HAEM; Lecture 1, 2, 3, 4 and 5 - Physiology of blood cells and haematological terminology, Deciding what is normal and interpreting blood count, Anaemia and polycythaemia, Iron deficiency and Flashcards
(221 cards)
<p>Where do blood cells originate from?</p>
<p>Bone marrow derived from pluripotent haemopoietic stem cells</p>
<p>What do pluripotent stem cells give rise to?</p>
<p>Lymphoid stem cells and multipotent myeloid stem cells/precursors -> which derives RBC, granulocytes, monocytes, platelets</p>
<p>How is the stem cell hierarchy organised?</p>
<p>What is an essential stem cell characteristic and how is this achieved?</p>
<p>Ability to self-renew and produce mature progeny -> when divides into 2, it divides into a stem cell and a cell capable of differentiating into mature progeny</p>
<p>How do RBC develop from stem cells?</p>
<p>Multipotent myeloid stem cells precursor can give rise to a proerythroblasts which gives rise to erythroblasts and then erythrocytes</p>
<p>What is the process of RBC production and what does it require?</p>
<p>Erythropoiesis which requires presence of erythropoietin</p>
<p>Where is erythropoietin synthesised?</p>
<p>By the kidney in response to hypoxia</p>
<p>What is the function and duration of RBC?</p>
<p>120d in bloodstream, with main function of transporting O2 and some CO2 -> destroyed by phagocytic cells in spleen</p>
<p>How do WBC develop from stem cells and what is needed?</p>
<p>Multipotent haemopoietic stem cells give rise to myeloblast which can give rise to granulocytes and monocytes -> cytokines such as G-CSF, M-CSF, GM-CSF with other interleukins</p>
<p>What is the function and duration of neutrophils?</p>
<p>Neutrophil survives 7-10h in circulation before migrating into tissues -> main function defence aginst infection, with phagoocytosing and killing MOs</p>
<p>What is the function and duration of eosinophils?</p>
<p>Myelocytes also give rise to eosinophils, spends less time in circulation than the neutrophil -> function is defence against parasitic infection</p>
<p>What is the function and duration of basophils?</p>
<p>Myeloblast also gives rise to basophil granulocytes; with role in allergic responses</p>
<p>What is the function and duration of monocytes?</p>
<p>Multipotent haemopoietic stem cell can also give rise to monocyte precursors and then monocytes -> spend several days in the circulation -> function: migrate to tissues and develop into macrophages and other specialised cells with phagocytic and scavenging function; also store and release iron</p>
<p>What is the function and duration of platelets?</p>
<p>Multipotent haemopoietic stem cell also gives rise to megakaryocytes and platelets which survive 10d in circulation -> function: primary homeostasis, contribute P/L which promotes blood coagulation</p>
<p>What is the function and duration of lymphocytes?</p>
<p>Lymphoid stem cells form T, B and NK cells which recirculate to lymph nodes and other tissues and then back to the blood stream, with intravascular life span variable</p>
<p>What is anisocytosis?</p>
<p>Red cells show more variation in size than normal</p>
<p>What is poikilocytosis?</p>
<p>Red cells show more variation in shape than normal</p>
<p>What is microcytosis?</p>
<p>Red cells are smaller than normal</p>
<p>What is macrocytosis?</p>
<p>Red cells are larger than normal</p>
<p>What is microcyte?</p>
<p>Red cell smaller than normal</p>
<p>What is a macrocyte?</p>
<p>Red cell larger than normal</p>
<p>What are the types of macrocytes?</p>
<p>Round, oval (caused in lack of vit B12) and polychromatic (when ribosomal RNA is degraded after the early release of RBC) macrocytes</p>
<p>What is microcytic?</p>
<p>Describing RC smaller than normal or anaemia with small RC</p>
<p>What is normocytic?</p>
<p>Describes RC that are of normal size or anaemia with normal sized RC</p>
What is macrocytic?
Describes RC that are larger than normal or anaemia with large RC
How would you describe the size of the cells in each of the blood films?
Left is anaemic with macroytes and Right is microcytic anaemia
What is the pale part of the RC caused by and how much is normal?
About a third of diameter is pale due to centre having less Hb so is paler (disk-shaped)
What is hypochromia?
Cells have a larger area of central pallor than normal
What causes hypochromia?
Lower Hb content and conc and flatter cell -> described as hypochromic cell which often goes with microcytosis
What is hyperchromia?
Cells lack central pallor
What causes hyperchromia?
Thicker than normal or shape is abnormal (spherocytes and irregularly contracted cells) -> described as hyperchromatic
What are spherocytes?
Cells that are approx. spherical in shape, with round regular outline and lack central pallor -> occur in hereditary spherocytosis which gets more and more spherical as the cell grows older (not all cells spherical)
How are spherocytes formed?
Result from loss of cell membrane without loss of equivalent amount of cytoplasm, so cell is forced to round up
What are irregularly contracted cells?
Irregular in outline but smaller than normal and have lost central pallor
What causes irregularly contracted cells?
Result from oxidant damage to the cell membrane and to Hb
What is polychromasia?
Increased blue tinge to cytoplasm of RC -> indicating RC is young which means the cells are being released prematurely
How can you detect young red cells?
Do a reticulocyte stain which exposes living RC to new methylene blue which precipitates as a network
What are the different shapes of poikilocytes?
