Session 4 Flashcards
(99 cards)
1
Q
What is anaemia?
A
Haemoglobin below the reference range for the normal population.
2
Q
What are the general signs and symptoms of anaemia?
A
Symptoms: shortness of breath, tiredness, cardiac failure, palpitations, headache
Signs: pallor, tachycardia, tachypnoea, hypotension
3
Q
Give examples of signs and symptoms specific to certain causes
A
Anaemia due to - The symptom/sign
Iron deficiency - Koilonychia - spooning of the nails
Vit B12 deficiency - Glossitis - enlarged shiny tongue
Thalassaemia - abnormal facial bone development
Iron deficiency - oesophageal webs (Plummer vinson syndrome)
Iron deficiency - angular stomatitis - inflammation of corners of the lips/mouth
4
Q
What are the three general stages at which anaemia can be caused and how at each one?
A
In the bone marrow - issues in erythropoiesis or haemoglobin synthesis
In the peripheral red blood cells - the structure of the RBCs or issues with the metabolism within them
During removal - loss of red cells or issues in the reticuloendothelial system
5
Q
Why might someone with chronic kidney disease have anaemia and how is this treated?
A
Loss of kidney function means kidneys aren’t as responsive in the haemostatic loop so produce less erythropoietin causing anaemia. these patients are given recombinant erythropoietin.
6
Q
How may issues within bone marrow cause anaemia?
A
- Empty bone marrow unable to respond to stimulus from EPO eg after chemotherapy or toxic insult such as parvovirus infection or in aplastic anaemia
- Marrow infiltrated by cancer cells or fibrous tissue (myelofibrosis) means the normal haemopoieticcells are reduced
7
Q
What is dyserythropoiesis?
A
Defective development of red blood cells
8
Q
What is anaemia of inflammation / anaemia of chronic disease?
A
- due to inflammatory cytokines, iron is not released for use in bone marrow from macrophages (macrophages are involved in recycling iron)
- Cytokines also cause reduced lifespan of red cells
- The marrow shows a lack of response to erythropoietin
Often has raised CRP and ferritin
Seen in: Renal disease, inflammatory conditions such as Rheumatoid arthritis, SLE, Inflammatory bowel disease (Ulcerative Colitis or Crohn’s), chronic infections
9
Q
What are Myelodysplastic syndromes (MDS) and how do they cause anaemia?
A
•Production of abnormal clones of marrow stem cells.
Pre cancer that can go on to develop into acute leukaemia. bone marrow produces lots of RBCs but because of acquired genetic changes they don’t develop properly so they are not allowed to enter the circulation.
10
Q
How may haemoglobin production be affected resulting in anaemia?
A
- Deficiencies in essential nutrients:
•Lack of iron: deficiency in Haem synthesis due to:
Iron deficiency
Anaemia of chronic disease (functional lack of iron)
•Lack of B12/folate: Deficiency in the building blocks for DNA synthesis resulting in
megaloblastic anaemia
- Mutations in the proteins encoding the globin chains e.g thalassaemia and sickle cell disease
11
Q
How might inherited defects in the red cell membrane lead to anaemia?
A
Some patients have inherited problems whereby the membrane isn’t formed properly for example in hereditary spherocytosis (RBCs become spherical), hereditary eliptocytosis (RBCs have elliptoid shape) and hereditary pyropoikilocytosis (very rare - multiple gene muations result in variety of shapes).
• The cells are less flexible and are damaged more easily and break up in the
circulation or are removed more quickly from the circulation by RES.
this results in a haemolytic anaemia.
12
Q
How might acquired defects in the red cell membrane lead to anaemia?
A
–Mechanical damage to red cells
•Heart valves can damage RBCs as they pass through, shearing them resulting in schistiocytes.
•Vasculitis
•MAHA (microangiopathies)
•DIC –disseminated intravascular coagulopathy in this schistiocytes can also be seen.
–Heatdamage
•Burns
–Osmoticchange
•Drowning
Another cause of ‘haemolytic’ anaemia
13
Q
How might anaemia develop from defects in red cell metabolism?
A
Red cell enzyme defects can lead to anaemia as energy is needed to maintain the membrane and cytoskeleton so if there’s not enough it cannot be fully maintain and is susceptible to damage or change in shape so recognised as abnormal by the spleen and removed.. this results in a haemolytic anaemia. energy also required to keep iron in its reduced state.
