Transcript Approach to anemia

Approach to anemia in adults
Brendan M. Weiss, MD
Director, Autologous Stem Cell Transplantation
Hematology-Oncology Service
Walter 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
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Iron deficiency 25%
Anemia of inflammation 25%
Hemoglobinopathy 25%
Hemolytic anemia/marrow failure 15%
Myelodysplasia 10%
Objectives
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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?
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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
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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
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Microcytic (MCV <80 fL)
Normocytic (MCV 80-100 fL)
Macrocytic (MCV >100 fL)
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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
Schrier, S. ASH Image Bank 2002;2002:100325
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
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
Distribution of Iron in Adults
Andrews N. N Engl J Med 1999;341:1986-1995
Stages of iron deficiency
Schrier, S. ASH Image Bank 2002;2002:100325
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Interpreting iron and ferritin
Ferritin
Falsely low
Falsely high
Iron
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, healthylooking 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
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Anti-epileptic drugs
Triamterene
Sulfmethoxazole
Trimethoprim
• B12 malabsorption
– Colchicine
– Neomycin
Evaluation of B12 levels
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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
Schrier, S. ASH Image Bank 2001;2001:100231
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
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
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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
AoCD
Anemia sec to CKD
Drugs/toxins
Endocrinopathies
Iron deficiency
Marrow infiltration
Nutritional (B12/folate
deficiency)
Sideroblastic anemia
Retic index >2% or ARC
>100,000/uL
Appropriate response to
blood loss or nutritional
supplementation
Hemolytic anemias
Pathophysiological Mechanisms Underlying Anemia of Chronic
Disease
• Inflammatory cytokines
(IL-6, TNF-a, IFN-g)
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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
Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023
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
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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
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Unexplained anemia
Anemia with additional cytopenias
Suspected hemoglobinopathy
Hemolytic anemias
Bone marrow aspiration and biopsy
• Treatment
– Non-response to therapy
– Hemolytic anemias
– Myelodysplasia
Questions?
www.ashimagebank.org
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
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Algorithm for the Differential Diagnosis among Iron-Deficiency Anemia, Anemia of Chronic
Disease, and Anemia of Chronic Disease with Iron Deficiency
Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023