Session 4 - Lecture 1 - Anaemia, B12 and Folate Metabolism Flashcards
1 - Dr Linda Barton, Consultant Haematologist lecture
Introduction to anaemia, Vitamin B12 and folate metabolism and megaloblastic anaemia
“Haematology - anaemia, how pts become anaemic, and in next few weeks, talk about some of the more common causes of anaemia – today going to introduce that by talking about vit B12 and folate def.”
2 - Objectives
[speech]
Definition of anaemia Mechanisms of anaemia ◦ Dyserythropoiesis ◦ Haemoglobin synthesis ◦ Loss of Blood ◦ Overactive RES Evaluation of aneamia ◦ Use of reticulocyte response and size of red cells Vit B12 and Folate deficiency and anaemia
“2. how pts might become anaemic: how red cells are produced to how they’re destroyed and how things can go wrong in that process leading to a pt becoming anaemic.
- Evaluating anaemia and the cause in pts who present to you. Mechanisms helpful bc some of the ways in which we have to evaluate, some of the things leads to sorts of lists of things, forget list can be unhelpful but if you understand it can go back to it that way
- vit B12 and folate def, and how deficiency of these substances can lead to pts becoming anemic.”
3 - What is anaemia?
Definition
Haemoglobin outside of the reference range for the normal population
Haemoglobin carries oxygen
Symptoms: shortness of breath, tiredness, cardiac failure, palpitations, headache
Signs: pallor, tachycardia, tachypnoea, hypotension
Other signs and symptoms specifically associated with the cause of anaemia
“So, ofc anaemia is when Hb is below ref range for that population, so that may be women of a certain age, or men of a certain age, or may be chidlrne, so you must always compare the Hb to the ref range provided, and if Hb below ref range we say pts anaemic. Ofc main functions of Hb is rly to carry O2 to tissues, and so pts who are anaemic will often present with breathlessness, tiredness, may have symptoms of cardiac failure, may have palpitations or headaches, may present with pale conjunctiva or look v pale, may be tachycardia (fast heart rate)< tachypnoeic (high RR) or hypotensive bc not enough blood in system. One of the things you have to remember is that anaemia is a sign of an underlying condition, so anaemia rly is just the thing that alerts you that there is something else happening, if you have a pt who is anaemic need to think about the underlying cause of the anaemia – have to then go on to see what the underlying cause will be. So signs and symptoms indicaiting underlying cause, pt may present with anaemic and iron deficient and altered bowel habit bc they have cancer of the colon causing them to bleed and lose iron and then other sympoms including blood in the stool.”
4 - Specific Signs
Definition
Iron deficiency- Koilonychia
Vit B12 deficiency- Glossitis
Thalassaemia-abnormal facial bone development
Iron deficiency- oesophageal webs (Plummer vinson syndrome)
Iron deficiency- Angular stomatitis
Also see also other lectures in this series
“A number of specific signs talked about in textbooks, don’t see terribly often –
- often hav shiny tongue (glossitis)
- abnormal bones bc blood cells overgrown in some of bones they don’t normally grow bc of the fact that the cells are not being produced properly
- oesophageal webs in pts who are sig iron def;
- angular stomatitis in iron def, cracking at edges of mouth
You’ll have a number of lectures on specific causes of anaemia so some of the specific signs and symptoms will be covered in those lectures.”
5 - Objectives
[slide]
Definition of anaemia Mechanisms of anaemia ◦ Dyserythropoiesis ◦ Haemoglobin synthesis ◦ Loss of Blood ◦ Overactive RES Evaluation of aneamia ◦ Use of reticulocyte response and size of red cells Vit B12 and Folate deficiency and anaemia
6 - Physiological Life Cycle of a Red Blood Cell
BONE MARROW - Erythropoiesis - Haemoglobin Synthesis --> PERIPHERAL RED BLOOD CELLS - Function - Structure --> REMOVAL Reticulo-endothelial System
“So how can pts drop their Hb? If we look at it from start to finish:
- RBCs are produced in BM by process called erythropoiesis, in BM they initially start as nucleated cells, and gradually nucleus becomes smaller and more pyknotic, extruded outside cell, from more blue colour to quite a pinky colour as the cytoplasm becomes more Hbinised.
- When RBCs go in circulation, circulate for 120 days normally – any problems with red cells, then lifespan can be sig shortened, leading to anaemia. Couple of sort of structural and functional (mechanical/enzyme-related) problems making pts anaemic – cells being taken out of circulation more prematurely.
- RES – place in which old/dmged RBCs removed, so if RES particularly active, can lead to anaemia bc cells can be taken out of circulation too quickly, so if cells damaged bc of other causes, spleen might take them out, not last 120 days, pt becomes anaemic unless BM can keep up with production of cells.”
7 - Why might anaemia develop? (overview)
[Speech]
- Erythropoiesis BONE MARROW - Haemoglobin Synthesis --> PERIPHERAL RED BLOOD CELLS - Structure - Metabolism --> Loss of red cells --> REMOVAL Reticulo-endothelial System
“The other rly important cause of anaemia in pts is blood loss: we have a closed system where we produce red cells, live for 120 days, and then they’re taken out of the circulation and their substances are broken down and re-used. But ofc if we break that closed system and lose red cells by bleeding then ofc unless our BM can keep up, then we will become anaemic bc we’re just simply losing cells.
So what we’ll do is we’ll start and go through each of these and look at potential causes and look at abnormalities in each of these processes which can lead to anaemia.”
8 - Why might anaemia develop?
