Anemia dan Peran Besi

dalam Kehamilan
wibowonoroyono@yahoo.com

Anemia
Anemia is not a diagnosis in
itself, but merely an objective
sign of disease.
Hb < 10.5
g/dL
Ery < 3.5
M/L

Hb
Main component of RBC
Transport O2 and CO2
1 g Hb hold 1.34 ml O2
RBC adult contains app. 600 g of Hb.
capable carrying 800 ml O2
Anemia: is decreased below N of Hb,
Anemia: is decreased below N of Hb,
Erythrocite count, or Hematocrit
Erythrocite count, or Hematocrit
Henrrys. 21st ed. 2007

MORPHOLOGIC CLASSIFICATION OF COMMON ANEMIAS

Hypochromic, Microcytic

(These are the 3 most common causes of anemia)

1. Iron deficiency
Low Serum Iron
High TIBC
Low ferritin
Increased platelets
Prominent anisocytosis
Poikilocutosis with small elliptocytes

2. Thalassemia minor
Target Cells (Sm)
Teardrops
Fine basophillic stippling
elliptocytes

Narrow RDW

3. Anemia of chronic disease (1/3)

Low serum Iron
Low TIBC
High ferritin

Normocytic, Normochromic
1. Anemia chronic disease (2/3)
Low serum Iron
Low TIBC
High ferritin

2. Iron deficiency (mild)

Low Serum Iron
High TIBC
Low ferritin

3. Renal disease
Low blood count
Echinocytes (renal failure)
Low EPO levels

4. Bone marrow failure (aplasia)

Depends on type of aplasia

5. Myelophthisis
Teardrops
(if many think myelofibrosis)
Elliptocytosis

Macrocytic
1. Megaloblastic: B12, folate, others Oval macrocytes, severe anisocytosis, Teardrops, Hyperseg. PMNs, pancytopenia
Very high LDH, Increased bilirubin (Jaundice)

2. Non-megaloblastic: sideroblastic: High serum iron, high ferritin, Marrow: ringed sideroblasts
Blood: dimorphic w/ hypo- micro- population, coarse basophillic stippling (pappenheimer bodies)
Aquired: usually more macrocytes
Hereditary: usually more microcytes

alcohol
liver dz
hypothyroid

CLASSIFICATION OF COMMON HEMOLYTIC ANEMIAS

Hereditary
Membrane defect
HS:
Spherocytosis (lifelong, familial)
reticulocytosis (+ osmotic frag. test)
neg direct coombs (rule out autoimmune)
FHx of splenectomy or cholelithiasis at a young age

HE:
elliptocytes

a. Hereditary Pyropoikilocytosis
eliptocytosis, shperocytes, microcytes, cells w/ weird
membranes that look like after a burn

b. Southeast Asia Ovalcytosis

eliptocytes with transverse ridge

Enzyme defect
G6PD
heinz bodies (Hb ppts stained by crystal violet)
blistered or shperocytic RBCs in hemolytic episode

Pyruvate Kinase
echinocytes
increased retics after splenectomy
desiccytes (dehydrated cells)

Hemoglobin defect (sickle cell)

Sickled cells
Reticulocytosis
Increased WBCs
Increased platlets
Howell-Jolly bodies
Target Cells (Sm)
Spherocytosis

SC:
Targeting
Dense cells
Boat (hot dog bun) cells

Acquired
Immune spherocytes (acute)
warm antibody: + direct coombs, +/-indirect,
cold antibodies: + cold agglutinins, +/-direct Coombs,
Hemolytic transfusion rxn: Coombs rxn
Red cell fragmentation
Fragmented RBCs, schistocytes, helmet cells, spherocytes
TTP: no platlets
Valvular: no thrombocytopenia
Other MAHA: thrombocytopenia

Infections (malaria; clostridia)

Metabolic ( PO4; Cu)
Chemicals, venoms, toxins, drugs (oxidants)
Physical forces (burns, fresh water
drowning)
Acquired membrane defect (PNH)
RCB morph. normal
+ Sucrose hemolysis test
+ Hamm test/acidified serum test (lyses in acid
serum)
Flow cytometry for CD 55 and 59
Very high
LDH, Hemosiderinurea, hemoglobinurea
Other
conditions:

Hypersplenia:
No morph. Abnormalities
Decrease in one or more cell elements
Asplenia: Target Cells (Lg), Howell-Jolly Bodies,
acanthocytes, myelocytes, giant platelets
Liver disease: Target Cells (Lg), Spur cells
Lead Poisening: course basophillic stippling (MCC)
EtOH binge: stomatocytes
LCAT deficiency: Target Cells (Lg)

The Three Basic

Measures
Measurement Normal

Range

A. RBC count

5 million

B. Hemoglobin

15 g% 12 to 17

C. Hematocrit 45

4 to 6

38 to 50

A x 3 = B x 3 = C - This is the rule of

thumb
Check whether this holds good in given results
If not -indicates micro or macrocytosis or
hypochro.

