approach to anemia in adults. background anemia is reduction of red cell mass diagnosis and...
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Approach to anemia in adults
Background
• Anemia is reduction of red cell mass
• 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
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
Etiology of anemia
• Iron deficiency 25%• Anemia of inflammation 25%• Hemoglobinopathy 25%• Hemolytic anemia/marrow failure 15%• Myelodysplasia 10%
First Step in Evaluation
Clinical PresentationClinical Presentation
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Approach• Detailed History
• Review of Systems
• Physical Exam
• Laboratory Evaluation– Prior documentation of CBC’s– CBC with RETICULOCYTE COUNT– Review peripheral blood smear
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HistoryFamily historyFamily history
Spherocytosis
Sickle cell
anemia
Thalassemia
DietDietVegetarian
Drugs/Toxins
Infection
Alcohol AbuseAlcohol AbuseFolate
deficiency
Liver disease
MalabsorptionMalabsorptionB12
Folate
Iron
ExposureLead
Chemotherapy
Peptic UlcerPeptic Ulcer
DiseaseDisease
DiverticulitisDiverticulitis
Colonic PolypsColonic Polyps
GI MalignancyGI Malignancycolorectal
esophageal
Recent SurgeryRecent Surgery
TravelTravel
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Microcytic AnemiaDrug Associated
Heme Synthesis AntagonistsHeme Synthesis AntagonistsPb – often normocyticAl – hemodialysis
AntibioticsAntibioticsIsoniazid Chloramphenicol
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Macrocytic Anemia and MacrocytosisDrug Associated
Folate Folate AntagonistsAntagonists
Methotrexate
Purine Purine AntagonistsAntagonists
Acyclovir
Mercaptopurine
Imuran
Alkylating AgentsAlkylating AgentsCytoxan
Altered Folate Altered Folate MetabolismMetabolism
Oral Contraceptives
Anticonvulsants
Triamterene
Sulfonamides
Pentamidine
Cobalamin Cobalamin MalabsorptionMalabsorption
Colchicine
Neomycin
Impaired Impaired Cobalamin Cobalamin UtilizationUtilization
Nitrous Oxide
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Normochromic Normocytic AnemiaDrug Associated
AntibioticsAntibioticsIsoniazidchloramphenicol
Anti-InflammatoryAnti-InflammatoryAu
Symptoms
Weakness
Fatigue
Dizziness
Headache
Chest pain
SOB / DOE
Palpitations
Cold intolerance Dysphagia
Jaundice
Hematemesis
Diarrhea
Constipation
Melena
Hematachezia Hematuria
Menorrhagia
Pica (clay, dirt,
chalk, ice)
Hematoma
Physical Exam
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Physical ExamOphtho exam
Flame hemorrhage
Papilledema
Exudates
Pallor
Blue sclera
Angular CheilitisIron Deficiency
GlossitisGlossitisB12 / Folate / Iron
Tachycardia
JaundiceLiver Disease
Hemolysis
Guiaic positive Splenomegaly
Malignancy
Infection
Liver disease
Chronic Hemolysis
Adenopathy
SkinSkinPallor
Ulcerations
Scars
Thin/Brittle, Spoon-shaped nails
Edema
NeurologicHeadache, fatigue Lack of concentration
Syncope
Paresthesias
Ataxia
Dementia
Erythropoetic therapy for anemia
• Chronic kidney disease– Improves survival– Improves quality of life– Decreases/increases vascular events
• Congestive heart failure– Improves LV function– Decreased hospitalization
• Cancer patients– Decrease fatigue– Improves quality of life– Increases mortality in solid tumors
What is anemia?