Best recognised are:
◦Glucose-6-phosphate dehydrogenase
◦Pyruvate kinase deficiency
14
Q
How could injury cause anaemia?
A
Bad injury resulting in a large blood loss may cause anaemia. for example, stab wound, car crash.
15
Q
How is the spleen adapted to help with large scale blood loss due to injury?
A
Blood can pool in the spleen to be utilised when needed.
16
Q
When does the spleen remove RBCs in anaemia?
A
The spleen and other tissues of RES removes damaged or defective red cells
•It will do this in many of the causes of anaemia eg membrane disorders, enzyme disorders, haemoglobin disorders
17
Q
What is a haemolytic anaemia?
A
red cells are destroyed more quickly as they are abnormal or damaged
18
Q
What is the difference between intravascular and extravascular haemolytic anaemia?
A
- Within the blood vessels is intravascular
- Outside (within the RES macrophages in spleen. Liver, bone marrow) is extravascular
19
Q
What is autoimmune haemolytic anaemia?
A
In this condition autoantibodies (ie Immunoglobulin -Ig – protein produced by own B lymphocytes) bind to the red cell membrane proteins
•Cells in the RES recognise part of the antibody, attach to it and remove it and the red cell from the circulation
20
Q
Give two examples of when anaemia can be multifactorial
A
- In myelofibrosis, the bone marrow becomes fibrotic so there’s reduced space and sop reduced erythropoiesis. as a result erythropoiesis starts in the spleen by a lot of the RBCs pool there so there’s further anaemia.
- In thalassaemia there’s a mutation in one of the genes that codes for the chains in haemoglobin. as a result haemoglobin synthesis is ineffective so erythropoiesis spreads to the liver and spleen but the new RBCs also have structural deformities so are removed by the RES which further contributes to the anaemia.
21
Q
what can we use to identify the type of anaemia in terms of evaluating it?
A
- By mechanism of anaemia
- By size –microcytic, normocytic, macrocytic
- By presence or absence of reticulocytosis
22
Q
What can reticulocyte count tell us about a patient with anaemia?
A
Reticulocyte count can tell us about whether erythropoiesis is occurring correctly at the bone marrow. High reticulocyte count shows that the bone marrow is appropriately creating reticulocytes in response to the anaemia. If the reticulocyte count is low or not as high as expected in a patient with anaemia, it shows there’s an issue with erythropoiesis in the bone marrow.
23
Q
What is the approach one should take when evaluating a patients anaemia when looking for a cause?
A
- is there an appropriate reticulocyte response?
If the answer to 1. is yes:
Is there evidence of haemolysis?
Yes - Cause?
No - Look for evidence of bleeding
If the answer to 1. is no:
what are the RBC indices?
(looking at whether anaemia is microcytic, normocytic or macrocytic)
24
Q
what types of anaemia would come with reticulocytosis?
A
•Acute blood loss •Splenic sequestration •Haemolysis –Immune mediated eg autoimmune or drug related –Non-Immune *Mechanical ~Heart valves ~Microangiopathic haemolytic anaemia (MAHA) *Haemoglobinopathies *Enzyme defects *Membrane defects
25
What types of anaemia would be seen with a low reticulocyte count?
```
Low MCV (Microcytic)
High MCV (Macrocytic)
Normal MCV (Normocytic)
```
26
What anaemias have a low MCV (microcytic)?
```
•Low MCV (Microcytic)
–Thalassaemia trait
–Anaemia of chronic
disease (though usually
normocytic)
–Iron deficiency
–Lead poisoning
–Sideroblastic anaemia (rare)
```
27
What anaemias have a high MCV (macrocytic)?
* Vitamin B12 deficiency
* Folate deficiency
* Myelodysplasia
* Liver disease
* Hypothyroidism
* Alcohol
28
what anaemias have a normal MCV (normocytic)?
```
Normal MCV (Normocytic)
◦Primary bone marrow failure -very rare
Aplastic anaemia
Red cell aplasia
◦Secondary bone marrow failure
Anaemia of chronic disease
Combined haematinic deficiencies (cause both macrocytic and microcytic so averages at normocytic)
Uraemia
Endocrine abnormalities
HIV infection
```
29
Where do we get Vit B12 from?
From meat, eggs, fish and cheese?
30
How do we take Vit B12 into the body?
