Dr. Judit Demeter Semmelweis Egyetem ÁOK., I.sz. Belgyógyászati Klinika Anaemias I Iron deficiency anaemia, ACD

Dr. Judit DemeterDr. Judit Demeter

Semmelweis Egyetem ÁOK., I.sz. Belgyógyászati KlinikaSemmelweis Egyetem ÁOK., I.sz. Belgyógyászati Klinika

Anaemias IAnaemias I

Iron deficiency anaemia, ACDIron deficiency anaemia, ACD

History taking in patients withHistory taking in patients with h haematological disease aematological disease 1.1.

Non-specific symptoms fatigue, fevers, weight loss

Symptoms relating to anaemia

reduced exercise capacity, angina, ankle oedema

Symptoms relating to neutropenia

recurrent oral ulceration, skin infections, sepsis

Evidence of compromised immunity

recurrent oropharyngeal infection

Details of haemostatic problems

easy bruising, bleeding episodes, rashes

Anatomical symptoms abdominal discomfort (spleen), CNS symptoms (spinal compr)

History taking in patients withHistory taking in patients with h haematological aematological disease disease 2.2.

Past medical history

Transfusion history

Drug history: prescribed and non-prescribed medications

Alcohol, tobacco consumption

Occupation, hobbies

Travel (HIV infection, malaria)

Family history: inherited haematological disorders

Normal RBC és PLT values (adult)Normal RBC és PLT values (adult)

Men Women

Determination Mean 95% range Mean 95% range

Red cell count, x 10 /l(or x 10 /l)

5,1 4,5-5,9 4,6 4,1-5,1

Hemoglobin, g/dl 15,3 14,2-16,9 13,9 12,2-15,0

Hematocrit, l/l x 100 45 41,8-49,0 41,4 38,6-45,7

MCV, fl 90 83-99 90 83-99

MCH, pg 30 28-32 30 28-32

MCHC, g/dl 33 32-36 34 32-36

Reticulocytes, ‰ 10 5-18 12 5-22

Reticulocytes, x 10 /l 50 25-100 55 25-120

Platelet count, x 10 /l 245 160-340 248 150-380

12

6

9

9

Normal peripheral blood smear, thin, homogenous part

Normal RBC morphology

1.1. 2.2. 3.3. 4.4. 5.5. 6.6.

1.: proerythroblast; 4.: oxyphil normoblast;

2.: basophil normoblast; 5.: polychromatophil RBC;

3.: polychromatophil normoblast; 6.: mature RBC

1.: proerythroblast; 4.: oxyphil normoblast;

2.: basophil normoblast; 5.: polychromatophil RBC;

3.: polychromatophil normoblast; 6.: mature RBC

Red blood cell maturation

Az anemiás beteg

Anaemias: Kinetic approachReduced RBC production

deficiency anaemias (hematinic deficiency) (iron, B12, folic acid)

bone marrow disorders ( aplastic anaemia,

isolated RBC-aplasia,

myelodsyplasia,

neoplastic infiltration)

Increased RBC destruction (hemolysis: RBC lifespan < 100 days)

congenital hemolitic anaemias (hereditary shaerocytosis,

sickle cell disease,

thalassaemia maior)

acquired hemolytic anaemias (Coombs positiv hemolytic anaemia

TTP-HUS)

Blood loss

apparent bleeding - hematemesis, melaena, metrorrhagia, epistaxis

occult bleeding - slowly bleeding ulcus or carcinoma.

Examination of the anaemic patient

• searching for signs of bleeding (at present or earlier)

• Signs of increased RBC destruction ( hemolysis?)

• Bone marrow suppression?

• Iron deficiency? Why?

• Folic acid or B12 deficiency?

Medical history melaena?

since what time?

drug intake? (NSAID-s)

geographical localisation?

Physical examination severity ?

tachycardia, dyspnoe, fever, hypotension

hepatosplenomegaly, lymphadenopathy?

(pallor)

icterus?

petechiae? Infections?

