Normocytic Anemia David Lee, MD, FRCPC. Normocytic anemia a heterogenous group of anemias...

Normocytic Anemia

David Lee, MD, FRCPC

Normocytic anemia

• a heterogenous group of anemias• normocytosis implies normal DNA

metabolism and hemoglobin synthesis

• no common pathophysiology

Approach to anemia

anemia

check MCV

MCV < 80microcytic

anemia

MCV 80 - 100normocytic

anemia

MCV > 100macrocytic

anemia

Approach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

If not, then consider a primary marrow problem (MDS, MM, infiltration…)

bone marrow investigation

Approach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

If not, then consider a primary marrow problem (MDS, MM, infiltration…)

bone marrow investigation

Anemia of chronic disease

• Anemia due to cytokines IL-1, TNF-, TGF- associated with chronic inflammation– rheumatoid arthritis– systemic lupus erythematosis– inflammatory bowel disease– chronic infections: osteomyelitis, TB

Anemia of chronic disease

• Mechanisms– defective iron utilization

• iron is present, but cannot be utilized by erythroid precursors

– impaired response to erythropoietin– ?blunted increase in erythropoietin in

response to anemia

Anemia of chronic disease

• usually normocytic, but 25% are microcytic

• usually mild to moderate anemia • anemia of chronic disease is a

diagnosis of exclusion• bone marrow often needed to rule

out other causes of anemia

Iron studies in IDA and ACD

Test IDA ACD

serum iron

low low

TIBC high normal or low

transf. sat.

low low

serum ferritin

low normal or increased

marrow iron

absent normal or increased

Anemia of chronic disease

• Treatment– treat the underlying cause– erythropoietin can be effective, but is

expensive

Anemia of chronic renal failure

• Mechanism:– mainly due to reduced production of

erythropoietin by diseased kidneys– also iron or folate deficiency, chronic

inflammation, shortened red cell survival

• Treatment– erythropoietin thrice weekly– dialysis

Anemia of endocrine failure

• Uncommon cause of anemia, but correctable– hypothyroidism– hypogonadism– pan-hypopituitarism

Approach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

If not, then consider a primary marrow problem (MDS, MM, infiltration…)

bone marrow investigation

Pure red cell aplasia

Pure red cell aplasia

• Very rare cause of normocytic anemia

• immune-mediated destruction of red cell precursors in the marrow

• reticulocyte count is low• treatment: immune suppression

Approach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

If not, then consider a primary marrow problem (MDS, MM, infiltration…)

bone marrow investigation

Hemolytic anemia

• Anemia due to increased rate of RBC destruction

• anemia occurs when rate of destruction exceeds production

Normal red cell turnover• normal RBC survival of ~ 120 days• macrophages of the reticuloendothelial

(RE) system removes RBC’s– unclear what marks a red cell for removal– spleen is major site of RBC clearance

• RE system is extravascular– 90% of normal RBC destruction occurs

without release of hemoglobin into circulation.

The fate of intravascular hemoglobin

free Hb tetramers)

Hbdimers

haptoglobin

haptoglobin-hemoglobin

complex

kidneys liver

metHb

binds tohemopexin &albuminferriheme (Fe3+)globin

Extravascular vs Intravascular hemolysis

Extravascular IntravascularTest Hemolysis Hemolysis

LD

bilirubin

haptoglobin N to absent absent

hemoglobinuria absent present

free Hb in plasma absent present

urine hemosiderin absent present

Causes of intravascular hemolysis

– Mechanical• prosthetic heart valve, tight AS• march & bongo drummer’s hemoglobinuria

– Microangiopathic• DIC, TTP, HUS

– Immunological• acute hemolytic transfusion reaction, PNH

– Infection• malaria• Clostridium welchii sepsis

– Enzymopathy• severe G6PD deficiency

Is there hemolysis?• Look for 3 lines of evidence:

