Transcript Anemia - Ronna

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 Presentation
Approach
• Detailed History
• Review of Systems
• Physical Exam
• Laboratory Evaluation
– Prior documentation of CBC’s
– CBC with RETICULOCYTE COUNT
– Review peripheral blood smear
6
History
Family history
Spherocytosis
Sickle cell
anemia
Thalassemia
Diet
Vegetarian
Drugs/Toxins
Infection
Alcohol Abuse
Folate
deficiency
Liver disease
Malabsorption
B12
Folate
Iron
Exposure
Lead
Chemotherapy
Peptic Ulcer
Disease
Diverticulitis
Colonic Polyps
GI Malignancy
colorectal
esophageal
Recent Surgery
Travel
7
Microcytic Anemia
Drug Associated
Heme Synthesis Antagonists
Pb – often normocytic
Al – hemodialysis
Antibiotics
Isoniazid
Chloramphenicol
8
Macrocytic Anemia and Macrocytosis
Drug Associated
Folate
Antagonists
Methotrexate
Purine
Antagonists
Acyclovir
Mercaptopurine
Imuran
Altered Folate
Metabolism
Cobalamin
Malabsorption
Oral
Colchicine
Contraceptives
Neomycin
Anticonvulsants Impaired
Triamterene
Cobalamin
Sulfonamides
Utilization
Pentamidine
Nitrous Oxide
Alkylating Agents
Cytoxan
9
Normochromic Normocytic Anemia
Drug Associated
Antibiotics
Isoniazid
chloramphenicol
Anti-Inflammatory
Au
10
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
Physical Exam
Ophtho exam
Flame hemorrhage
Papilledema
Exudates
Pallor
Blue sclera
Angular Cheilitis
Iron Deficiency
Glossitis
B12 / Folate / Iron
Tachycardia
Jaundice
Liver Disease
Hemolysis
Guiaic positive
Splenomegaly
Malignancy
Infection
Liver disease
Chronic Hemolysis
Adenopathy
Skin
Pallor
Ulcerations
Scars
Thin/Brittle, Spoonshaped nails
Edema
Neurologic
Headache, fatigue
Lack of concentration
Syncope
Paresthesias
Ataxia
Dementia
13
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 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. 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
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
Microcytic Anemias
Fe Deficiency Anemia
26
Iron
Serum Iron
TIBC
Ferritin
Iron Deficiency*



Sideroblastic

NL

Thalassemia

NL

Anemia of Chronic
Disease



*Iron Saturation:  Serum Iron / TIBC <10% = Iron deficiency;
most common cause of microcytosis
 Ferritin < 10 ng/ml
27
Iron Deficiency – Etiologies
• History – GI (blood loss, diarrhea/constipation),
menses, coagulopathy, urine color (coke-colored
[bilirubin] OR red [hematuria, hemoglobinuria])
• Guaiac stools
– Office DRE
– Hemocult cards as outpatient
• Colonoscopy / EGD
• PT / APTT, UA
28
Iron
• % of oral iron absorbed = 10%
• Daily oral requirement for males and nonmenstruating non-pregnant females = 10mg (Daily
loss = 1 mg)
• Daily oral requirement for menstruating females =
20 mg (Daily loss = 1.5 – 2 mg)
• Daily oral requirement for pregnant females = 30
mg: 150mg ferrous sulfate OR 250mg ferrous
gluconate (Daily needs = 4 – 6 mg)
29
30
Chronology of Iron Loss
31
Stages of iron deficiency
Normal
Iron deficiency
without
anemia
Iron deficiency
with mild
anemia
Severe iron
deficiency
Marrow RE iron 2-3+
stores
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
33
Iron
Iron-Rich Foods
Quantity
Oysters
Beef liver
Prune juice
Clams
Walnuts
Ground beef
Chickpeas
Bran flakes
Pork roast
Cashew nuts
Shrimp
Raisins
Sardines
Spinach
3 ounces
3 ounces
1/2 cup
2 ounces
1/2 cup
3 ounces
1/2 cup
1/2 cup
3 ounces
1/2 cup
3 ounces
1/2 cup
3 ounces
1/2 cup
Approximate Iron Content
(mg)
13.2
7.5
5.2
4.2
3.75
3.0
3.0
2.8
2.7
2.65
2.6
2.55
2.5
2.4
34
Iron homeostasis
Andrews N. N Engl J Med 1999;341:1986-1995
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, 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
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/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
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 mcg/L
Appropriate response to
blood loss or nutritional
supplementation
Hemolytic anemias
Pathophysiological Mechanisms Underlying Anemia of Chronic
Disease
Pathophysiology of AoCD
• Inflammatory cytokines (IL6, 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
Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023
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
How Do I Distinguish Intravascular From
Extravascular Hemolysis?
• Intravascular – RBC fragments: incompatible
PRBC transfusion; MAHA




