IDA, ACI, SDA Flashcards
● Cells are smaller than usual
MICROCYTIC
MICROCYTIC
● Size:
<6 um
● Caused by 1 or more cell division due to the depression of mean corpuscular hemoglobin concentration (MCHC)
MICROCYTIC
● Anemia = division of RBC making the cell
MICROCYTIC
● Microcytic also inhibit
HYPOCHROMIA
● ↓ MCHC = ↓ overall hemoglobin concentration (no red or pink coloration of blood) =
HYPOCHROMIC
● Due to the problem of hemoglobin (there would be an impairment with the hemoglobin in the hemoglobin synthesis or an abnormality to heme or globin)
HYPOCHROMIC
● Components of a Hemoglobin:
(any abnormality of the two can cause a defect in the hemoglobin)
Heme and Globin
● Under a larger classification of anemia
- IRON DEFICIENCY ANEMIA (IDA)
- IRON DEFICIENCY ANEMIA (IDA)
● Etiology: A cause of anemia where in there is an (?)
abnormal iron metabolism
ANEMIA OF ABNORMAL IRON METABOLISM:
- Iron Deficiency Anemia
- Anemia of Chronic Disease (Sideroblastic Anemia)
Normal Hgb production and synthesis is dependent on (3 major requirement of Hb to be functional):
● Polypeptide chain (Adult Hb: Alpha & Beta chains)
● Protoporphyrin IX
● Iron (needs to be integrated to the Hgb in order to function well)
● Polypeptide chain (?)
● Protoporphyrin IX
Adult Hb: Alpha & Beta chains
(needs to be integrated to the Hgb in order to function well)
● Iron
The body contains approx:
4,000 mg Fe (60%: in form of Hgb)
IRON METABOLISM
For storage
For use
Largest source of iron is from the ingestion of food
For storage
For storage
Diet (?) → Mucosal cell (oxidized by the cells of the (?) to become Fe3+ or ferric form) → passed onto the bloodstream (transported to the bloodstream and(?) where it can be stored; Fe3+ will be bound to a storage protein known as (?) → forms FERRITIN
Fe2+ or ferrous form
duodenum and jejunum
liver
Apoferritin
: a storage protein that carries iron up to the bloodstream in which once the Fe3+ will go to bloodstream it will become a Ferritin
Apoferritin
: storage form of iron in the liver cells
Ferritin
stores metabolically active iron which we can get anytime if our body demands increased iron use
Ferritin
Iron → bloodstream → mononuclear phagocytic cells in the BM and other tissues
For use
: storage protein that transports Fe2+, Fe3+, and Apoferritin in the blood stream
Transferrin
carries iron from the bloodstream to the bm
Transferrin
: incorporates the iron to the hemoglobin.
Mononuclear phagocytic cells
: process in which the mononuclear phagocytic cells will incorporate the ferrous to rbc (hemoglobin)
Ropheocytosis
FACTORS AFFECTING IRON ABSORPTION
Promote Absorption
Reduce Absorption
Ferrous form
Promote Absorption
Ferric Form
Reduce Absorption
Inorganic Form
Promote Absorption
Organic Form
Reduce Absorption
Acids (HCl, Vit. C)
Promote Absorption
Alkalis (antacids, pancreatic juices)
Reduce Absorption
Solubilizing agents (Sugar, Amino Acids)
Promote Absorption
Precipitating agents: phosphates
Reduce Absorption
Iron Deficiency
Promote Absorption
Iron Excess
Reduce Absorption
Increased erythropoiesis
Promote Absorption
Decreased erythropoiesis, infection
Reduce Absorption
Iron in [?] form will be stored in ferritin
ferric
: stomach; increases the chance of the iron to be absorb
HCl
: medications
● antacids
: alkaline, so if iron is exposed in this kind of environment, it will have less absorption or decrease absorption rate in the intestines
● pancreatic juices
it will have less absorption or decrease absorption rate in the intestines
● pancreatic juices
● Iron is absorbed in an increased level
Iron Deficiency
● faster absorption because cells needs it
Iron Deficiency
● Regulatory hormones will try to block the absorption of iron to the intestines
Iron Excess
● absorption should not exceed
Iron Excess
● There is a need for you to absorb the iron so that it can be stored also in some parts of the cell
Increased erythropoiesis
● Iron absorption is also decreased
Decreased erythropoiesis, infection
IDA is caused mainly by 4 reasons:
- INTAKE OF IRON IS INADEQUATE FROM THE LEVEL OF DEMAND OF THE BODY.
- THE NEED FOR IRON EXPANDS AND COMPENSATION IS NOT MET
- IMPAIRED ABSORPTION OF IRON
- CHRONIC LOSS OF HEMOGLOBIN FROM THE BODY
Fe lost is not replaced
1mg/day
● Normally,[?] of Iron is lost and if the lost iron is not replaced by intaking or from the diet, then that could lead to the erythrocyte/ RBC being slowly starved of iron.
1mg/day
● Usually, Fe is lost in the
mitochondria of desquamated cells.
when our cells die in the skin, they slough off =
desquamate
the [?] has iron content
mitochondria
inside the cells that was desquamated is the
mitochondria
● Although, the body conserves iron from the [?], but it is not enough because the level that was lost is not the same to what the body can conserve
senescent RBC
● A replacement of [?] of iron from the diet every day is needed to maintain the RBC production.
