ANEMIA OF ABNORMAL IRON METABOLISM P2

Question 1

Common among hospitalized patients
- Chronic inflammatory condition: E.g.
-___________
-__________ (tuberculosis, HIV,
malignancies)

Answer 1

Rheumatoid arthritis
- Chronic infections

Question 2

ETIOLOGY
- originally called ____________________
- BUT chronic blood loss is not part of this
- correct term: ____________________
- ___________ is the unifying factor
- central feature: SIDEROPENIA with abundant iron stores
- cause:
- IMPAIRED FERROKINETICS → IRON-RESTRICTED ERYTHROPOIESIS
- IMPAIRED ERYTHROPOIESIS
- SHORTENED RBC LIFE SPAN

Answer 2

ANEMIA OF CHRONIC DISEASE
ANEMIA OF CHRONIC INFLAMMATION
inflammation
SIDEROPENIA

Question 3

IMPAIRED FERROKINETICS
-__________is an acute phase reactant
- produced by the liver during inflammation in response to _________
(produced by macrophages)
- increase Hepcidin → increase breakdown of Ferroportin →
decrease iron release in the blood
- Iron becomes less available to bacteria
- not harmful in acute periods BUT when hepcidin levels are
chronically high → diminished RBC production

Answer 3

Hepcidin
IL-6
what organ hepcidin - liver

Question 4

_____________second iron-related acute phase reactant that
leads to anemia of chronic inflammation
- iron-binding protein in the granules of neutrophils
- higher avidity for iron than transferrin
- prevent phagocytized bacteria from using intracellular
iron for their metabolic processes
- provide protection for the phagocyte from oxidized iron
that forms when ROS are produced during phagocytosis

Answer 4

lactoferrin

Question 5

Lactoferrin
during infection and inflammation → lactoferrin is
released into the blood and extracellular spaces with the
death of neutrophils → it will scavenge iron to prevent it
from making oxidative damage
- this makes Lactoferrin _______________
- Lactoferrin carry the iron and bind to macrophages and
liver cells where iron will be taken up and salvaged

Answer 5

ANTI-INFLAMMATORY

Question 6

IMPAIRED FERROKINETICS
____________
- but due to high Hepcidin, cells cannot acquire iron directly
- erythroblasts do not have __________receptors
- results to__________________
- iron is abundant in storage BUT unavailable to
developing erythroblasts
- BM examination with iron stains: (+) iron in macrophages
but not in erythroblasts
= ___________________________

Answer 6

Lactoferrin
lactoferrin
Functional iron deficiency
IRON-RESTRICTED ERYTHROPOIESIS

Question 7

DIMINISHED ERYTHROPOIESIS
- production of inflammatory cytokines
- macrophages: __________
- activated T-cell:_____________
- leads to:
- impairment of the proliferation of erythroid progenitor cells
- diminishes their response to EPO
- decrease production of EPO by the kidney

Answer 7

TNF-a, IL-1
IF-gamma
EPO and Erythropoiesis

Question 8

• extracellular mechanism but without clear identification to date
• inflammation appears to increase production of hemophagocytic
  macrophages

Answer 8

SHORTENED RBC LIFE SPAN

Question 9

LABORATORY DIAGNOSIS
- _______ anemia
- HGB _______
- without ____________
-_____________, __________
- Coexisting iron-deficiency: _________, ____________-
- _______________, ________ in due to inflammatory condition

Answer 9

Mild anemia
HGB 8-10 g/dL
reticulocytosis
Normocytic, normochromic
Microcytic, hypochromic cells
leukocytosis and thrombocytosis

Question 10

LABORATORY DIAGNOSIS
- Iron studies:
________________
_______________
_________________
__________________
_______________

Answer 10

low serum iron and TIBC
increase serum ferritin
increase Free Erythrocyte Protoporphyrin
Decrease Hemoglobin content of reticulocytes
Normal Serum transferrin receptor

Question 11

LABORATORY DIAGNOSIS
- BM:
- _________________ consistent with the lack of
reticulocytes in the peripheral blood
- ____________: confirms abundant stores of iron in macrophages
but not in RBC precursor
- examination is usually not required in the dx evaluation

