Iron Deficiency - the Huronia Nurse Practitioner`s Network

Transcript Iron Deficiency - the Huronia Nurse Practitioner`s Network

Approach to Lows of the CBC

Huronia Nurse Practitioner Conference September 26, 2014 Lauren Gerard, MD, FRCP Hematologist Royal Victoria Hospital [email protected]

Objectives

    Review the “CBC” and blood films To develop a differential diagnosis of anemia To appreciate blood work requiring immediate attention Red flags….when to refer!

Parts of the CBC

      RBC = # of RBCs per liter MCV = mean cell volume   Normal for adult 80 – 100 Normal in pediatrics slightly lower MCH = avg. amount of Hb in an individual cell  Decreased in hypochromic anemias  Total mass of Hb / # RBCs in volume of blood MCHC = avg. concentration of Hb in a cell  Increased in HS and Hb SS RDW = reflection of anisocytosis  Ddx: IDA, reticulocytosis, blood transfusion etc  Normal = uniform population of cells HCT = measures the volume of red blood cells compared to the total blood volume (red blood cells and plasma)

Parts of the CBC: Hemoglobin

    Automated cell counter from a tube of well-mixed EDTA-anticoagulated blood filled to a predetermined level. RBCs are lysed, all forms of hemoglobins are converted to the colored protein cyanomethemoglobin and measured by a colorimeter. False readings: inadequate sample (due to insufficient volume or inadequate anticoagulation) Hemoglobin is quantified based on its absorption characteristics. False elevations:   Hyperlipidemias Hyperbilirubinemia   high white blood cell count high serum protein can

Indications for Peripheral Blood Film

     Anemia NYD, Jaundice NYD Thrombocytopenia or neutropenia Features of MPD of LPD DIC (n.b. acutely fragments may be absent) Suspicion of parasitic disease

General Approach to the Anemia

   Acute vs. Chronic  Look at previous CBCs Anemia alone or multiple cell lines affected  Multiple cell lines affected is more concerning for primary bone marrow disorder Detailed PMH/Social/family history  Anemia can result from a number of other systemic causes

Approach to Anemia

     Start with the MCV!

Microcytic < 80 fL Normocytic 80-100 fL Macrocytic > 100 fL What determines size of red cell?

  Hemoglobin is negative regulator of cell division Less hemoglobin = extra division = smaller cells

Low (Microcytic ) Ferritin Anemia MCV Normal Reticulocyte Count High (Macrocytic) Measure B12, (folate) Low (<20) Fe Def High Low Normal ACD or Hb-opathy Hemolyisis Or Blood Loss ACD Renal Disease BM Failure Establish Cause Normal Low Consider Bone Marrow Biopsy Replace Establish Cause

Microcytic Anemias

Case # 1

      31 female with Hemoglobin 88g/L Symptoms:  Fatigue, otherwise well PMH:   IBS G2P2 Meds:  None Family Hx:  None Exam:  Normal

CBC (incl platelet Count) Hemoglobin WBC Count 88 10 Platelet Count 488 Neutrophils 7.0

Lymphocytes 3.0

Monocytes Eosinophils Basophils Hematocrit RBC Count MCV RDW MCH MCHC MPV 1.2

0.0

.294

4.71

62.4

18.8

18.7

299 9.5

130 - 180 g/L 4.0 - 11.0 x10E9/L 150 - 400 x10E9/L 2.0 - 7.5 x10E9/L 1.0 - 4.0 x10E9/L 0 - 1.0 x10E9/L 0 - 0.7 x10E9/L 0 - 0.3 x10E9/L 0.390 - 0.540 L/L 4.00 - 6.00 x10E12/ 78 - 96 fL 10.0 - 14.5 % 28.0 - 32.0 pg 310 - 360 g/L 5.0 - 15.0 fL L H H L L CRITICAL H CRITICAL L

What is your Differential of Microcytic Anemia?