1 mg
● If you have an inadequate intake eventually, [?] will be decreased since it is the source of RBCs iron (not present in the diet)
iron stores
● If the [?]:
↓ hemoglobin production (hemoglobin needs iron) = not present in the diet = anemia
iron stores are decreased
a. Iron needs increase →
no compensation
● no compensation for
iron needs
Iron needs increase → no compensation
● usually occurs during
infancy, childhood, adolescence, pregnancy and nursing (breastfeeding)
● during infancy, childhood, adolescence, the body needs an iron for
rapid growth
● need a lot of iron so that the body can grow in synchrony with RBC production.
babies
● [?] with no compensation = anemia.
↑ iron needs
- IMPAIRED ABSORPTION OF IRON
a. Malabsorption
b. Genetic mutations
c. Decreased stomach acidity
: most of the nutrition including iron is being malabsorbed (not absorbed properly)
Celiac disease
● A mutation in the regulatory protein called
matriptase 2 protein
: a regulatory protein which normally would keep hepcidin inactivated or not triggered but in a normal condition, so that it won’t stop ferroprotein to help in iron absorption
● Matriptase 2 Protein
: a regulatory/blocking hormone that blocks the absorption of iron in the intestinal lumen by binding to ferroportin
Hepcidin
: helps in the absorption of iron to the intestinal lumen in the absence of hepcidin
Ferroportin
In the mutation of matriptase 2, it activates
hepcidin
: increased in production = ferroportin will be inactivated = iron will not be absorbed in the lumen of the intestine = low iron or absorption
Activation of hepcidin
: continues production of hepcidin
● Activation of matriptase
: one of the factors that promote absorption
● acidity
if the stomach has a [?], that means that iron could not be absorbed very well
decreased acidity
example: [?] has something to do with GIT (stomach: acidic part of our body)
gastrectomy or bariatric surgery
: ferric is not reduced back to ferrous (Fe2+ or ferrous is the absorbable form of iron)
↓ stomach acidity
an alkaline; it will bind iron and decrease the rate of iron absorption
● Antacids
Loss of small amount of [?] from the body develops over a prolonged period of time.
heme iron
● Overtime, [?] decreases until it impairs with heme/iron production
iron content
- CHRONIC LOSS OF HEMOGLOBIN FROM THE BODY:
: the iron in the hemoglobin is passed out in the urine
Hemolysis (Paroxysmal Nocturnal Hemoglobinuria)
Due to hemolysis
Hemolysis (Paroxysmal Nocturnal Hemoglobinuria)
we can detect Hgb in urine
Hemolysis (Paroxysmal Nocturnal Hemoglobinuria)
: due to ulcerations (affects the absorption of iron)
Chronic GIT bleeding
: due to increased alcohol or aspirin ingestion (affects the absorption of iron in the GIT tract)
Gastritis
: specially hookworm, whipworm and schistosoma spp. (involved in causing iron deficiency anemia)
Parasitosis
: means that there is inflamed mucosal lining of the intestines (affects the absorption of iron)
Diverticulitis
: seen in females
Prolonged menorraghia (menstruation)/fibroid tumors/uterine malignancy
loss of RBC overtime = ↓ RBC count and iron stores are pressured to release iron so that the body can produce more Hgb and more RBC
Prolonged menorraghia (menstruation)/fibroid tumors/uterine malignancy
Renal diseases: such as
kidney stones, tumor or chronic UTI
IDA PATHOGENESIS
● RBC development is normal
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
● No evidence of iron deficiency in this phase
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
RBC production continues to rely on iron available in the transport compartment
STAGE 2
Exhaustion of the storage pool of iron (severely decreased iron stores/ferritin)
STAGE 2
Anemia not evident
STAGE 1& 2
Hgb and hct are low
STAGE 3
Iron deficiency: readily display frank anemia
STAGE 3
Compensation is remarkably slow (no iron available)
STAGE 3
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON Aka
Latent/subclinical IDA
the body’s iron reserve is sufficient to maintain the transport and functional compartments (the iron reserve is still sufficient)
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
● PB: will not exhibit anemia yet
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
STAGE 2
Iron stores or serum ferritin begins to decrease (first) but the Hgb will still appear Normal
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
RBC survival is 120 days: before iron is depleted, normal RBCs are already prodyced (RBC has enough iron and normal Hgb)
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
In 120 days that the iron stores are continuously depleting, it’s still not very obvious because RBC can still compensate with it (iron stores are not yet needed due to the presence iron)
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
Anemia is not evident (no evidence of IDA)
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
STAGE 2
● BM (iron staining): (-) iron stores
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
: very invasive; not performed unless there are no correlations with the symptoms and signs that a patient present
BM aspiration
In this stage there is really no evidence of leukemia: test should not be performed (usually skipped)
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
ongoing decrease in the iron store
STAGE 1: PROGRESSIVE LOSS OF STORAGE IRON
: transport compartment.