Answer 11

Hypoproliferation of the RBCs:
Prussian blue

Question 12

DILEMMA
- IRON DEFICIENCY ANEMIA (IDA)
- Iron deficiency may be missed due to increase in ___________
levels associated with the inflammation
- serum ferritin values in the ___________ range are most equivocal
(may mean 2 things)
- verify coexistence of IDA and chronic inflamm by measuring the ______ in the serum.
- increase in IDA
- normal in anemia of chronic inflammation
__________________
- rise dramatically in IDA (high numerator)
- normal in anemia of chronic inflammation

Answer 12

serum ferritin
30-100 ng/mL
sTfRs
sTfRs / log ferritin

Question 13

TREATMENT
-_______: can correct anemia of chronic inflammation
- need ____________________ because of the
presence of functional iron deficiency (Iron stores are
unavailable)
- costly treatment → only for selected patients
-____________________: best course of treatment
-__________________ are being investigated

Answer 13

EPO
IRON administration concurrently
Alleviation of underlying condition
Anti-Hepcidin therapies

Question 14

Diseases that interfere with the
production of protoporphyrin →
ANEMIA (Protoporphyrin synthesis
review Chapter 7 Rodak’s)
- iron is abundant in the BM
- Prussian Blue stain: (+)
mitochondrial iron surrounding the
nucleus in erythroblasts awaiting
incorporation into heme
-__________________: hallmark of
the sideroblastic anemias

Answer 14

Ring (Ringed) Sideroblasts

Question 15

Hereditary and
Acquired conditions
__________________
- pharmacologic
doses help
stimulate heme
synthesis
- cofactor in the
1st step of
porphyrin
synthesis

Answer 15

• Pyridoxine (Vit B12)

Question 16

Hereditary
- _____________
-_______________
Acquired
-________________
-____________

Answer 16

hereditary
- Autosomal
- X- linked
Acquired
- Primary Sideroblastic anemia
- Secondary Sideroblastic Anemia - caused by drugs and bone marrow toxins

• Antitubercular drugs
• Chloramphenicol
• Alcohol
• Lead
• Chemotherapeutic agents

Question 17

ACQUIRED: LEAD POISONING
- Certain drugs: _________________
- Other toxins: Heavy metals (_________ - significant public health
concern)
- adult exposure to leaded compounds at work
-____________ living in older homes (lead paint used prior to _______)
- dust in renovations and peeling/pealed paint
- lead leached from service pipes by improperly treated drinking
water
-____________ is concerning in children because is affects the ________ and __________
- symptoms: ________, _______, ________, ________

Answer 17

Chloramphenicol, Isoniazid
Lead
adults and children
1970
Lead poisoning
CNS and hematologic system
Peripheral neuropathy, abdominal cramping, vomiting, seizures

Question 18

ACQUIRED: LEAD POISONING
- lead interfered with porphyrin synthesis at several steps:
1. Conversion of ______________
by ALA dehydratase (aka PBG synthase)
- results to accumulation of ALA

Answer 18

Aminolevulinic acid (ALA) to porphobilinogen (PBG)

Question 19

ACQUIRED: LEAD POISONING
- lead interfered with porphyrin synthesis at several steps:
2. Incorporation of Iron into ______________
- accumulation of iron and protoporphyrin in the mitochondria

Answer 19

Protoporphyrin IX by ferrochelatase (aka
heme synthase)

Question 20

ACQUIRED: LEAD POISONING
- accumulated ALA is measurable in ______
- accumulated protoporphyrin is measured in an extract or RBCs as
FEP/ZPP

Answer 20

urine

Question 21

Anemia if present is most often _________, _______
- however, Chronic exposure will lead to _________
- degree of anemia is more profound in ________
- Reticuloyte count - quite _______ suggesting hemolytic component
- studies show impairment of the Pentose-phosphate shunt by
lead w/c makes cells sensitive to oxidant stress
- BM: erythroid hyperplasia; hypoplastic (some)
- __________ - classic findings assoc with lead toxicity
- lead inhibits Pyrimidine-5’-nucleotidase involved in breakdown of
rRNA in retics → undegrades ribosomes aggregate → basophilic
stippling

Answer 21

Normocytic, normochromic
Microcytic, hypochromic
Children
elevated
Basophilic stippling