     Thalassemia Anemic of Chronic Disease (ACD)    Hepcidin prevents eggress of iron from enterocytes Reduced RBC lifespan Inflammatory cytokines interfere w/ Epo prodn Iron Deficiency      Chronic blood loss (GI, hemolysis, menstruation) Nutritional deficiency Malabsorption (Celiac, H. Pylori, gastric resection, achlorydia) Pregnancy, lactation Hookworm infestation Lead Sideroblastic Anemia

Case #1

 Ferritin 10  Iron deficiency anemia (ferritin < 30)    Ferritin <18 LR 41 Ferritin 18-45 LR 3.12 Ferritin >100 LR 0.13

 But in the setting of inflammation   In inflammation, ferritin may increase 3-fold Iron studies (TSAT) < 20% may be helpful Guyatt et al. Am J Medicine 1990;88:205-209

Serum Iron  TIBC = %Transferrin Saturation

(TIBC = total iron binding capacity)

Serum Iron Normal (20-40%) Iron def:  serum Fe  TIBC  %saturation ACD:  serum Fe N or  TIBC  %saturation

Cannot R/O Fe def

The Blood Film

Red Blood Cell Platelet White Blood Cell http://meds.queensu.ca/medicine/deptmed/hemonc/macro/slide14.html

Case #1

Hypochromic (1/3), microcytic Low Hb Low MCV High RDW

Pencil cell

Case #1

 Once you have diagnosed iron deficiency, what is next most important issue to answer? A.

Does the patient have malabsorption of iron or a poor diet? B.

Does the patient have a source of blood loss?

Does the patient have chronic vs acute iron deficiency?

Is there concomitant thalassemia?

Fe deficiency - Causes

 Too much OUT   Increased blood loss Increased iron requirements: use of ESAs, pregnancy, post-bleeding recovery  Too little IN   Inadequate absorption:   Loss of enterocytes: resection, celiac disease, IBD Antacids, H.pylori, excess dietary bran, tannins, phytates, starch, competition with other metals rare mutations: DMT1, transferrin, TMPRSS6

Causes of Iron Deficiency

Always think about, look for, and treat the underlying cause!

Case #1 – Iron Deficiency Anemia

  History:  No GI causes of blood loss    Normal diet (not vegetarian) 2 pregnancies last 4 years Heavy periods since menarche  Changes pad/tampon q1-2 hours x 6 days Family History:   Mother & aunt– heavy periods, easing bruising Brother – excessive bleeding with dental extraction

Treatment of Iron Deficiency

    Treat underlying cause if possible Iron replacement  BID to TID dosing      Ferrous gluconate Ferrous sulfate Ferrous fumarate Proferrin Feramax 30mg/300mg 60mg/300mg 100mg/300mg 11mg po BID 150mg po OD Take on empty stomach with vitamin C At least 3 months…

Poor Response to oral Iron

   Lack of response within 4 to 6 weeks of therapy with a minimum of 100 mg po od elemental dose  Expect reticulocytosis in 7 days  Increase in Hgb by 10g/L in 14 - 28 days  SO LONG AS NO BLEEDING: normalize Hgb in 6 to 8 weeks Review:   Compliance/Side effects (especially constipation) Food inhibitors of iron absorption:   Oats, bran, rye Tea  Calcium Rule Out:  H.Pylori (19% of cases)     Celiac disease – even in absence of symptoms (5%) Atrophic gastritis (26%) Achloryhydric gastric atrophy – acid is required to solubilize and reduce dietary iron On going blood loss

IV Iron

 If oral iron is not tolerated, is not effective or severe anemia  Intravenous Iron   Iron Sucrose (Venofer) Ferumoxytol (Feraheme)  Iron Dextran (Infufer, Dexiron)

Case #1 Summary

   Iron deficiency anemia  completely with oral iron supplementation resolved Management of heavy menses:  Mirena IUD placement VWD Investigations   VWF antigen – 20%, Activity- 20%, Factor VIII 50% Consistent with mild VWD type 1

Case #2:

