#52: Anemia: Tips and tools for diagnosis and treatment

August 14, 2017 | By Matthew Watto, MD

Master the anemia algorithm, and take a deep dive on iron deficiency, anemia of chronic kidney disease, anemia of chronic inflammation, causes of macrocytic anemia, plus random clinical pearls in this discussion with international expert, Dr. David P. Steensma, Senior Physician from Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School.

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Cases from Kashlak Memorial:

• 62 yo M with diabetes and chronic kidney disease, asymptomatic hemoglobin (Hgb) 10, mean corpuscular (MCV) 90, and Creatinine (Cr) 1.9?
• 72 yo F with hypertension, asymptomatic Hgb of 11, MCV 85 and Cr 0.6.
• 72 yo F with breast cancer in remission after lumpectomy, adjuvant chemo, and radiation therapy treated 6 years ago presents with fatigue and some dyspnea on exertion. Hgb 9.6, MCV 102.

Clinical Pearls:

1. Anemia defined: 1968 WHO criteria used in epidemiologic studies = Hemoglobin (Hgb) under 12 gm/dL in women and under 13 gm/dL in men. Values don’t account for race, altitude, or other patient factors. Anemia is more common with advanced age, but NOT normal and should be worked up!
2. Anemia Algorithm: Dr. Watto’s anemia algorithm adapted from this interview (see below)
3. Mean corpuscular (cell) volume (MCV): Average RBC size. Under 80 = microcytic. Between 80-95 (up to 100) = normocytic. Above 95 (or 100) is macrocytic.
4. Red cell distribution width: Measures degree of variation among size of RBCs. Normal range 11.5% to 14.5%. Above 14.5% suggests wide range of RBC sizes.
5. Reticulocyte count: Measures percentage of reticulocytes (immature RBCs) in peripheral blood. High in acute blood loss, hemolysis, exogenous erythropoietin (EPO), iron or B12 repletion. Low in bone marrow (BM) ablative disorders, lack of substrate (e.g. iron), low EPO, and conditions that impair erythropoiesis.
6. Corrected reticulocyte count OR reticulocyte index above 2% suggests appropriate bone marrow response. If under 2%, then BM response insufficient for degree of anemia.
   1. Corrected reticulocyte count = reticulocyte count x (patient Hct/goal Hct).
   2. Reticulocyte index = accounts for increased RBC survival in patients who are anemic. Correction factor applied based on degree of anemia.
7. Microcytic anemia: MCV close to or under 80. Think iron deficiency, thalassemia, and sometimes anemia of chronic inflammation.
8. Normocytic anemia: MCV 80-100. Most difficult differential, but usually anemia of CKD, or chronic inflammation. If no acute bleeding, then check reticulocyte count. Consider checking serum EPO level. If low, then patient might respond to an erythropoietin stimulating agent (ESA).
9. Macrocytic anemia: Things to consider: alcohol use (or liver disease), culprit medications (e.g. methotrexate, azathioprine, hydroxyurea, metformin, proton pump inhibitors), check B12, folate, TSH.  If no answer, then refer for BM biopsy.
10. Iron deficiency anemia: Ferritin <20 suggests iron deficiency. Soluble transferrin receptor (sTfR) is inversely related to iron levels in blood. It is NOT sensitive to inflammation. High sTfR level indicates iron deficiency even if ferritin elevated.
11. Anemia of CKD: Hypoproliferative, normocytic (usually), and normochromic anemia. Must rule out other causes. Etiology = decreased renal erythropoietin synthesis +/- decrease RBC half life +/- absolute or functional iron deficiency (e.g. bleeding or inflammation respectively).
12. Anemia of Chronic Inflammation: High ferritin, low TIBC, normal serum iron, and normal or slightly high transferrin saturation (serum iron divided by TIBC). These patients rarely respond to oral iron therapy. IV iron recommended by Dr. Steensma.
13. Erythropoiesis-stimulating agents: E.g. darbepoetin, or erythropoietin. Correct iron deficiency prior to use. Goal iron saturation above 20%. KDIGO recommends iron saturation above 30% and ferritin above 500 in patients with CKD (weak recommendation). Ferritin cut-off is controversial. If >800, then person is clearly iron replete. Keep Hgb between 10-12 gm/dL in CKD not requiring dialysis, and above 9 gm/dL in CKD requiring dialysis.
14. Oral versus IV iron: Oral iron poorly tolerated. IV iron more costly, but safe and effective. Dr. Steensma still recommends oral iron daily NOT every other day.
15. Vitamin C and oral iron absorption: Evidence that Vitamin C modestly boosts absorption, but clinical benefit unclear and more expensive. Consider for patients with low acidity (e.g. on PPI therapy).
16. Vitamin B12 deficiency: Check serum or urine methylmalonic acid (MMA). If level below 400, then treat to normalize Hgb. Use intramuscular B12 (cyanocobalamin) if neurologic involvement.
17. Elevated Vitamin B12 level: If high in patient NOT on supplementation, then consider myeloproliferative neoplasm! These are associated with increased production of transcobalamin, a B12 binding protein.
18. Myelodysplastic syndrome: Likely diagnosis if unexplained macrocytic anemia. Commonly treated with Azacitidine, Decitabine, or Lenalidomide. All three meds are FDA approved for MDS. Side effects include cytopenias. Lenalidomide can also cause rash, and neuropathy.