The Three Derived

Indicies
Measurement Normal
A. RBC count
B. Hemoglobin
C. Hematocrit

5 million
15 g%
45

Range
4 to 6
12 to 17
38 to 50

MCV
C A x 10
= 90 f
MCH B A x 10
= 30 pg
MCHC
B C x 100 = 33%

Anemia
Reticulocyte count

Low

Iron def. severe

ACD in some
cases
Thalassemia
trait
(reticulocyte
count may
elevated
Sideroblastic
anemia
Lead poisoning
(rare in adult)

Not elevated

Elevated

MCV

Hemolysis or blood loss

Normal

High
Cobalamin
(vitamin B12)
deficiency
Folate deficiency
Treatment with
drugs that
interfere with DNA
synthesis and cell
division
Prior cancer
chemotheraphy
Myelodysplasia
Hypathyroidism
Liver disease

No symptoms or
signs of blood
loss

History or physical
examination findings
of acute or chronic
blood loss

Hemolysis

Blood Loss

Acquire
d

Bone marrow
aplasia/hypoplasia
renal insufficiency
Pure red blood cell
aplasia
Myelofibrosis
Myelophihisis
Myelodysplasia (most
causes)
Anemia or chronic
disease (most cases)
Mixed microcytic and
macrocytic anemias
Iron deficiency (mild to
moderate)
Hemoglobinopathies
with reight shified
oxygen dissociation
curves (physiologic
anemia)

Immune hemolysis
Autoimmune
Drug-induced
Allommune
Traumatic
(microangiopathic and
machroangiopathic)
hemolysis TTP/HUS/HELLP
DIC
Vasculifis (rare causes)
Eclampsia
Malignant hypertension
Proshetic heart valves
Arterial grafis
Hypersplenism
Membrane abnormalities
Aconthocytes (spur cells)
Echinocytes (burr cells)
Paraxysmal noctumal
Hemoglobunuria
Thermal injury (burns)
Infection
Malaria
Babesiasis
Bartanellosis
Clostridia toxin
Osmotic damage
Fresh water drowning

Inherited/congenita
l

RBC membranopathies
Sperocytosis
Eliptocytosis
Pyropoililocytosis
Stomatocytosis
RBC enzymopathies
G6PD deficiency
Pyruvate kinase deficiency
Other rarer deficiencies of
enzymes of Errloden
Meyerhef pathway, hexase
monophosphate shunt, or
nucleotide metabolism
HEmoglobinopathies
Thalassemias
Hemoglobines S, C, D, E
Unstable hemoglobins
Other rarer
Hemoglobinopathies

RPI (reticulocyte
production index)

Ineffective erythropoiesis: RPI <

2.0
Effective erythropoiesis: RPI > 2.0

Calculation to give indication of marrow red cell production

Two mathematical corrections to reticulocyte count
i. During intense erythropoietic stress maturation time in
bone marrow may be shortened from usual 3.5 days
to as little as 1 day
ii. Also corrected for hematocrit to allow a correction for
the patients degree of anemia
Retic (%) x Hct/45

Corrects for normal hematocrit

RPI =
maturation time, days
Hct Mat.
40-50
30-40
20-30
10-20

Time
1.0
1.5
2.0
2.5

Clinical significance of immature

reticulocyte fraction determined by
automated reticulocyte counting.
IRF of 0.23 or less in patients with anemia refects
bone marrow that is non responsive or under
responsive to the anemia. Patients with an increased
IRF (IRF > or = 0.23) may require further
examination to clarify the cause of the anemia.