Vit B12 binds with Haptocorrin which is produced by our salivary glands. this complex then passes through the stomach and into the intestines. In the stomach there are parietal cells which produce hydrochloric acid and intrinsic factor (IF). this intrinsic factor exits the stomach and enters the small intestine. Pancreatic proteases in the small intestine break off the haptocorrin and the IF binds with the Vit B12 where it travels through the small intestine and IF-B12 complex binds with a receptor in the terminal ileum where the vitamin B12 is absorbed and IF destroyed.Once internalised B12 forms a complex with transcobalamin II and is released into the bloodstream for delivery to various tissues which possess specific receptors for the transcobalamin II-B12 complex
31
Why does vitamin B12 deficiency take so long to present?
Body stores can last from 3-6 years
32
What are the causes of low Vit B12
Dietary Deficiency: Vegan diet; poor diet
Lack of intrinsic factor : Pernicious anaemia (An autoimmune disease affecting gastric parietal cells causing lack of intrinsic
factor); gastrectomy
Disease of the ileum: Crohn’s disease; ileal resection; tropical sprue
Lack of Transcobalamin (transports B12 in the circulation): Congenital deficiency
33
Where does dietary folate come from?
Folate present in most foods, yeast, liver and leafy greens especially rich source
34
How long can we store folate for?
5mg stores for about 3-4 months
35
Where does absorption of folate occur?
Absorption occurs in the duodenum and jejunum
36
Where may a folate deficiency come from?
Dietary deficiency - poor diet
Increased use -
pregnancy, increased erythropoiesis eg haemolytic anaemia, severe skin disease (e.g psoriasis, exfoliative dermatitis)
Disease of the duodenum and jejunum - proximal small bowel disease eg coeliac disease, Crohn’s disease
Lack of methylTHF - drugs which inhibit dihydrofolate reductase enzyme (eg Methotrexate)
Others: alcoholism (multifactorial); urinary loss of folate in liver disease and heart failure; other drugs eg anticonvulsants
37
How are B12 and folate used in the body?
* Both B12 and folate play a role in converting homocysteine to methionine and the 2 vitamins are dependent on one another to do this.
* Vitamin B12 is responsible for reactivating folic acid, back into tetrahydrofolate, the form of folic acid which the body can use.-so low B12 causes a functional folate deficiency
* THF is essential for: serine-glycine conversion, histidine catabolism, purine synthesis, and most importantly, thymidylate synthesis which is needed throughout the body for DNA synthesis
* On the other hand, vitamin B12 needs folic acid to reduce homocysteine MTHF gives off its methyl group to vitamin B12 (cobalamin), which becomes methylcobalamin. At the same time, the MTHF folic acid is converted back into its bioactive form, tetrahydrofolate
* Methylcobalamin then gives off its methyl group to homocysteine, to create methionine
* Methionine is converted to S-adenosyl methionine (SAM) –one of the most important things for the production of various neurotransmitters and for DNA methylation.
38
Why does Vit B12 and folate deficiency cause a megaloblastic anaemia?
•So….both folate and Vit B12 deficiency ultimately lead to thymidylate deficiency
•In the absence of thymine, uracil is incorporated into DNA instead
•DNA repair enzymes detect the error and DNA strands are destroyed
•This causes asynchronous maturation between the nucleus and the cytoplasm.
–The nucleus (lacking DNA) does not fully mature,
–The cytoplasm ,in which RNA production and haemoglobin synthesis continues, matures at the normal rate.
Both B12 and folate necessary for nuclear divisions and nuclear maturation. When deficient, nuclear maturation and cell divisions lag behind cytoplasm development. This 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
39
What megaloblastic features are shown in a peripheral blood film for someone with megaloblastic anaemia as a result of a B12/folate deficiency?
* macrocytic red cells
* anisopoikilocytosis with tear drops
* hypersegmented neutrophils
* Can see white cell precursors also
40
As B12/folate deficiency progresses what else can develop?
Pancytopenia can develop ie low platelets and neutrophils too
41
How can Vit B12 or folate deficiency lead to neurological disease?
```
Vitamin B12 (not folate) deficiency is also associated with neurological disease – focal demyelination affecting the spinal cord, peripheral nerves and optic nerves.
•Folate deficiency in pregnancy can cause neural tube defects
```
42
How can we test for megaloblastic anaemia?
