Approach to anemia in adults Brendan M. Weiss, MD Director, Autologous Stem Cell Transplantation Hematology-Oncology Service Walter Reed Army Medical Center

Approach to anemia in adults

Brendan M. Weiss, MDDirector, Autologous Stem Cell Transplantation

Hematology-Oncology ServiceWalter Reed Army Medical Center

09 November 2006

Background

• Anemia is reduction of red cell mass• It may be due to systemic diseases or a

primary hematologic disorder• Diagnosis and treatment is essential

– Identify a potentially life threatening disorder– Identify a treatable systemic disease– Identify a disease for which primary treatment

of anemia improves outcomes

Erythropoetic therapy for anemia

• Chronic kidney disease– Improves survival– Improves quality of life– Decreases vascular events

• Congestive heart failure– Improves LV function– Decreased hospitalization

• Cancer patients– Decrease fatigue– Improves quality of life

Etiology of anemia

• Iron deficiency 25%• Anemia of inflammation 25%• Hemoglobinopathy 25%• Hemolytic anemia/marrow failure 15%• Myelodysplasia 10%

Objectives

• Definition of anemia• Interpretation of important laboratory tests• General approaches by classification• Emerging concepts

– Anemia of inflammation (chronic diseases)– Anemia in the elderly

• Indications for referral

Disclaimers

• Provide a general approach to anemia• Will not address

– Unusual causes– Primary hematologic disorders– Special populations

• Athletes• International aspects• High altitude

– Hemoglobinopathies

What is anemia?

• Must be interpreted in context• Acute v. chronic• Gender• Race• “Normal” 5% of healthy general population

may be outside normal range

Normal hemoglobin (g/dL) ranges

White African

Male Female Male Female

12.7-17.0(13.5-17.5)*

11.6-15.6(12.0-15.5)*

11.3-16.4 10.5-14.7

Tefferri A Mayo Clin Proc 2005 from NHANES-II, *Mayo Clinic

Essential laboratory tests in the evaluation of anemia

• Hemoglobin – amount of lysed pigment in a volume of blood

• Mean corpuscular volume – size of red blood cells

• Red cell distribution width – measure of variation of cell size

• Red blood cell count – absolute number of red blood cells per volume

• Platelet count• White blood cell count• Peripheral blood smear

Useful tests in selected cases

• Ferritin• Iron panel• Soluble transferrin receptor• Peripheral blood smear• Creatinine• Reticulocyte count• B12/folate level• TSH

• Homocysteine• Methylmalonic acid• SPEP• ANA• CRP/ESR• Bone marrow aspirate and biopsy

Diagnostic approach to anemia

1. Review prior CBCs

2. Take comprehensive history and physical

3. Classify anemia by MCV– Microcytic (MCV <80 fL)– Normocytic (MCV 80-100 fL)– Macrocytic (MCV >100 fL)

• Mild macrocytosis MCV 100-110 fL• Marked macrocytosis MCV >110 fL

4. Order appropriate additional tests

Case 1

• 52 year old male construction worker with chief complaint of fatigue for 2 months. He now reports getting dyspneic when climbing ladders or carrying heavy loads at work. He says, “I never go to doctors.”

• PMH None, PSH appendectomy, FH adopted, SH tobacco 20 py, drinks 2 beers daily, Medications occasional motrin

• Physical exam unremarkable• ROS occasional crampy abdominal pain

Case 1

• Hgb 10.2 gm/dl, MCV 78 fL, RDW 19.5, Platelets 450,000/dL

• How do you classify the anemia?

Case 1

• Ferritin 5• Fecal occult blood test is positive

Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.

Schrier, S. ASH Image Bank 2002;2002:100325

Features of iron deficiency anemia

• Clinical– Symptoms of anemia– Evidence of blood loss– Pica (very specific)

• Laboratory– Microcytic anemia (occasionally normocytic)– Elevated RDW– Elevated platelet count– Low serum iron, ferritin and elevated TIBC

Andrews N. N Engl J Med 1999;341:1986-1995

Distribution of Iron in Adults



Stages of iron deficiency

Interpreting iron and ferritin

Ferritin Iron

Falsely low Falsely high Falsely low Falsely high

Hypothyroidism Fever Circadian variation

Circadian variation

Ascorbate deficiency

Inflammation Infection Iron ingestion

Infection Inflammation Sideroblastic and aplastic anemia

Liver disease Maligancy Ineffective erythropoeisis

Ascorbate deficiency

Liver disease

Case 2

• 48-year-old white man is referred for a new anemia. He is an executive in a software company and reports fatigue and dyspnea while backpacking

• ROS negative. • Physical examination: He is a normal, healthy-

looking man, perhaps pale, with a clean tongue. The results of his chest, abdomen, and neurologic exams are all normal.

