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Metabolism, Endocrinology and Haematology > Anaemia, Vitamin B12, Folate metabolism and megaloblastic anaemia > Flashcards

Anaemia, Vitamin B12, Folate metabolism and megaloblastic anaemia Flashcards

1
Q

What is anaemia?

A

Haemoglobin concentration lower than the normal range. The normal range varies with age sex and ethnicity.

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2
Q

What are the symptoms of anaemia?

A

Can be relatively mild due to slow onset; the body adjusts to the lower levels of haemoglobin by increasing other factors. In acute onset anaemia, the symptoms are more severe: Fatigue Dyspnoea Palpitations Headache Patients with underlying vascular disease may experience angina and intermittent claudication.

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3
Q

What are the clinical signs of anaemia?

A

Pallor Tachycardia Systolic murmur

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4
Q

Why does anaemia develop?

A

In the bone marrow:

  • reduced erythropoiesis (dyserythropoiesis)
  • abnormal haemoglobin synthesis

In peripheral blood cells:

  • abnormal structure/function
  • abnormal metabolism

Removal

  • excess blood loss
  • abnormal function of reticuloendothelial system
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5
Q

What is the reticuloendothelial system?

A

A network of cells and tissues that have the ability to phagocytose. They are either found freely circulating in the blood or fixed to various tissues; alveoli (pulmonary alveolar macrophages), liver sinusoids (Kupffer cells), skin, spleen (macrophages) and joints. Also known as mononuclear phagocyte system.

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6
Q

What are the three different classes of anaemia?

A
  • Macrocytic (large cells)
  • Microcytic (small cells)
  • Normocytic (average sized normal)
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7
Q

What are the types of macrocytic anaemia?

A
  • B12 or folate deficiency
  • Liver disease
  • Alcohol excess
  • Haemolytic anaemia
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8
Q

What are the types of microcytic anaemia?

A
  • iron deficiency
  • anaemia of chronic disease
  • thalassaemia
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9
Q

What are the types of normocytic anaemia?

A

Most common type of anaemia

  • sickle cell disease
  • early iron deficiency
  • anaemia of chronic disease
  • blood loss
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10
Q

What causes abnormal erythropoiesis (dsyerythropoesis)?

A
  • Damage to the bone marrow through exposure to
    • benzene
    • chemotherapy
    • ionising radiation
    • cancer cells or fibrous tissue (myefibrosis)
  • Parovirus infection
  • Autoimmunity
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11
Q

What happens in abnormal erythropoiesis?

A
  • Pancytopenia
    • low RBC (anaemia)
    • low WBC (leucopenia)
    • low platelets (thrombocytopenia)
  • Aplastic anaemia
    • the inability of haematopoietic stem cells to produce mature RBC
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12
Q

What pathology from outside the bone marrow can result in abnormal erythropoiesis?

A

Chronic kidney disease leads to an insufficient erythropoietin production and the rate of erythropoiesis slows down resulting in anaemia.

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13
Q

What causes abnormal haemoglobin synthesis?

A
  1. Iron deficiency anaemia
  2. Anaemia of chronic disease
  3. Globin gene mutation
    • sickle cell disease
    • thalassaemia
  4. Deficiencies in the building blocks of DNA synthesis
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14
Q

What is anaemia of chronic disease?

A

anaemia caused by the functional loss of of iron which limits haemoglobin synthesis.

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15
Q

What are the two major examples of globin gene mutations?

A
  • Sickle cell anaemia (mutation altering the funcation of the haemoglobin molecule)
  • Thalassaemia (mutation altering the amount of haemolgobin produced)

mutations or deletions of genes that encode the globin proteins can result in abnormal haemoglobin production leading to anaemia.

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16
Q

Explain how anaemia can be cause by deficiencies in building blocks for DNA synthesis

A

Deficiency in Vitamin B12 (cobalamin) and folate (vitamin B9).

  1. Erythrocytic progenitor cells are unable to synthesise DNA.
  2. Lag in nuclear maturation and cell divison behind cytoplasmic development.
  3. Large (mega) RBC precursors are released into the blood stream with large nuclei and open chromatin
  4. Causes megoloblastic anaemia (large sized cells of ‘blast’/progenitor origin)
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17
Q

What is the most common cause of macrocytic anaemia?

A

Megaloblastic anaemia.

18
Q

What is classed as macrocytic anaemia?

A

mean corpsular volume > 100fl

19
Q

How would you identify megaloblastic anaemia on a blood film?

A
  • Erythrocytes frequently show an oval morphology (macro ovalocytes)
  • The size of RBC are larger than the nucleus of small lymphocytes
20
Q

What can also accompany severe deficiency macrocytic anaemia?

A
  • Neutropenia (low levels of neutrophils)
  • Thrombocytopenia (low levels of platelets)
21
Q

What is a source of folate/vitamin B9?