Examination of the anamic patient II

Anaemia in pregnancyAnaemia in pregnancy

• Dilutional anaemia: red cell mass ↑ by ~ 30% plasma volume ↑ by ~ 60%

The normal Hb concentration: 10-11g/dl

• Iron deficiency is a common problem

Cause of ↑ Fe requirements Amount of additional Fe

↑ Red cell mass ~ 500 mg

Fetal requirements ~ 300 mg

Placental requirements ~ 5 mg

Basal losses over pregnancy

~ 250 mg (1.0-1.5 mg/d)

Reticulocytes in the peripheral blood smear – brillantcresilblue staining

Retikulocyte shift in anaemia

With increasing severity of the anaemia and increasing erythropoetic stimulation, the reticulocytes leave BM increasingly earlier .

Thus their maturation time in the periphery increases from 1 to 3 days.

Polychromatophilia in reticulocytosis

A retiukulociták nagyobbak és nincs centrális halvány középük (nem bikonkávak)

The amount of iron passing from mucosal cells into the body is determined by the rate of erythropoiesis and the state of body iron stores.

Iron homeostasis

-Anaemia is typically the first clue to iron deficiency, but an isolated haemoglobin measurement has both low specificity and low sensitivity.

- improve sensitivity by

including measures of iron-deficient erythropoiesis such as

- the transferrin iron saturation,

- mean corpuscular haemoglobin concentration, - erythrocyte zinc protoporphyrin,

- percentage of hypochromic erythrocytes or

- reticulocyte haemoglobin concentration.

However, these results changes in iron def. indistinguishable from ACD.

The optimal dg:

serum ferritin as an index of iron stores and

serum transferrin receptor as a index of tissue iron deficiency.

Receiver operating characteristic (ROC) curves showing the sensitivity and specificity of various tests for the diagnosis of iron deficiency [ferritin, red cell protoporphyrin, transferrin saturation, mean red cell volume (MCV), and red cell volume distribution width (RDW)]. Note that, at any given level of sensitivity or specificity, serum ferritin outperforms all the other tests shown

Testing for iron-deficiency

Hypochromasia, anulocytesHypochromasia, anulocytes

Causes of iron deficiencyCauses of iron deficiencyReproductive system

menorrhagia

GI tract oesophagitis, oesophageal varices, hiatus hernia, peptic ulcer, IBD, haemorrhoids carcinoma: stomach, colorectal

Malabsorption coeliac disease, atrophic gastritis, gastrectomy

Dietary vegans, elderly

Physiological growth spurts, pregnancy

Others PNH, frequent blood donation, hookworm

Blood loss in gastrointestinal diseaseBlood loss in gastrointestinal disease

ACUTE Immediately following acute haemorrhage - RBC indices usually normal

ACUTE ON CHRONIC RBC indices show low normal or marginally ↓, film shows mixture of normochromic & hypochromic RBCs (dimorphic)

CHRONIC RBC indices show established chronic Fe deficiency features ↓ MCV, MCH, platelets often ↑

Control of iron absorption

Pathways of iron absorption and excretion in an intestinal mucosal cell.

Normal iron absorption is 1 mg/day with a total daily intake of 10 mg.

Iron absorption: enhanced in iron deficiency, and diminished in iron overload.

Factors influencing the absorption of dietary iron

Absorption of heme ironAmount of heme iron, especially in meatContent of calcium in the mealFood preparation (time, temperature)

Absorption of nonheme ironIron statusAmount of potentially available nonheme ironBalance between positive and negative factors

Positive factorsAscorbic acidMeat or fish

Negative factorsPhytate (in bran, oats, rye fiber) Polyphenols (in tea, some vegetables and cereals)

Dietary calciumSoy protein

•Transferrin (Tf)

•Transferrin receptor (TfR)

•Ferritin

•Iron regulatory protein 1 and 2 (IRP1 and IRP2), the cellular iron sensing proteins

•Divalent metal transporter 1 (DMT1, Nramp2, DCT1, Solute carrier family 11, member 2 (Slc11a2)), the duodenal iron transporter

•Ferroportin (Ireg1, Slc11a2, Mtp1), the cellular iron exporter

•Hephaestin, which likely cooperates with ferroportin for exporting iron to transferrin.

