Session 4- Introduction to anaemia & Vitamin B12 and folate metabolism Flashcards
define anaemia
a haemoglobin concentration lower than the normal range which varies
clinical signs of anaemia
glossitis, spoon shaped nails, angular chelitis
-Pallor • Tachycardia • Systolic flow murmur • Tachypnoea • Hypotension
symtoms of anaemia
Shortness of breath • Palpitations • Headaches • Claudication • Angina • Weakness & Lethargy • Confusion
key clinical point of anaemia
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
specific signs associated with the cause of anaemia
Koilonychia
Glossitis
Angular stomatitis
Abnormal facial bone
development
Rare in recent times as
preventable with early diagnosis
Thalassaemia
koilonychia
(Spoon shaped nails)
Iron deficiency
glossitis
(inflammation & depapillation of tongue)
Vitamin B12 deficiency
angular stomatitis
(Inflammation of corners of the mouth)
Iron deficiency
why might anaemia develoop- bone marrow
Reduced or dysfunctional erythropoiesis Abnormal Haem synthesis Abnormal globin chain synthesis
why might anaemia develop- peripheral red blood cells
abnormal structure
mechanical damage
abnormal metabolism
removal- spleen
why might anaemia develop
increased removal by reticuloendothelial system
what is the role of erythropeitin in the hormonal control of erythropoiesis
when there is low blood oxygen pericytes in kidney sense hypoxia and produce erythropoietin
EPO travels in bloodstream and binds to receptors on erythblasts in bone marrow and stimulates red cell production
increased number of red cells in blood
high blood oxygen
negative feedback on pericytes
why might anaemia develop in reduced or dysfuntional erythpoiesis
Anaemia can result from marrow being
unable to respond to EPO
myelofibrosis
anaemia of chronic disease
myelodysplastic syndroms
myelofibrosis
If marrow is infiltrated by cancer cells
or fibrous tissue (myelofibrosis) the
number of normal haemopoietic cells is
reduced
anaemia of chronic disease
In Anaemia of chronic disease e.g. in
rheumatoid arthritis, iron is not made
available to marrow for rbc production
myelodysplastic syndrome
In rare forms of blood cancer called myelodysplastic syndromes abnormal clones of marrow stem cells limit the capacity to make both red and white blood cells
why might anaemia develop- defects in haemoglobin synthesis
Defects in the haem synthetic
pathway can lead to
Sideroblastic anaemia
Insufficient iron in diet can lead to iron deficiency anaemia (not enough iron to make Haem) Anaemia of chronic disease can result in a functional iron deficiency (sufficient iron in body but not made available for erythropoiesis
mutations in the genes encoding the globin chain proteins
• α Thalassaemia
• β Thalassaemia
• Sickle cell disease
why might anaemia develop- defects in red cell metabolism
G6DPH deficiency
pyruvate kinase deficiency
why might anaemia devlop- excessive bleeding
Chronic bleeding
• Heavy menstrual bleeding
• Repeated nosebleeds
• Haemorrhoids
Occult gastrointestinal bleeding
(blood lost in stool)
• Ulcers (stomach or
small intestine)
• Diverticulosis
• Polyps in large intestine
• Intestinal cancer
• Kidney or bladder tumours (blood
lost in urine)
autoimmune haemolytic anaemia
autoantibodies bind to the red cell membrane
proteins causing them to be recognised by
macrophages in the spleen and destroyed
2 key features can help to work out the cause of an anaemia
- The rbc size – macrocytic, microcytic, normocytic (big, small, normal)
- The presence or absence of reticulocytosis (has the marrow responded normally?)