Question 22

ACQUIRED: LEAD POISONING
- Treatment: ______________ is usually successful for
acquired sideroblastic anemias
- Lead poisoning: Treatment
- _______________
are often used to chelate the lead → excreted in the urine

Answer 22

removal of the drug or toxin
calcium disodium edetate (CaNa2EDTA) and/or dimercaprol

Question 23

_______________
- Diseases characterized by impaired production of the porphyrin
component of heme
- often used to refer to the hereditary conditions that impair
production of ____________
- when an enzyme in heme synthesis is missing, products from the
earlier stages in the pathway accumulate in cells that actively
produce heme like RBC and hepatocytes
- excess porphyrins leak from the cells and excreted in the __________ which allows diagnosis

Answer 23

PORPHYRIAS
protoporphyrins
urine and feces

Question 24

PORPHYRIAS
- some accumulated products are fluorescent
- deposition in skin can lead to __________ with severe burns
on sunlight exposure
- accumulation during childhood leads to fluorescence of
developing teeth and bones
- only ______ of the porphyrias have hematologic manifestation, the
others have greater effects in liver cells
- fluorescence of some accumulated compounds can be used
diagnostically
- BM: erythroblasts will be bright red under fluorescent
microscope

Answer 24

photosensitivity
3

Question 25

IRON OVERLOAD
PRIMARY
-_____________
SECONDARY
- ____________________
Excess iron → toxic effects

Answer 25

• Hereditary hemochromatosis
• Chronic anemias and their treatment

Question 26

ETIOLOGY
- Body’s rate of iron acquisition exceeds the rate of loss
(___________)
- Excess iron → store excess (FERRITIN) → HEMOSIDERIN →
storage is overwhelmed → damage to organs

Answer 26

1 mg

Question 27

IRON OVERLOAD
ETIOLOGY
- Acquired: __________________:
accumulation of iron due to repeated transfusion
- ___________________: cause the BM to develop a
compensatory erythroid hyperplasia → Erythroblasts
downregulate HEPCIDIN production by secreting
_____________→ more iron is absorbed and recycled than
normal
-______________: leads to excessive
accumulation of iron
__________ is secondary to the hereditary hemolytic
anemia (Secondary / Acquired Iron Overload)

Answer 27

TRANSFUSION-RELATED HEMOSIDEROSIS
HEREDITARY HEMOLYTIC ANEMIA
ERYTHROFERRONE
CHRONIC HEMOLYTIC ANEMIA
- iron loading

Question 28

IRON OVERLOAD
ETIOLOGY
- ______________ result of mutations in genes for protein
controlling iron kinetics (see table - next slide)
- feedback regulation of iron is impaired and the body
continues to absorb iron even when stores are full
= _________________________
- ________________________ general phenotype that
can be produced by various genotype when a gene for an
iron-regulatory protein is mutated
- failure of normal regulation as a result of mutation leads to
excessive absorption ans storage od iron

Answer 28

Hemochromatoses
TRUE HEREDITARY IRON OVERLOAD
HEREDITARY HEMOCHROMATOSIS

Question 29

• involved the Hereditary Hemochromatosis (HFE) gene
• gene involved in the first 2 mutations known to produce
  hereditary hemochromatosis
• gene on the short arm of ____________
• encodes HLA class I-like molecule closely linked to HLA-A
• occurs in approx ________________northern Europeans

Answer 29

Homozygous Hereditary Hemochromatosis
chromosome 6
5 of 1000

Question 30

Normal HFE protein binds to B2-microglobulin intracellularly
which is necessary for HFE to appear on the cell surface where it
interacts with transferrin then HFE is released

Answer 30

Hereditary Hemochromatosis (HFE)

Question 31

PATHOGENESIS
- first cellular reaction to excess iron is to form______________ (non-metabolic active form of ferritin)
- when storage if full, free iron (ferrous) accumulates
intracellularly
- if (+) oxygen: ferrous iron initiates the generation of
superoxide and other free radicals → peroxidation of
membrane lipids (cell, mitochondrial, nuclear and lysosomal
membrane) → cell death (due to irreversible membrane) damage)
- cell respiration will be compromised
- Lysosomal enzymes will be released intracellularly
- ________________: act to moderate the effects and interrupt
the chain reaction BUT still overwhelmed

Answer 31

ferritin and hemosiderin
Vitamin C and E