transferrin
When the RBC has lost its iron = ↓serum iron & free iron and transferrin
STAGE 2
transferrin in the serum contains iron (used up; no use for it to circulate if no iron is attached)
STAGE 2
because the bulk of circulating RBCs are produced during adequate iron availability so the overall hemoglobin measurement is still present (iron is used up in transferrin, but still attached to Hb)
STAGE 2
Hb: normal (no tests are required)
STAGE 1 & 2
: signifies an onset of iron deficient erythropoiesis (but we don’t have a way to know it unless we go to bone marrow to see the reticulocytes and hemoglobin)
↓ retic hemoglobin in STAGE 2
: smaller RBCs will be released from the bone marrow
↑ RDW in STAGE 2
muscles and other iron-dependent tissues will be affected
STAGE 2
↓ serum iron and serum ferritin
STAGE 2
: transferrin is empty (↑ capacity to carry iron)
↑ TIBC in STAGE 2
: is an indirect measure of transferrin’s binding capacity
Total iron binding-capacity (TIBC) in STAGE 2
: clump at the surface of the RBC to capture more iron
↑ Transferrin receptors in STAGE 2
↓ Transferrin
STAGE 2
: is a portion of hemoglobin where iron is integrated so the iron holds onto it; this is where iron is attached; iron will accumulate because there’s no protein attached into it (clumping on empty RBC)
Free erythrocyte protoporphyrin (FEP) in STAGE 2
: decreases because it’s a compensatory mechanism of the body (inactivates due to lack of iron)
Hepcidin in stage 2
a natural response of the body against iron depletion
Hepcidin in stage 2
● BM (Prussian blue BM iron staining): (-) Hemosiderin or any iron containing cells/protein are
STAGE 2
: storage protein of iron that is usually stained in the bone marrow; not present due to lack of iron = iron deficient erythropoiesis
hemosiderin in STAGE 2
Hb: normal
STAGE 1 & 2
Anemia is evident (w/ s&s; cbc shows abnormalities of rbc cells, Hb, and Hct)
STAGE 3
↑ FEP, ↑ Transferrin receptors , ↑ EPO (very prominent)
STAGE 3
: a hormone that compensates to anemia by increasing the amount of rbc (anemia still persist due to lack of iron)
↑ EPO
No specific signs and symptoms
IDA
GENERAL SYMPTOMS AND SIGNS OF ANEMIA
● Fatigue
● Shortness of breath
● Palor
● Palmar crease (for dark-skinned individuals)
(for dark-skinned individuals)
● Palmar crease
IDA HIGH RISK INDIVIDUALS
Menstruating women/childbearing ages
Adolescent girls
Growing children
LOW RISK
Men
Post menopausal women
: inadequate iron-containing food in the diet w/ loss of rbc, iron and no compensation
Menstruating women
: needs to have adequate iron level otherwise they are predispose to having IDA during pregnancy (needs a lot of iron content because it is needed for fetus’ growth)
Childbearing ages (24 or 25 y/o)
prone to IDA especially during pregnancy
Childbearing ages (24 or 25 y/o)
: breastfeeding w/ low iron (IDA) affects the baby
Nursing newborns
due to rapid growth (rapid erythropoiesis = more iron = more hemoglobin & more normal rbcs)
Adolescent girls ; Growing children
IDA is rare (there is only 1 mg/day that is being lost)
Men ; Post menopausal women
there is no rate of association to IDA
Men ; Post menopausal women
DEVELOPMENT OF IDA IS POSSIBLE IN
REGULAR ASPIRIN AND ALCOHOL INGESTION
HOOKWORMS (N. amerricanus, A. duodonale), WHIPWORM (T. trichuria), AND SCHISTOSOMA SPP. (S. mansoni, S. haematobium)
EXERCISE (SOLDIERS W/ PROLONGED MANEUVERS/RUNNERS)
: causes decrease acidity in the stomach = decrease/malabsorption of iron
Gastritis and Chronic bleeding
: attach their sucking/ventral teeth of the lumen of the intestine and suck blood; blood loss is 0.03 ml per day
N. americanus
: blood loss is 0.15-0.25 ml per day
A. duodonale
(normal blood loss: )
1mg/day
: least effect on IDA
T. trichuria (whipworm)
blood loss is 0.05 ml per day
T. trichuria (whipworm)
: iron is lost through urine
S. mansoni and S. haematobium
: is an exercise induced-hemoglubinuria
March hemoglubinuria
the rbc`s are hemolysed due to foot pounding trauma (the iron will be salvaged and will be excreted in the urine
March hemoglubinuria
urine is (+) hemoglubinuria)
March hemoglubinuria
CLINICAL FEATURES Aside from general manifestations:
PARASTHESIA
GLOSSITIS
AGULAR CHEILOSIS
DIFFICULTY SWALLOWING DUE TO WEBS OF TISSUE IN B/W ESOPHAGUS AND HYPOPHARYNX
CHRONIC GASTRITIS; SPELOMEGALY
: eating disorder for non-edible things
PICA
: due to IDA there is spooning of fingernails (spoonlike/sagging/curvy fingernails attached to the skin)
Koilonychias
Atrophy (↓size) of the tongue due to excessive soreness
GLOSSITIS
IDA proliferates in the epithelial cells that makes up the tongue = soreness = tongue atrophies
GLOSSITIS
Cracking at the mouth corners
AGULAR CHEILOSIS
RBC is Normochromic/Normocytic
Early IDA
Microcytic/Hypochromic
Later stages IDA
Anisocytosis/Poikilocytosis (unique shape: pencil shape elliptocytes)
Severe IDA
Decreased reticulocytes
Retiulocytopenia
Slightly increased platelet
Slight thrombocytosis
Decreased
Serum Iron
Reduced to 0 (stage 1: decreased, stage 2: cont. decreasing; stage 3: depleted)
Serum ferritin
SREENING TESTS FOR IRON DEFICIENCY ANEMIA
- CLASSIC PICTURE
IRON PROFILE TESTS
- SERUM FERRITIN
- SERUM IRON
- TOTAL IRON BINDING CAPACITY (TIBC)
- % SATURATION OF TIBC
- FREE ERYTHROCYTE PROTOPORPHYRIN (FEP)
- BONE MARROW ASSESSMENT
IDA 1. CLASSIC PICTURE