   74 year old man with Hb 92 g/L PMH:  Life long smoker, Type 2 DM, HTN, Dyslipidemia, Coronary artery disease, CABG CHF grade III/IV, Rheumatoid Arthritis, Recurrent UTIs Medications  ASA, Plavix, Metformin, Ramipril, Lasix, Metoprolol

CBC (incl platelet Count) Hemoglobin WBC Count 92 10 Platelet Count 250 Neutrophils 7.0

Lymphocytes 3.0

Monocytes Eosinophils Basophils Hematocrit RBC Count MCV RDW MCH MCHC MPV 1.2

0.0

.294

4.71

78 13 18.7

299 9.5

Case #2

  Iron Studies  Ferritin 120   TIBC – 0.40

Iron Saturation 0.22

Blood Film  Microcytic hypochromic

Table 1: Laboratory values to distinguish causes of microcytic anemia Laboratory marker (ref range)

Blood film Ferritin (12 – 192  g/L) Serum Iron (10 - 30  mol/L) Transferrin saturation (0.20 - 0.50) Total iron-binding capacity (42 – 72  mol /L) Reticulocytes 30 - 90) E9/L Red cell distribution (11.0 - 15.0) % Mean corpuscular volume ( 82.0 - 97.0 fL) Red blood cell 4.30 - 5.60 E12/L Mean cell hemoglobin (27.0 - 32.0 pg) Hemoglobin (115 - 155 g/L) Soluble transferrin receptor (10-30 nmol/L) Serum hemoglobin electrophoresis

Iron deficiency anemia

Hypochromia, pencil-shaped forms < 40  g/L < 10 < 15% > 72 Low Low   mol/L mol/L > 14.5% < 80 fL Low – normal < 120 g/L in women < 130 g/L in men > 30 nmol/L Normal

Anemia of chronic disease

Variable High Low Normal Low Low Normal 80 – 100 fL Normal Low Low < 30 nmol/L Normal

Thalassemia minor

Uniform size, target cell Normal Normal Normal Normal to high Normal to high Normal Out of proportion low Normal to high Low Variable 10-30 nmol/L Variable†

Clues to Microcytic Anemia

MCV < 80 fl Serum Iron TIBC / Serum Iron BM Perls stain Iron Def. Anemia Chronic Infection Thalassemia Hemoglobinopathy Lead poisoning Sideroblastic ↓↓ ↑↑ / LOW 0 ↑↑ N N ↑↑ ↓↓ ↓↓/ Low or Normal N

+ + + + + +

N N N

+ + + + + + + +

Anemia of Chronic Disease

1) Iron restricted erythropoiesis 2) Blunted erythropoietin response IL-6 Lipopolysaccharides Inflammation ↓Oral absorption Iron trapping within RES Andrews. Blood 2008;112:219

Anemia of Chronic Disease

    Presents as normocytic or microcytic anemia Usually does not cause “severe” anemia Can be challenging to differentiate from iron deficiency Treatment   Treat underlying cause (if possible) Treatment of Anemia (if symptomatic)  Consider IV iron + Erythropoeitin

Macrocytic Anemias

Case #3

    45F with Hb 108 MCV 112 PMH  Hyperthyroism - treated with radioactive iodine  Ulcerative colitis (mild) Meds:  Synthoid Social Hx:  Non-smoker, minimal ETOH

What is the DDx of Macrocytic anemia?

 Round      Liver disease Hypothyroid Alcohol Reticulocytosis Drugs  Oval  Myelodysplastic syndrome  Megaloblastic    B12 Deficiency Folate Deficiency Drugs   Folate: Methotrexate DNA: Hydroxyurea, azathioprine, AZT

Investigations of Macrocytosis

       Liver disease Hypothyroid Alcohol Drugs Reticulocytosis Myelodysplastic syndrome Megaloblastic (B12, folate, other drugs) • • • • • • • • Blood film Liver enzymes, INR, albumin TSH Alcohol and Drug history Retic count CBC  look at other cell lines Serum B12 (RBC folate)