•HFE, mutations responsible for the common form of hereditary hemochromatosis

•TFR2, mutations responsible for a rare form of hereditary hemochromatosis

•Hemojuvelin, a hepcidin regulator, mutations responsible for the common form of juvenile hemochromatosis

•Hepcidin, the key negative regulator of

intestinal iron absorption + macrophage iron release.

Mutations cause a rare form of juvenile hemochromatosis.

Role of specific proteins in iron metabolism

Some truths’ about ferritin — the cellular storage protein for iron

- a huge protein, consisting of light and heavy chains, which can store up to 4500 atoms of iron within its spherical cavity -an acute phase reactant, and, along with transferrin and the transferrin receptor, is a member of the protein family that orchestrates cellular defense against oxidative stress and inflammation

Much of the stored iron is accessible for metabolic needs. Ferritin within erythroid precursors may be of special importance in the donation of iron for heme synthesis, Ferritin measured clinically in plasma is usually apoferritin, a non-iron containing molecule.

The plasma level generally reflects overall iron storage 1 ng of ferritin per mL → 10 mg of total iron stores.

A normal adult male: plasma ferritin level of 50 to 100 ng/mL = iron stores of appr. 500 to 1000 mg

A serum ferritin <10 to 15 ng/mL is 99 percent specific for making a diagnosis of iron deficiency.

An elevated serum ferritin ( in the absence of infection or inflammation) suggests the presence of an iron overload state.

Distribution of body iron in men and women

70 kg man 60 kg woman _________ ___________

Iron stores - transferrin, ferritin, hemosiderin 1.4 g 0.3 g*

Hemoglobin 2.5 g 1.9 g

Myoglobin 0.14 g 0.13 g

Heme enzymes 0.01 g 0.01g

_______________________________________________________________

TOTAL 4.05 g 2.34 g

Normal Fe deficiencywithout anemia

Fe deficiency with mild anemia

Severe Fe deficiency with severe anemia

Marrow reticuloendo-thelial iron

2+ to 3+ None None None

Saturation (SIron/TIBC), percent

20-50 30 <15 <10

Hemoglobin, g/dL

Normal Normal 9 to 12 6 to 7

Red cell morphology

Normal Normal Slight hypochromia

Hypochromia and mikrocyt

serum ferritin, ng/mL

20 to 200 <20 <15 <10

Other tissue changes

None None None Nail and epithelial changes

Laboratory tests in iron deficiency of increasing severity

KN born: 1961

2007 Abdominal cramps, bloody stool,colonoscopy : M Crohn

2009 aug prolapsus rectiStatus: pallor

no perimalleolar anasarca no tachycardia, but systolic murmur

RDV: stool Weber: +

FBC: Ht: 0,18 Hb: 54 g/l ret: 35 % MCV: 65 fl (n: 80-97) WBC : norm CRP: 0 Plt : 582 G/l INR norm serumiron: 3,0 TIBC: 87,8 serum folic acid, serum B12 : normal

soluble transferrin receptor :27,6 (norm: 1,9- 4,4) serumferritin: 7 ng/ml (norm: 10-120)

NormNormal curveal curve

MikrocytosisMikrocytosis

Cell-Dyn 3500

Target RBCs, slight hypochromasiaTarget RBCs, slight hypochromasia

Target RBCs in thalassaemia minor

Anisocytosis, microcytosis in irondeficiency

Anulocytes, hypochromasia in iron-deficiency

Anaemias – morphological approach

Change of RBC indices in the course ofChange of RBC indices in the course of

successful iron treatmentsuccessful iron treatment

1999.10.01:1999.10.01: vvsvvs: 4.16 : 4.16 HgbHgb:72 :72 HtHt: 25 MCV:61: 25 MCV:61




Coexisting disease interfering with marrow responseInfection

Inflammatory disorder (eg, rheumatoid arthritis) Concomitant malignancy Coexisting folic acid and/or vitamin B12 deficiency

Bone marrow suppression from another cause

Dg. incorrect, diff. diagnosisThalassemia Lead poisoning Anemia of chronic disease (anemia of chronic inflammation) Copper deficiency (zinc toxicity) Myelodysplastic syndrome/refractory sideroblastic anemia

Patient not taking the medication

Medication is being taken but is not being absorbed cont’d

Causes of failure to respond to oral iron therapy

Medication is being taken but is not being absorbed

Enteric coated product: coating is not dissolving

Malabsorption of iron (eg, sprue, atrophic gastritis)

Agents interfering with absorption (eg, antacids, tetracycline,

tea)

Continued blood loss

-Cause treatable (eg, bleeding peptic ulcer)

-Cause not treatable (eg, Osler Weber Rendu

disease) or not by oral iron (eg, renal

failure

responding to Epo)

Cont.