– 1. Damaged red cells on the blood film– spherocytes (immune hemolysis, HS)– red cell fragments (microangiopathic anemias)

– 2. Marrow response to hemolysis– polychromasia on blood film– reticulocytosis– erythroid hyperplasia in marrow

– 3. Biochemical evidence of RBC destruction

– increased unconjugated bilirubin– increased lactate dehydrogenase– decreased/absent haptoglobin

Approach to normocytic anemia

Is there increased red cell production?

check reticulocyte count

normocytic anemia

increased

Is there evidence of hemolysis?

hemolytic anemia

yes

Is there evidence of:- renal failure anemia of renal failure- endocrine failure anemia of endocrine failure- chronic inflammation anemia of chronic disease

normal or decreased

recent bleed

no

If not, then consider a primary marrow problem (MDS, MM, infiltration…)

bone marrow investigation

An approach to hemolytic anemia

Immune Non-immune

Congenital Acquired

Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)

• RBC enzymes(eg. G6PD deficiency)

• Hemoglobin

• Infections sepsis malaria

• Mechanical prosthetic heart valve microangiopathic HA

• Autoimmune

• Alloimmune

• Drug-induced

(other causes of immune hemolysis are rare)

Hemolytic anemia

An approach to hemolytic anemia

Immune Non-immune

Congenital Acquired

Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)

• RBC enzymes(eg. G6PD deficiency)

• Hemoglobin

• Infections sepsis malaria

• Mechanical prosthetic heart valve microangiopathic HA

• Autoimmune

• Alloimmune

• Drug-induced

(other causes of immune hemolysis are rare)

Hemolytic anemia

Immune hemolysis

• most frequent cause of hemolysis• due to IgG or complement on red

cells– tags the red cell for phagocytosis– spherocytes if incomplete

phagocytosis– lysis of RBC occurs if complement

cascade goes to completion

Autoimmune hemolysis

• Most common type of immune hemolysis

• primary (idiopathic)• secondary

– autoimmune hemolysis secondary to:• autoimmune condition (such as SLE)• infection• lymphoma or CLL

Diagnosis of immune hemolytic anemia

– 1. Direct Antiglobulin Test (DAT or direct Coomb’s test)

– detects IgG or complement on patient’s red cells– the vast majority of patients with active immune hemolysis will

have a positive DAT.

– 2. Indirect Antiglobulin Test (IAT, indirect Coomb’s test)

– detects antibody in patient’s serum against red cell antigens– A positive IAT does not necessarily mean hemolysis is occurring -

It may simply mean allo-immunization due to previous exposure to “foreign” red cell antigens (past pregnancy or transfusion).

– 3. Peripheral Blood Film: spherocytes

Treatment of autoimmune hemolysis

• treat the underlying cause, if there is one

• stop suspect drugs if possible• prednisone• transfuse RBC’s, if needed

An approach to hemolytic anemia

Immune Non-immune

Congenital Acquired

Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)

• RBC enzymes(eg. G6PD deficiency)

• Hemoglobin

• Infections sepsis malaria

• Mechanical prosthetic heart valve microangiopathic HA

• Autoimmune

• Alloimmune

• Drug-induced

(other causes of immune hemolysis are rare)

Hemolytic anemia

Hereditary spherocytosis

• most common inherited red cell membrane disorder

• 1/5000 in northern European populations

• autosomal dominant• caused by mutations in the genes

that encode RBC membrane cytoskeleton proteins.

loss of membrane = loss of SA = loss of deformability = increased splenic clearance

Normal

Hereditary spherocytosis

membrane

cytoskeleton

Hereditary spherocytosis

• Spherocytes are cleared by the spleen more rapidly– lack of deformability means they

cannot squeeze through the sieve-like slits of the spleen.

