Iron Deficiency: Grey Matters Segment

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• Symptoms often precede development of anemia!
  • Therefore, iron deficiency is a clinical syndrome and anemia is a late-stage complication
• Why do these symptoms occur?
  • Low iron in body → Body prioritizes using available iron to replenish heme → Iron is redirected to the bone marrow and away from other highly metabolically active tissues, where it is used for cellular respiration
    • Examples:
      • Muscles → Generalized Weakness
      • Brain → Neuropsychiatric symptoms
        • Pica
        • Restless leg syndrome
      • General neuropsychiatric symptoms:
        • Fatigue and poor exercise tolerance, depression, insomnia, difficulty with cognitive tasks

Deep Dive 1: How do we diagnose iron deficiency?

• FERRITIN
  • Protein used to store iron
    • Found primarily in the liver and macrophages (reticuloendothelial system)
  • How is ferritin measured?
    • Small amounts are leaked into serum
  • WHO 2020 Guideline Recommendation: Ferritin cutoff of 15 ng/mL for adults without inflammation or infection → diagnosis of iron deficiency
    • NOTE: Very sensitive, but misses many iron deficient patients!
  • Choosing a ferritin cutoff can be challenging!
    • Ferritin cutoffs initially came from studies in the 1970s
      • Presumed normal iron stores based on the absence of anemia or TSAT level (source 1, 2)
    • Each value will have its own sensitivity and specificity
      • Cutoff of 15 ng/mL
        • Sensitivity of 59%; Specificity of 99%
      • Cutoff of 45 ng/mL
        • Sensitivity of 85%; Specificity of 92%
        • Physiological studies suggest iron stores and hemoglobin stop increasing in response to iron supplementation at a ferritin of 50ng/mL (source 1, 2).
        • The American Gastroenterological Association recommends using a ferritin of 45ng/mL to diagnose iron deficiency in anemic patients.
    • It is unclear if ferritin cutoffs should be different for those with or without anemia
      • Most studies are on anemic patients, but others use a mixed population of anemic and non-anemic patients
  • What if the ferritin level is not definitive but iron deficiency is still suspected?
    • Examples: Ferritin 45-100 ng/mL or with other possible causes such as inflammation
    • Consider a time-limited treatment with iron
    • British Society of Gastroenterology Recommendation: Rise in hemoglobin of at least 1g/dL 2 weeks AFTER treatment → diagnosis of iron deficiency!
• TSAT
  • What is TSAT?
    • Transferrin is the protein that transfers iron around the body. It contains binding sites for iron. Transferrin saturation, or TSAT is an estimation of how many of those binding sites are currently being occupied by iron. Calculation: iron over total iron binding capacity (TIBC)
      • Note: TIBC is a measure of all proteins which can carry iron in the blood (including transferrin but also albumin), but is often used as a surrogate for transferrin given the ease of testing
  • What are the challenges of using TSAT?
    • Not a lot of guidance on optimal TSAT cutoff in patients without inflammation
    • It may not add much discriminatory value beyond ferritin!
    • Should be measured in a fasting AM sample
      • Iron (and thus TSAT) are affected by time of day, recent meals, hemolysis
    • TSAT below 16-20% can suggest iron deficiency, but should be used in combination with other tests
  • MEAN CORPUSCULAR VOLUME
    • NEW drop → very concerning for iron deficiency!
      • Mean corpuscular volume (MCV) is typically consistent through life
      • A new decrease in MCV is concerning for iron deficiency, as other uses of acute MCV drop are rare (lead poisoning, sideroblastic anemia)
  • TOTAL IRON BINDING CAPACITY
    • Elevation can suggest iron deficiency
  • MEAN CORPUSCULAR HEMOGLOBIN
    • Decrease can suggest iron deficiency
  • RETICULOCYTES
    • Decrease can suggest iron deficiency
• How do we  diagnose iron deficiency in the setting of chronic inflammation?
  • Diagnosis becomes less certain!
    • There is less data to support decision making
    • Most data is in patients with CHF, CKD, or IBD and extrapolated to other patients with inflammation
    • Inflammation affects iron testing
      • (IL-6) → Hepcidin release and drop in available iron
      • Increase in ferritin release
        • NOTE: This is mostly ferritin without iron attached (apoferritin)
      • Transferrin is an acute phase reactant. So inflammation -> decreased transferrin and TIBC -> increase in TSAT
  • Recommendations: In the setting of chronic inflammation, recommendations vary
    • Ferritin < 100 or 100-300 ng/mL with transferrin saturation <20% → diagnosis of iron deficiency!
      • Specific to patients with chronic heart or kidney disease or inflammatory bowel disease
      • 2017 American Journal of Hematology
    • Ferritin cutoff of 70 ng/mL in inflammation or transferrin saturation <20% → diagnosis of iron deficiency!
      • 2020 WHO
  • TSAT may be more useful in patients with chronic inflammation than those without chronic inflammation
    • Some advocate for TSAT<20% suggesting iron deficiency in the presence of inflammation, even with higher ferritin levels
      • Hematology 2020
    • For patients with HFrEF, TSAT less than 20% may both outperform ferritin cutoffs and identify patients with an increased mortality risk (1, 2).
  • NOTE: For patients with CKD, the sensitivity of these cutoffs is still poor
    • Many iron deficient patients with CKD may be missed!
    • We do not discuss diagnosis of iron deficiency in patients with ESRD here, as this has a different approach.
• So what is the GOLD STANDARD for diagnosing iron deficiency anemia?
  • Bone marrow biopsy!
    • This is more invasive, less practical, rarely performed
  • Clinically relevant standard for diagnosis:
    • Improvement in the following with iron supplementation:
      • Symptoms
      • Hemoglobin
      • Iron studies