•Low Hb
•High MCV (only 75%)
•Blood film shows ‘megaloblastic’ features
•High bilirubin and LDH due to increased cell destruction and increased cell production.
•Check B12 and serum folate at the same time as often can be deficient in both.
•Vit B12 test is a poor test so if borderline, repeat
•If indeterminate
–Check plasma total homocysteine (tHcy) and/or
–plasma methylmalonic acid (MMA)
•Check for anti-Intrinsic Factor antibodies
–if no evidence of food malabsorption or other clear cause
43
What is the treatment for Vit B12 and folate deficiency?
```
• Folate
– Oral folic acid
• Vit B12
– Pernicious anaemia: Hydroxycobalamine
(intramuscular) for life
• Beware hypokalaemia (low potassium)
– Other cause: oral cyanocobalamine
```
44
Why would giving oral cyanocobalamine be useless for someone with pernicious anaemia?
They lack intrinsic factor so wouldn't be able to absorb it so intramuscular hydroxycobalamine is given instead.
45
Why might you need to be careful when giving a patient with B12 deficiency a blood transfusion?
Heart adapts by becoming enlarged and pumps faster as B12 deficiency progresses so giving a transfusion can cause high output cardiac failure.
46
When should improvement be seen after treatment for B12/folate deficiency?
```
Day post start
of treatment - Improvement expected
1-2 days - Bilirubin, LDH fall
3-4 days - Reticulocyte count rises
10 days - Hb starts to rise, MCV starts to fall
14 days - Disappearance of hypersegmented neutrophils
2 months - Resolution of anaemia
3-6 months - Resolution of neuropathy
```
47
What is megaloblastic anaemia?
Vitamin B12 and/or folate deficiency causes a
deficiency in building blocks for DNA synthesis. this results in the red cells not forming properly and causing this type of anaemia. Red cells become enlarged ie this is a form of a macrocytic anaemia
48
What is microcytic anaemia?
• Erythrocytes smaller than normal (microcytic)
often combined with:
• Reduced rate of haemoglobin synthesis
• Cells often paler than normal (hypochromic)
49
How can microcytic anaemias be divided?
1. Due to reduced haem synthesis: iron deficiency, lead poisoning, anaemia of chronic disease, sideroblastic anaemia
2. Due to reduced globin chain synthesis: α thalassaemia, β thalassaemia
50
What does TAILS stand for?
```
The types of microcytic anaemia:
Thalassaemia
Anaemia of chronic disease
Iron deficiency
Lead poisoning
Sideroblastic anaemia
```
51
How does Iron deficiency cause anaemia?
Insufficient iron for haem synthesis
52
How does lead poisoning cause anaemia?
Acquired defect. Lead inhibits enzymes involved in haem synthesis
53
How does anaemia of chronic disease cause anaemia?
Hepcidin results in functional iron deficiency
54
What is sideroblastic anaemia?
Inherited defect in haem synthesis.
55
What is α thalassaemia?
Deletion or loss of function of one or more of the four α globin genes
56
What is β thalassaemia?
Mutation in β globin genes leading to reduction or absence of the β globin
57
How is iron used in the body?
Essential element in all living cells
```
Required for:
•Oxygen carriers:
Haemoglobin in red cells
Myoglobin in myocytes
•Co-factor in many enzymes:
Cytochromes (oxidative phosphorylation)
Krebs cycle enzymes
Cytochrome P450 enzymes (detoxification)
Catalase
```
Free iron potentially very toxic to cells
Complex regulatory systems to ensure the safe absorption, transportation and utilisation.
The body has no mechanism for excreting iron.
58
Explain how Iron can change oxidation states
* Iron can exists in a range of oxidation states
* Ferrous iron (Fe2+) and Ferric iron (Fe3+) most common
* Fe2+is the reduced form Fe3+is the oxidised form
* Dietary iron consists of haem iron (Fe2+) and non-haem (mixture of Fe2+and Fe3+). Ferric iron must be reduced to ferrous iron (Fe2+) before it can be absorbed from diet
Ferrous can change to ferrous in an oxidation reaction to produce ferric iron and an electron. this takes place in an alkaline pH.
Ferric iron can combine with an electron in a reduction reaction to produce ferrous iron. This takes place in an acidic pH
59
How much iron is required in your diet?
Need 10-15mg/day iron in diet
60
Where is hepcidin produced?
Liver
61
What type of iron is used in haemoglobin?
