Session 7 ILO's Introduction to anaemia, B12 & folate metabolism and megaloblastic anaemia

Question 1

Define the term anaemia

Answer 1

A haemoglobin concentration lower
than the normal range.

Normal range will vary with age, sex and ethnicity so the point at which a patient becomes anaemic depends on these parameters

Question 2

Understand the important causes of microcytic anaemia

Answer 2

Microcytic anaemia (decreased RBC size):

TAILS:
- Thalassaemia
- Anaemia of chronic disease
- Iron deficiency
- Lead poisoning
- Sideroblastic anaemia
Serum Iron studies will help you determine which one of TAILS microcytic anaemia is caused by

• Reduced haem synthesis (iron deficiency, lead poisoning, anaemia of chronic disease, sideroblastic anaemia)
• Reduced global chain synthesis (alpha-thalassaemia or beta-thalassaemia)

Question 3

Understand the important causes of normocytic anaemia

Answer 3

Normocytic anaemia (normal RBC size):
- Mostly acquired e.g. as a result of disease = anaemia of chronic disease (ACD) or anaemia of inflammation
- Also can be congenital or can be a complication from a particular medication
Causes: primary bone marrow failure (aplastic anaemia), secondary bone marrow failure (e.g. ACD, uraemia, HIV)

Question 4

Understand the important causes of macrocytic anaemia

Answer 4

Macrocytic anaemia (increased RBC size):

Causes:
- Vit B12 deficiency
- Folate deficiency,
- Myelodysplasia
- Liver disease
- Alcohol toxicity

E.g. in
- Megaloblastic anaemias
- Macronormoblastic anaemias
- ‘Stress’ erythropoiesis

Question 5

What causes the signs and symptoms of anaemia?

Answer 5

Haemoglobin carries O2. General signs and symptoms therefore related to insufficient delivery of O2 to tissues

Question 6

Outline the symptoms of anaemia (8)

Answer 6

• Shortness of breath
• Palpitations
• Headaches
• Claudication
• Tachypnoea
• Angina
• Weakness & Lethargy
• Confusion

Question 7

Outline the signs of anaemia (5)

Answer 7

• Pallor
• Tachycardia
• Systolic flow murmur
• Tachypnoea
• Hypotension

Question 8

Discuss the specific signs associated with the causes of anaemia

Answer 8

Question 9

Discuss a key clinical point about anaemia

Answer 9

Anaemia in itself is not a diagnosis but a manifestation of an underlying disease state and it is important to establish the cause of the anaemia

Question 10

What is a key clinical point about folate.

Answer 10

Question 11

Outline the common clinical features and important underlying causes of haematinic deficiency (iron, vitamin B12 or folate deficiency)

Iron deficiency

Answer 11

Iron deficiency - most common nutritional disorder worldwide:

Clinical features: sign not a diagnosis, extreme fatigue, weakness, pale skin, fast heartbeat or shortness of breath

• Physiological effects of anaemia….
• Tiredness
• Pallor
• Reduced exercise tolerance (due to reduced oxygen carrying capacity)
• Cardiac – angina, palpitations, development of heart failure
• Increased respiratory rate
• Headache, dizziness, light-headedness
• Pica (unusual cravings for non-nutritive substances e.g. dirt, ice)
• Cold hands and feet
• Epithelial changes
  Could be due to:
• Insufficient intake/poor absorption
• Physiological reasons e.g. pregnancy * Pathological reasons e.g. bleeding

Underlying causes:

• Insufficient iron in diet
  e.g. Vegan & vegetarian diets
• Malabsorption of iron
  e.g. Vegan & vegetarian diets
• Bleeding
  e.g. Menstruation, gastric bleeding due to chronic NSAID usage
• Increased requirement
  e.g. Pregnancy, rapid growth
• Anaemia of chronic disease
  e.g. Inflammatory bowel disease

Question 12

Outline the common clinical features and important underlying causes of haematinic deficiency (iron, vitamin B12 or folate deficiency)

Folate deficiency

Answer 12

Folate deficiency

Clinical features:

• Those related to anaemia
• Reduced sense of taste
• Diarrhoea
• Numbness and tingling in feet and hands (paraesthesia)
• Muscle weakness
• Depression

Underlying causes:
* Dietary deficiency (Poor diet)
* Increased requirements:
- Pregnancy
- Increased erythropoiesis e.g. haemolytic anaemia
- Severe skin disease (e.g. psoriasis, exfoliative dermatitis)
* Disease of the duodenum and jejunum (e.g. coeliac disease, Crohn’s disease)
* Drugs which inhibit dihydrofolate reductase (e.g. Methotrexate)
* Alcoholism (poor diet and damage to intestinal cells)
* Urinary loss of folate in liver disease and heart failure

Question 13

Outline the common clinical features and important underlying causes of haematinic deficiency (iron, vitamin B12 or folate deficiency)

Vitamin B12 Deficiency

Answer 13

Vit B12 deficiency:

Clinical features:
* Those related to anaemia
* Glossitis & mouth ulcers
* Diarrhoea
* Paraesthesia
* Disturbed vision
* Irritability

Underlying causes:
* Dietary deficiency (Vegan diet lacking B12 supplementation)
* Lack of intrinsic factor (Pernicious anaemia)
*Diseases of the ileum (Crohn’s disease, ileal resection, tropical sprue)
*Lack of transcobalamin (congenital defect)
*Chemical inactivation of B12 e.g. frequent use of anaesthetic gas nitrous oxide
*Parasitic infestation (rare tapeworm found in fish can trap B12)
* Some drugs can chelate intrinsic factor (e.g. hypercholesterolaemia drug Cholestyramine)

Question 14

Describe Pernicious anaemia

Answer 14

• Decreased or absent Intrinsic factor (IF) causes progressive exhaustion of B12 reserves.
• Autoimmune disease
• 2 types of Antibody (Ab) :
• Blocking Ab (more common) blocks binding of B12 to IF.
• Binding Ab prevents receptor mediated endocytosis.