Case #3

 CBC  Only anemia with macrocytis  Liver enzymes - normal  Unconjugated bilirubin 41  LDH: 450 (elevated)  TSH 3 (normal)  Vitamin B12 < 40 pmol/L  RBC folate – not performed

Case #3

Low Hb MCV 120

Seen with Megaloblastic Anemias

Hypersegmented neutrophil (>5 lobes)

B12 Deficiency

B12 Deficiency - Treatment

    Identify etiology  Refer for OGD – rule out celiac disease Pernicious Anemia  Refer for OGD - Increased risk of gastric cancer (3%) B12 replacement  B12 1000 mcg IM (if severe)   Oral supplementation – high dose may be just as effective even if pernicious anemia Watch for rebound hypokalemia   Hyperseg PMNs – 14 days Reticulocytosis 3-4 days  Normalization of Hgb by 8 weeks Food: eggs, milk, cheese, milk products, meat, fish, shellfish and poultry

Case #4

    72 year old woman PMH  Breast cancer  Treated with mastectomy and chemotherapy 8 years ago  Awaiting CABG for CAD Hb 95 MCV 105 Surgeon notes that she was started on iron p.o. for a Hgb of 109 g/ L.

CBC (incl platelet Count) Hemoglobin WBC Count 95 2.5

Platelet Count 72 Neutrophils 0.8

Lymphocytes 1.0

Monocytes Eosinophils Basophils Hematocrit RBC Count MCV RDW MCH MCHC MPV 0.7

0.0

.294

4.71

105 12 18.7

299 9.5

Case #4

How would you manage this patient?

Start i.v. iron as she has not had response to oral iron B.

Check her RBC folate and vitamin B12 stores; then replace Refer to a hematologist for further evaluation Liase with anesthesia to ensure usage of cell saver etc.

Case #4

 Investigations:  Liver enzymes – normal    INR – 1.0, PTT – 29 B12 – 800, RBC folate – 1000 Reticulocyte Count - 15

Low Hb MCV 105

Case #4

Seen with MDS

Pelger-Huet anomaly (dumb-bell nucleus)

Case #4: Summary

    Macrocytic anemia with other cytopenias (pancytopenia) Previous chemotherapy Low reticulocyte count  Suggests primary bone marrow failure Likely mylodysplastic syndrome (MDS)

Normocytic Anemia

Normocytic Anemia Reticulocyte Count Low Generalized Disorders Anemia of Chronic Disease Renal dysfunction Early/combined nutritional deficiencies Primary bone marrow disorders Marrow infiltration/infection Aplastic anemia MDS Elevated No Hemolysis Evidence of Hemolysis?

(  LDH,  bilirubin,  haptoglobin) Hemolytic Anemia Blood Loss Intrinsic & Extrinsic causes

Hemolytic Anemia (  LDH,  bilirubin,  haptoglobin)

Intrinsic Causes

Memebranopathies Hereditary Spherocytosis Hereditary eliptocytosis Enzymopathies G6PD Deficiency PK Deficiency Hemoglobinopathies Sickle cell

Extrinsic Causes

Immune Mediated Autoimmune Hemolytic Transfusion reaction Microangiopathic Hemolytic Anemia (MAHA) TTP/HUS DIC Mechanical heart valve

Normocytic Anemia Investigations

 Reticulocyte count  If elevated RBC loss or destruction  Hemolytic Markers  LDH, Haptoglobin, Bilirubin  Nutritional Markers  Iron indices and B12 (RBC folate)  May have combined deficiency  Direct Antiglobulin Test (DAT)  If positive suggests immune hemolysis  Peripheral blood film

Low Hb Normal MCV

Hemoglobinopathy Sickle Cell

G6pd slide G6PD Deficiency

Bite Cell

Case #5

    45 year old woman  Hb 105, MCV 92 fl, WBC 4, Plt 300 Otherwise well Family Hx:  Brother had splenectomy as child Investigations:  Reticulocyte count – 300 (elevated)  Unconjugated bili – 42, LDH 550, Haptoglobin undetectable  Abdo U/S – mild splenomegaly (16 cm) What Additional Investigations Should We Order?