Ferrous, Fe 2+
62
Where does absorption of iron occur and what type is absorbed?
In the duodenum and upper jejunum. Ferrous iron is absorbed (Fe2+). Ferric iron is reduced to ferrous iron in the acidic conditions of the stomach.
63
Name some good sources of Haem Iron
```
Liver
Kidney
Beef Steak
Beef burger
Chicken
Duck
Pork chop
Salmon/Tuna
```
64
Name some good sources of non-haem iron
```
Fortified cereals
Raisins
Beans
Figs
Barley
Oats
Rice
Potatoes
```
65
What is the difference between haem iron and non-haem iron?
Haem iron is purely ferrous iron whereas non-haem iron is a mixture of ferrous and ferric iron.
66
Explain the dietary absorption of iron
The mixture leaving the stomach, called the chyme, contains the haem and non-haem iron. It passes over enterocytes in the duodenum and upper jejunum. The haem iron can be readily absorbed into the enterocytes whereas non-haem iron must reduced from ferric to ferrous iron by ferrireductase. Ferrireductase uses Vit C as a cofactor. The ferrous iron then passes through divalent methyl transporter 1 (DMT1), where it joins a labile pool of iron. This iron can either be stored in the enterocyte as ferric iron by the protein ferritin, or leave the cell through the basolateral surface of the enterocyte into the blood through ferroportin. Hephaestin converts the ferrous iron to ferric iron as it leaves the enterocyte and two molecules of ferric iron bind to transferrin where it can be transported around the body in the blood.
67
Why is divalent methyl transporter 1 (DMT1) considered a cotransporter?
For every molecule of iron that enters the enterocyte, one proton leaves through the transporter.
68
How is the amount of iron that enters the blood regulated?
Hepcidin inhibits ferroportin by causing it to be degraded which prevents iron leaving the enterocyte.
69
What factors affect absorption of non-haem iron from food?
```
Negative influence:
•Tannins (in tea)
•Phytates (e.g. Chapattis, pulses)
•Fibre
•Antacids (e.g. Gaviscon)
First three can bind non-haem iron in the intestine. Reduces absorption. Gaviscon make stomach conditions less acidic so less reduction to Fe 2+
```
Positive influence:
Vitamin C & Citrate
•Prevent formation of insoluble iron compounds
•Vit C also helps reduce ferric to ferrous iron
70
Explain how iron in the body is divided between functional and stored iron.
Total iron in the body ~3350 mg
```
Functional (available) iron
•Haemoglobin (~2000 mg)
•Myoglobin (~300 mg)
•Enzymes e.g. cytochromes (~50 mg)
•Transported iron (in serum mainly in transferrin) (~3 mg)
```
Stored iron (~1000 mg)
Ferritin (soluble)
•Globular protein complex with hollow core
•Pores allow iron to enter and be released.
Haemosiderin
•Aggregates of clumped ferritin particles, denatured protein & lipid. (insoluble)
•Accumulates in macrophages, particularly in liver, spleen and marrow.
71
How do cells take up Iron?
1) Fe3+bound transferrin binds transferrin receptor and enters the cytosol through receptor-mediated endocytosis.
2) Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+.
3) The Fe2+transported to the cytosol via DMT1.
4) Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin (FPN1), or taken up by mitochondria for use in cytochrome enzymes
72
How is Iron recycled in the body?
•
Only small fraction of total daily iron requirement gained from the diet.
•Most (>80%) of iron requirement met from recycling damaged or senescent red blood cells
•Old RBCs engulfed by macrophages (phagocytosis)
•Mainly by splenic macrophages and Kupffer cells of liver
•Macrophages catabolise haem released from red blood cells
•Amino acids reused and Iron exported to blood (transferrin) or returned to storage pool as ferritin in macrophage.
73
How is overall iron absorption regulated?
* Depends on dietary factors, body iron stores and erythropoiesis
* Dietary iron levels sensed by enterocytes
* Control mechanisms
* Regulation of transporters e.g. ferroportin
* Regulation of receptors e.g. transferrin receptor & HFE protein (interacts with transferrin receptor)
* Hepcidin and cytokines
* Cross talk between the epithelial cells and other cells like macrophages
74
How does hepcidin regulate iron absorption?
Hepcidin is a negative regulator of iron absorption.
Hepcidin induces internalisation and degradation of ferroportin
•Hepcidin synthesis is increased in iron overload.