● Anisocytosis (varying size and volume of RBCs)
o Increased RDW: >15 %
● Microcytosis
● Hypochromia
● RBC indices o Decreased MCV, MCH, MCHC
● RBC count: decreased
● Hematocrit: decreased
For differential diagnosis of Iron Deficiency Anemia (important test to differentiate anemia)
IRON PROFILE TESTS
● Reflects body’s iron stores
- SERUM FERRITIN
- SERUM FERRITIN ● Normal value:
12-300 ug/dL
● Sensitive indicator of iron depletion
- SERUM IRON
- SERUM IRON ● Normal value:
50-160 ug/dL
● Assay for serum transferrin
- TOTAL IRON BINDING CAPACITY (TIBC)
- TOTAL IRON BINDING CAPACITY (TIBC) ● Normal value:
250-400 ug/dL
● Ratio of serum iron: TIBC (transferrin)
- % SATURATION OF TIBC
- % SATURATION OF TIBC ● Normal value:
20-55%
● Builds up in RBC
- FREE ERYTHROCYTE PROTOPORPHYRIN (FEP)
- FREE ERYTHROCYTE PROTOPORPHYRIN (FEP) ● Normal value:
10-99 ug/dL
Intracellular storage for metabolically active iron which can be readily integrated to hemoglobin
- SERUM FERRITIN
Decreased in Stage I (first one to deplete)
- SERUM FERRITIN
A little bit difficult to measure due to the marked diurnal measurement (normally increased in the morning)
- SERUM IRON
There is 30% difference: it is highest in the morning, lowest in the afternoon or night time
E.g. Morning: 80 ug/dL, Afternoon/Night: 50 ug/dL
- SERUM IRON
Very sensitive indicator (assessment in the right time)
- SERUM IRON
Decreased in IDA Stage I and esp. Stage II
- SERUM IRON
Increased in IDA Stage II (capacity of transferrin increases because there is no longer iron stored)
- TOTAL IRON BINDING CAPACITY (TIBC)
Decreased in Stage II (<15%; the important tests are TIBC and % Saturation of TIBC)
- % SATURATION OF TIBC
: a part in hemoglobin where iron is integrated
FEP
Increased in IDA Stage 3
- FREE ERYTHROCYTE PROTOPORPHYRIN (FEP)
● Other specialized test
- BONE MARROW ASSESSMENT
● Not performed unless required
- BONE MARROW ASSESSMENT
● Decreased M:E ratio
- BONE MARROW ASSESSMENT
has the most dramatic morphological change in the cytoplasm and nucleus
● Rubricytes/Polychromatic Normoblast (Stage IV)
● N:C Asynchrony (structure of bm)
- BONE MARROW ASSESSMENT
● Decreased production of hemoglobin (due to absence of iron)
- BONE MARROW ASSESSMENT
o cytoplasm matures slower compared to the nucleus (cytoplasm maturation is lagging)
- BONE MARROW ASSESSMENT
o cytoplasm is bluish due to decreased hemoglobin caused by IDA (no Hb = no pink coloration)
- BONE MARROW ASSESSMENT
o second and third stage:
hemoglobin production
o fourth stage (rubricyte):
dawn hemoglobinization (normal: cytoplasm is pinkish)
Aside from the iron deficiency anemia, anemia is also commonly associated with systemic diseases including CHRONIC INFLAMMATORY CONDITIONS
- ANEMIA OF CHRONIC INFLAMMATION
- ANEMIA OF CHRONIC INFLAMMATION Older name:
Anemia of Chronic Disease
the most common anemia among hospitalized patients (due to the long term running disease)
- ANEMIA OF CHRONIC INFLAMMATION
Overtime you can developed this kind of anemia
- ANEMIA OF CHRONIC INFLAMMATION
CHRONIC INFLAMMATORY CONDITIONS
o Rheumatoid arthritis
o Chronic infections (i.e., Tuberculosis)
o Human Immunodeficiency Virus Infection
o Malignancy
● Originally called as “Anemia of Chronic Disease”
ANEMIA OF CHRONIC INFLAMMATION
thought to be caused by blood loss (only limited to IDA)
ANEMIA OF CHRONIC INFLAMMATION
inflammation is the unified factor among the aforementioned general type of conditions
ANEMIA OF CHRONIC INFLAMMATION
ANEMIA OF CHRONIC INFLAMMATION CHARACTERIZED BY
“Sideropenia”
↑ iron stores (serum ferritin) but ↓ serum iron (used for Hgb synthesis)
ACI
: both iron stores and serum iron are both decreased
IDA
● Acute phase reactant
- HEPCIDIN
Aside for being the hormone that are being produced by the hepatocyte which regulates the absorption/realease of iron
- HEPCIDIN
● Level usually responds to IL-6 during inflammation
- HEPCIDIN
● Iron level in the serum is affected due to inhibited absorption, and release
- HEPCIDIN
: a cytokine that responds to an inflammation
Interleukin-6
= ↑ Hepcidin (↓ iron level)
↑ IL-6
Hepcidin: Iron level (normal)
↓ Hepcidin: ↓ Iron level
↑ Iron: ↑ Hepcidin
■ The body responds to [?] by decreasing hepcidin
↓ Iron level
: ferroportin will not be affected
■ ↓ Hepcidin
: extracts the iron from the hepatocytes to store it from the plasma so that it can be utilized by the hemoglobin
● Ferroportin
gets the iron from the hepatocyte (the cell that stores iron)
● Ferroportin
■ To prevent overloading of iron
↑ Hepcidin
: ferroportin will be inactivated = the absorption and release of iron in the plasma will be inhibited as well (normal)
↑ Hepcidin
■ Inflammation = [?] Hepcidin (APR)
↑
storage from ferritin is not released
↑ Hepcidin
■ Hepcidin level: corresponds to low iron level and inflammation (stimulation of IL-6) = ↓ Iron level in serum
↑ Hepcidin
● Available iron in the serum before inflammation in the body will be sequestered by the macrophage and hepatocytes → disable its use for foreign organisms (their metabolism)
- HEPCIDIN
● Chronic inflammation → chronic increase → diminished erythropoiesis
- HEPCIDIN
o Bacteria, parasites or other foreign materials that could harm the body needs iron for their metabolism
- HEPCIDIN
o Macrophage and hepatocytes try to get all the available iron = ↓ serum iron.