Direct Antiglobulin Test (DAT) and Blood Film

Case #5

Spherocytes – round RBC lacking central pallor

Spherocytes DDx:

Immune mediated Hereditary spherocytosis

Case #6

    57 year old woman, previously well Brought to ED feeling “generally unwell”, headache and husband noted mild confusion Physical exam – normal Investigations:   Hb 98 g/L, MCV 94fL, WBC – normal, Plts 34 x 10 9/L CT head - normal

Case #6

 What is your next step in this patients management?

 A) Discharge patient and reassure that likely related to a viral illness    B) Discharge to be seen in hematology clinic within 2 – 4 weeks C) Urgent peripheral blood film D) Start on B12 supplement

Case #6

   What would you like to know on history?

What investigations would you order?

Investigations:         Reticulocyte count 408 LDH 568 Haptoglobin < 0.06

Indirect bilirubin 55 Direct Antibody test: negative PT 11.0 sec, PTT 31.0 sec Creatinine 120 umol/L Urinalysis: + blood B.

 A.

What is her most likely diagnosis?

Warm Autoimmune Hemolytic anemia Oxidative hemolysis Acute blood loss Disseminated Intravascular Coagulation Thrombotic Thromocytopenia Purpura

Fragments

Case #6

Microangiopathic Hemolytic Anemia

          DIC HUS/ TTP Gestation-related   HELPP AFLP Malignant HTN Catastrophic Antiphospholipid Syndrome Medication induced Endotheliopathies  Ticlopidine, Clopidogrel   Mitomycin C Calcineurin Inhibitors Valvulopathies Kidney rejection Scleroderma crisis, lupus, APLA crisis March hemoglobinuria

Anemia Algorithm

Anemia Microcytic: Iron Deficiency Thalassemia Anemia of chronic disease Sideroblastic anemia MCV Normocytic: (next page) Macrocytic: Megaloblastic - Folate, B12 Drugs Myelodysplasia Alcohol Liver Disease Reticulocytosis Thyroid disease

Anemia Algorithm

Anemia Microcytic: Iron Deficiency Thalassemia Anemia of chronic disease Sideroblastic anemia MCV Normocytic: (next page) Blood film Serum ferritin, iron studies Hgb electrophoresis Macrocytic: Megaloblastic - Folate, B12 Drugs Myelodysplasia Alcohol Liver Disease Reticulocytosis Thyroid disease Blood film exam (Serum B12) RBC folate Liver enz, TSH Retic count

Normocytic Retic Count Low

Generalized Disorders - Anemia of chronic disease - Chronic renal failure - Nutritional deficiencies - Toxins, drugs Primary Bone marrow - Hematologic - Infiltration/Infection High

Hemorrhage Hemolysis (Hematinic)

Normocytic Retic Count Low

Generalized Disorders - Anemia of chronic disease - Chronic renal failure - Nutritional deficiencies - Toxins, drugs Primary Bone marrow - Hematologic - Infiltration/Infection Blood film Ferritin, Iron studies Creatinine TSH, B12 Exam/Abdom. ultrasound High

Hemorrhage Hemolysis (Hematinic) Bili, LDH Haptoglobin

Normocytic Retic Count Low

Hemorrhage Hemolysis (Hematinic) Bili, LDH Haptoglobin Direct Antiglobulin Test

When to refer to Hematology?

  Anemia with  Thrombocytopenia     Leukopenia Macrocytic Anemia Evidence of hemolysis Red cell fragmentation Anemia with Hb < 100

Conclusions

   Many types of anemia have a “non hematologic cause”…look for it and treat it whenever possible The most important investigation of normocytic anemia is the reticulocyte count.

Peripheral blood film can provide important diagnostic clues.

Questions?

Email: [email protected]