Name a bone marrow cause (1)
[Slide]
Reduced erythropoiesis
Or /dyserythropoiesis/
BONE MARROW - Haemoglobin Synthesis --> PERIPHERAL RED BLOOD CELLS - Structure - Metabolism --> Loss of red cells --> REMOVAL Reticulo-endothelial System
“Start with erythropoiesis itself, what can go wrong with erythropoiesis?”
9 - Reduced erythropoiesis
IMBALANCE
1) Stimulus: Hypoxia (low blood O2- carrying ability) due to
- Decreased RBC count
- Decreased amount of hemoglobin
- Decreased availability of O2
- Lack of response to the haemostatic loop – eg in chronic kidney disease the kidney stops making EPO
2) Kidney (and liver to a smaller extent) released erythropoietin.
3) Erythropoietin stimulates red bone marrow.
- 1. Empty bone marrow unable to respond to stimulus from EPO eg after chemotherapy or toxic insult such as parvovirus infection or in aplastic anaemia
2. Marrow infiltrated by cancer cells or fibrous tissue (myelofibrosis) means the normal haemopoietic cells are reduced
4) Enhanced erythropoiesis increases RBC count.
5) O2- carrying ability of blood increases.
Homeostasis: Normal blood oxygen levels
“Well erythropoiesis can be reduced bc of a no. of diff reasons. Um, so if you remember EP is driven by hormone erythropoietin which is produced by the kidney, and the kidney is stimulated to produce this by low O2 levels in blood, stimulates BM to produce RBCs, carry more O2, so amount of EPO goes down. If you have a pt who has kidney dmg, although pt might be hypoxic, kidneys may not be able to produce EPO – chronic renal failure pts often anaemic. If problem with BM, for example, in rare conditions like aplastic anaemia, BM devoid of all cells, doesn’t matter how much EPO produced, your BM just not going to produce enough RBCs so pt becomes anaemic. If BM infiltrated with haematological malignancy or metastatic cancer then there may not be enough space for normal red cells to grow so pt will become anaemic.”
10 - Dyserythropoiesis
Dyserythropoiesis
• Anaemia of Inflammation or anaemia of Chronic Disease
• Iron is not released for use in bone marrow
• reduced lifespan of red cells
• the marrow shows a lack of response to erythropoietin.
• Seen in: Renal disease, inflammatory conditions such as Rheumatoid arthritis, SLE, Inflammatory bowel disease (Ulcerative Colitis or Crohn’s), chronic infections
- Clinical clue: Often ^ CRP and ferritin
Myelodysplastic syndromes (MDS) • Production of abnormal clones of marrow stem cells
“There’s also dyserythropoiesis in anaemia of chronic inflammation or chronic disease, will talk about in subsequent lectures, in that condition, pts have a lot of cytokines produced, effect of cytokines leads to difficulty in releasing iron from macrophages so red cels in BM don’t have enough iron to make Hb, reduced lifespan and marrow shows lack of response to erythropoietin. In BM itself hav primary BM disorders, abnormality or genetic change occurring in stem cells, produce daughter cells which are abnormal, often red cells will be abnormal, so not allowed out into circulation so pts become anaemic.”
11 - Why might anaemia develop?
Bone Marrow Cause 2
- Erythropoiesis
BONE MARROW
HAEMOGLOBIN SYNTHESIS
--> PERIPHERAL RED BLOOD CELLS - Structure - Metabolism --> Loss of red cells --> REMOVAL Reticulo-endothelial System
“So the main function of RBCs we said was to carry Hb, so what happens if you just don’t make enough Hb, what conditions can cause you to not make as much Hb as “
12 - Defects in Haemoglobin synthesis
Deficiencies in essentials
Lack of iron: deficiency in Haem synthesis
◦ Iron deficiency
◦ Anaemia of chronic disease (functional lack of iron)
- See Iron lecture
Lack of B12/folate: Deficiency in the building blocks for DNA synthesis
◦ Megaloblastic anaemia
Mutations in the proteins encoding the globin chains
◦ Thalassaemia
◦ Sickle cell disease
- See Session 5
“what conditions can cause you to not make as much Hb as
12) you should do? Well we can have def in essential components that are required to make Hb, so if you lack iron bc iron def, then you will not be able to make Haem molecule and remember that globin chains have haem molecuels in them so not able to make Hb. If you lack B12 and folate, then def in DNA, your DNA isn’t right, cells aren’t maturing correctly, get anaemia bc of that. And also if you have mutations in genes that encode globin chains – Hb made out of globin chains, if you have mutations in globin chains then again you may develop Hbopathies, also lead to anaemia, unable to make globin correctly, will be talking about that in another lecture.”
13 - Why might anaemia develop?
Peripheral red blood cell cause.
[speech]
- Erythropoiesis BONE MARROW - Haemoglobin Synthesis --> PERIPHERAL RED BLOOD CELLS - (STRUCTURE) MEMBRANE - Metabolism --> Loss of red cells --> REMOVAL Reticulo-endothelial System
“So, when we talk about the what could go wrong in the structure of red cells, there aren’t many structures in mature RBCs, if you think about it, you have a sort of empty membrane, no nucleus, lots of cytoplasm in which there’s lots of Hb, so what we’re talking about rly here is abnormalities of red cell membrane, now remember I gave a lecture in BL, mentioned how sophisticated the red cell membrane works – it;’s a lipid bilayer, RBCs have a biconcave shape, plenty of membrane, excessive membrane, allows them to fold and squeeze into v small vessels, so you can see if there were abnormalities in that membrane, and red cells not q so flexible, might be broken down get damaged as you try to go through small vessels”
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