Haem 9 and 10 - Iron deficiency / Vit B12 and Folic Acid deficiency Flashcards
Most of the iron ins in Hb. So what does low iron mean?
Low iron = low Hb = anaemia
Iron is incorporated into protoporphyrin ring in Haem.
The crucial role is to hold onto O2
Most (but not all) iron is recycled. How might we lose iron?
- Desquamated cells of skin and gut
- Bleeding - menstruation / pathological
Men need about 1mg, women - 2mg/day
Human diet - provides 12-15mg iron/day
Iron can only be absorbed in what state?
Fe2+ (ferrous).
Ferric (Fe3+) cannot be absorbed.
Cups of tea make it worse, orange juice helps
How can iron absorption at the gut be altered?
- Iron enters gut epithelial cell.
- On the basement membrane of the epithelial cell –> ferroportin is the iron transporter to blood.
- Ferroportin levels regulated by hepcidin (small chain aa - produced in liver)
High iron = High hepcidin = low ferroportin = low absorption
Intracellularly, iron can be converted into …… and it is bound to ….. in the plasma.
Iron can be converted into ferritin.
Bound to transferrin in plasma.
Occurs in duodenal cells among other cells
What does transferrin do and how can it be measured?
Holds onto iron in circulation
Can be measured by:
- Measuring transferrin
- Measuring transferrin saturation
(3. Total iron binding capacity, TIBC)
Erythropoietin is released mainly by kidneys in response to hypoxia. What effects does it have
Stimulates red cell precursors to survive, grow and differentiate
What is anaemia of chronic disease? (ACD)
Anaemia in patients who are unwell. No bleeding, no marrow infiltration, no iron/b12/folate deficiency.
No obvious cause except they’re unwell
What are the laboratory signs of being ill (for ACD)
- C-reactive protein (mark of infection/inflammation)
- Erythrocyte sedimentation rate (increases in inflammation)
- Acute phase response - look for increases in ferritin, F8, fibrinogen, immunoglobulins
What are some associated conditions of ACD
- Chronic infections e.g. TB/HIV
- Chronic inflammation e.g. RA/SLE
- Malignancy
- Misc - cardiac failure
Describe the pathogenesis of ACD
Cytokines prevent usual flow of iron from duodenum to RBC (e.g. via transferrin) - block in iron utilisation
Main cytokines involved = TNF-a, ILs
What do cytokines do to prevent iron utilisation in ACD?
Cytokines:
- Stop erythropoietin synthesis
- Stop iron flowing out of cells
- Increase production of ferritin
- Increase death of red cells
Consequences are - make less red cells, more red cells die, less availability of iron (as its stuck in cells/ferritin)
What are the causes of iron deficiency
- MAIN CAUSE = bleeding (menstrual / GI)
- Increased use (e.g. growth/pregnancy)
- Dietary deficiency
- Malabsorption (e.g. coeliacs)
When would you do a full GI investigation?
If good diet and no coeliac antibodies
If: male, women over 40, post-menopausal, woman with scanty menstrual loss
What are full GI investigations?
- Upper GI endoscopy
- Duodenal biopsy
- Colonoscopy
If find nothing - small bowel meal and follow through
If GI tests come back negative, where else could you examine?
Urinary blood loss (kidneys)
Antibodies for coeliac disease
What are the laboratory parameters that could be measured?
- MCV
- Serum iron
- Ferritin
- Transferrin (=Total Iron Binding Capacity, TIBC)
- Transferrin saturation (should be 20-40%)
What are 3 causes of low MCV
- Iron deficiency
- Thalassaemia trait
- ACD (can have low/normal MCV)
i.e. if low MCV, could be due to any of the above causes
Serum iron is not a good reflection of total iron. How is serum iron affected in iron deficiency, ACD, Thalassaemia?
Iron deficiency = low serum iron
ACD = low serum iron
Thalassaemia = normal serum iron
i.e. low serum iron could be due to iron deficiency or ACD, either one
How can we confirm thalassaemia trait
Hb electrophoresis - confirms an additional type of Hb present
Why is ferritin test such a sick test
It is LOW in iron deficiency
HIGH in chronic disease (ACD)
Ferritin is an acute phase protein that goes up when were unwell
HOWEVER, if patient has BOTH iron deficiency AND chronic underlying disease, ferritin may be normal. Eg if they had RA + bleeding ulcer
So, LOW ferritin confirms iron deficiency, but normal ferritin doesn’t exclude iron deficiency. Good way to see if “normal” ferritin isn’t ideal is if they have high CRP/ESR
How is transferrin and transferrin saturation affected in iron deficiency and in ACD
Iron deficiency - transferrin goes up. Low saturation
Chronic disease - transferrin = normal/low. Normal saturation
Upon finding someone is iron deficient, what investigations are done
- Anti-coeliac antibodies
- Anti-helicobacter antibodies
- Duodenal biopsy
- Upper and lower GI Endoscopy (and colonoscopy) - to look for a source of bleeding
What are the lab test results if classic iron deficiency?
EVERYTHING LOW except transferrin
Hb, MCV, Serum iron, Ferritin, Transferrin saturation = low
Transferrin = high
What are the lab test results if ACD?
Hb, serum iron = LOW
MCV, transferrin = LOW / NORMAL
Transferrin saturation = normal
Ferritin = HIGH or normal
What are the lab test results if thalassaemia?
Hb and MCV = low
Serum iron, ferritin, transferrin, transferrin saturation = normal
You can also use a blood film to check for iron deficiency, how?
Pencil cell (RBC)
What is B12 required for?
- DNA synthesis
2. Nervous system integrity
What is folic acid required for?
