Session 7: Introduction to anaemia and vitamin B12 and folate metabolism

Question 1

Define anaemia

Answer 1

A haemoglobin concentration lower than the normal range.

Question 2

What are the causes of microcytic anaemia?

Answer 2

Symptoms: reduced rate of haemoglobin synthesis, erythrocytes smaller than normal, cells paler than normal( hypochromic)
Thalassaemia
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic anaemia( sufficient iron, but cannot put it into haem)
TAILS

Question 3

What are the causes of macrocytic anaemia?

Answer 3

Vitamin B def, folate def, myelodysplasia( immature blood cells in BM do not develop), liver disease, alcohol toxicity

Question 4

What are the causes of normocytic anaemia?

Answer 4

Primary bone marrow failure( aplastic anaemia), secondary bone marrow failure( ACD, Uraemia, HIV)

Question 5

What are signs and symptoms of anaemia?

Answer 5

Insufficient O2 for tissues, shortness of breath, palpitation, headaches, angina, weakness, lethargy, confusion, pallor, tachycardia, hypotension
Iron def: spoon shaped nails, inflammation of corners of mouth
Vit B def: inflammation of tongue
Thalassaemia: abnormal facial bone

Question 6

Haematinic deficiency(iron): what are its clinical features and causes?

Answer 6

Causes: insufficient iron in diet( esp vegan, vegetarian), malabsorption of iron, bleeding( gastric due to NSAID, mestrual cycle), increased requirement( pregnancy, rapid growth), anaemia of chronic disease( inflammatory bowel disease)
Clinical features: Epithelial changes( swollen ends of mouth, glossy tongue, spoon nails), cold hands and feet, pica, tiredness, pallor, reduced exercise tolerance, angina, development of heart failure.

Question 7

Describe roles and complications associated with haematinic replacement treatment

Answer 7

GI side effects: nausea, abdominal pain
Can lead to excess iron: transfusion associated haemosiderosis or hereditary haemochromostosis

Question 8

Give examples of good dietary sources of haem and non-haem iron

Answer 8

Haem: liver, kidney, beef steak, beef burger, chicken, duck, pork chop, salmon
Non-haem: fortified cereals, raisins, beans, figs, barley, oats

Question 9

Give an overview of iron absorption, transport, and metabolism

Answer 9

Absorption: occurs in duodenum and upper jejunum. Divalent metal transporter 1(DMT1) facilitates uptake of non-haem ferrous iron( Fe2+) from lumen. Ferric iron( Fe3+) is reduced to ferrous iron before uptake by DMT1. Haem is then degraded to form ferrous iron.
Control mechanisms: Hepcidin- negative regulator. Increases in iron overload, decreases in high erythropoietic activity. Induces degradation that blocks iron transport

Question 10

How does iron deficiency lead to anaemia?

Answer 10

There is insufficient iron to make Haem. Intially iron stores from tissues are used, but anaemia develops after depleted.

Question 11

Give an overview of the storage of iron

Answer 11

Functional/available iron: haemoglobing and myoglobin, being transported
Stored: ferritin( soluble)- globular protein with hollow core, pores allow iron to enter and be released. Haemosiderin( insoluble)- contains ferritin, denatured protein, and lipid. Accumulates in macrophages, esp liver, spllen and marrow.

Question 12

Give an overview of cellular iron uptake

Answer 12

fe3+ bound transferrin binds transferrin( binds to and transports iron) receptor and enters cytosol receptor-mediated endocytosis. fe3+ within endosome released by acidic microenvironment and reduced to fe2+. fe2+ transported to cytosol via DMT1. Once inside cytosol, fe2+ can be stored in ferritin, exported by ferroportin( FPN1), or taken up by mitochondria for use in cytochrome enzymes.

Question 13

Factors affecting absorption of non-haem iron from food

Answer 13

Negative: tannins( in tea), fibre, antacids
Positive: vitamin C and citrate- prevent formation of insoluble iron compounds, helps reduce ferric to ferrous iron

Question 14

HoGive an overview of iron recycling

Answer 14

Most iron requirement met through recycling damaged or senescent red blood cells. Old RBCs engulfed by splenic macrophages and kupffer cells of liver. Macrophages catabolise haem released from RBC. Amino acids reused and iron exported to blood through transferrin or returned to storage as ferritin macrophage.

Question 15

How is iron deficiency anaemia diagnosed?

