Macrocytosis and Macrocytic Anaemias

Question 1

What cell does macrocytosis refer to?

Answer 1

RBC’s

Question 2

What is macrocytosis?

Answer 2

Anaemia in which the red cells have a larger than normal volume

Question 3

What measurement assesses RBC size?

Answer 3

MCV – Mean Corpuscular (cellular) Volume

Question 4

What is the units of MCV?

Answer 4

Femtolitres (1femtolitre = 10-15L).

Question 5

What would the blood results be of a patient with macrocytic anaemia?

Answer 5

• Low Hb
• Low RCB’s
• High MCV

Question 6

What would the blood results be of a patient with macrocytosis (without the anaemia)?

Answer 6

• Normal Hb
• Normal RBC’s
• High MCV

Question 7

On a blood film, what is the size of RBC’s normally comparable to?

Answer 7

The nucleus of lymphocytes

Question 8

If a RBC is smaller than the nucleus of a lymphocyte then it can be described as?

Answer 8

Microcytic

Question 9

If a RBC is larger than the nucleus of a lymphocyte then it can be described as?

Answer 9

Macrocytic

Question 10

Outline what the causes of an apparent macrocytosis can be grouped into

Answer 10

1. True - megaloblastic or non-megaloblastic

2. Spurious (false)

Question 11

What is an erythroblast/normoblast?

Answer 11

A normal red cell precursor with a nucleus

Question 12

What is the basic structure of a mature red cell?

Answer 12

Flexible cell membrane surrounding soluble proteins and electrolytes

Question 13

Do red cell precursors have a nucleus?

Answer 13

No – the reticulocyte doesn’t, but the other precursors do (erythroblasts)

Question 14

Where are red cell precursors usually found?

Answer 14

Bone marrow

Question 15

What is a reticulocyte?

Answer 15

An immediate precursor of the red cell that has lost its nucleus, but still has a little bit of RNA in it

Question 16

Outline 3 things that happen to erythroid cells in bone marrow as they develop.

Answer 16

• Accumulate Hb
• Reduce in size
• Stop dividing and lose nucleus (regulated by Hb content)

Question 17

Describe megaloblastic development.

Answer 17

Involves the development of an abnormally large nucleated red cell precursor with an immature nucleus.

Question 18

What are megaloblastic anaemias characterised by? (in terms of what is defective and what is preserved)

Answer 18

Predominant defects in DNA synthesis and nuclear maturation, with relative preservation of RNA and haemoglobin synthesis

Question 19

What happens in more mature erythroblasts?

Answer 19

Division reduces and apoptosis increases

Question 20

What happens in the few erythroblasts that survive as ‘megaloblasts’? What does this lead to? And why does this make a patient anaemic?

Answer 20

Cytoplasm development occurs normally and triggers enucleation

• this leads to a ‘bigger-than-normal’ red cell.
• the patient is anaemic because there are FEWER of these big red cells

Question 21

What is the end result in enucleation?

Answer 21

Nucleus is more immature, and chromatin is less condensed

Question 22

The larger cell size in megaloblastic anaemia is not due to an increase in the size of the developing cell but ….

Answer 22

A failure to become smaller

Question 23

Suggest some causes of megaloblastic anaemia.

Answer 23

• B12 deficiency
• Folate deficiency
• Others – drugs, rare inherited abnormalities

Question 24

Why does lack of B12 or folate cause megaloblastic anaemia?

Answer 24

B12 and folate are essential co-factors for nuclear maturation, enabling chemical reactions that provide enough nucleosides for DNA synthesis

Question 25

B12 and folate biochemical reactions are interlinked Name 2 ‘cycles’ which these are involved in.

Answer 25

1. Methionine cycle | 2. Folate cycle

Question 26

What is the folate cycle important for? And what reaction does folic acid specifically catalyse?

Answer 26

Important for nucleoside synthesis Conversion of uridine to thymidine in nucleoside synthesis (know for exams!!!)

Question 27

What does the methionine cycle do?