- HEPCIDIN
o Therefore, the Hgb will now be deprived of Hgb synthesis
- HEPCIDIN
o Overtime, both hemoglobin and erythropoiesis are affected because hemoglobin needs iron and if there is no more iron, the rate of erythropoiesis will be decreased
- HEPCIDIN
● Second Acute Phase Reactant
- LACTOFERRIN
● Iron binding protein in the granules of neutrophils
- LACTOFERRIN
● Prevents phagocytized bacteria from using intracellular iron for their use
- LACTOFERRIN
● During inflammation, it is released into the plasma-> scavenges the iron at the expense of the transferrin
- LACTOFERRIN
● Causing RBCs to be deprived of plasma iron source
- LACTOFERRIN
- LACTOFERRIN
o (?) salvaged all the available iron in the serum. The bacteria will then target the iron in the(?). [?] will try to protect the iron content intracellularly, so it will prevent the bacteria to use the(?). Macrophages engulf the (?). (?) also acts on the bacteria.
Macrophage and hepatocytes
RBCs/ WBCs
Lactoferrin
intracellular iron
phagocytized bacteria
Neutrophil
o If the bacterial component enters the cell, due to phagocytosis, it can use the iron inside but if there is [?] inside them, it can’t be used.
- LACTOFERRIN
o Inflammation = ↑ neutrophil, WBC value, and leukocytosis
- LACTOFERRIN
o has a higher affinity for iron than transferrin. Thus, when it will be released into the plasma, it will scavenge all the iron available in the plasma at the expense of the transferrin.
- LACTOFERRIN
o However, during inflammation because of the release of lactoferrin, it will get all the iron because it has a higher affinity to iron. Thus, it cannot utilize/transfer the iron to the BM because after collecting the iron in the plasma, the [?] will bind to macrophages and hepatocytes
- LACTOFERRIN
o Macrophage and hepatocytes are also trying to get all the available iron in the circulation so that the foreign materials could not use it.
- LACTOFERRIN
o The RBC does not have a receptor for [?] that is why they don’t have access to the iron that was scavenged by [?]
- LACTOFERRIN
● Increased level of [?] → binds some iron
- FERRITIN
: gets the iron, bring it to the BM, so that it can be incorporated to the hemoglobin of the developing RBCs.
o Transferrin
● Although high in level → release of iron to developing RBC’s → slowed
- FERRITIN
● Although high in level → release of iron to developing RBC’s → slowed
- FERRITIN
● Similar to IDA → iron restricted erythropoiesis
- FERRITIN
Aside from the problem with hepcidin and with lactoferrin because usually, if hepcidin is increased in level, the release of iron from the [?] will be inhibited or inactivated.
- FERRITIN
The developing RBCs do not have a receptor for (?). Thus, it does not have access to [?]. Thus, iron now is not available for hemoglobin synthesis.
- FERRITIN
As erythrocytes mature, there is no iron. The hemoglobin is defective.
- FERRITIN
: contains a lot of iron derived from hepcidin and lactoferrin
o (+) macrophages
signifies that the iron level, iron stores or stored iron is normal or in high level
o (+) macrophages
: because it does not have access to the stored iron
o (-) erythrocytes
it does not have a receptor for lactoferrin and ferritin
o (-) erythrocytes
lactoferrin steals iron from transferrin
o (-) erythrocytes
stored iron is not released because hepcidin is increased and ferritin could not be accessed by RBC because they don’t have the receptor for ferritin (problem in ACI)
o (-) erythrocytes
- SERUM IRON:
no serum available (stolen by macrophage and lactoferrin)
ACI
LOW
- TOTAL IRON BINDING CAPACITY:
Because it cannot bind to transferrin because there is no serum iron in the circulation
ACI
LOW
- TRANSFERRIN SATURATION:
ACI
LOW TO NORMAL
- TRANSFERRIN RECEPTOR:
It signifies that the transferrin receptors are present in the cells because the transferrin receptor is a determinant that intracellular iron is still intact.