A

Green leafy vegetables such as broccoli, sprouts or peas.

22
Q

Who is at risk of folate deficiency?

A

Those with higher demands:

  • pregnant women
  • lactating women

Those wih lower absorption:

  • alcoholics
    • inadequate intake and damage to intestinal walls
  • Elderly
23
Q

How is folate absorbed by the body?

A
  • absorbed in the intestine
  • converted to tetrahydrofolate (FH4) by intestinal cells
  • enters portal circulation
  • stored in the liver
24
Q

What is the role of tetrahydrofolate in metabolism?

A
  • Acts as a one carbon carrier that accepts cabons from molecules such as serine, glycine, histidine and formate.
  • Attached carbons are oxidised or reduced to provide carbons for other metabolic reactions.
    • Thymidine and purine bases (adenine and guanine) require a one carbon pool for synthesis
  • allows the transfer of methyl groups to vitamin B12
25
Q

What can folate deficiency cause in pregnancy?

A

Neural tube defects in the developing fetus.

26
Q

Where do we get Vitamin B12 from in our diet?

A

Only obtained from food of animal origin e.g.

  • meat
  • fish
  • eggs
  • dairy
  • marmite
27
Q

Who is at risk of Vitamin B12 deficiency?

A
  • Vegans
  • Elderly
28
Q

What dosage of supplement should people on a vegan diet take?

A

10ug daily or 2mg weekly

29
Q

How is vitamin B12 from the diet absorbed?

A
  • B12 is released from proteins by proteases
  • free B12 forms a complex with haptocorrin proteins
  • haptocorrin-B12 complex is digested by pancreatic proteases in the small intestine
  • B12 is released and binds to intrinsic factor (glycoprotein)
    • B12-intrinsic factor complex can be internalised by receptors of the ileum
      • deficiency in intrinsic factor can cause pernicious anaemia
  • Internalised B12 forms a complex with transcobalamin II
  • B12-transcobalamin II complex is released into the blood stream and binds to specific tissue receptors
30
Q

Where is dietary B12 taken up and stored?

A

Roughly half is stored by the liver where it is sufficent to supply B12 demands of the body for ~3-6 years.

31
Q

What is pernicious anaemia?

A

Anaemia cause by a lack of B12 absorption due to a deficiency in the glycoprotein - intrinsic factor.

32
Q

What metabolic reactions is B12 required for?

A
  1. Methyl group transfer from:
    • L-methylmalonyl-CoA -> Succinyl-CoA
  2. Methyl group transfer from tetrahydrofolate (FH4) converting:
    • homotcysteine -> methionine
33
Q

How does vitamin B12 deficiency affect folate deficiency?

A

A lack of B12 ‘traps’ folate in a stable methyl-FH4 state preventing its use as a one carbon store and cannot be used in DNA synthesis.

This is known as functional folate deficiency; there is an adequate dietry supply of folate but it cannot be used due to a lack of vitamin B12

34
Q

What is the treatment for vitamin B12 deficiency?

A

Vitamin B12 replacement therapy (hydroxocobalamin) given intramuscularly on alternate days for 2 weeks follow by once every 3 months.

An intramuscular injection is given over oral administration because of a deficiency in absorption (pernicious anaemia; deficiency in intrinsic factor).

For diet related B12 deficiency oral B12 tablets can be taken.

35
Q

What is the treatment for folate deficiency?

A

Oral folic acid taken daily for ~4 months.

IMPORTANT: check patients vitamin B12 levels before starting folic acid as improvement could maks an underlying B12 deficiency and lead to neurological diseases.

36
Q

What is subacute degeneration of the cord?

A

Degeneration of the posterior and lateral columns of the spinal cord caused by vitamin B12 deficiency. This causes reversible peripheral neuropathy.

The onset of this disease is gradual and primarly presents with weakness, numbness and itngling in legs arms and trunk that progressively worsens. Changes in mental state can develop.

Eventually, if untreated, the condition will result in irreversible nerve damage.

IMPORTANT: always seek urgent advice from a haemotologist if neurological involvement is suspected in a patient with B12 deficiency.

37
Q

What are other causes of macrocytic anaemia?

A
  • Chronic excessive alcohol consumption
    • alcohol has weak anti-folate effects
    • poor dietary intake is common in alcoholic pts.
  • Liver disease unrelated to alcohol
  • Hypothyroidism
  • Haemolytic anaemia
    • increased proportion of reticulocytes in blood relative to mature RBC (reticulocytes are larger than mature RBC)
38
Q

What are the clinical signs of Vitamin B12 deficiency?

A

atrophic glossitis (shiny tongue)

39
Q

What is the life span of a RBC?

A

120 days

40
Q

What are common clinical finding in dsyerythropoesis?

A

increase in C reactive protein and ferritin

Metabolism, Endocrinology and Haematology (5 decks)

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