Answer 27

Produces s-adenosyl methionine, a methyl donor (potential impact on DNA, RNA, proteins, lipids, folate intermediates)

Question 28

What do B12 and folate both catalyse?

Answer 28

The conversion of homocysteine to methionine

Question 29

What is the folate cycle important for?

Answer 29

The DNA cycle and nucleic acid synthesis

Question 30

What is the methionine cycle aka?

Answer 30

The methylation cycle

Question 31

What is the measurement of things like homocysteine and other metabolites useful for?

Answer 31

Diagnosing B12/folate deficiency * Some of the metabolites may increase

Question 32

What is vitamin B12 also known as?

Answer 32

Cobalamin

Question 33

What kind of pH do we need for vitamin B12 to be released from foods?

Answer 33

Acidic

Question 34

What is the role of intrinsic factor?

Answer 34

Intrinsic factor is secreted into the lumen of the stomach from gastric parietal cells in response to the presence of food in the stomach

Question 35

What is the route taken by vitamin B12 and intrinsic factor after having been in the stomach?

Answer 35

B12 and intrinsic factor travel together into the proximal small bowel where the pancreas secretes its enzymes, creating an alkaline environment in which B12 can finally bind to intrinsic factor

Question 36

What does the B12-intrinsic factor complex do?

Answer 36

Travels to the terminal ileum where there are cubulin receptors to which it binds, and then becomes internalised

Question 37

Where does B12 and intrinsic factor become absorbed?

Answer 37

Terminal ileum

Question 38

Outline some potential areas of the body where vitamin B12 deficiency can occur.

Answer 38

* From mouth * Pancreas * Stomach * Small bowel

Question 39

What kind of stomach problems can results in a vitamin B12 deficiency?

Answer 39

Basically anything that reduces acid production * Pernicious anaemia * Atrophic gastritis * PPI's/H2 receptor antagonists * Gastrectomy/bypass

Question 40

What kind of diet can result in vitamin B12 deficiency?

Answer 40

Veganism/vegetarianism

Question 41

What kind of pancreatic problems can results in a vitamin B12 deficiency?

Answer 41

Chronic pancreatitis

Question 42

What kind of jejunum problem can result in a vitamin B12 deficiency?

Answer 42

* Bacterial overgrowth | * Coeliac disease

Question 43

What kind of duodenal problem can result in a vitamin B12 deficiency?

Answer 43

* Resection | * Crohn's

Question 44

What is pernicious anaemia?

Answer 44

An autoimmune condition resulting in the destruction of gastric parietal cell

Question 45

What is the effect of destruction of gastric parietal cells in PA?

Answer 45

Intrinsic factor deficiency, with B12 malabsorption and deficiency.

Question 46

What is pernicious anaemia associated with?

Answer 46

* Atrophic gastritis. * Personal or family history of other autoimmune disorders e.g. hypothyroidism, vitiligo, Addison’s disease Look out for a question about a person with hypothyroidism who has become anaemic !!!

Question 47

What are dietary folates converted to?

Answer 47

Monoglutamate

Question 48

Where is monoglutamate absorbed?

Answer 48

In the jejunum – both actively and via diffusion

Question 49

Think B12 is absorbed Below folate. | ileum vs jejunum

Answer 49

T

Question 50

Where is folate absorbed?

Answer 50

Jejunum

Question 51

Where is B12 absorbed?

Answer 51

Ileum

Question 52

What foods to we get vitamin B12 from?

Answer 52

Animals - meat, eggs etc

Question 53

What foods do we get folate from?

Answer 53

Leafy green veg

Question 54

Outline causes of folate deficiency.

Answer 54

1. Inadequate Intake (from diet) 2. Malabsorption - coeliac, crohn's 3. Excess Utilisation - haemolytic, pregnancy, 4. Drugs - Anticonvulsants.

Question 55

What anticonvulsant can predispose someone to a folate deficiency?

Answer 55

Phenytoin

Question 56

What signs and symtoms are common to both folate and vitamin B12 deficiency?