ACI
- SERUM FERRITIN:
Iron is stored but not used up due to hepcidin, lactoferrin and even increased in ferritin, no receptor for developing RBCs.
ACI
NORMAL TO HIGH
- FREE ERYTHROCYTE PROTOPORPHYRIN:
Due to failure to incorporate iron to heme
Like IDA, failure to incorporate iron to FEP (accumulation)
ACI
ELEVATED
- RETIC HGB:
Due to iron restricted erythropoiesis
ACI
DECREASED
● Mild anemia
ACI
● Hgb concentration: 8-10g/ dL without reticulocytosis
Due to iron restricted erythropoiesis
ACI
● N/N: normochromic, normocytic
ACI
● May co-exist with IDA
IDA w/ ACI: contributes to having more iron deficiency
ACI
● Leukocytosis thrombocytosis (or both)
also manifested due to chronic inflammation probably a bacterial or viral infection
ACI
BONE MARROW ● Hypoproliferation
ACI
BONE MARROW ● Not usually required for diagnostic evaluation.
ACI
● Therapeutic administration of Erythropoeitin → to correct ACI
ACI
● Concurrently, iron is administered because serum ferritin remains unavailable.
ACI
There is no iron, the Hgb cannot be developed. The developing RBCs are starved of the iron that’s needed.
ACI
The serum profile itself is enough unless there are special cases you like to confirm.
ACI
: can cause a dilemma in diagnosis because iron deficiency might be missed
o: ↑ serum ferritin
o (?) Diagnosis for (?) requires ↓ serum ferritin since it is first to decline = confusion in diagnosis
IDA w/ ACI
ACI
IDA
: used to distinguish IDA from ACI
Soluble transferrin receptor
: intracellular cpt cannot acquire iron
o Transferrin receptor usually accumulates in the surface of the cells so that it can get more iron
o ↓ iron = ↓ iron store
o ↑ transferrin receptor: accumulation in the cell
IDA
: normal intracellular iron
o ↓ to normal (v/v) transferrin receptor: intracellular iron is normal
ACI
↑ RBC (hyperproliferative) = administer erythropoietin to raise RBC
ACI
Even though the erythropoietin can increase RBC, the RBC still lacks iron.
ACI
RBC do not have access to ferritin, so you need to administer it together with iron so that iron can be incorporated in the RBC that was stimulated by the erythropoietin therapy
ACI
- SIDEROBLASTIC ANEMIA (SDA) CLASSIFICATION
A. X LINKED AND AUTOSOMAL HEREDITARY FORM
B. ACQUIRED
1. PRIMARY SIDEROBLASTIC ANEMIA (REFRACTORY)
2. SECONDARY SIDEROBLASTIC ANEMI
Refractory anemia: (+) sideroblastic rings/sideroblasts
- PRIMARY SIDEROBLASTIC ANEMIA (REFRACTORY)
Problem in the bone marrow
- PRIMARY SIDEROBLASTIC ANEMIA (REFRACTORY)
Usually acquired, drugs or toxins that affects bone marrow
- SECONDARY SIDEROBLASTIC ANEMIA
- SECONDARY SIDEROBLASTIC ANEMIA Example:
o Antitubercular drugs
o Chloramphenicol
o Alcohol
o Lead (usually and very important)
o Chemotherapeutic agents
● Iron is abundant in the bone marrow
- SIDEROBLASTIC ANEMIA (SDA)
● Iron → heme: defective
- SIDEROBLASTIC ANEMIA (SDA)
- SIDEROBLASTIC ANEMIA (SDA)
● Hallmark of the disease:
Ringed sideroblasts
There is no problem in iron
- SIDEROBLASTIC ANEMIA (SDA)
The problem here is that iron cannot be incorporated to heme
- SIDEROBLASTIC ANEMIA (SDA)
Normoblast: will have iron deposits in the mitochondria; it will surround the nucleus (sideroblastic ring appearance/ ringed sideroblast)
- SIDEROBLASTIC ANEMIA (SDA)
The most important relationship of sideroblastic anemia to iron is that [?] will be incorporated into the [?] by [?] to the [?] (last stage of heme synthesis)
Fe2+
protoporphyrin rings
ferrochelatase
heme
- X LINKED RECESSIVE TRAIT:
male (more common)
- AUTOSOMAL RECESSIVE TRAIT:
(rare)
- HEREDITARY TYPE PATHOPHYSIOLOGY
decreased delta aminolevulinic acid synthase activity
Delta aminolevulinic acid synthase problems:
A. Reduced affinity for pyridoxal cofactor
B. Increased sensitivity to degrading mitochondrial protease
- HEREDITARY TYPE CLINICAL PRESENTATION/CONSEQUENCE
Hereditary sideroblastic anemia: infancy, early adulthood
- HEREDITARY TYPE Patient manifests:
a. Iron overload
b. Mild to moderate splenomegaly and hepatomegaly
c. Diabetes related to iron deposits in pancreatic cells (Type 2)
d. Cardiac arrhythmia due to accumulating iron in myocardial cells
due to the disruption of the steps in heme production = accumulation of iron (60% of the iron: to be incorporated to hemoglobin and accumulated to the RBCs)
a. Iron overload
both in the serum and intracellularly
a. Iron overload
● Anemia: severe
- HEREDITARY TYPE SDA
- HEREDITARY TYPE SDA ● Hgb concentration:
6.0 g/dL (very low)
● Blood picture:
Microcytosis/hypochromia with anisocytosis (change in shape: dimorphic), poikilocytosis (predominance of target cells)