Question 15

Describe the role and complications associated with haematinic replacement treatment

Iron deficiency

Answer 15

Treatments:

Iron deficiency:
- Dietary advice
- Oral iron supplements (Safest, first-line therapy for most patients but many experience GI side effects and compliance with treatment poor)
- Intramusclar iron injections
- IV iron
- Blood transfusion (Only used if severe anaemia with imminent cardiac compromise)

Response:
* Improvement in symptoms
* 20g/L rise in Hb in 3 weeks

• RISK is that excess iron can be deposited in organs as haemosiderin and iron promotes free radial formation and organ damage
• RISK of transfusion associated haemosiderosis or hereditary haemochromostosis

CHECK SLIDES FOR MORE DETAIL ABOUT RISKS

Question 16

Describe the role and complications associated with haematinic replacement treatment

Vitamin B12 deficiency

Answer 16

Vit B12 deficiency - caused by pernicious anaemia:
- Intramuscular Hydroxocobalamin (not oral)
- RISK of hypokalaemia at the beginning of treatment due to increased K+ requirement as erythropoiesis increases back to normal rate

Vit B12 deficiency - other causes (not pernicious anaemia):
- Oral Hydroxocobalamin
- Note: blood transfusion in patients with severe B12 deficiency anaemia can cause high output cardiac failure

Question 17

Describe the role and complications associated with haematinic replacement treatment

Folate deficiency

Answer 17

• Oral folic acid

Complications:
- Serious allergic reaction
- Skin rash that may include itchy, red, swollen, blistered or peeling skin.
- Wheezing.
- Tightness in the chest or throat
- Mouth, face, lips, tongue or throat start swelling.

Question 18

List the different causes of microcytic anaemia

Answer 18

Question 19

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

Answer 19

Haem Iron (in ferrous form)
- associated with haemoglobin from animals
i.e. liver kidney, beef steak, beef burger, chicken, duck, pork chop, salmon/tuna

Non Haemoglobin iron (Either Fe2+ or fe3+) needs to all be converted to ferrous form, to be absorbed - ferric iron needs to be reduced to serous iron
fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes

Question 20

Give an overview of iron absorption, transport, uptake, storage and metabolism

Answer 20

Absorbtion:
- Dietary iron (haem Fe2+ or non-haem Fe2+ and Fe3+) is absorbed by DMT1 (vit C is a co-factor in Fe3+ reduction) into the enterocytes of the small intestine

Transport:
- First, Fe2+ needs to be converted to Fe3+
- Two Fe3+ can bind to transferrin which can transport iron around the body

Storage:
- Iron needs to be stored in the ferric form of Fe3+ bound to ferritin (soluble)
- Haemosiderin are aggregates of clumped ferritin (insoluble) which accumulate in macrophages mainly in liver, spleen and marrow

Uptake into tissues:
- Occurs by receptor mediated endocytosis
- Fe3+ bound with transferrin enters cell by receptor mediated endocytosis
- Fe3+ released by acidic environment in endosome and is reduced to Fe2+
- Fe2+ transported to cytosol via DMT1
- Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin or taken up by mitochondria

Question 21

Understand how iron deficiency leads to anaemia

Answer 21

Anaemia develops if the supply of iron is inadequate for the requirements of haemoglobin synthesis

Question 22

Describe how iron deficiency anaemia is diagnosed

Answer 22

Iron deficiency anaemia is diagnosed by:
- Plasma ferritin (gives a definitive diagnosis)
- But, normal or increased plasma ferritin does not exclude iron deficiency!
- CHr (reticulocyte haemoglobin content) can test for functional iron deficiency

Question 23

Appreciate how iron overload can occur

Answer 23

Iron overload can occur by:

1. Transfussion associated haemosiderosis
   - Repeated blood transfusions cause gradual accumulation of iron
   - Iron chelating agents (e.g. desferrioxamine) can reduce this, but can’t prevent it
   - Accumulation of iron in liver, heart and endocrine organs
2. Hereditory haemochromatosis
   - Autosomal recessive disease from mutation in HFE gene
   - HFE proteins normally interacts with the transferrin receptor reducing the affinity for iron-bound transferrin
   - HFE also promotes hepcidin expression through signalling pathways in the liver
   - Too much iron enters the cells and accumulates in end organs
   - Treatment with venesection

Question 24

Describe the causes of Hereditary Haemochromatosis

Answer 24

Causes:
Hereditary haemochromatosis is an autosomal recessive disease characterised by excessive absorption of dietary iron. As there is no system for the excretion of excess iron, iron accumulates in tissues and organs disrupting normal function. The most susceptible organs include liver, adrenal glands, heart, joints, and pancreas. Patients therefore present with cirrhosis, adrenal insufficiency, heart failure arthritis or diabetes.

Question 25

Describe the treatment of Hereditary Haemochromatosis

Answer 25

Therapeutic phlebotomy to remove excess iron.

Question 26

Describe how you can evaluate anaemia

Answer 26