Am J Clin Pathol. 1997 Jul;108(1):69-73.

haematologica 2005; 90:1133-1134

Pentingkah besi?
AQ: al Hadid

Fungsi Besi

Penyusun hemoglobin

Penyusun cytochrome
myoglobin

Berikatan dengan O2 SDM

Pengatur suhu badan

Aktivitas Otot

Metabolisme Catacholamine

Immune system T cell

antibodi

Perkembangan dan fungsi otak

Katalis fungsi thyroid

Gejala kekurangan bes

Iritabilitas
Tidak bisa konsentrasi lama
Tidak pedulian
Prestasi kerja menurun
Gangguan perilaku
Pica
struktur dan fungsi jaringan
epitel rusak
terutama rambut, kulit, kuku,
lidah, mulut, hypopharyng
dan
lambung

Mudah terkena infeksi

Restless legs syndrome
alopecia areata

Pic
Kebiasaan makan/menelan
a sesuatu yg tidak
lazim

tanah (geophagia)
Kanji (amylophagia)
ice (pagophagia)

Biasanya merupakan manifestasi kekurangan

besi dan gejala akan hilang bila sudah diterapi

Deficiensi besi (pada usia 6-24 bln)

Kesulitan bicara
Kesulitan koordinasi dan
keseimbangan motorik

Tidak dapat melakukan konsentrasi

Tidak responsif

Kemampuan motorik jelek

Deviasi mental dan

psychomotor

Tidak bisa memusatkan perhatian

Daya ingat jelek

Kemampuan kosa kata buruk: kademik,

membaca, menulis dan aritmatik

Kacau, mudah tersinggung

Poor performance in test

Konsentrasi besi di otak

Tertinggi saat lahir

Menurun saat disapih

Meningkat pada awal

Myelinisasi

maksimum pada ekspresi Tf

mRNA

Iron Concentration In Brain

100%
Myelination

75%

50%
Maximum

25%

Birth

2 Years

10 Years Adult Human

Def. Besi, Infeksi, Pertumbuhan

fisik

T cell dan antibodi berkurang

Cell mediated immunity defective

Kemampuan membunuh bakteri

memburuk
Kapasitas pertahanan lekosit menurun

Cognitive composite scores over time, comparing

infant iron status groups within middle- and
low-socioeconomic status (SES) families

Low SES, chronic iron deficiency

Midle SES, Chronic Iron Deficiency
Low SES, Good Iron Status
Middle SES, good Iron Status

125

Cognitive Scores

115
105
95
85
75

11

13

15

17

19

Age, y
Lozoff, B. et al. Arch Pediatr Adolesc Med
2006;160:1108-1113.

Enzyme activity in muscle from iron-deficient rats

expressed as a percentage of control activity

Tissue variable

Enzyme activity
%

Mitochondrial pyruvate-malate
oxidase

30 3

Mitochondrial succinate oxidase

29 5

Mitochondrial cytochrome
oxidase

66 9

Mitochondria content in muscle

72 8

Muscle cytochrome oxidase

activity

48 7

Values are means SEM. P < 0.01, significantly different from

control.
1

J. Nutr. 131: 568S580S, 2001.

Iron Deficiency in Children With AttentionDeficit/Hyperactivity Disorder

(r =0.31;P
<.02)

Pearson t test, P
<.001

Konofal, E. et al. Arch Pediatr Adolesc Med 2004;158:1113-1115

Grade of Iron Deficiency

Indicator of Iron Deficiency

II

III

BMS
FER
IBC
TfR
SBC
ZPP
PTS
HGB
MCV
MCH

Diagnostic accuracy of various indicators of iron deficiency for detecting different grades of iron
deficiency. The principal characteristic of each grade is as follows: I, storage iron depletion; II, irondeficient erythropoiesis; III, overt iron deficiency anemia. BMS, bone marrow staining for iron; FER,
ferritin; HGB, hemoglobin; IBC, (total) iron binding capacity; MCH, mean corpuscular hemoglobin;
MCV, mean corpuscular volume; PTS, percent transferrin saturation; SBC, sideroblast count; TfR,
transferrin receptor; ZPP, zinc protoporphyrin. Modified from Hastka et al. [34]

Ferritin:

140
0
100
0

RelationShip between Bone Marrow Iron

Stores
and Serum
ferritin 63
69
116

500

100
50

Iron
Deplation

Ferritin g/l

The Best Marker for Iron

Deficiency

10

Absent

Present

Bone Marrow Iron

Stores

Increase
d

Ali. Et al. CMA Journal.1978;118-945

100
Serum ferritin (g/L)

80
60
40
20
0

10

20

30

40

50

60

Age (years)
1 ug ferritin roughly equivalent to 8 - 10 mg
storage Iron
1 ug ferritin equivalent to 120 ug iron/kg
Adult woman 30 ug/L ferritin
Bothwell TH, Chalton RW, Cook JD, Finch CA. Iron Metabolism in man. Blackwll
Scinetific , Oxford. 1979