•Decreased by high erythropoietic activity.
75
How does anaemia of chronic disease / anaemia of chronic inflammation cause anaemia?
The inflammatory condition e.g rheumatoid artrhritis, chronic infection, malignancy causes the release of cytokines e.g IL6 from immune cells. this causes increased production of hepcidin in the liver causing increased inhibition of ferroportin. this in turn decreases iron release from reticuloendothelial system and decreased absorption in the gut. this reduces plasma iron and so inhibits erythropoiesis in the bone marrow.
Cytokines can also directly inhibit erythropoietin production by the kidneys and directly inhibit erythropoiesis in the bone marrow however the effects from this aren't as prominent as from the reduction in plasma iron concentration.
76
Give an overview of iron homeostasis in the body
```
Roughly 2500mg of iron is held within erythrocytes and roughly 20mg of this is lost each day through erythrocyte destruction by macrophages in the reticuloendothelial system (mainly in the spleen). the same 20mg of iron in erythrocytes is replaced each day by erythrocyte production in bone marrow (erythropoiesis). this iron is exchanged from the labile plasma iron pool which consists of roughly 2-3mg of iron (Fe3+ bound to transferrin). between 10-20mg/day of iron is taken in from diet and about 2-3mg of that is absorbed and added to the plasma iron pool. iron is also mainly stored in the liver (100mg) and that is constantly being turned over. we lose about 1-2mg (about 3.5mg in pregnancy) of iron each day through:
•Desquamation of epithelia
•Menstrual bleeding
•Sweat
•Pregnancy
```
77
What is the most common nutritional disorder worldwide?
Iron deficiency
78
Is iron deficiency a diagnosis?
Iron deficiency is a sign not a diagnosis! Clinician must always seek to determine underlying reason why patient is iron deficient.
79
What causes iron deficiency?
Insufficient iron in diet e.g. Vegan & vegetarian diets
Malabsorption of iron e.g. Vegan & vegetarian diets
Bleeding e.g. Menstruation, peptic ulcer
Increased requirement e.g. Pregnancy, rapid growth
Anaemia of chronic disease e.g. inflammatory bowel disease
80
Who are the groups most at risk of iron deficiency?
* Infants
* Children
* Women of child bearing age
* Geriatric age group
81
Why does iron requirement for women over 50 decrease?
Go through menopause and stop menstruating
82
Why do women require more iron than men?
Women need to replace iron lost through menstruation
83
What are the signs and symptoms of iron deficiency?
Signs & Symptoms:
•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:
Angular cheilitis
Koilonychia (spoon nails)
Glossy tongue with atrophy of lingual papillae
84
What would be seen in a FBC for a patient with iron deficiency?
FBC results in iron deficiency anaemia:
•Low mean corpuscular volume (MCV)
•Low mean corpuscular haemoglobin concentration (MCHC)
•Often elevated platelet count (>450,000/μL)
•Normal or elevated white blood cell count
•Low serum ferritin, serum iron and %transferrin saturation, raised TIBC
•Low Reticulocyte Haemoglobin Content (CHr)
85
What would be seen in a peripheral blood smear for someone with iron deficiency?
* RBCs are microcytic and hypochromic in chronic cases
* Anisopoikilocytosis: change in size and shape
* Sometime pencil cells and target cells
86
How do we test for iron deficiency?
* Plasma ferritin commonly used as indirect marker of total iron status -Ferritin is predominantly a cytosolic protein but small amounts are secreted into blood where it functions as an iron carrier.
* Reduced plasma ferritin definitively indicates iron deficiency
* BUT.. Normal or increased ferritin does not exclude iron deficiency - Because…ferritin levels can also increase considerably in cancer, infection, inflammation, liver disease, alcoholism
* CHr(reticulocyte haemoglobin content) recommended by NICE to test for functional iron deficiency
* CHr remains low during inflammatory responses etc. -CHr is also low in patients with thalassaemia so can’t be used in this setting
87
How is iron deficiency treated?
* Dietary advice
* Oral iron supplements -Safest, first-line therapy for most patients but many experience GI side effects and compliance with treatment poor
* Intramuscular iron injections
* Intravenous iron
* Blood transfusion -Only used if severe anaemia with imminent cardiac compromise
88
What kind of response is expected after treatment for iron deficiency?
Response
•Improvement in symptoms
•20g/L rise in Hb in 3 weeks
89
Why is excess iron dangerous?