Body weight (kilograms) = BW 68 kgHemoglobin concentration (g/dL) = Hgb 5,5 g/dlConcentration of elemental iron in the parenteral product (mg/mL) = C* 12,5 mg/mlAssumptions:

Blood volume is 65 mL per kilogramHemoglobin concentration to be corrected to 14.0 g/dLNo additional iron to be given for repletion of body storesIntermediate calculations:Blood volume (dL) = 65 (mL/kg) x body weight (kg) ÷ 100

(mL/dL) 65x68/100=44,2 dlHemoglobin deficit (g/dL) = 14.0 - patient hemoglobin conc. 8,5 g/dlHemoglobin deficit (g) = hemoglobin deficit (g/dL) x blood volume

(dL) 8,5x44,2=375 gIron deficit (mg) = hemoglobin deficit (g) x 3.3 (mg Fe/g Hgb) 375x3.3=1237,5 mgVolume of parenteral iron product required (mL) = Iron deficit (mg)

÷ C(mg/mL) 99 ml= 20 ampullaFinal calculations:Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145)Volume of product required (mL) = BW x (14 - Hgb) x (2.145) ÷ C

CALCULATION OF PARENTERAL IRON DOSE

Anaemia of chronic diseases (ACD)

Anemia of chronic disease - bone marrow iron stain

Anaemia in rheumatoid diseaseAnaemia in rheumatoid disease

Autoimmune phenomena

warm antibody AIHA, DAT+

film show show reticulocytosis

Drug related problems Chronic blood loss, macrocytosis from antimetabolite immunosuppressives: azathioprine, Mtx, oxidative haemolysis to dapsone, sulfasalazine (rare AIHA due to NSAID), unforeseeable marrow aplasia

2 to other organ problems

hypersplenism, Felty’s syndrom, renal failure in SLE

irondeficiency ACD: Anaemia of

chronic disorders

Combined causes

Normal

Determination of soluble transferrin receptor

Myelodysplastic syndrom- refractory anaemia with ringsideroblasts

Need based on estimation of lost blood volume:

Ø

Need based on hemoglobin concentration:

Hgb <7 g/dL:RBC transfusion indicated. If the patient is otherwise stable, the patient should receive 2 units of packed RBC, following which the patient's clinical status and circulating HgB should be reassessed

Hgb 7 to 10 g/dL:Correct strategy is unclear

Hgb >10 g/dL: RBC transfusion not indicated

High risk patients:Patients >65 and/or those with cardiovascular or respiratory disease may tolerate anemia poorly.

Such patients may be transfused when Hgb <8 g/dL.

GUIDELINES FOR RED CELL TRANSFUSIONS IN ADULT

ANAEMIA

reticulocyta A

reticulocyta

Hemolízis

B

Vérvesztés

E

normocytás an

macrocytás

an

Coombs +

Coombs neg

Fe n/ TVK

ferritin

Fe

TVK ferritin

Fe

TVK ferritin

Thalassaemia

AIHA

Gyógyszerek

lép tap

hypersplenia

lép nem tap

D

MAHA (DIC,

TTP/HUS) (PNH,

malária)

K rónikus betegséget

kísérő anaemia

Csontvelővétel

(sideroblastos an)

Vashiányos an Ólommérgezés

I

reticulocyta

Hemolizis

Lép nem tap

Microcytás an.E Microcytás an.

Krónikus betegséget

kísérő anaemia

Vashiányos an.

Ólommérgezés

Fe n/TVK n/ ferritin

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Dr. Judit Demeter Semmelweis Egyetem ÁOK., I.sz. Belgyógyászati Klinika Anaemias I Iron deficiency anaemia, ACD