Goal: Listeners will apply a basic algorithmic approach to the diagnosis and classification of anemia.

Learning objectives:
After listening to this episode listeners will…

1. Recognize anemia elderly men and women
2. Diagnose and manage the most common causes of anemia (iron deficiency, CKD, anemia of chronic inflammation)
3. Classify anemia by MCV
4. Determine the most important lab values reported in a CBC
5. Interpret iron studies
6. Identify when to order additional testing like EPO, TSH, B12, folate
7. Utilize and interpret reticulocyte count for normocytic anemias
8. Determine dose and route for iron repletion
9. Determine dose and route for B12 repletion
10. Identify patients with macrocytic anemia requiring a bone marrow biopsy
11. Recall the three FDA approved agents for myelodysplastic syndrome and their common side effects

Disclosures: Dr. Steensma is on the data safety monitoring committee for Janssen, and has clinical trials sponsored by Amgen.

Time Stamps
00:00 Intro
01:18 Listener feedback
04:05 Announcement: We’re looking for on air correspondents to join The Curbsiders
05:05 Picks of the week
11:12 Getting to know our guest
17:50 Case #1 Normocytic anemia
19:15 Defining anemia (WHO criteria)
21:10 Epidemiology of anemia
23:45 Normocytic anemia
25:55 Erythropoietin for diagnosis and treatment
28:22 Anemia of CKD or chronic inflammation?
31:37 Discussion of ferritin and soluble transferrin receptor
33:47 Case #1 Conclusion
35:45 Hemoglobin targets in CKD
36:53 Case #2 Microcytic anemia
37:43 Correct reticulocyte count and reticulocyte index
40:45 Deciding on dose and route for iron repletion
43:44 Does vitamin C improve iron absorption?
45:27 Case #3 Macrocytic anemia
46:54 Vitamin B12 deficiency
51:54 Medication related B12 deficiency
52:35 Myelodysplastic syndrome
55:00 Side effects of common MDS treatments
56:18 Take home points
57:35 The Curbsiders post game analysis
64:16 Outro

Links from the show:

1. Colossal (film) by Nacho Vigalondo 2016
2. Pulgasari (1985) North Korean Giant Monster film with english subtitle on YouTube
3. Master of None (TV show) by Aziz Ansari on Netflix
4. When Breath Becomes Air (book) by Paul Kalanithi
5. Anemia algorithm app (FREE) by Dr. Steensma on iTunes
6. Improving outcomes in geriatric anemia: a guide to the differential diagnosis of treatable causes by Dr. Steensma and Dr. Koffman from Medscape
7. Nomogram for EPO level versus Hemoglobin. Kidney International 2004
8. Calculator: Absolute Reticulocyte Count & Reticulocyte Index from MDCalc
9. Vitamin C and oral iron absorption. Scand J Haematol 1980.
10. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease 2012
11. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015