* Excess iron can exceed binding capacity of transferrin
* Excess iron deposited in organs as haemosiderin
* Iron promotes free radical formation & organ damage
```
Fenton reaction
Fe2+ + H2O2→ Fe3+ + OH•+ OH−
Fe3+ + H2O2 → Fe2+ + OOH• + H+
Hydroxyl and hydroperoxyl radicals can cause damage to cells:
•Lipid peroxidation
•Damage to proteins
•Damage to DNA
```
90
What two conditions are associated with excess iron?
* Transfusion associated haemosiderosis
| * Hereditary haemochromostosis (HH)
91
What is transfusion associated haemosiderosis?
•Repeated blood transfusions give gradual accumulation of iron
•400ml blood = 200mg iron
•Problem with transfusion dependent anaemias such as thalassaemia & sickle cell anaemia
•Iron chelating agents such as desferrioxamine can delay but do not stop inevitable effects of iron overload.
Accumulation of iron (haemosiderin) in liver, heart & endocrine organs:
•Liver cirrhosis
•Diabetes mellitus
•Hypogonadism
•Cardiomyopathy
•Arthropathy
•Increased skin pigmentation
92
What is Hereditary Haemochromatosis?
* Autosomal recessive disease caused by mutation in HFE gene (on Chr 6)
* HFE protein normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
* Mutated HFE cant bind to transferrin so the negative influence on iron uptake is lost
* Too much iron enters cells
* Iron accumulates in end organs causing damage
* Treat with venesection
```
Results in:
•Liver cirrhosis
•Diabetes mellitus
•Hypogonadism
•Cardiomyopathy
•Arthropathy
•Increased skin pigmentation
```
93
What are the normal haemoglobin ranges?
```
Age - Normal Haemoglobin range (g/L)
2 yrs 95 – 140
6 yrs 110 – 140
12 yrs 115 – 145
Adult (Male) 130 – 180
Adult (Female) 115 – 165
```
94
Give a detailed explanation of what folate does?
Once absorbed, folate is converted to tetrahydrofolate (FH4) by intestinal cells before entering the portal circulation and much of this is taken up by the liver which acts a store. The role of tetrahydrofolate in metabolism is to act as a one-carbon carrier, accepting carbon units from sources such as serine, glycine, histidine and formate. Once attached to FH4, these carbons can be oxidised or reduced and used to provide carbons for other metabolic reactions. The collection of the various one carbon forms of FH4 is referred to as the “one-carbon pool”. Recipient reactions of carbon from this one-carbon pool include the synthesis of the base thymidine required for DNA synthesis, synthesis of the purine bases adenine and guanine required for both DNA and RNA synthesis and transfer of methyl groups to vitamin B12.
95
What is anaplastic anaemia?
The term aplastic anaemia refers to an inability of haematopoietic stem cells to generate mature blood cells
96
Where is Vit B12 stored?
The liver takes up about half of the dietary B12 released into the circulation and acts as a store of this vitamin which is sufficient to supply B12 requirements of the body for ~3-6 years.
97
What does vit B12 do in the body?
Vitamin B12 is required for just two metabolic reactions in the body. It transfers a methyl group from L-methylmalonyl-CoA to form Succinyl-CoA and is also required for the transfer of a methyl group from FH4 to homocysteine to form methionine. This latter reaction has a consequence for folate metabolism since a lack of B12 will effectively “trap” folate in the stable methyl- FH4 form thereby preventing its use in other reactions such as synthesis of nucleotides required for DNA synthesis. This leads to a “functional folate deficiency”
98
What is a functional folate deficiency? And how is this related to vit B12?
Vit B12 deficiency leads “functional folate deficiency” despite an adequate dietary supply of folate (there's enough folate but it cannot be used). The consequences of B12 and folate deficiency therefore overlap since both have a detrimental impact on DNA synthesis which manifests itself in blood where ongoing red cell production is essential.
99
What is subacute degeneration of the cord?
Vitamin B12 deficiency more often results in a reversible peripheral neuropathy but can also result in a serious condition called Subacute combined degeneration of the cord which refers to degeneration of the posterior and lateral columns of the spinal cord. The onset is gradual and patients initially present with weakness numbness and tingling in legs, arms and trunk that progressively worsens. Changes in mental state may also develop and eventually the condition will result in irreversible nervous system damage.