• Must be interpreted in context• Acute vs. 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
(12.8-17.7)*
11.6-15.6
(11.5-15.4)*
11.3-16.4
(12.8-17.7)*
10.5-14.7
(11.5-15.4)*
Tefferri A Mayo Clin Proc 2005 from NHANES-II, Mayo Clinic
*CHCS current values
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• Chronic hepatitis panel
• Homocysteine• Methylmalonic acid• SPEP• ANA• CRP/ESR• Bone marrow aspirate and
biopsy
• Haptoglobin• LDH
Diagnostic approach to anemia
1. Review prior CBCs2. Take comprehensive history and physical3. 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. Reticulocyte Count (classification of proliferation)5. 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
Microcytic Anemias
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Fe Deficiency Anemia
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Iron
Serum IronSerum Iron TIBC TIBC Ferritin Ferritin
Iron Deficiency*Iron Deficiency*
SideroblasticSideroblastic
ThalassemiaThalassemia
Anemia of ChronicAnemia of ChronicDiseaseDisease
NLNL
NLNL
**Iron Saturation:Iron Saturation: Serum Iron / TIBC <10% = Iron deficiency; ; most common cause of microcytosis
Ferritin < 10 ng/ml
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Iron Deficiency – Etiologies
• History – History – GI (blood loss, diarrhea/constipation), GI (blood loss, diarrhea/constipation), menses, coagulopathy, urine color (menses, coagulopathy, urine color (cokecoke-colored -colored [bilirubin] OR [bilirubin] OR redred [hematuria, hemoglobinuria]) [hematuria, hemoglobinuria])
• Guaiac stoolsGuaiac stools– Office DRE– Hemocult cards as outpatient
• Colonoscopy / EGDColonoscopy / EGD• PT / APTT, UAPT / APTT, UA
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Iron• % of oral iron absorbed = % of oral iron absorbed = 10%10%
• Daily oral requirement for males and non-menstruating Daily oral requirement for males and non-menstruating non-pregnant females = non-pregnant females = 10mg 10mg (Daily loss = (Daily loss = 1 mg1 mg))
• Daily oral requirement for menstruating females = Daily oral requirement for menstruating females = 20 mg20 mg (Daily loss = (Daily loss = 1.5 – 2 mg1.5 – 2 mg))
• Daily oral requirement for pregnant females = Daily oral requirement for pregnant females = 30 mg30 mg:: 150mg ferrous sulfate 150mg ferrous sulfate OROR 250mg ferrous gluconate 250mg ferrous gluconate (Daily (Daily needs = needs = 4 – 6 mg4 – 6 mg))
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Chronology of Iron Loss
Stages of iron deficiencyNormal Iron deficiency
without anemia
Iron deficiency with mild anemia
Severe iron deficiency
Marrow RE iron stores
2-3+ 0 0 0
Plasma iron level
75-150 Normal or reduced
Normal or reduced
Reduced
Iron binding capacity
300-400 Normal or elevated
Normal or elevated
Elevated
Hemoglobin 13-15 13-15 9-10 6-7
Hypochromia Not present Not present Slight or not present
Profound
Microcytosis Not present Not present Slight or not present
Present
Ferritin 12-300 <4 <4 <4
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Iron
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Iron-Rich Foods Quantity Approximate Iron Content (mg)
Oysters 3 ounces 13.2Beef liver 3 ounces 7.5
Prune juice 1/2 cup 5.2Clams 2 ounces 4.2
Walnuts 1/2 cup 3.75Ground beef 3 ounces 3.0
Chickpeas 1/2 cup 3.0Bran flakes 1/2 cup 2.8Pork roast 3 ounces 2.7
Cashew nuts 1/2 cup 2.65Shrimp 3 ounces 2.6Raisins 1/2 cup 2.55
Sardines 3 ounces 2.5Spinach 1/2 cup 2.4
Iron homeostasis
Andrews N. N Engl J Med 1999;341:1986-1995
Interpreting iron and ferritinFerritin 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
Case 2 laboratory results
• B12 level 100 pg/mL, folate >20 ng/mL
Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.