Answer 15

1. Plasma ferritin: iron carrier, gives total iron. Low= iron def, but normal or increased does not exclude iron def as ferritin levels can increase in cancer, infection, inflammation, liver disease, alcoholism.
2. Recticulosyte haemoglobin content( CHr): for functional iron def. Low= inflammatory response OR thalassaemia, so cannot be used here
3. Low mean corpuscular volume( MCV): average size of RBC
4. Low mean corpuscular haemoglobin concentration( MCHC)
5. Elevated platelet count, WBC count
6. Low serum ferritin, iron, % transferrin saturation, raised TIBC( total iron binding capacity) means iron supply in body low, low recticulyte haemoglobin content( CHr)

Question 16

How does iron overload occur?

Answer 16

1. Transfusion associated haemosiderosis: iron accumulation from repeat blood transfusion. Transfusion dependant anaemia thalassaemia and sickle cell anaemia common issue. Desferrioamine- iron chelating( removing) agent can delay but not stop overload. Leads to liver cirrhosis, DM, slate grey skin colour.
2. Heriditary haemochromatosis: mutated HFE gene, cannot control iron uptake, too much enters cells, organ damage. Leads to liver cirrhosis, DM, increased skin pigmentation

Question 17

Describe causes and treatment of Hereditary haemochromatosis

Answer 17

Autosomal recessive disease caused by mutation in HFE gene. HFE protein normally reacts with transferring receptor, reducing its affinity for iron bound transferrin. HFE also promotes hepcidin( regulates iron absorption, high leves decrease absorption) expression through activation of signalling pathways in liver. Mutated HFE results in loss of negative influence on iron uptake and too much iron enters cells and accumulaes in end organs causing damage. Treated with venesection( drawing blood regularly).
Leads to: liver cirrhosis, DM, increased skin pigmentation etc

Question 18

Vitamin B haeminitic def: what are its causes and clinical signs?

Answer 18

Causes: dietary def, pernicious anaemia (progressive exhaustion of b12 due to decreased/absent intrinsic factor. Autoimmune disease), disease of ileum( Chron’s disease), chemical inactivation of b12( frequent use of nitrous oxide gas), parasitic infestation( tapeworm in fish can trap b12).
Symptoms: anaemic signs, mouth ulver, diarrhoea, distrubed visison, irritability, paraethesia( tingling sensation)

Question 19

Folate haeminitic def: what are its causes and clinical signs?

Answer 19

Folate: abundant in green leafy vegetables, stored in liver
Causes of def: poor diet, increased requirements( pregnancy, haemolytic anaemia- increased erythropoiesis, sever skin disease-psoriasis), duodenum and jejunum disease- coeliac, alcoholism( poor diet and damage to intestine), urinary loss of folate in liver disease and heart failure.
Symptoms: anaemic signs, reduced sense of tast, diarrhoea, numbness and tingling in feet and hands, muscle weakness, depression
Should be taken before conception and for 1st 12 weeks to prevent neural tube defect.

Question 20

How do inflammatory conditions lead to anaemia of chronic disease?

Answer 20

Cytokines released by immune cells:
1. Inhibit erythropoietin porduction by kidney- leads to inhibition of erythropoiesis in BM, leads to anaemia.
2. Increased production of hepcidin( prevents iron overload) by liver, inhibition of ferroportin( transports iron in cells). Decreased iron released from recticuloendothelial sysmtem, decreased absorption of iron in gut, leads to anaemia.

Question 21

How are folate and vitamin B linked?

Answer 21

Lack of B12 will trap folate in stable form, preventing its use in other reactions like DNA synthesis

Question 22

Why do folate and B12 def cause megaloblastic anaemia?

Answer 22

Both def lead to thymidine def, therefore U is incorporated into DNA instead of T. DNA repair enzymes detect these errors and repair them. Results in asynchronous maturation between nucleus and cytoplasm. Nucleus does not fully mature and cytoplasm matures at normal rate.
Both def can lead to low platelets and neutrophils

Question 23

What lab results can you expect to find in a patient with megaloblastic anaemia?

Answer 23

Low: haemoglobin, erythrocyte count, recticulocyte count
High: MCV, serum ferriting, LDH( plasma lactate dehydrogenase due to increased cells destruction and production), bilirubin.
BM: increased cellularity
Platelet and leucocyte typically low, but can be normal

Question 24

What is the treatment for vit B12 and folate def?

Answer 24

Folate: oral folic acid
Vit B12:
for pernicious anaemia( lack of intrinsic factor, cells that make stomach lining are attacked): IM medication. Beware of hypokalaemia, due to incerase K+ reuirements as erythropoiesis increases.
For other causes: oral medication.
Blood transfusion in pts with severe anaemia can lead to high output cardiac failure.

Question 25

Sideroblastic anaemia: causes

Answer 25

Sufficient iron, but unable to put it into haem. Due to high alcohol use, vitamin B6 def