and some dairy products.
  • foods that contain tannins, such as grapes, corn, and sorghum.
  • foods that contain phytates or phytic acids, such as brown rice and whole-grain wheat products.
  • foods that contain oxalic acids, such as peanuts, parsley, and chocolate.
  • Eat a diet rich in iron

Cereals High In Iron & Iron Fortified Cereals

  • Cereals High In Iron & Iron Fortified Cereals – Active Iron.
  • Rice Krispies 30.4mg/100g (US) 8.0mg/100g (UK & Ireland)
  • Cornflakes 28.9mg/100g (US) 8.0mg/100g (UK & Ireland)
  • Quaker Quick Oats 19.8mg/100g.
  • Wheat Biscuits 12mg/100g.
  • Bran Flakes 8.8mg/100g.
  • Muesli 8.8mg/100

Foods That May Hinder Iron Absorption

  • Phytate, or phytic acid, is found in foods like whole grains, cereals, soy, nuts, and legumes.
  • Even a small amount of phytate can significantly decrease iron absorption
  • Calcium (like iron) is an essential mineral, which means the body gets this nutrient from the diet. Calcium is found in foods such as milk, yogurt, cheese, sardines, canned salmon, tofu, broccoli, figs, turnip greens, and rhubarb and is the only known substance to inhibit the absorption of both non-heme and heme iron.