Hereditary spherocytosis• Clinical features:

– clinical severity varies– most have mild to moderate anemia– splenomegaly, cholelithiasis, jaundice may

occur

• Laboratory features– hemolytic anemia with spherocytes– osmotic fragility test– negative DAT

Hereditary spherocytosis

• Treatment– most patients do not need treatment– splenectomy– counsel patient and family about

inheritance

An approach to hemolytic anemia

Immune Non-immune

Congenital Acquired

Defects of: • RBC membrane/skeleton (eg. Hereditary spherocytosis)

• RBC enzymes(eg. G6PD deficiency)

• Hemoglobin

• Infections sepsis malaria

• Mechanical prosthetic heart valve microangiopathic HA

• Autoimmune

• Alloimmune

• Drug-induced

(other causes of immune hemolysis are rare)

Hemolytic anemia

G6PD deficiency

• Most common inherited red cell enzymopathy– up to 10% of those with African and

Mediterranean descent

• X-linked• hemolysis is due to increased

oxidative damage to red cells

G6PD deficiency

• clinical severity highly variable – Most experience little or no anemia

unless exposed to precipitating event or drug

– precipitants:• infections• sulfa, primaquine, dapsone• fava beans

G6PD deficiency

• Laboratory diagnosis– bite cells– Heinz bodies– measure G6PD level

• Treatment– supportive– avoid precipitants– counsel patient/family

Anemia cases1. A 45 year old woman presents to your office with a 2 week history of increasing fatigue and jaundice. Nohepatomegaly or splenomegaly on examination.

Hb 85 (120-150) g/LMCV 97.5 (80-96) fLRDW 19.8 (11.5-14.5)WBC 13.4 (4 - 10) x 109/LPlatelets 457 (150-450) x 109/L DAT positiveIAT positive

LD 301 (94-172) U/LT bili 53 (0-17) mol/Ldirect bili 2serum haptoglobin absentReticulocytes 357 (18-94) x 109/LPeripheral blood smear: some spherocytes

2. You are the ER doc in a remote town, 2 hours from a tertiary care hospital. At 2300h, a 57 year old man isbrought to the ER by his wife because of acute confusion and disorientation. She thought he had the “flu” forthe past 4 days because he has had a fever, headache, and was feeling unusually tired. He has been on nomedications and he had previously been well.

Hb 70 g/LMCV 98 fLWBC 14.8 x 109/Lplt 76 x 109/Lretics 267 x 109/Lblood smear RBC fragments

polychromasiathrombocytopenianeutrophilia with left shift

creatinine 97 mol/LPT normalPTT normal

2. You are the ER doc in a remote town, 2 hours from a tertiary care hospital. At 2300h, a 57 year old man is

3. A 30 year old woman with a 1 year history of rheumatoid arthritis, involving hands, wrists, On NSAIDS.

ESR 57 mm/hrHb 108 g/LMCV 80 fLRDW 18.5WBC 8.2 x 109/LPlt 317 x 109/LRetics 89 x 109/L

4. A previously healthy 67 year old man with recurrent pneumonia.

Hb 103MCV 98WBC 3.9Plt 153Retics 56Peripheral blood smear: rouleaux

What next?

urea creatinine normalLD 216Coombs negbili normal

serum protein electrophoresis: IgG kappa monoclonal protein with depression of IgA, IgM and polyclonalIgG.

Bone marrow investigation: excessive number of plasma cells

Skeletal survey: numerous lytic lesions in the axial skeleton and cranium.

Case 3. A 72 year old woman with a history of rheumatoid arthritis is found tohave a hemoglobin of 97 g/L (120-160) and an MCV of 79 fL (80-100). Thewhite blood cell and platelet counts are normal. Review of the peripheral bloodsmear does not show much abnormality. She takes ibuprofen twice a day forher joint symptoms.

1. What is the differential diagnosis for her microcytic anemia?

2. What other items on history and physical would be helpful?

3. What other investigations are indicated?

Case 3. A 72 year old woman with a history of rheumatoid arthritis is found to

This is case 3 from the iron lecture