Chapter 12: Red cell disorders - Anemia of Diminished Erythropoiesis

Question 1

Deficiency of … is the most common nutritional deficiency in the world and results in clinical signs and symptoms that are mostly related to anemia

Answer 1

iron

Question 2

What protein regulates the absorption of iron?

Answer 2

Hepcidin, secreted from the liver in an iron-dependent fashion.

Question 3

Fill in: In general, high iron levels in the plasma … hepcidin production, whereas low iron levels …. it

Answer 3

In general, high iron levels in the plasma -enhance- hepcidin production, whereas low iron levels -suppress- it

Question 4

In what other situation will hepcidin levels rise?

Answer 4

In the face of systemic inflammation. Inflammatory mediators like IL-6 have a direct effect on hepatocytes. Or during ineffective hematopoiesis (which is marked by increased numbers of erythroblasts in the bone marrow)

Question 5

Fill in: Thus, when hepcidin concentrations are elevated, such as when serum iron levels are … (1) or there is … (2), ferroportin levels … (3) and more iron is incorporated into cytoplasmic ferritin and is lost by excretion.

Answer 5

1. high 2. systemic inflammation 3. fall

Question 6

Fill in: Conversely, when hepcidin levels are low, such as when there is … (1), … (2), or the genetic defects that lead to primary hemochromatosis , the basolateral transport of iron is increased.

Answer 6

1. iron deficiency 2. ineffective hematopoiesis

Question 7

In what situations does iron deficiency arise?

Answer 7

• Chronic blood loss
• Low iron intake and poor bioavailability because of predominantly vegetarian diets
• Increased demands during pregnancy and infancy are not met.
• Malabsorption, like with celiac disease.

Question 8

If you look at this picture, what is different than usual?

Answer 8

These are red blood cells with iron deficiency anemia. Note the increased central pallor of most of the red cells (hypochromic) and the fact that they’re smaller (microcytic). Scattered, fully hemoglobinized cells, from a recent blood transfusion, stand out in contrast.

Question 9

What is a key regulator in anemia of chronic inflammation and why?

Answer 9

High levels of plasma hepcidin, the elevated hepcidin levels are caused by proinflammatory cytokines such as IL-6, which increase hepatic hepcidin synthesis (so there’s more iron excretion and automatically there’s less iron for the production of red blood cells).

Question 10

What is the function of the protein hepcidin?

Answer 10

It circulates to the duodenum where it binds ferroportin and induces its internalization and degradation.

Question 11

What happens during chronic inflammation when hepcidin levels are high?

Answer 11

Ferroportin is downregulated, this prevents the transfer of iron to erythroid precursors.

Question 12

What are the two principal causes of megaloblastic anemia?

Answer 12

Folate deficiency and vitamin B12 deficiency.

Question 13

What will result from a folate or vitamin B12 deficiency and why?

Answer 13

Disturbed proliferation and maturation of erythroblasts. Deficiency in folate of B12 results in inadequate synthesis of thymidine, one of the building blocks of DNA. This is because folate and B12 are both essential factors for the synthesis of thymidylate, essential for DNA replication.

Question 14

What is meant by nuclear-cytoplasmic asynchroncy?

Answer 14

Folate or B12 deficiency result in impaired DNA synthesis. So in dividing cells, DNA synthesis is impaired but RNA not. Thus, RNA synthesis in the cytoplasm happens at a normal rate while DNA synthesis in the nucleus is impaired.

Question 15

What does nuclear-cytoplasmic asynchrony result in (or in general what does DNA impairment of red blood cells result in)?

Answer 15

This maturational derangement contributes to the anemia in several ways:

• Red cell progenitors are so defective that they undergo apoptosis (ineffective hematopoiesis).
• Other progenitors only mature after fewer cell divisions
• Granulocyte and platelet precursors are also affected.

Question 16

What is pancytopenia?

Answer 16

Anemia, thrombocytopenia and granulocytopenia.

Question 17

What are common morphologic features of megaloblastic anemia?

Answer 17

Bone marrow is markedly hypercellular and contains numerous megaloblastic erythroid progenitors. In the peripheral blood hypersegmented neutrophils can be found.

Question 18

If you look at this picture, what kind of anemia is this and why?

Answer 18

Megaloblastic anemia. The picture shows a hypersegmented neutrophil with a six-lobed nucleus.

Question 19

Just know that the pathogenesis/pathways of folate and B12 deficiencies will not (or only briefly) be discussed here, since they are barely mentioned in the lecture. The text is on page 456-457.

Answer 19

Okay

Question 20

What can be a cause of vitamin B12 deficiency?

Answer 20

Pernicious anemia, which is believed to result from an autoimmune attack on the gastric mucosa that suppresses the production of intrinsic factor

Question 21

A quick read about vitamin B12 absorption:

Answer 21

1. Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin.
2. On entering the duodenum, haptocorrin–B12 complexes are processed by pancreatic proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa.
3. The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubilin, a receptor for intrinsic factor, and are taken up into enterocytes.
4. The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes to plasma transcobalamin, which delivers vitamin B12 to the liver and other cells of the body.

Question 22

What is aplastic anemia?

Answer 22

A disorder in which multipotent myeloid stem cells are suppressed, leading to bone marrow failure and pancytopenia.

Question 23

The pathogenesis of aplastic anemia is not fully understood, but two major etiologies have been invoked. These are of intrinsic and extrinsic cause. What are these?

Answer 23

Intrinsic: abnormality of stem cells. Extrinsic: immune-mediated suppression of marrow progenitors

Question 24

Describe the extrinsic etiology of aplastic anemia (don’t learn this by heart).

Answer 24

The hypothesis is that active T cells suppress hematopoietic stem cells that have been antigenically altered by exposure to drugs, infectious agents, or other unidentified environmental insults. Th1 cells produce cytokines like IFN-γ and TNF that suppress and kill hematopoietic progenitors.

Question 25

Describe the intrinsic etiology of aplastic anemia. (don’t learn this by heart).

Answer 25

Observations show an intrinsic stem cell abnormality caused by inherited defects in telomerase (premature senescence of hematopoietic stem cells).

Question 26

What causes myelophthisic anemia?

Answer 26

Extensive infiltration of the marrow by tumors or other lesions (most commonly associated with metastatic breast, lung, or prostate cancer).

Question 27

What is meant by polycythemia or erythrocytosis?

Answer 27

It denotes an increase in red cells per unit volume of peripheral blood