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

2. History taking in patients with haematological disease 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)

3. History taking in patients with haematological disease 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

4. Normal RBC és PLT values (adult)

5. Normal peripheral blood smear,
thin, homogenous part

6. Normal RBC morphology

7. Red blood cell maturation1. 2. 3. 4. 5. 6.
1.: proerythroblast; 4.: oxyphil normoblast;
2.: basophil normoblast; 5.: polychromatophil RBC;
3.: polychromatophil normoblast; 6.: mature RBC

8. Anaemias: Kinetic approach
Reduced 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.
Az anemiás beteg

9. 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?

10. Examination of the anamic patient II
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?

11. Anaemia 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
~ mg
Basal losses over pregnancy
~ 250 mg ( mg/d)

12. Reticulocytes in the peripheral blood smear – brillantcresilblue staining

13. 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.

14. Polychromatophilia in reticulocytosis
A retiukulociták nagyobbak és nincs centrális halvány középük (nem bikonkávak)

15. Iron homeostasis
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.

16. serum transferrin receptor as a index of tissue iron deficiency.
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.

17. Testing for 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

18. Hypochromasia, anulocytes

19. Causes of iron deficiency
Reproductive 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

20. Blood 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 ↑

21. 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.

22. Factors influencing the absorption of dietary iron
Absorption of heme iron
Amount of heme iron, especially in meat
Content of calcium in the meal
Food preparation (time, temperature)
Absorption of nonheme iron
Iron status
Amount of potentially available nonheme iron
Balance between positive and negative factors
Positive factors
Ascorbic acid
Meat or fish
Negative factors
Phytate (in bran, oats, rye fiber)
Polyphenols (in tea, some vegetables and cereals)
Dietary calcium
Soy protein

23. Role of specific proteins in iron metabolism
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.

24. 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.

25. Distribution of body iron in men and women
70 kg man kg woman _________ ___________
Iron stores - transferrin, ferritin, hemosiderin 1.4 g 0.3 g*
Hemoglobin g 1.9 g
Myoglobin g g
Heme enzymes g 0.01g
_______________________________________________________________
TOTAL g g

26. Laboratory tests in iron deficiency of increasing severity
Normal
Fe deficiency
without anemia
Fe deficiency with mild anemia
Severe Fe deficiency with severe anemia
Marrow reticuloendo-thelial iron
2+ to 3+
None
Saturation (SIron/TIBC), percent
20-50 30
<15
<10
Hemoglobin, g/dL
9 to 12
6 to 7
Red cell morphology
Slight hypochromia
Hypochromia and mikrocyt
serum ferritin, ng/mL
20 to 200
<20
Other tissue changes
Nail and epithelial changes

27. 2007 Abdominal cramps, bloody stool, colonoscopy : M Crohn
KN born: 1961
Abdominal cramps, bloody stool,
colonoscopy : M Crohn
2009 aug prolapsus recti
Status: 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: )

30. Normal curve
Mikrocytosis
Cell-Dyn 3500

31. Target RBCs, slight hypochromasia

32. Target RBCs in thalassaemia minor

33. Anisocytosis, microcytosis in irondeficiency

34. Anulocytes, hypochromasia in iron-deficiency

36. Anaemias – morphological approach

38. Change of RBC indices in the course of successful iron treatment: :
vvs
vvs
: 4.16
: 4.16
Hgb
Hgb
:72
:72 Ht Ht
: 25 MCV:61
: 25 MCV:61 : :
vvs
vvs
: 4.56
: 4.56
Hgb
Hgb
:107
:107 Ht Ht
: 34 MCV:74
: 34 MCV:74 : :
vvs
vvs
: 4.87
: 4.87
Hgb
Hgb
:125
:125 Ht Ht
: 39 MCV:79
: 39 MCV:79 : :
vvs
vvs
: 4.83
: 4.83
Hgb
Hgb
:138
:138 Ht Ht
: 41 MCV:86
: 41 MCV:86

39. Causes of failure to respond to oral iron therapy
Coexisting disease interfering with marrow response
Infection
Inflammatory disorder (eg, rheumatoid arthritis)
Concomitant malignancy
Coexisting folic acid and/or vitamin B12 deficiency
Bone marrow suppression from another cause
Dg. incorrect, diff. diagnosis
Thalassemia
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

40. Medication is being taken but is not being absorbed
Cont.
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)

41. CALCULATION OF PARENTERAL IRON DOSE
Body weight (kilograms) = BW 68 kg
Hemoglobin concentration (g/dL) = Hgb 5,5 g/dl
Concentration of elemental iron in the parenteral product (mg/mL) = C* 12,5 mg/ml
Assumptions:
Blood volume is 65 mL per kilogram
Hemoglobin concentration to be corrected to 14.0 g/dL
No additional iron to be given for repletion of body stores
Intermediate calculations:
Blood volume (dL) = 65 (mL/kg) x body weight (kg) ÷ (mL/dL) 65x68/100=44,2 dl
Hemoglobin deficit (g/dL) = patient hemoglobin conc. 8,5 g/dl
Hemoglobin deficit (g) = hemoglobin deficit (g/dL) x blood volume (dL) 8,5x44,2=375 g
Iron deficit (mg) = hemoglobin deficit (g) x 3.3 (mg Fe/g Hgb) 375x3.3=1237,5 mg
Volume of parenteral iron product required (mL) = Iron deficit (mg) ÷ C(mg/mL) 99 ml= 20 ampulla
Final 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

42. Anaemia of chronic diseases (ACD)

43. Anemia of chronic disease - bone marrow iron stain

44. Anaemia 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

45. ACD: Anaemia of chronic disorders
Determination
of soluble
transferrin
receptor
irondeficiency
ACD: Anaemia of chronic disorders
Combined causes
Normal

46. Myelodysplastic syndrom- refractory anaemia with ring
sideroblasts

47. GUIDELINES FOR RED CELL TRANSFUSIONS IN ADULT
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.

49. Krónikus betegséget kísérő anaemia
reticulocyta
Microcytás an.
Hemolizis
Microcytás an.E
Fe n/
TVK n/ 
ferritin 
Lép nem tap
Vashiányos an.
Krónikus betegséget kísérő anaemia
Ólommérgezés