5.2 Microcytic Anemias

Question 1

What is the underlying cause of microcytic anemia?

Answer 1

A decreased production or availability of hemoglobin
Normally, RBC progenitor cells undergo cellular division to produce progressively smaller cells that become the final RBC
When the Hb is low, the cells divide an extra time to preserve Hb concentration in the cells, but they are then small

Question 2

What is Hb made of and how can this knowledge be used to remember the causes of microcytic anemia?

Answer 2

Hemoglobin = Heme + Globin
Heme = Iron + protoporphyrin
A decrease of any of these components leads to a decrease in Hb and Microcytic anemia
Iron deficiency anemia and anemia of chronic disease both have low iron
Sideroblastic anemia has low porphyrin
Thalassemia has low globin

Question 3

What are the forms of iron that are consumed?

Answer 3

Heme: meat-derived (more readily absorbed)

Non-heme: vegetable derived

Question 4

Where in the body is Iron absorbed from food?

Answer 4

In the duodenum by enterocytes

Question 5

Explain the different proteins used to transport, bind, and store Iron in the body

Answer 5

Enterocytes absorb iron from the duodenum and then transport the iron out of the cell via ferroportin–remember that not many cells have this molecule and therefore the body has a hard time eliminating iron once it has it, this is one control point that determines how much iron goes into the body
Transferrin transports Fe in the blood to the liver and bone marrow macrophages for storage
Stored iron is bound to ferritin which prevent Fe from forming free radicals

Question 6

What are the four key measurements of Fe in the body?

Answer 6

Serum Iron: direct measure of Fe in the blood
Total Iron Binding Capacity: Measures Transferrin molecules in the blood
% Saturation: % of transferrin molecules bound to iron (normal around 30%)
Serum Ferritin: iron stores in bone macrophages and liver

Question 7

What is the most common cause of Iron deficiency in general and in different age groups?

Answer 7

Usually dietary lack or blood loss
Infants: breast feeding
Children: poor diet
Adults: males–PUD, females–menorrhagia or pregnancy
Elderly: colon polyps/carcinoma in western world, hookworms in developing world

Other: malnutrition, malabsorption, gastrectomy

Question 8

Describe the stages of Iron deficiency and how it progresses to a microcytic anemia

Answer 8

1) As iron levels drop in the body, storage iron is depleted first in order to maintain the iron levels in the serum, decreased ferritin and increased TIBC
2) As the stores dry up, serum iron begins to be depleted, decreased serum iron, decreased % saturation
3) Once the stores and serum iron levels have dropped, there begins to not be enough iron for heme production so marrow makes fewer, but normal sized RBC’s = normocytic anemia
4) Eventually, as iron Hb levels continue to drop, the marrow will begin to produce microcytic and hypochromic RBC’s worsening the anemia

Question 9

What is koilonychia?

Answer 9

Spoon shaped nails

Sign of hypochromic anemia, especially Fe deficiency caused

Question 10

What is Pica?

Answer 10

Persistent craving and compulsive eating of non-food substances

Question 11

What are the clinical signs of Iron deficiency anemia?

Answer 11

Anemia, koilonychia, pica (think of someone trying to eat anything to get some iron)

Question 12

What is RDW

Answer 12

RBC distribution width

Measure of the variation in RBC size

Question 13

Which laboratory measures of iron tend to move in opposite directions?

Answer 13

Ferritin and TIBC

Question 14

What are the lab values that would be expected in iron deficiency anemia?

Answer 14

Microcytic, hypochromic RBC’s with an increased RDW
Decreased ferritin, Increased TIBC, Decreased serum Iron, Decreased % saturation
Increased FEP (free erythrocyte protoporphyrin)

Question 15

The RBC should be roughly the same size as the nucleus of what cell type?

Answer 15

Lymphocyte

Question 16

Plummer-Vinson syndrome

Answer 16

Iron deficiency anemia associated with esophageal webs and atrophic glossitis
Typically presents with anemia, dysphagia, and beefy red tongue

Question 17

Middle aged man presents with weakness, fatigue, dyspnea, pale skin, headaches, and lightheadedness. What condition should be considered and what underlying cause is most likely?

Answer 17

Sx point to anemia that could be due to iron deficiency
If this is the case, the most common cause of iron deficiency is either dietary lack or blood loss
For a middle aged man in the USA, PUD should be considered early on
If older, consider colon polyps and carcinoma

Question 18

Patient found to have anemia, a beefy red tongue, and difficulty swallowing. Potential Dx?