Deep Dive 2: How do we approach a premenopausal woman with suspected heavy menstrual bleeding?

• How common is iron deficiency in women?
  • VERY!
    • Prevalence (iron deficiency) = 11-20% of women in America
      • Recent data found a prevalence of 40% of women 21 years and younger
      • Note:  Estimated that 39% of women have heavy menstrual bleeding
        • Significantly underdiagnosed!
    • Prevalence (iron deficiency anemia) = 30-32% of women worldwide (source 1, 2)
      • About half of the cases of anemia are due to iron deficiency!
• The common hemoglobin normal ranges may lead to underdiagnosis!
  • Lower limit of normal Hg= 12 in women, 13 in men
    • However, when given iron, women’s Hgb approached that of men!
      • This suggests physiologic Hg may be more similar between women and men then we think, and women with anemia and/or iron deficiency may be underdiagnosed! 
      • WHO is reviewing their guidelines, and these ranges may change.
• Iron deficiency is a leading cause of “years lived with disability” in women!
  • Risk factors:
    • Menstruation
    • Underdiagnosed heavy menstrual bleeding
    • Lower circulating blood volume (compared to men)
    • Fewer red blood cells (compared to men)
• What symptoms might your patient with iron deficiency (without anemia) have?
  • Reminder! Low iron → Depletion of local iron in muscles and brain
  • Symptoms associated with iron deficiency and/or heavy menstrual bleeding:
    • Restless leg syndrome, Pica
    • Insomnia, fatigue, depression
    • Decreased ability to exercise or work
    • Decreased quality of life
    • Note:Iron supplementation can lead to improved exercise capacity in non-anemic runners!
• What are best practices for taking a menstrual history?
  • Heavy menstrual bleeding is bleeding of enough volume that affects quality of life
    • The classic definition is 80mL per menstrual cycle, but strict quantification is unreliable and impractical!
  • During an interview, start with open-ended questions, followed by more detailed questions
    • Patients may have normalized their HMB and so a careful history is still important…
    • Example: Your patient changes their pad 3 times per day
      • Ask them: “Is the reason that the pads are fully soaked, or another reason?”
  • Findings in the history that suggest heavy menstrual bleeding (HMB)
    • Bleeding >7 days
    • Passing clots larger than a quarter (or > 1 inch)
    • Episodes of gushing
    • Overnight “accidents” (e.g. bleeding through products overnight)
    • Adaptive behaviors
      • Changing products every couple of hours
      • Wearing extra products or protective padding
      • Lifestyle changes to accommodate heavy menstrual bleeding
  • Supplemental tools to the history
    • Pictorial charts
      • Pictorial Bleeding Assessment Chart (PBAC)
        •  Very high scores have a good sensitivity for HMB, but not the best specificity (8% in one study- source 1, 2, 3).
        • Can be useful for tracking bleeding over time
    • Menstrual multi-attribute scale
      • Quantifies how menstrual cycle affects quality of life (such as whether someone’s social life, daily routine, or relationships are affected by their cycle)
      • Validated tool (source 1, 2)
    • FIGO-AUB System 1 and FIGO-AUB System 2
      • Standardized parameters and terminology for abnormal uterine bleeding (AUB)
      • Developed by International Federation of Gynecology and Obstetrics (FIGO)
    • Additional resources to help guide the evaluation of heavy menstrual bleeding!
  • PRO TIP: Negative or invalidating experiences from providers leads to many women not seeking care…
    • Every patient is different!
    • May not be aware of what is considered “average” menstrual volume
    • Substantial variation between what different individuals consider light and heavy flow
    • Many parents do not discuss menstruation with their children
• Are there any guidelines for screening for iron deficiency in women?
  • Of 22 different guidelines for HMB, only 3 recommended initial iron testing
  • Pregnancy guidelines
    • Recommend checking a blood count but no screening iron tests.
    • Many advocate for screening for iron deficiency in pregnancy. Particularly as there is evidence that perinatal iron deficiency without anemia can shunt heme from the developing brain and contribute to neurodevelopmental delay
• Heavy menstrual bleeding is a symptom, not a diagnosis. Something is causing the abnormal bleeding!
  • What is the standard work up for HMB?
    • CBC
    • Coagulation studies
    • Iron testing
    • TSH
    • Pregnancy test
    • Endocrine testing and a pelvic exam
      • May be warranted based on a patient’s history
    • Ultrasound
      • If there is concern for structural cause or for patients 40 years and older
    • NOTE: HMB since menarche + a personal or family history of bleeding → consider coagulopathy!
      • Seen in as many as one third of patients with HMB
        • 13% of HMB patients have von willebrand disease
  • What about treatment?!
    • Remember to treat both HMB and iron deficiency
      • Prevents further iron depletion
      • Can be a diagnostic aid. Iron deficiency persists after HMB stops, a secondary process may be driving iron deficiency!
    • For more information on the treatment of iron deficiency, see the “Five Pearls” Core IM episode on iron deficiency

Deep Dive 3: When is a gastrointestinal evaluation appropriate in premenopausal women?