Human Body Iron (70-kg male)

mg
2600

65.0

Ferritin

450

11.2

Hemosiderin

400

10.0

Nonheme enzymes

400

10.0

Myoglobin

138

3.5

Cytochromes

0.2

Transferrin

0.1

4000

100.0

Fe requirment (mg/day) ---

Hemoglobin

Total (%)

Dietary iron (mg/day) ----

Total body iron

age (years)

Ferritin (g/L)

Gestation (Weeks)
Br J Haematol 37:145-149. (1997)

NORMAL
Iron Status

Storage
iron

Depletion of Functional
Iron Compounds

Depletion of
Storage Iron

IDE
IDA
(Stage II) (Stage III )

(Stage I)

compartment

Threshol
d for IDE

Transport Iron (fow of iron to the

functional

iron

Threshold
for IDE
c om

pou
nds

Functional Iron Compartment

(hemoglobin, myoglobin, cytochromes, etc.)

Hemoglobi
n

Schemati
c
changes
of the
analytes
Typical
laboratory
profile

Ferritin
sTfR
TfR-F Index
Ferritin 22-203 g/L
sTfR 1.15-2.75 mg/L
TfR-F Index 0.63-1.8
Hb(women (117-153 g/dL
Hb (men) 128-168 g/L

Ferritin<22 g/L
TfR-F Index >1.8
sTfR <2.75 mg/L
Hb(women)> 117 g/dL
Hb (men)>128 g/L

sTfR>2.75 mg/L
Ferritin<22 g/L
TfR-F Index >2.2
Hb(women)> 117
g/dL
Hb (men)>128 g/L

sTfR>3.6 mg/L
Ferritin<22 g/L
Hb(women)<117 g/dL
Hb (men)<128 g/L
TfR-F Index >2.8

Our
population
Total (n=65)
men (n=22)
Women (n=43)

n=40 (61.5%)
n=19 (86.4%)
n=21 (48.8%)

n=8 (12.3%)
n=3 (13.6%)
n=5 (11.6%)

n=17 (26.2%)
n=0 (0%)
n=17 (39.5%)

n=0 (0%)
n=0 (0%)
n=0(0%)

Microctic
(MCV = <80 fl)
Sideroblasti
c Anemia

Anemia of
chronic
disease
IDA
Globulin deficeincy

NON-MEGAL OBLASTIC
Chronic Liver Disease
Alcoholism
Refractory Anemia

VITAMIN B12 DEFICIENCY

Intristic Factor Absent
Bowel Disease (Ileum)
D. Latum Infecton

Thalassemia

Normocytic
(MCV = <80-100
fl)
DECREASED OR
NORMAL
RETICULOCYTE
Bone Marrow will be
COUNT
one of the
following :
Acellular
*Aplastic Anemia
Normal Cells
* Neoplasma
* Urernia
Hypercellular
* Myeloma
* Myelofibrosis

ENZYME
DEFICIENCY

G6PD
Pyruvate kinase

INCREASED
RETICULOCYTE COUNT
Look for
evidence of
hemolytic
MEMBRANE
DISORDER
Acanthocytosis
Ovalocytosis
Stomatocytosis
Spherocytosis
Target Cells
Pyropoikilocytosis

of intrinsic
Origin
Hemoglobin
Proximal Nocturnal
HEmoglobinuria
Hemoglobin
Disorders
ABNORMAL
HEME
Phorphyria
ABNORMAL
GLOBINS
Hgb S
Hgb H
Hgb C

Microctic
(MCV = <100 fl)
MEGALOBLASTIC
NON-B12/NONFOLIC ACID ANEMIA
Malignancy
CMML
FOLIC ACID
DEFICIENCY
Alcoholism
Diet Intake
Drug Inhibition

Antibody mediated
(HDN)
INFECTION
Babesia
Malaria

CHEMICAL and
PHYSICAL AGENTS
Aldoment
Cephalosporin
Penicillin
Burn Injury
MECHANICAL
March Hemoglobunuria
Heart Valve Prostheses

Expected Haemoglobin Increase in

Relation to the Iron Dose

Estimated
absorption (%/mg)

Hb increase
(g/dL)day

35

4014

0.07

105

2425

0.14

195

1835

0.19

390

1245

0.22

Dose (mg)/day

Functional iron indexes in adults given calcium

supplements with meals (test group) or no
supplement (control group) for 6 mo (study 2)1
Baseline

3 mo

6 mo

139 4

138 4

136 4

0.412 0.013

0.413 0.013

0.416
0.013

222 18

232 14

226 18

143 3

143 4

139 4

0.423 0.010

0.427 0.010

0.424
0.009

Test group (n = 11)