Answer 18

Plummer-Vinson syndrome

Question 19

Explain pathophysiology for anemia of chronic disease

Answer 19

Associated with chronic inflammation or cancer
Most common anemia in hospitalized patients
Chronic disease leads to production of acute phase reactants that include Hepcidin which sequesters iron in storage sites by preventing transfer from macrophages to erythroid precursors, and by suppressing EPO
Hepcidin locks down iron to hide it from bacteria, but the low iron leads to low heme and low Hb and anemia

Question 20

What are the labs in anemia of chronic disease?

Answer 20

High ferritin: high stores of iron
Low TIBC: opposite to ferritin
Low serum iron: only iron in body available for use
Low % saturation: follows serum levels
High Free Erythrocyte Protoporphyrin: low iron leaves normal protoporphyrin levels without a buddy to bind to to make heme

Question 21

What is the basic, ultimate, underlying cause of Sideroblastic anemia?

Answer 21

Defective protoporphyrin synthesis which leads to low heme, low Hb, and microcytic anemia

Question 22

What is the rate-limiting step in the synthesis of heme/protoporphyrin?

Answer 22

Conversion of Succinyl CoA to aminolevulinic acid (ALA) by aminolevulinic acid synthetase (ALAS) with B6 as a cofactor

Question 23

What is the last step in the production of heme from protoporphyrin?

Answer 23

Protoporphyrin is added to iron to make heme in the mitochondria by Ferrochelatase

Question 24

What does Prussian Blue Stain highlight?

Answer 24

Iron

Question 25

Explain why ringed sideroblasts form in sideroblastic anemia

Answer 25

Protoporphyrin is synthesized in the mitochondria of erythroid precursors, and it is also in the mitochondria that it is bound to Fe to make heme.
If there is a defect in the production of protoporphyrin, iron is still sent to the mitochondria for heme production, but it instead builds up in the mitochondria and cannot leave.
Mitochondria generally encircle the nucleus in a ring and therefore create a ring of iron-laden mitochondria around the nucleus

Question 26

In siderblastic anemia, where is the iron located and accumulated?

Answer 26

In the mitochondria

Question 27

What is the common congenital cause of sideroblastic anemia?

Answer 27

ALAS enzyme deficiency

Aminolevulinic acid synthetase (the rate limiting step in protoporphyrin synthesis)

Question 28

What are some causes of acquired sideroblastic anemia?

Answer 28

Alcoholism: mitochondrial poison preventing protoporphyrin synth.
Lead poisoning: denatures proteins including ALAD and ferrocheletase preventing protoporphyrin synth.
Vit B6 deficiency: cofactor for rate limiting step in protoporphyrin synth with ALAS, commonly seen in isoniazid treatment

Question 29

Explain the lab findings in sideroblastic anemia

Answer 29

Think iron-overloaded state
High ferritin because the iron is overflowing from erythroid precursor cells
Low TIBC
High serum iron and high % sat
The iron will accumulate in erythroid precursors to the point where it damages the cell and kills it. Iron spills out and is taken up by marrow macrophages leading again to an iron overloaded state.

Question 30

Patients with thalassemia are protected against what disease?

Answer 30

Plasmodium falciparum malaria

Question 31

How is thalassemia a cause of anemia?

Answer 31

Thalassemia is a defect in the production or synthesis of globin which is an essential part of Hb
Low Hb = microcytic anemia

Question 32

What are the normal types of Hb and their make-up in the human?

Answer 32

HbF (alpha2, gamma2)
HbA (alpha2, beta2)
HbA2 (alpha2, delta2)

Question 33

What generally causes alpha thalassemia?

Answer 33

Generally gene deletion

There are 4 genes for alpha globulin–2 on each copy of chromosome 16

Question 34

Describe the different types of alpha thalassemia

Answer 34

Deletion of any combination of the 4 copies of alpha globulin gene
1 gene lost: asymptomatic
2 genes lost: mild anemia with increased RBC count
cis deletion: both on same chromosome, worse outcome for offspring, more common in Asians
trans deletion: one on each chromosome, better for offspring, Africans
3 genes lost: severe anemia, beta chains form tetramers (HbH) that damage RBC’s
4 genes lost: lethal in utero (hydrops fetalis), gamma chains form tetramers (Hb Barts) seen on electrophoresis

Question 35

Beta-thalassemia minor has a specific type of cell that is seen on blood smear, what is this cell, and explain why it forms.