Haptoglobin – low
Hemopexin – low
Hemoglobinuria
Urine hemosiderin – elevated; evidence of recent
(up to 3 months) intravascular hemolysis
• Extravascular – microspherocytes: AIHA
 Haptoglobin – normal; unless hemolysis is severe
 Direct Coomb’s test – positive
65
-Thalassemia Trait
66
-Thalassemia Major
67
Warm-Antibody Hemolytic Anemia
68
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
69
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.
Target Cells
Fe deficiency – microcytic
Hemoglobinopathies (thalassemias, Hb C,S and E) - microcytic
Liver disease – normocytic / macrocytic
Abetalipoproteinemia – normocytic / macrocytic
71
Hyposplenism – normocytic
Tear Drop Cells (Dacryocytes)
Thalassemias – especially 
Myelodysplastic syndromes
Bone marrow replacement – fibrosis, malignancy
72
Schistocytes
Vasculitis
Also: -thalassemia
Malignant HTN
ARF
DIC
TTP/HUS
Mechanical valve
Microangiopathic
Hemolytic Anemias
(MAHAs)
73
Nucleated Red Blood Cells
Acute blood loss
Severe hemolytic anemia
Marrow infiltration
Myeloproliferative syndrome
74
Spherocytes
Transfusion – most common in clinical practice
Alloimmune hemolytic anemia (e.g. ABO
incompatibility)
Autoimmune hemolytic anemia
G6PD deficiency
Hereditary spherocytosis
Hypophosphatemia
Burns
C perfringens sepsis
75
Bite Cell (Degmacyte)
G6PD deficiency
MAHA - sometimes
76
Heinz-Body Anemia
G6PD deficiency
supravital stain – crystal violet
77
Sickle Cells
78
Howell-Jolly Bodies
Hyposplenism
Splenectomy
Hemolytic anemias – sometimes
DNA fragments
79
Basophilic Stippling
Pb poisoning
thalassemias
hemoglobinopathies
ribosomal RNA fragments
80
Pappenheimer Bodies in Siderocytes
MDS – esp sideroblastic anemias
Post splenectomy
Pb poisoning
Hemolytic anemias
ribosomal RNA + Fe
81
Rouleaux
Multiple myeloma
Waldenström’s macroglobulinemia
Pregnancy
Inflammation
Erythrocytosis
82
RBC Agglutination
Cold-agglutinin (IgM) hemolytic anemia (EBV, Mycoplasma pneumoniae)
Waldenström’s macroglobulinemia
Warm antibody (IgG) hemolytic anemia
83
Polychromatophilia (Polychromasia)
Hyperproduction
Hyposplenism
are reticulocytes
84
Elliptocytes
Hereditary
Macrocytic anemias
Fe deficiency anemia
85
Burr Cells (Echinocytes)
Renal failure
Liver disease – sometimes
Storage artifact
86
Spur Cells (Acanthocytes)
Liver disease – most commonly EtOH related
Abetalipoproteinemia
Neuroancanthocytosis
87
Stomatocytes
Normal
Liver disease
Hereditary
Malignancy
88