Normochromic/normocytic
- HEREDITARY TYPE SDA
● Bone marrow: remarkable hyperplasia
- HEREDITARY TYPE SDA
● BM (Prussian blue BM iron staining): (+) excessive iron stored in macrophages
- HEREDITARY TYPE SDA
● 40% are ringed sideroblastic (seen in polychromatophilic and orthochromatophilic stages)
- HEREDITARY TYPE SDA
- HEREDITARY TYPE SDA
- SERUM FERRITIN:
high (because it is not used up)
- HEREDITARY TYPE SDA
- SERUM IRON:
high (because there’s no need for the ferritin to compensate since the iron in the serum is high and not used in hemoglobin synthesis)
- HEREDITARY TYPE SDA
- TRANSFERRIN SATURATION:
high
- HEREDITARY TYPE SDA
- TIBC:
normal
- HEREDITARY TYPE SDA
- FEP:
low to normal (differentiatial study for ACI and IDA)
: ↑ FEP
o doesn’t have the serum iron which can incorporated to FEP to complete heme resulting in the accumulation of FEP
IDA and ACI
: ↓ FEP
o FEP is made up of protoporphyrin 9 (disruption in the previous stages = protoporphyrin 9 will not be formed)
o protoporphyrin 9 → poryphyrin rings → FEP
porphyrin rings that makes up the FEP
SDA
Pyroxidine theraphy
- HEREDITARY TYPE SDA
Delta aminolevulinic acid synthase has reduced affinity for pyridoxal cofactor
- HEREDITARY TYPE SDA
: common acquired cause of SDA
- LEAD POISONING
Lead interferes with porphyrin synthesis during these steps:
A. CONVERSION OF AMINOLEVULINIC ACID TO PHORPHOBILINOGEN BY ALA DEHYDRATASE (1st step)
B. INCORPORPATION OF IRON INTO PROTOPORPHYRIN IX BY FERROCHELATASE (2nd and last step)
Interference of the delta-aminolevulinic conversion to phorphobilinogen by using aminolevulinic acid (ALA) dehydrase = accumulation of amino levulinic acid because it does not convert to phorphobilinogen
A. CONVERSION OF AMINOLEVULINIC ACID TO PHORPHOBILINOGEN BY ALA DEHYDRATASE (1st step)
: usually measurable/excreted in urine
Aminolevulinic acid
Lead interferes in the incorporpation of iron into protoporphyrin IX to form heme
B. INCORPORPATION OF IRON INTO PROTOPORPHYRIN IX BY FERROCHELATASE (2nd and last step)
Accumulates iron and protoporphyrin IX, because protoporphyrin IX needs iron to complete heme synthesis
B. INCORPORPATION OF IRON INTO PROTOPORPHYRIN IX BY FERROCHELATASE (2nd and last step)
will then be measurable in the RBC as FEP
Protoporphyrin IX
: ↓ FEP (because protoporphrins are not formed)
Hereditary sideroblastic anemia
: ↑ FEP (because it accumulates and the iron cannot be incorporated in it)
Lead Poisoning
Early onset: Normocytic/Normochromic
- LEAD POISONING
Chronic exposure: Microcytic/Hypochromic
- LEAD POISONING
: highest risk of lead poisoning (shows dramatic degree of anemia due to increase rate of erythropoiesis and developing rbcs)
Children
: mild effect of lead poisoning
Adults
CLASSICAL FINDING:
BASOPHILIC STIPPLING
Usually related to lead poisoning but it cannot be diagnostic because basophilic stippling can also be seen in other anemias, however there is higher degree of basophilic stippling in lead poisoning
BASOPHILIC STIPPLING
: caused by the inhibition of an enzyme called Pyrimidine 59 nucleotidase
Basophilic stippling
breakdowns ribosomal ribonucleic acid (present in reticulocytes)
Basophilic stippling
non-nucleated → Pyrimidine 59 nucleotidase will finish off the maturation by removing the ribosomal RNA in the reticulocyte
mature rbc
stained as pinkish salmon pink
mature rbc
: inhibits Pyrimidine 59 nucleotidase → ribosomal RNA will then aggregate in the cytoplasm of reticulocytes causing stippling appearance (remnants are left instead of being removed by Pyrimidine 59 nucleotidase)
Lead poisoning
Reticulocyte count: Increased
- LEAD POISONING
Suggest a hemolytic component (hemolysis during lead poisoning because heme cannot be formed)
- LEAD POISONING
Iron cannot be incorporated into protoporphyrin IX, therefore no heme will be formed, which in turn results to no hemoglobin causing low levels of oxygen
- LEAD POISONING
: is usually shut down during lead poisoning; the distribution of oxygen via this pathway is inhibited; cells become sensitive to oxidant stress causing hemolysis (PPP is responsible for releasing antioxidants together with the Rapoport pathway) = oxidative environment : hemolysis
Pentose Phosphate Pathway (PPP)
● Removal of drug (poisoning)
- LEAD POISONING
: used to chelate the lead present in the body so it can be excreted in the urine
- LEAD POISONING
● EDTA salt
• Diseases characterized by impaired production of heme (can be hereditary or acquired)
PORPHYRIAS
• Acquired types are usually associated with enzyme deficiency.