Answer 35

Target cell
Forms because in beta-thalassemia minor they are beta/beta+ meaning there is a small defect in the production of beta globulin causing less Hb to be present in RBC’s
Less Hb is like deflating the RBC and this allows for a bleb to form in the middle of the cell that fills with Hb making a target-like appearance

Question 36

Which anemia is microcytic, hypochromic, has target cells? What is the principle laboratory finding in this anemia?

Answer 36

beta-thalassemia minor

Labs show most significantly: increased HbA2 as well as increased HbF and decreased HbA

Question 37

What is Beta-thalassemia major, and how does it generally present?

Answer 37

(beta0/beta0) meaning both copies of beta globulin gene are messed up
Causes severe anemia that presents several months after birth because the HbF is protective for the first few months after birth

Question 38

What are some SSx of beta-thalassemia major and what is the pathophysiology?

Answer 38

Pathophys: unpaired alpha chains precipitate and damage the RBC membrane resulting in ineffective hematopoiesis and extravascular hemolysis (removal of RBC’s by spleen)
SSx: Massive erythroid hyperplasia causing:
1) expansion of hematopoiesis in skull (crewcut appearance on x-ray), and facial bones (chipmunk facies)
2) extramedullary hematopoiesis causing HSM
3) risk of aplastic crisis with parvovirus B19 infection which infects erythroid precursors

Question 39

What is the treatment and complications for beta-thalassemia?

Answer 39

They are dependent on chronic blood transfusions

A bag of blood is essentially a bag of iron and leads to issues with secondary hemochromatosis

Question 40

What would a blood smear and labs show in beta thalassemia major?

Answer 40

Microcytic, hypochromic RBC’s, target cells, nucleated RBC’s (extramedullary hematopoiesis often leads to nucleated RBC’s slipping out)
Electrophoresis would show HbA2 and HbF with little to no HbA

Question 41

A fetus died in utero and is found to have a blood disorder. Electrophoresis shows Hb Barts. Dx?

Answer 41

Hb Barts are tetramers of gamma globulin. These form in utero because of a genetic deletion of all 4 alpha globulin genes making production of alpha globulin impossible. HbF is normally made of alpha and gamma so all that is left is gamma.
Gamma tetramers damage the RBC’s, baby develops hydrops fetalis and dies

Question 42

What is hydrops fetalis? Polyhydramnios?

Answer 42

Abnormal accumulation of fluid in 2 or more fluid compartments in a fetus.
Polyhydramnios: too much amniotic fluid

Question 43

Which of the thalassemias is most common in Africans?

Answer 43

Trans deletion of alpha globulin genes

Question 44

Which of the thalassemias is most common in asians?

Answer 44

Cis deletion

This is worse than a trans deletion and may explain the high rates of spontaneous abortion in asia

Question 45

Which of the microcytic anemias has HbH on electrophoresis?

Answer 45

alpha thalassemia with three gene deletion
low levels of alpha globulin leads to beta globulin with nothing to bind except itself so it forms beta tetramers known as HbH

Question 46

How are the genetic defects different between alpha and beta thalassemia?

Answer 46

alpha is generally a deletion

beta is generally a mutation

Question 47

Which microcytic anemia has high ferritin, low TIBC, low serum iron, low % sat?

Answer 47

Anemia of chronic disease

has lots of iron, but it is stored away so the stores are high and the serum is low

Question 48

Which of the microcytic anemias has low ferritin, high TIBC, low serum iron, low % sat?

Answer 48

Iron deficiency anemia

no iron in the stores or in the serum

Question 49

Which of the microcytic anemias has high ferritin, low TIBC, high serum iron, high % sat?

Answer 49

Sideroblastic anemia

Iron overload putting lots of iron everywhere

Question 50

Of the thalassemia’s which will cause death in utero, and which will show Sx several months after birth?

Answer 50

Death in utero comes from complete deletion of all alpha globin genes leading to complete inability to form alpha globin

Sx appearing few months after birth is also a very serious condition but is beta thalassemia major where the baby doesn’t miss the beta’s until starts converting from gamma to beta globin