Transcript 1. dia - I. Belgyógyászati Klinika

Anaemias I
Iron deficiency anaemia, ACD
Dr. Judit Demeter
Semmelweis Egyetem ÁOK., I.sz. Belgyógyászati Klinika
History taking in patients with haematological disease
1.
Non-specific symptoms
fatigue, fevers, weight loss
Symptoms relating to
anaemia
Symptoms relating to
neutropenia
Evidence of compromised
immunity
Details of haemostatic
problems
Anatomical symptoms
reduced exercise capacity,
angina, ankle oedema
recurrent oral ulceration,
skin infections, sepsis
recurrent oropharyngeal
infection
easy bruising, bleeding
episodes, rashes
abdominal discomfort
(spleen), CNS symptoms
(spinal compr)
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
Normal RBC és PLT values (adult)
Women
Men
Determination
Red cell count, x 106 / l
(or x 1012 /l)
Hemoglobin, g/dl
Mean
95% range
Mean
95% range
5,1
4,5-5,9
4,6
4,1-5,1
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 109 /l
50
25-100
55
25-120
Platelet count, x 109 /l
245
160-340
248
150-380
Normal peripheral blood smear,
thin, homogenous part
Normal RBC morphology
Red blood cell maturation
1.
2.
3.
4.
5.
6.
1.: proerythroblast;
4.: oxyphil normoblast;
2.: basophil normoblast;
5.: polychromatophil RBC;
3.: polychromatophil normoblast;
6.: mature RBC
Anaemias: Kinetic approach
Reduced RBC production
deficiency anaemias (hematinic deficiency) (iron, B12, folic acid)
A
z
bone marrow disorders ( aplastic anaemia,
a
isolated RBC-aplasia,
n
e
myelodsyplasia,
m
neoplastic infiltration)
i
á
Increased
RBC destruction (hemolysis: RBC lifespan < 100 days)
s
congenital hemolitic anaemias
(hereditary shaerocytosis,
b
e
sickle cell disease,
t
thalassaemia maior)
e
g
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?
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?
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
↑ Red cell mass
Fetal requirements
Placental requirements
Basal losses over
pregnancy
Amount of additional Fe
~ 500 mg
~ 300 mg
~ 5 mg
~ 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)
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.
-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.
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
Hypochromasia, anulocytes
Causes of iron deficiency
Reproductive
system
GI tract
menorrhagia
Dietary
oesophagitis, oesophageal varices,
hiatus hernia, peptic ulcer, IBD,
haemorrhoids carcinoma: stomach,
colorectal
coeliac disease, atrophic gastritis,
gastrectomy
vegans, elderly
Physiological
growth spurts, pregnancy
Others
PNH, frequent blood donation,
Malabsorption
hookworm
Blood loss in gastrointestinal disease
ACUTE
Immediately following acute
haemorrhage - RBC indices
usually normal
ACUTE ON CHRONIC
RBC indices show low normal
CHRONIC
or marginally ↓, film shows
mixture of normochromic &
hypochromic RBCs
(dimorphic)
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 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
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.
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
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
reticuloendothelial 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
KN born: 1961
2007 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: 10-120)
Normal curve
Mikrocytosis
Cell-Dyn 3500
Target 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 of
successful iron treatment
1999.10.01: vvs: 4.16 Hgb:72 Ht: 25 MCV:61
1999.10.30: vvs: 4.56 Hgb:107 Ht: 34 MCV:74
1999.12.10: vvs: 4.87 Hgb:125 Ht: 39 MCV:79
2000.04.19: vvs: 4.83 Hgb:138 Ht: 41 MCV:86
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
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)
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) ÷ 100
(mL/dL) 65x68/100=44,2 dl
Hemoglobin deficit (g/dL) = 14.0 - 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
Anaemia of chronic diseases (ACD)
Anemia of chronic disease - bone marrow iron stain
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
hypersplenism, Felty’s syndrom,
renal failure in SLE
2 to other organ
problems
Determination
of soluble
transferrin
receptor
irondeficiency
ACD:
Anaemia of
chronic
disorders
Combined
causes
Normal
Myelodysplastic syndrom- refractory anaemia with ring
sideroblasts
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.
ANAEMIA
reticulocyta
reticulocyta
reticulocyta
A
Hemolízis
Hemolizis
B
Coombs +
Coombs neg
AIHA
Gyógyszerek
lép tap
Microcytás
E an.
Microcytás an.E
Vérvesztés
Fe n/
TVK
ferritin
Fe
Fe n/
TVK
TVK
n/ 
ferritin
ferritin 
normocytás an
macrocytás
an
Fe
TVK
ferritin
Thalassaemia
lép nem tap
LépDnem tap
hypersplenia
MAHA
(DIC,
TTP/HUS)
(PNH,
malária)
Krónikus
Krónikus
betegséget
betegséget
kísérő
kísérő
anaemia
anaemia
Csontvelővétel
Vashiányos an
Vashiányos an.
Ólommérgezés
I
Ólommérgezés
(sideroblastos
an)