Unit 13: Anemias and Iron Disorders

What are microcytic anemias characterized by?

What are microcytic anemias characterized by?

microcytic RBC’s, often hypochromic

typically due to defected hgb synthesis

What are the 2 categories of causes of microcytic anemias?

1. deficiency heme synthesis

   1. lack of iron = IDA

   2. defective iron utilization = sideroblasic anemia

   3. porphyrias

2. deficient globin synthesis = thalassemias

Where is iron found in humans for metabolic or enzymatic functions?

• hgb** majority

• myoglobin

• cytochrome enzymes in every cell in body

• transferrin

What are the storage forms of iron? What should you think about regarding each?

ferritin = piggy bank

hemosiderin = savings account at bank

What is total body iron? How much of that is found within heme?

total = 3.7g

within heme = 2/3 so about 2.5 g of total

How does the body tightly control metabolism of iron?

95% of daily iron needs met by using recycled iron

rest is absorbed via diet (5%)

excess dietary iron excreted w/o being absorbed

internal iron CANNOT be excreted and can be toxic if too much

How can children easily take in too much iron?

eating gummy vitamins bc they taste good

About how much iron does each person lose daily?

1 mg

through sweat, loss of intestinal cells (iron stored here), urine/bile

Why do females lose more iron daily compared to others?

menstruation, pregnancy, nursing

Fe 3+

ferric iron

transferrin associated iron, storage iron

Fe 2+

ferrous iron

carries O2 = heme iron

• hgb, myoglobin, cytochrome enzymes

Non-heme iron (grains and veggies) absorption

changed from Fe3+ to Fe2+ by enzymes in enterocytes

harder to absorb

** vegetarian’s/vegan’s bodies must work harder

Heme iron (meat) absorption

already in Fe2+

more easily absorbed

Where is iron absorbed in the body?

proximal portion of duodenum → then couples with transferrin in blood

goes back in Fe3+ form in order to move around the body

Where is Fe 3+ taken after it’s been absorbed?

taken to bone marrow by transferrin to make new RBC’s or to be stored as ferritin

incorporated into body cells as cytochrome enzymes

Characteristics of ferritin

• water soluble

• composed of ½ protein

• short term storage

• limited storage capacity (piggy bank)

• soluble form does not stain w/ Prussian blue but will stain if clustered in siderosomes

What is the name of the protein that makes up ½ of ferritin when it is not attached to iron?

apoferritin

Distribution of ferritin

• primarily intracellular

• circulates between tissues and plasma (equilibrium)

What is plasma ferritin a good indicator of?

iron stores

Hemosiderin characteristics

• larger aggregates than ferritin

• insoluble

  • 50% lipid, carb protein

  • 50% iron, including denatured ferritin

• yellow/brown aggregates unstained

• stains blue with Prussian blue stain

Hemosiderin distribution

bone marrow - good indicator of overall stores

other tissues

Iron stores/reserves available for males and females

males = 1000mg

females = 300-500mg

When there is an increased demand for iron, which storage type is used first?

ferritin used first bc more easily accessible, then hemosiderin used

Do both ferritin and hemosiderin have to be depleted to consider someone iron deficient?

yes

With no absorption, how long would it take for a male to use up his normal reserves of iron?

8 years

How much iron do women lose each month due to menstruation?

30-40mg

What are causes of iron deficiency?

insufficient Fe in diet

increased demand

absorption problems

blood loss

Insufficient iron in diet

#1 nutritional deficiency in the WORLD

one of the leading causes of anemia in US (not #1)

Increased demand leading to iron deficiency

• multiple pregnancies

• periods of significant growth and development

• in infants - “milk babies”

  • as baby’s are using less formula and breast milk, iron needs aren’t being met through normal milk at 6 months-1 year

Absorption problems leading to iron deficiency

• celiac disease

• defective gastric function - achlorhydria (stomach does not produce acid)

• gastrectomy (bariatric surgery)

Blood loss leading to iron deficiency

• #1 cause in US

• females = heavy menstruation

• males = GI bleeds from ulcers, colon cancer, hemorrhoids

If males have an iron deficiency, what should your first thought be until proven otherwise?

cancer

What’s another name for IDA?

sideropenic anemia

IDA PBS

micro-hypo

**RBC’s smaller than lymphocyte nucleus

IDA lab testing for bone marrow iron stores

• only performed when non-invasive tests cannot diagnose

• stain bone marrow aspirate specimen with Prussian blue

• normal marrow has about 30-60% developing erythroblasts w/ blue iron particles in them

• in IDA no stainable iron found but marrow cellularity normal-increased

Sideroblastic anemia based on bone marrow lab testing

abnormal Fe in normoblasts

What is siderocyte stain of PBS used for?

• Prussian blue

• other iron utilization problems, not IDA

• looking for abnormal iron granules

  • hemosiderin granules - Pappenheimer bodies on Wright’s stain

What diseased states cause decreased serum iron concentration?

• IDA

• chronic infections

• cancer

What diseased states cause increased serum iron concentration?

• iron overloads

• intravascular hemolysis

• multiple transfusions (no way to get rid of)

True or False: Most serum iron is transferrin complexed?

true

IDA lab testing of TIBC

total iron binding capacity

• measures transferrin capacity to carry iron

• increased in IDA - body makes more transferring to capture what little iron already available

• decreased in chronic diseases and cancer

How many Fe 3+ can transferrin carry?

