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

86

Burr Cells (Echinocytes)

Renal failureLiver disease – sometimesStorage artifact

87

Spur Cells (Acanthocytes)

Liver disease – most commonly EtOH relatedAbetalipoproteinemiaNeuroancanthocytosis

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Stomatocytes

NormalLiver diseaseHereditaryMalignancy