- DNA synthesis
2. Homocystine metabolism
Folate and B12 affect all rapidly dividing cells, including?
- Bone marrow
- Epithelial surfaces of mouth and gut
- Gonads
- Embryos
What are the clinical features of B12/Folate deficiency?
- Anaemia - weak, tired, short of breath (low Hb)
- Jaundice
- Glossitis and angular cheilosis
- Weight loss, change of bowel habit
- Sterility
With B12/Folate deficiency, MCV is?
Higher MCV
B12/Folate deficiency can cause macrocytic or megaloblastic anaemia
What are causes of macrocytic anaemia
- Vit B12/folate deficiency
- Liver disease /alcohol
- Hypothyroid
- Drugs e.g. azathioprine
- Haematological disorders (myelodysplasia, aplastic anaemia, reticulocytosis (e.g. chronic haemolytic anaemia))
Reticulocyte = young red cell
What is meant by megaloblastic?
So what is happening in megaloblastic anaemia
Morphological change in the red cell precursors within bone marrow
Megaloblastic anaemia = asynchronous maturation of the nucleus and cytoplasm in the erythroid series (maturing RBC seen in bone marrow)
What is the normal red cell maturation process
Erythroblast —> normoblast (early/intermediate/late) –> reticulocyte —> circulating red blood cell
What features may we see in peripheral blood with megaloblastic anaemia
- Anisocytosis
- Large red cells
- Hypersegmented neutrophils
- Giant metamyelocytes
NB thyroid disease can’t be a cause of MEGALOBLASTIC anaemia
Megaloblastic = to do with DNA synthesis
3 tests you would do if someone had a macrocytosis
- Vit B12
- Folate
- Liver function test
- Thyroid function tests
- Reticulocyte count
Name 2 possible underlying clinical disorder for hyperhsegmented neutrophil
- Folate deficiency
2. B12 deficiency
When might there be increased demand for folate
Physiologically - pregnancy / adolescence / premature babies
Pathologically - malignancy / erythoderma / haemolytic anaemias
Describe how a lab diagnosis of folate deficiency is achieved
- FBC and film
2. Folate levels in the blood
What are the consequences of folate deficiency?
- Megaloblastic, macrocytic anaemia
- Neural tube defects in developing foetus
- Increased risk of thrombosis in association with variant enzymes involved in homocysteine metabolism
How can folate deficiency affect neural tube
- Spina bifida
2. Anencephaly
High levels of homocysteine are associated with
- Atherosclerosis
- Premature vascular disease
Folic acid needed to convert homocysteine into methionine - as homocysteine slightly toxic
What are classic B12 deficiency presentations
- Macrocytic anaemia (low Hb, high MCV) with pins and needles
- Glossitis, fall over when they close their eyes, loss of proprioception (Rombergs sign)
B12 deficiency can affect both central and peripheral nerves. Name some neurological problems of B12 deficiency
- Bilateral peripheral neuropathy
- Subacute combined degeneration of the cord
- Optic atrophy
- Dementia
Things to look for in a history (checking if B12 deficiency?)
- Paraesthesiae
- Muscle weakness
- Difficulty walking
- Visual impairment
- Psychiatric disturbance
When examining B12 deficiency, what signs may you notice
- Absent reflexes and upgoing plantar responses
What can cause Vit B12 deficiency
Poor absorption
Reduced dietary intake - vegans at risk (B12 comes from animal produce)
Infections/infestations - abnormal bacterial flora, tropical sprue, fish tapeworm
What are the 2 forms of B12 absorption
- Slow and inefficient - gets absorbed across duodenum (SI)
- (Intrinsic factor made in parietal cells of stomach) –> B12 must combine with intrinsic factor —> B12-IF binds to ileal receptors (MAJOR METHOD) - occurs in SI
Which 3 things are essential for B12 absorption
- Intact stomach
- Intrinsic factor
- Functioning SI
What may cause impaired B12 absorption
- Reduction in intrinsic factor - post gastrectomy / gastric atrophy / antibodies to intrinsic factor or parietal cells
- Small bowel diseases - Crohns, coeliac disease, surgical resection
What is pernicious anaemia
Autoimmune condition - associated with severe lack of intrinsic factor
(peak at age 60, family history)
Pernicious anaemia is associated with a decreased life expectancy, how
In males, risk of stomach cancer
What antibodies could cause pernicious anaemia
- Intrinsic factor antibodies (occasionally found in other conditions)
- Parietal cell antibodies (90% adults with pernicious anaemia)
Which infections predispose to B12 deficiency
- H pylori (tested via stool)
- Giardia
- Fish tapeworm
- Bacterial overgrowth (tested via breath test)
Which drugs are associated with low B12
- Metformin
- PPIs e.g. omeprazole
- Oral contraceptive
Quickly describe the shillings test
Drink radioactive B12. If lots of excretion of radioactivity in urine, thats good, B12 being absorbed.
i.e. normally, B12 should be present in urine
Test repeated with addition of intrinsic factor (Schillings test part 2)
If they are not absorbing B12, what could be the causes?
Pernicious anaemia
Small bowel disease
(or hadn’t corrected B12 deficiency before test)
If you suspect they are B12 deficient, but B12 normal and they’re mildly anaemic - what can you do
- Measure methylmalonyl acid
also maybe measure homocysteine, look for anti-intrinsic factor antibodies
How is B12 treated
Injections of B12 (3X a week for 2 weeks, then every 3 months)
IF neurological involvements - keep doing B12 injections on alternate days until no further improvement (3 weeks), then every 2 months - controversial
Only do Shillings, anti-intrinsic factor, or anti-parietal antibody tests after?
After we know that they have B12 deficiency
B12 deficiency is usually a problem with?
Absorption