Hemoglobin (g/L)
Hematocrit
Zinc protoporphyrin
(mg/L)

Control group (n = 13)

Hemoglobin (g/L)
Hematocrit

Zinc
mg
18 supplemental
286Ca
(CaCO3)
17
277
for
196
1x
protoporphyrin
SEM. The test group consumed226
1200
each
day
(mg/L)
mo;
the control group received no supplemental calcium. There were no significant effects
of group, time, or a group 3 time interaction.
Am J Clin Nutr 1998;68:96102

Plasma ferritin concentration in adults given calcium

supplements with
meals (test group) or no supplement (control group) for
Plasma ferritin (mg/L)
6 mo (study 2)1
Time (weeks)
Test group
Control group
0

47 + 7

47 + 7

43 + 6

36 + 6

47 + 6

34 + 7

49 + 6

44 + 7

46 + 6

44 + 9

10

49 + 7

41 + 9

12

47 + 8

40 + 8

14

46 + 6

42 + 7

16

45 + 7

41 + 10

18

49 + 6

39 + 9

20

49 + 7

40 + 8

22

51 + 6

39 + 9

24

50 + 7

38 + 8

26

50 + 7

38 + 7

Am J Clin Nutr 1998;68:9610

Modes of Therapy

Oral therapy
Parenteral administration by IM route
Intravenous route
Blood Transfusion
Recombinant Human Erythropoietin

ORAL IRON

Recommended dose for oral therapy is 80 160 mg elemental iron

per day
Dose limiting GI side effects occur in 30% of patients
Lack of compliance is common. Different studies show compliance
of 36% - 42%
Adverse effects of oral iron are :
- Bloating, diarrhea
- Heart burn
- Stomach pain
- Constipation
- Nausea
- Dark stools
Patients who respond well to oral iron require a long time (months)
to reach target Hb and have to suffer from iron deficiency for
extended period unnecessarily

Oral iron preparations

Iron (II) Salts
-

Iron
Iron
Iron
Iron

sulphate
fumarate
succinate
gluconates

Iron (III) Polymaltose Complex

- Iron polymaltose complex dextriferron (IPC) is
one of the few available oral iron compounds that belongs
to so called slow-release iron preparations. The advantages
are , firstly, its favorable side-effect profile and secondly, it
can be taken with meals. Moreover , IPC has lower toxicity
due to reduced formation of oxygen radicals and thus
decreased plasma lipid peroxidation

Iron compounds in combined preparations

- Such as adding ascorbic acid is useful adjunct
for stabilization of iron ions against oxidation and increases
the absorption of iron but can lead to increased side effects
due to rapid release

Oral Iron Preparations

Generic

Tablet

Contents in mg)

Ferrous sulphate

325

Ferrous Fumerate

325

Ferrous Gluconate

325

(39)

Polysaccride iron

150

(150)

(Iron

(65)
(107)

Text book of Harrison 14th Edition

Ferrous Salts
Advantages

Efficacious
Economical

Disadvantages

More than 30% patients experiences GI disturbances with

full treatment dose of 100 200 mg

Absorption is affected with certain foods & drugs

Attempts to enhance absorption can increase the

incidences of gastrointestinal side effects

Efficacy and tolerability of Iron

Polymaltose Complex vs. Ferrous
sulphate.
IPC treatment is as effective
as ferrous sulphate or ferrous
fumarate regarding the indication of latent anemia of pregnancy
Geisser P et al, Schweiz Apoph Ztg 1987; 125 ( 14):393-398

Iron therapy with IPC is as efficient as with ferrous sulfate and

it is considerably better tolerated than ferrous sulphate Jacobs. et al.,
Hematology 2000;5:77-83

Iron is equally bioavailable for hemoglobin synthesis from IPC

and ferrous salt Jacobs. et al., J. Med. 1984 ; 15;367-377
Ferrous sulfate increase plasma MDA (Malondialdehyde), a
marker of lipid peroxidation, supporting he notion that ferrous
iron may aggravate oxidative tissue damage. No change in
redox status was fond after treatment with iron-polymaltose
complex (K.Erichsen et al. Aliment Pharmacol Ther 2005; 22:831-38)

Sensitivitas & Specifisitas

Serum Ferritin pada Anemia Defisiensi Besi
Serum ferritin
(ug per L)

Sensitivity (%)

Specificity (%)

Likelihood ratio*

< 200

94

71

3.2

< 45

85

92

11.1

< 15

59

99

54.5