Case 2

• Hemoglobin 9.2 gm/dl• Mean corpuscular volume (MCV)112 fL• White blood cells 3,400/ul normal

differential• Platelets 132,000/ul

Spurious macrocytosis

• Red blood cell clumping– Cold agglutinins– Paraproteinemia

• Intracellular hyperosmolality– Hyperglycemia

• Leukemic cells counted as RBCs– Marked leukocytosis as in CLL

Common drugs associated with macrocytosis

• Marrow toxin and interference with folate metabolism– Alcohol

• Marrow toxin– Chemotherapy: methotrexate, hydroxyurea,

cyclophosphamide…– Zidovudine

• Altered folate metabolism– Anti-epileptic drugs– Triamterene– Sulfmethoxazole– Trimethoprim

• B12 malabsorption– Colchicine– Neomycin

Evaluation of B12 levels

Falsely low• Folate deficiency• Multiple myeloma• Waldenstrom’s macroglobulinemia• Recent nuclear scan• First trimester• Transcobalamin I def• Advanced age

Falsely normal• Increase in transcobalamin I and III• Myeloproliferative disorders• Severe liver disease

Indications for testing of metabolites of B12 and folate

• Borderline B12 and folate levels• Existing conditions that perturb B12/folate

levels• When both B12/folate are low to confirm

B12 deficiency• In pts with clearly low levels, for which

there is an alternative explanation (eg. an alcoholic with a high MCV, low B12 but no anemia)

Interpretation of MMA/Hcy

MMA Hcy Diagnosis

Increased Increased B12 deficiency confirmed, folate deficiency possible

Normal Increased Folate deficiency likely; B12 deficiency <5%

Normal Normal B12 deficiency very unlikely**

From Hoffman R et al, Hematology: Basic Principles and Practice, 3rd Edition

B12 responsive disorders in the ambulatory setting

• Retrospective review of 456 patients evaluated for B12 deficiency in an HMO setting

• 95 patients with hematologic and neurologic abnormalities given therapeutic trials

• Clinical response occurred in 37/95 (38.9%)• B12, MMA, Hcy levels were normal in 55%, 23%

and 50%, respectively, of responders• If therapy, had been restricted to patients with

both low or intermediate B12 levels and increased metabolites, 63% of responders would not have been treated

Solomon LR, Blood 2005

Case 2 laboratory results

• B12 level 100 pg/mL, folate >20 ng/mL



B12 supplementation

• B12 load– B12 1000 mcg IM qd x 7 then qwk x 4 then q

month– B12 1000 mcg IM tiw x 2 weeks, qwk x 8– B12 2000 mcg po x 2 months

• B12 maintenance– B12 1000 mcg IM q month life– B12 1000 mcg po qd for life

• Folate 1 mg po qd x 30 days

Case 3

• 45 year old African-American female presents with fatigue for 6 months. She now only works 6 hours a day at her secretarial job and is now dyspneic climbing 2 flights of stairs at home.

• PMH: Hypertension, depression, G6P6• PSH: C-section x 2, breast biopsy – benign• FH: Father – multiple myeloma, Mother – DM2 on

hemodialysis, 2 younger siblings are well• SH: No tobacco or alcohol• ROS: Joint pains for about 6 months, intermittent chest

pain worse with deep breathing• Medications: Lisinopril, aspirin, venlafaxine

Case 3

• Hemoglobin 8.0 gm/dL • MCV 81 fL• WBC 3,200/uL• Platelets 450,000/uL

Lab results

• Ferritin 25 ng/mL• Fe 20 mcg/dL Iron Sat 10% TIBC 200

mcg/dL• LDH WNL Hcy WNL

Management of iron deficiency

• Rule out blood loss, reason for negative iron balance– Gastrointestinal– Genitourinary– Poor iron absorption– Pregnancy– Pulmonary hemosiderosis– Intravascular hemolysis– Erythropoeitin