Schrier, S. ASH Image Bank 2001;2001:100231
B12 supplementation
• B12 load– B12 1000 mcg IM/SC qd x 7 then qwk x 4 then q
month– B12 1000 mcg IM/SC tiw x 2 weeks, qwk x 8– B12 2000 mcg po x 2 months
• B12 maintenance– B12 1000 mcg IM/SC 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– May 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 is released when ligand (diferric transferrin) is not bound (i.e. iron deficient states)
• sTfR 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 mcg/L
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 DiseasePathophysiology of AoCD
• 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
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
Anemia in the elderly
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• 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
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How Do I Distinguish Intravascular From Extravascular Hemolysis?
• Intravascular – RBC fragments: incompatible PRBC transfusion; MAHA
• Extravascular – microspherocytes: AIHA
Haptoglobin – low Hemopexin – low Hemoglobinuria Urine hemosiderin – elevated; evidence of recent
(up to 3 months) intravascular hemolysis
Haptoglobin – normal; unless hemolysis is severe Direct Coomb’s test – positive
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-Thalassemia Trait
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-Thalassemia Major
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Warm-Antibody Hemolytic Anemia
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Is It Possible to Have a Hemolytic Anemia with a Normal or Low Reticulocyte Count?
• You bet! Can happen:
coexisting bone marrow hypoproduction Ab mediated destruction of RBC precursors in marrow Folate deficiency with chronic hemolysis Renal failure – decreased EPO B19 Parvovirus infection
Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.
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
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Target Cells
Fe deficiency – microcyticHemoglobinopathies (thalassemias, Hb C,S and E) - microcyticLiver disease – normocytic / macrocyticAbetalipoproteinemia – normocytic / macrocyticHyposplenism – normocytic
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Tear Drop Cells (Dacryocytes)
Thalassemias – especially Myelodysplastic syndromesBone marrow replacement – fibrosis, malignancy
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Schistocytes
Vasculitis
Malignant HTN
ARF
DIC
TTP/HUS
Mechanical valve
Microangiopathic Hemolytic Anemias
(MAHAs)
Also: -thalassemia
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Nucleated Red Blood Cells
Acute blood lossSevere hemolytic anemiaMarrow infiltrationMyeloproliferative syndrome
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Spherocytes
Transfusion – most common in clinical practiceAlloimmune hemolytic anemia (e.g. ABO incompatibility)Autoimmune hemolytic anemiaG6PD deficiency
Hereditary spherocytosisHypophosphatemiaBurnsC perfringens sepsis
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Bite Cell (Degmacyte)
G6PD deficiencyMAHA - sometimes
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Heinz-Body Anemia
G6PD deficiency supravital stain – crystal violet
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Sickle Cells
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Howell-Jolly Bodies
HyposplenismSplenectomyHemolytic anemias – sometimes
DNA fragments
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Basophilic Stippling
ribosomal RNA fragmentsPb poisoningthalassemiashemoglobinopathies
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Pappenheimer Bodies in Siderocytes
MDS – esp sideroblastic anemiasPost splenectomyPb poisoningHemolytic anemias
ribosomal RNA + Fe
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Rouleaux
Multiple myelomaWaldenström’s macroglobulinemiaPregnancyInflammationErythrocytosis
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RBC Agglutination
Cold-agglutinin (IgM) hemolytic anemia (EBV, Mycoplasma pneumoniae)Waldenström’s macroglobulinemiaWarm antibody (IgG) hemolytic anemia
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Polychromatophilia (Polychromasia)
HyperproductionHyposplenism
are reticulocytes
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Elliptocytes
HereditaryMacrocytic anemiasFe deficiency anemia
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Burr Cells (Echinocytes)
Renal failureLiver disease – sometimesStorage artifact
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Spur Cells (Acanthocytes)
Liver disease – most commonly EtOH relatedAbetalipoproteinemiaNeuroancanthocytosis
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Stomatocytes
NormalLiver diseaseHereditaryMalignancy