dr. judit demeter semmelweis egyetem Áok., i.sz. belgyógyászati klinika anaemias i iron...
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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
1999.10.30:1999.10.30: vvsvvs: 4.56 : 4.56 HgbHgb:107 :107 HtHt: 34 MCV:74: 34 MCV:74
1999.12.10:1999.12.10: vvsvvs: 4.87 : 4.87 HgbHgb:125 :125 HtHt: 39 MCV:79: 39 MCV:79
2000.04.19:2000.04.19: vvsvvs: 4.83 : 4.83 HgbHgb:138 :138 HtHt: 41 MCV:86: 41 MCV:86
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