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Iron Deficiency Anemia

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Other Names

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

Background

  • This page refers to all forms of Iron Deficiency (ID)
    • Iron Deficiency Nonanaemia (IDNA) characterized by ID without anemia
    • Iron-deficiency Anemia (IDA) characterized by ID with anemia

History

Epidemiology

  • Prevalence of Iron Deficiency[1]
    • Female: Affects 15-35%
    • Male: Affects 3-11%
  • Iron Deficiency Anemia
    • Studies estimate 0-2% of all athletes[2]
    • Female: Has been described as high as 15%[3]

Pathophysiology

  • General
    • Spectrum of disease resulting 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 including sweating[4], hematuria[5], gastrointestinal bleeding[6]
    • These processes may seem insignificant but can accumulate over time
  • Dietary Iron
    • Difficult to replenish iron stores through diet alone
    • Partly do to bioavailability: haem (15–35%), non-haem (2–20%)[7]
    • Some athletes may prefer vegan or vegetarian intake
    • Low energy availability (intentional or unintentional)
  • Iron requirements
    • Athletes have higher dietary iron requirement relative to the general population
  • Hemoglobin
    • Hemoglobin is normal in 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
    • Efficiency of energy metabolism

Physiology

  • Iron metabolism
    • Not endogenously synthesized by 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 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, 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 total iron status
    • A value of 1 ng/mL of ferritin corresponds to about 5 to 9 mg of stored iron[8]
    • 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[9]
    • When elevated, suppresses absorption 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[10]
  • Ascorbic Acid/ Vitamin C
    • Shown to increase non-heme iron absorption by up to 300%[11]

Etiology of Iron Deficiency

  • 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[12]
    • Among female athletes, the serum ferritin level decreased 14 to 9 ng/mL by the end of the season[13]
    • 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[14]
    • In part due to less iron consumption compared to men[15]

Dietary Intake

  • Recommended Dietary Intake[16]
    • 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%
    • May represent 10% of dietary intake but 1/3 of absorbed iron
  • Non-Heme Iron
    • Sources: plants and animal based foods
    • Bioavailability 2-20%[17]
    • For this reason, vegetarians are at increased risk of ID[18]
    • 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[19]

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


Risk Factors

  • Female Athlete
    • In part due to blood loss from menstruation[20]
    • In part due to less iron consumption compared to men[21]
  • Sports
    • Distance running
    • Cross country

Differential Diagnosis


Clinical Features

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

Evaluation

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 dietcian
    • They can perform nutritional analysis and counselling
    • 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

Classification

  • Not applicable

Management

Prognosis

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 unabsured iron in the intestinal lumen[26]
    • 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[27]
    • Hepcidin increases following exercise and diurnal increases during the day may limit absorption in the evening

Oral Preparations

  • General
    • Ferrous sulfate, gluconate and fumarate 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[28]
  • Ferrous Sulfate (FeSO4)
    • Most frequently prescribed iron supplement
    • 100 mg per day can increase athletes iron stores 30-50% over 6-8 weeks[29]
    • 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[30]
  • Other formulations
    • Iron amino acid chelates iron, preventing it from binding to dietary inhibitors[31]
    • Lipophilic chelate is absorbed before hydrolysis which may protect against GI side effects
  • Ferrous bisglycinate chelate
    • may reduce GI distress, 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)
    • Goal is to minimize GI upset by delaying iron release in intestine
    • Studies report better tolerability[32]
    • Therapeutic efficacy is debated[33], however a meta-analysis showed benefit[34]
  • 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[35]

Optimal Treatment Protocol

  • Daily Dosing
    • Most commonly employed method
  • 24 hours following oral dose of iron > 40 mg
    • Iron absorption is suppressed for 24 hours, likely as a result of mucosal block mechanism and hepcidin[36]
    • Any further iron ingestion during this period is likely limited, may also increase GI distress
  • Split Dosing
    • Stoffel et al: No more effective than supplementing once daily[37]
    • Among athletes, single dose was superior to split dose for rise in hemoglobin[38]
  • 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[39]
    • McCormick et al: serum ferritin response similar to daily despite 50% lower total dosage over 8 weeks[40]

Parenteral Iron

  • General
    • Can be administered IM (intramuscular) or IV (intravenous), although IV is far more commonly used
    • Effective because it bypasses gut, circumvents side effects and absorption issues
    • Degree of increase in serum ferritin is greater in a shorter period of time compared to oral
    • Can provide significant increase within 7-15 days (compared to 4-12 orally)
  • Indications
    • Reserved for athletes with severe stages of ID or IDA
    • Consider in athletes where rapid improvement in iron stores are required
    • When gastrointestinal complications render oral iron therapy impractical
    • When 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 rapid increase in iron stores
    • Overwhelming majority of athlete studies report no significant changes endurance capacity or performance[41][42]
    • 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

Transdermal Iron Supplementation

  • General
    • Novel approach with the goal of bypassing the gut and avoiding invasiveness of IV admin
    • Not currently recommended yet but may have utility in future with more conclusive evidence of efficacy
  • Ferric Pyrophosphate (FPP)
    • May represent one iron formulation that works transdermal
    • Enhanced by iontophoresis[43], microneedle systems[44]
  • McCormick et al: use of commercial iron patch did not significantly increase iron stores in 14 endurance runners[45]

Prevention

  • Eat diet rich in iron

Rehab and Return to Play

Rehabilitation

  • Needs to be updated

Return to Play

  • Ultimately, at the discretion of the physician
  • Primarily driven by degree of symptoms
  • Should be able to progress through a return to play protocol

Complications

  • Fatigue, malaise
  • Decreased exercise performance
  • Need for blood transfusion

See Also


References

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  2. Garza D, Shrier I, Kohl HW, Ford P, Brown M, Matheson GO. The clinical value of serum ferritin tests in endurance athletes. Clin J Sports Med. 1997;7:46-53.
  3. Sinclair LM, Hinton PS. Prevalence of iron deficiency with and without anemia in recreationally active men and women. J Am Diet Assoc. 2005;105:975-978.
  4. Waller MF, Haymes EM. The effects of heat and exercise on sweat iron loss. Med Sci Sport Exer. 1996;28(2):197–203.
  5. Jones GR, Newhouse I. Sport-related hematuria: a review. Clin J Sport Med. 1997;7:120–6.
  6. Gaudin C, Zerath E, Guezennec CY. Gastric lesions secondary to long-distance running. Dig Dis Sci. 1990;35(10):1239–43.
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  10. Hallberg L, Brune M, Erlandsson M, Sandberg AS, Rossander- Hultén L. Calcium: effect of different amounts on nonheme and heme iron absorption in humans. Am J Clin Nutr. 1991;53(1):112–9.
  11. Diaz M, Rosado JL, Allen LH, Abrams S, García OP. The efficacy of a local ascorbic acid-rich food in improving iron absorption from Mexican diets: a field study using stable isotopes. Am J Clin Nutr. 2003;78(3):436–40.
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Created by:
John Kiel on 3 January 2021 15:23:43
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