reticulocytes
• Immature red blood cells (i.e. those which have just
been released from the marrow into blood)
• No nucleus & eliminate remaining mitochondria
• Typically compose ~1% of all red blood cells and take
~ 1 day to mature into erythrocytes
macrocytic anaemia
FAT RBC
foetus- increased folate demand in late pregnancy
alcohol- toxicity towards bone marrow + secondary likely B12/Folate deficiency
hypoThyrodism- low thyroid hormones affect hormones involved in haemopoiesis
reticulocytes- secondary to blood loss, many reticulocytes are produced
B12/Folate- deficiency/pernicious- thymine deficiency- uracil used - constant DNA repaire - nucleus never matures, glossitis
Cirrhosis/ chronic liver disease- not fully confirmed yet, maybe excess cholesterol deposition
megaloblastoc anaemia
• Interference with DNA synthesis during erythropoiesis causes development of nucleus to be retarded in relation to maturation of cytoplasm • Cell division delayed and erythroblasts continue to grow to form megaloblasts which give rise to larger red cells
macronormoblastic erythropoiesis
• Normal relationship between development of nucleus and cytoplasm is retained but erythroblasts are larger than normal and give rise to larger red cells
stress erythropoiesis
Conditions associated with a high reticulocyte count (reticulocytes are larger than normal red cells) • High level of erythropoietin leads to an expanded and accelerated erythropoiesis
microcytic anaemia
TAILS
These anaemias present with a reduced RBC size that are often pale (hypochromic)
Thalassaemia: Reduced/absent synthesis of a globin chain in haemoglobin → abnormal facial bone
development as the bone marrow tries to ramp up haemopoiesis
Anaemia of chronic disease: Reduced iron availability (covered in a few slides)
Iron deficiency: insufficient iron available to meet haem synthesis requirements
Lead poisoning: inhibits haem synthesis enzymes
Sideroblastic anaemia: genetic defect in haem synthesis
normocytic anaemia
These anaemias present with normal sized RBCs
Acute blood loss: blood volume has been lost, but no effect on RBC structure/size
Bone marrow failure (aplastic): either inherited or acquired, the bone marrow stem cells can no
longer produce sufficient RBCs to meet the demands of the body.
Chronic disease: Reduced iron availability
Destruction (haemolytic): abnormal excess breakdown of RBCs
what causes folate deficiency
• 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
symtoms of folate deficiency
Those related to anaemia • Reduced sense of taste • Diarrhoea • Numbness and tingling in feet and hands • Muscle weakness • Depression
vitamin B12 absorption
• B12 released from food proteins by proteolysis in stomach where it then binds to haptocorrin • Haptocorrin B12 complex digested by pancreatic proteases in small intestine releasing B12 which then binds intrinsic factor (produced by gastric parietal cells). • Intrinsic factor–B12 complex binds to cubam receptor which mediates uptake of complex by receptormediated endocytosis into enterocytes • After lysosomal release in enterocytes, B12 exits via basolateral membrane through MDR1 • Binds to transcobalamin in blood and transported around bloodstream
causes of B12 deficiency
-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)
symptoms of b12 deficiency
Those related to anaemia • Glossitis & mouth ulcers • Diarrhoea • Paraesthesia • Disturbed vision • Irritability
symotoms of subacute combined degeneration of the cord
degeneration of posterior and lateral columns of the spinal cord
• Gradual onset weakness, numbness & tingling in arms, legs & trunk which progressively worsens. • Changes in mental state
how can folate/ b12 defiency affect the nervous system
• Folate deficiency in pregnancy can cause neural tube defects • Vitamin B12 deficiency associated with focal demyelination
why do b12 and folate deficiency cause a megaloblastic anaemia
• Vitamin B12 and folate are both necessary for
nuclear division and maturation.
• When B12 and folate are deficient, nuclear
maturation and cell divisions lag behind
cytoplasm development.
• Leads to large red cell precursors with
inappropriately large nuclei and open
chromatin. The mature red cells are also
large leading to a macrocytic anaemia
anisopikilocytosis
variance in size and shape
treatment of vitamin b12 deficiency
For Pernicious anaemia: Hydroxycobalamine intramuscular (NOT oral) for life
For other causes of B12 deficiency: oral cyanocobalamine
what is Hb1AC
glycated haemoglobin which is when Hb is linked to a sugar
what is haemoglobinaemia
excess haemoglobin in the blood. If the normal reticuloendothelial pathway for removal of red blood cells is overwhelmed or haemolysis is very severe (e.g. due to incompatible blood transfusion), a direct breakdown of red blood cells rusults in release of haemoglobin into the circulation
coombs test
autoantibody test for autoimmune haemoltyic anaemia
what is pernicious anaemia
autoantibodies interfering with the production or function of intrinsic factor
Intrinsic factor is essential for the absorption of vitamin B12 in the ileum. Without intrinsic factor, vitamin B12 deficiency will occur and production of red blood cells will be impaired causing anaemia. “Pernicious” means “deadly”. Pernicious anemia was often fatal in the past before vitamin B12 treatments were available.