Answer 56

* Sx/signs of anaemia. * Weight loss, diarrhoea, infertility. * Fatigue. * Sore tongue (glossitis). * Jaundice. * Developmental problems.

Question 57

What problem tends to manifest more greatly with vit B12 deficiency?

Answer 57

Neurological problems ** Think B12 for Brain **

Question 58

How does B12 deficiency result in neurological problems?

Answer 58

Affects myelin

Question 59

What neurological problems arise with vitamin B12 deficiency?

Answer 59

* Posterior/dorsal column abnormalities * Neuropathy * Dementia * Psychiatric manifestations

Question 60

Neurological findings may occur in the absence of haematological findings.

Answer 60

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Question 61

What condition arises if folic acid is given without B12 replacement?

Answer 61

Subacute combined degeneration of the cord

Question 62

What are the lab findings in macrocytic anaemia?

Answer 62

1. Macrocytic anaemia  red cells low. 2. Blood film findings 3. Pancytopenia (all cells low) in some patients

Question 63

What is the characteristic blood film appearance seen in lab of macrocytic anaemia due to vitamin B12 or folate deficiency?

Answer 63

Macro-ovalocytes + Hypersegmented neutrophils (more than the normal 3-5 nuclear segments).

Question 64

What is pancytopenia?

Answer 64

Decrease in RBC's, WBC's and platelets

Question 65

How should megaloblastic anaemia be treated?

Answer 65

The cause should be treated

Question 66

How is pernicious anaemia treated?

Answer 66

With vitamin B12 (hydroxycobalamin in Europe) injections for life (note – high dose oral hydroxycobalamin may be effective) Folic acid tablets (5mg per day) orally

Question 67

What is the last resort treatment for pernicious anaemia?

Answer 67

Red cell transfusion – only if there is potential life-threatening anaemia

Question 68

What does non-megaloblastic macrocytosis occur due to?

Answer 68

Red cell membrane changes

Question 69

Suggest some causes of non-megaloblastic macrocytosis.

Answer 69

* Alcohol * Liver disease * Hypothyroidism * Marrow failure (associated with anaemia)

Question 70

If there is isolated macrocytosis, think about excess alcohol intake

Answer 70

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Question 71

What does megaloblastic macrocytosis occur due to?

Answer 71

A problem of the nucleus

Question 72

What is spurious macrocytosis?

Answer 72

‘false macrocytosis’ – the size of the mature red cell is normal, but the MCV is measured as being high

Question 73

What is spurious macrocytosis usually due to?

Answer 73

A mis-interpretation by the analyser.

Question 74

What are the 2 potential causes of spurious macrocytosis?

Answer 74

1. Increased reticulocyte numbers | 2. Cold agglutinations

Question 75

What do increased reticulocyte numbers occur due to?

Answer 75

Occurs as a marrow response to acute blood loss or red cell breakdown (haemolysis).

Question 76

Why does increased reticulocyte numbers result in spurious macrocytosis?

Answer 76

Reticulocytes are bigger than mature red cells, and are analysed along with these for the MCV measurement

Question 77

Why does cold agglutinins result in spurious macrocytosis?

Answer 77

The clumps of ‘agglutinated’ red cells are registered as 1 ‘giant’ cell

Question 78

The reticulocyte count is raised in acute situations because the body is trying to counteract blood loss or haemolysis by producing more red blood cells.

Answer 78

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Question 79

How may some patients with PERNICIOUS ANAEMIA appear?

Answer 79

Mildly jaundiced

Question 80

Why do people with pernicious anaemia appear mildly jaundiced?

Answer 80

Due to intramedullary haemolysis There is ineffective erythropoiesis, meaning red cells die prematurely in the marrow. Haemoglobin and lactate dehydrogenase (LDH) are then released from dead red cells. And haemoglobin is converted to bilirubin.

Question 81

What can complicate severe megaloblastic anaemia? Why?

Answer 81

Pancytopenia * Nuclear maturation defects can affect multiple lineages