Oral iron supplementation

• Goal: 150-200 mg elemental iron daily• Administration

– DO NOT give with food– Give 2 hrs from antacids– DO give with ascorbic acid 250 mg

• Gastrointestinal intolerance (~20%)– Decrease daily elemental iron dose

• Switch from sulfate to gluconate or elixir– Give with food (will decrease absorption)

Oral iron supplementation

• Measuring response– Expect Hgb increase of 2 gm/dL in 2 weeks– Assess compliance/drug interactions

• Duration– 4-6 months after iron “replete” to allow for

restoration of storage iron– At least until ferritin>50

• NB: all anemia does not respond to iron!!!

Case 3 continued

• Pt returns after 3 months of oral iron therapy

• She remains fatigued, but improved, and has increasing complaints of joint pain

• Hgb 10.0 gm/dL, MCV 88 fL, RBC Count 4 million, Reticulocyte 1.0%, Iron saturation 30%, Ferritin 80

Soluble transferrin receptor

• Truncated portion of membrane receptor that is increased in iron deficiency

• sTf is normal in anemia of chronic diseases– Transferrin-receptor expression is negatively

affected by inflammatory cytokines• Useful in clarifying anemia of chronic

disease and iron status

AoCD versus iron deficiency

Punnonen K Blood 1997; Goodnough L N Engl J Med 2005

Interpreting reticulocyte counts

• Reticulocytes are erythrocytes new to peripheral circulation

• Need to correct for degree of anemia– Reticulocyte index = Retic % x [Pt Hct/NlHct]– Absolute reticulocyte count = Retic % x RBC

number• Appropriate reticulocytosis

– Reticulocyte index >2%– Absolute reticuocyte count >100,000/mcl

Differential diagnosis based on degree of reticulocytosis

Retic index <2% or ARC <100,000 mcg/L

Retic index >2% or ARC >100,000/uL

AoCD Appropriate response to blood loss or nutritional supplementation

Anemia sec to CKD

Drugs/toxins

Endocrinopathies Hemolytic anemias

Iron deficiency

Marrow infiltration

Nutritional (B12/folate deficiency)

Sideroblastic anemia

Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023

Pathophysiological Mechanisms Underlying Anemia of Chronic Disease

• Inflammatory cytokines (IL-6, TNF-a, IFN-g)– Increase storage iron– Inhibit EPO production– Blunted EPO response– Impair BM erythropoiesis

• Production of hepcidin– Inhibits GI iron absorption– Inhibits release of iron from macrophages and hepatocytes

Anemia in the elderly

• A public health crisis?– 10-30% of elderly are anemic

• Consequences– Decreased physical performance– Increased mortality in CHF patients– EPO improved LV function in elderly CKD

patients treated with EPO• About 30% have “unexplained anemia”

Guralnik J Hematology: ASH Education Book 2005

Unique etiologies of anemia in the elderly

• Dysregulated inflammatory response• Age-related decline in renal function• Blunted hypoxia-erythropoeitin sensing• Loss of hematopoeitic stem cell reserve• Sarcopenia• Decreased sex steroids• Frequent co-morbidities• Polypharmacy

Guralnik J Hematology: ASH Education Book 2005

Indications for hematology referral

• Diagnosis– Unexplained anemia– Anemia with additional cytopenias– Suspected hemoglobinopathy– Hemolytic anemias– Bone marrow aspiration and biopsy

• Treatment– Non-response to therapy– Hemolytic anemias– Myelodysplasia


Maslak, P. ASH Image Bank 2002;2002:100375

Figure 1. Peripheral blood smear of a patient with plasma cell leukemia contains lymphoplasmcytoid lymphocytes and circulating plasma cell

Questions?www.ashimagebank.org

Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023

Algorithm for the Differential Diagnosis among Iron-Deficiency Anemia, Anemia of Chronic Disease, and Anemia of Chronic Disease with Iron Deficiency

Documents

Approach to anemia in adults Brendan M. Weiss, MD Director, Autologous Stem Cell Transplantation Hematology-Oncology Service Walter Reed Army Medical Center