• How common are lesions found on endoscopic evaluation?
  • Data for men and women of all ages with asymptomatic iron deficiency anemia (mean age 63.7 years old)
    • Premenopausal women included but those with HMB excluded
    • Found a culprit lesion in 89% of patients, 13% had cancer
    • If no culprit lesion is found, can consider video capsule endoscopy (detection rate: 35 to 77%).
  • But how common are lesions in premenopausal women?
    • For asymptomatic premenopausal women with iron deficiency undergoing endoscopic evaluation, lesions were found in 5.9-6.5% of patients
      • Lesions included gastritis, hemorrhoids
      • Only 1 case of colon cancer detected
    • Rates of GI cancer in younger patients is increasing! Exact incidence is uncertain, studies are inconsistent
      • Meta-analysis of 70 studies:
        • 0.1% risk in patients <50 years old
        • Included men
      • Meta-analysis of 10 studies
        • 0.2% risk of upper GI malignancy (premenopausal women)
        • 0.9% risk of lower GI malignancy (premenopausal women)
        • Included those with GI symptoms (higher risk)
  • Cancer risk is not equal for all premenopausal women and risk may be higher based on:
    • • Age
      • GI symptoms
      • Medical or social history
      • Family history of GI cancer
• What non-invasi ve workup can be pursued for premenopausal women with iron deficiency?
  • Serologic testing for celiac disease
    • Evaluates for celiac disease
    • Should be evaluated WITH or WITHOUT of GI symptoms
  • Consider H Pylori stool antigen testing
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  • Fecal occult blood testing → flawed test!
    • 58% sensitivity; 84% specificity
      • Many lesions only bleed intermittently and thus may be missed on such testing
• When should you refer your premenopausal patient with iron deficiency for bidirectional endoscopy?
  • Must balance risks and benefits
    • Evaluates for malignant and benign GI causes
    • Serious complications do occur
      • 5 per 1000 colonoscopies (including complications from both colonoscopy and procedural sedation)
  • Recommended for premenopausal women WITH GI symptoms
  • When to refer patients WITHOUT GI symptoms?
    • American Gastroenterological Association’s 2020 Clinical Practice Guidelines recommends bidirectional endoscopy.
      • Assumes no other “unequivocal” cause of iron deficiency anemia
      • Notes that “at particularly at younger ages, the benefit of endoscopy to detect the extremely rare gastrointestinal malignancies is likely diminished compared with the risks”. This age is uncertain
      • Note: Critics point out broad use of this guideline would be costly!
    • Expert suggestion:
      • Evaluate ALL premenopausal women with iron deficiency for heavy menstrual bleeding and GI symptoms
      • If heavy menstrual bleeding is detected, treat this and iron deficiency, and see if iron deficiency resolves.
      • Consider bidirectional endoscopy for women with:
        • GI symptoms
        • No evidence of heavy menstrual bleeding (or other cause of iron deficiency)
        • Iron deficiency which does not resolve with treatment of HMB (or other cause of iron deficiency)
        • Personal or family risk factors for malignancy
        • Patients 40 years or older

Contributors

Shreya Trivedi, MD, ACP Member – Editor
Nicholas Villano, MD – Host, Editor, MOC questions
Allison Trainor, MD – Host, Editor
Jason Freed, MD - Guest
Angela Weyand, MD – Guest *
Malcolm Munro, MD – Guest*

Reviewers

Elliot Tapper, MD*
Adam Strauss, MD

Angela Weyand, MD*
Consultant: Aptevo Therapeutics, Inc., Bayer Healthcare, Bioverativ Therapeutics, Inc., Genentech, Genzyme Corporation, Kedrion Biopharma, Inc., Takeda Pharmaceutical Company
Other: Novo Nordisk, Pfizer, Takeda Pharmaceutical Company

Elliot Tapper, MD*
Grant/ Contract: Madrigal; Consultant: Mallinckrodt Hospital Products, Inc., Novo Nordisk, Valeant Pharmaceuticals North America, Takeda Pharmaceuticals International, Inc.

Malcolm Munro, MD*
Consultant: AbbVie, CooperSurgical, Inc., Daiichi Sankyo, Inc., Shield Therapeutics, Sumitomo Dainippon Pharma, U-Vision-360, and Vifor Pharma.

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date: March 13, 2024

Expiration Date: March 12, 2027

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