PORPHYRIAS
The products from earlier stages (?) in the pathway accumulate in the cells that actively produce heme proteins such as RBC and hepatocytes. These [?] can also be excreted in the urine or feces or be deposited in body tissues.
porphyrins
PORPHYRIAS
• Clinical features:
Photosensitivity & Psychosis due to deposition of porphyrins.
PORPHYRIAS
• Hematologic manifestations:
congenital erythropoietic porphyria & erythropoietic protoporphyria
• Urine may appear portwine red in color
PORPHYRIAS
● Diseases characterized by impaired production of the porphyrin component of heme due to enzyme deficiencies
PORPHYRIAS
● Maybe acquired (lead poisoning/hereditary)
PORPHYRIAS
: one of the most common cause of enzyme problems because it affects the function of enzymes in converting one compound to another (accumulation of Delta aminolevulinic acid)
Lead poisoning
When an enzyme in heme synthesis is missing, the earlier stages in the pathway will accumulate in the erythrocyte and hepatocyte.
PORPHYRIAS
Excess porphyrins leak from cells as they die and this will be excreted in the urine and feces which allows diagnosis
PORPHYRIAS
The enzymes in porphobilinogen, hydroxymethylbilane, Uroporphyrinogen III, Coproporphyrinogen III, and Protoporphyrinogen IX has the porphyrins but because of the deficiency.
PORPHYRIAS
Enzyme deficiency: 1) uroporphyrinogen III cosynthase is deficient, the hydroxymethylbilane will accumulate, 2) uroporphyrinogen decarboxylase is deficient, uroporphyrinogen III will accumulate
PORPHYRIAS
These accumulations of porphyrins will accumulate in the erythrocytes → porphyrins leaks out of the rbc, especially to those that are already old (near to die: 120 days) → excreted in the urine which can be used to diagnose
PORPHYRIAS
TYPES OF PORPHYRIAS
A. CONGENITAL ERYTHROPOIETIC PORPHYRIA (CEP)
B. ERYTHROPOIETIC PROTOPORPHYRIA (EPP)
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
Porphyrins accumulate in the cells/tissue when you view it under the microscope = [?] = patient having porphyrias is photosensitive (burning sensation when exposed to sunlight)
(+) fluorescence
The fluorescence of accumulated compound can be diagnostic (usually used to diagnose FEP in SDA =[?])
(+) rbc fluorescence
BM testing: RBC will appear as [?] under a fluorescent microscope (ability to fluoresce/photosensitivity is used to differentiate the porphyrias)
bright red
● Photosensitive + Hemolytic anemia
A. CONGENITAL ERYTHROPOIETIC PORPHYRIA (CEP)
● Photosensitive but mild
B. ERYTHROPOIETIC PROTOPORPHYRIA (EPP)
● Most severe
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
● Photosensitive + microcytic + hypochromic + reticulocyte is seen
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
Reticulocytes will try to respond to the problem in the heme (BM compensation)
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
Hereditary: abnormal reticulocytes
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
Lead poisoning: reticulocytes can compensate unless in heavy cases that it affects the bone marrow
C. X-LINKED ERYTHROPOIETIC PROTOPORPHYRIA (XLPEP)
Results when the body’s state of iron acquisition exceeds the rate of iron loss.
HEMOCHROMATOSIS
It can be acquired or hereditary (mutations affecting the proteins of iron metabolism).
HEMOCHROMATOSIS
The body’s first reaction is to store excess iron in the form of ferritin, then in the form of hemosiderin within cells.
HEMOCHROMATOSIS
In the presence of Oxygen, free ferrous iron initiates the generation of superoxide and other free radicals, which results in the PEROXIDATION of membrane lipids.
HEMOCHROMATOSIS
Results to damage of cell membrane, nuclear membrane, mitochondrial and lysosomal membranes.
PEROXIDATION
These events ultimately affect cellular respiration, enzyme digestion, cell death and organ damage.
PEROXIDATION
Hemosiderin also deposits into tissues and organs leading to further organ damage.
HEMOCHROMATOSIS
• Skin-
golden color
• Liver -
cirrhosis-induced jaundice and subsequent cancer
• Pancreas -
diabetes mellitus •
Heart -
congestive heart failure
Screening Test: transferrin saturation
HEMOCHROMATOSIS
Treatment: Iron-chelating drugs to bind excess iron for excretion; Desferrioxamine
HEMOCHROMATOSIS
IDA Serum iron
↓
ACI Serum iron
↓
SDA Serum iron
↑
IDA Serum TIBC
↑
SDA Serum TIBC
↓
ACI Serum TIBC
N-↓
IDA Serum ferritin
↓
ACI Serum ferritin
N-↑
SDA Serum ferritin
↑
IDA Iron stores
↓
ACI Iron stores
N-↑
SDA Iron stores
↑
IDA Hb A2
N-↓
ACI Hb A2
N
SDA Hb A2
N
IDA Hb F
N
ACI Hb F
N
SDA Hb F
N-↑
IDA % sideroblasts
↓
ACI % sideroblasts
↓
SDA % sideroblasts
↑
IDA ZPP
↑
ACI ZPP
↑
SDA ZPP
↑(↓)