2

What components make up TIBC?

1/3 serum iron

2/3 unbound iron binding capacity

IDA lab testing of transferring % saturation

calculation using serum iron and TIBC

% saturation = serum iron/TIBC X 100%

decreased in iron deficiency, increased in iron overload

IDA lab testing of serum ferritin

• tissue ferritin in equilibrium w/ serum ferritin so good indicator of iron stores

• decreased in IDA

• normal to increased in ACD

• increased in sideroblastic anemia and thalassemia

IDA lab testing of sTfR

• serum transferrin receptor assay

• looking for receptor for transferring (parking spot)

• receptor expressed on all cells in proportion to Fe use

• IDA = sTfR is double normal

• ACD = normal values

Which is the better indicator of IDA: serum ferritin or sTfR?

sTfR

IDA lab testing of FEP or Znpp

• free erythrocyte protoporphyrin

• theory: RBC accumulates excess protoporphyrin bc Fe not present to bind protoporphyrin

• testing via fluorescence studies

• early value to chance as iron stores used

Does FEP/ZnPP elevate before or after anemia develops?

before - good tool to detect developing IDA in milk babies

What is another diseased state where FEP/ZnPP is elevated?

lead poisoning

IDA lab testing of RDW

• red cell distribution width

• SD of MCV divided by MCV

• corresponds to level of aniso

RDW reference range

11.5-14.5%

but human eyes cannot distinguish <16%

RDW levels related to IDA and thalassemias

IDA = elevated

thalassemia = normal or slightly elevated

What are the stages of developing IDA?

1. iron depletion = both stores used up

2. iron deficient erythropoiesis = decreased serum iron, increased TIBC, may see 2 populations of cells

3. iron deficiency anemia = hgb decreases, progression of cell size and color

IDA vs Thalassemia

IDA

• MCV decreases proportionately as anemia develops

• ex. low MCV = low hgb

thalassemia

• defect of globin synthesis - Fe is fine

• MCV much lower for given conc. of hgb and hct compared to IDA

• body compensates by making more RBC’s

Symptoms of IDA

• pallor/fatigue

• pica = ice/crunchy foods, clay, starch

• koilonychia (spoon nails)

• glossitis (smooth tongue)

Resolution of IDA

find cause and remove if possible

• ulcer, GI bleed, diet, heavy menstruation

give iron - typically oral as ferrous sulfate

after transfusion

What happens to RPI after IDA treatment

initially increases and then levels off

Sideroblastic anemia

micro-hypo

iron utilization problem

• Fe present and available in marrow

• Fe cannot be inserted into protoporphyrin ring

• Fe accumulates in mitrochondria

• Fe-laden mitochondria seen on Prussian blue as “ringed sideroblasts” in marrow

What do “ringed sideroblasts” look like?

iron (blue) in a ring around nucleus of cell

What are causes of sideroblastic anemia?

• inherited enzyme defects in heme synthesis (RARE)

• acquired

Acquired sideroblastic anemia

myelodysplastic syndromes and malignancies

toxic effects

• alcohol abuse / some drugs

• lead poisoning which blocks enzymes such as ferrochelatase causing basophilic stippling

  • lead accumulates in cells → aggregated ribosomes, mitochondria, siderosomes'

  • only seen in stained preps

PBS findings in sideroblastic anemia

• dimorphic RBC population

• aniso and poikylo

• polychromasia

• hypochromic/normochromic cells

• teardrop cells

• basophilic stippling

• pappenheimer bodies

Other lab values associated with sideroblastic anemias

• decreased RBC, hgb, hct

• increased iron stores/total body iron

  • elevated serum iron and percent saturation of transferrin

  • elevated ferritin/hemosiderin

  • ringed sideroblasts

Treatment of sideroblastic anemias

transfusion dependent

• may lead to iron overload

• can be treated with iron chelator such as desferrioxamine

Anemia of chronic disease

• ranges from normo-normo to micro-hypo

• AKA anemia of inflammation

What are some chronic diseases that may cause ACD?

• chronic infections: sub-acute bacterial endocarditis, TB

• inflammatory disease

• autoimmune diseases: SLE and RA

• malignancies

Mechanisms that contribute to ACD

• block in Fe release from macrophages to marrow in normal Fe recirculation

• failure to trigger EPO release

• decrease in RBC survival

• marrow suppressive effect of cytokines and interleukins

Degree of anemia with ACD

usually not severe

fluctuates with activity of underlying condition

Is ACD the next most common anemia behind IDA from blood loss?

yes

Iron studies in ACD

• serum iron = low

• TIBC = low to normal

• % saturation = low to normal

• serum ferritin = normal to increased**

• ZnPP = increased

• sTfR = normal

Hemosiderosis

increased deposits of hemosiderin in phagocytic system

• reticulo-endothelial system

• macrophages very full

Examples of Hemosiderosis

• multiple transfusions

• sideroblastic anemia

• high iron in diet

• increased absorption with chronic alcoholism

Hemochromatosis

more severe form of iron overload

common genetic abnormality

• involves deficiency of hepcidin

• european ancestry

Where does the iron deposit in hemochromatosis?

reticuloendothelial system and soft organs

• pancreas = diabetes

• skin = melanin-like pigment

• liver = enlarged and decreased function

• gonads = hypogonadism (females = ovaries)

How to treat hemochromatosis

with iron chelator drugs and phlebotomy to remove excess cells and iron