Spherocytes, irregularly contracted cells, sickle cells, target cells, elliptocytes, fragments
What are target cells?
Cells with accumulation of Hb in the centre of the area of central pallor
Where do target cells occur?
Obstructive jaundice, liver disease, haemoglobinopathies and hyposplenism
What are elliptocytes?
Elliptical in shape, occurring in hereditary elliptocytosis and iron deficiency
What are sickle cells?
Sickle or crescent shaped, resulting from polymerization of HbS when present in high conc
What are fragments/schistocytes?
Small pieces of RC which indicates that RC has fragmented - RBC under a lot of stress or RBC has shattered for some reason
What are rouleaux?
Stack of RC, resembling a pile of coins, resulting from alterations in plasma proteins -> due to change in plasma proteins
What are agglutinates?
RC agglutinates are different from rouleaux as they are irregular clumps rather than tidy stacks -> result from Ab on surface of cells, usually autoimmune
What is a Howell-Jolly body and what is it caused by?
Nuclear remnant in a RC, with commonest cause due to lack of splenic function
What is leucocytosis?
Too many WC
What is leucopenia?
Too few white cells
What is neutrophilia?
Too many neutrophils
What is neutropenia?
Too few neutrophils
What is lymphocytosis?
Too many lymphocytes
What is eosinophilia?
Too many eosinophils
What is thrombocytosis?
Too many platelets
What is thrombocytopenia?
Too few platelets
What is erythrocytosis?
Too many RBC
What is reticulocytosis?
Too many reticulocytes
What is lymphopenia?
Insufficient lymphocytes
What is an atypical lymphocyte?
Abnormal lymphocytes -> usually used to describe abnormal cells in infectious mononucleosis
What is left shift?
Increase in non-segmented neutrophils or neutrophil precursors in blood -> caused by infection cuz bone marrow is pushing out RBC
What is toxic granulation?
Heavy granulation of neutrophils (occurs in sepsis)
What is the cause of toxic granulation?
Infection, inflammation and tissue necrosis (but also occurs in pregnancy)
What is a hypersegmented neutrophil?
Increase in average number of neutrophii lobes (>5) or segments
What causes hypersegmentation of neutrophils?
Lack of vit B12 or folic acid
What is a reference range?
Derived from carefully defined reference popn -> with a range derived
What is a normal range?
Vague concept with no clear definition, derived from textbook rather than from popn
What percentage of the healthy popn will have results falling in a normal range?
90%
What can 'normal' be affected by?
Age, gender, ethnic origin, physiological status, altitude, nutritional status, cigarette smoking, alcohol intake
What affects Hb in the blood?
Altitude effects cause Hb to increase at higher altitude and decrease at lower altitiude
How is a reference range determined?
Samples collected from healthy volunteers with defined characteristics -> analysed using instrument techniques used with patient samples and data is analysed via appropriate technique
What is an appropriate statistical technique to analyse data?
Data with normal distribution can be analysed by determining the mean and s.d. and taking mean +/- 2SD as 95% range
What do these abbreviations mean in a full blood count - WBC, RBC, Hb, PCV, Hct?
WBC - WBC count in given vol of blood (x10^9/l), RBC - RBC count in a given vol of blood (x10^12/l), Hb - Hb conc (g/l), PCV (packed cell volume (l/l), Hct - haematocrit (l/l)
What do these abbreviations mean in a full blood count - MCV, MCH, MCHC, platelet count?
MCV - mean cell volume (fl), MCH - mean cell Hb (pg), MCHC - mean cell Hb conc (g/l), platelet count - number of platelets in given volume of blood (x10^9/l)
How do you do a RBC, WBC and platelet count?
Used to be counted visually at first using microscope and diluted sample of blood; now counted in large automated instruments enumerating electronic impulses generated when cells flow between light source and sensor/when cells flow through an electrical field
How is Hb measured?
Spectrometer initially converting Hb to stable form and measuring light absorption at a specific wave length (now an automated instrument)
How is PCV/Hct measured?
Initially by centrifuging a blood sample
How is MCV measured?
Initially calculated by dividing total volume of RBC in sample by number of RBC in sample but now determined indirectly by light scattering/interruption of electrical field
**What does MCV correlate with?
Cell size with smaller size meaning
What is MCH?
Amount of Hb in a given volume of blood divided by the number of RBC in the same volume (Hb/RBC)
What is MCHC?
Amount of Hb in a given volume of blood divided by proportion of sample represented by RBC (Hb/PCV or Hct)
What is the difference between MCH and MCHC?
MHC is absolute amount of Hb in individual red cell which in anaemia parallels the MCV; MCHC is conc of Hb in red cell -> MCH= average amount of Hb in a RBC and MCHC= related to shape of the cell
How is MCHC measured?
Electronically, based on light scattering
What correlates with MCHC?
Hypochromia
How do you interpret a blood count?
Check cell line, clues in clinical history, leucocytosis/leucopenia, clues in blood count, cell size; learn to interpret WBC with differential, Hb, MCV, platelet count, looking at absolute count not percentage
How do you interpret polycythaemia?
Means many cells but specifically relates to many RBC in circulation -> causes Hb, RBC and PCV/Hct to be increased compared with normal subject of same age and gender
How do you evaluate polycythaemia?
Start with clinical history and physical examination (splenomegaly, bdominal mass, cyanosis) -> compare with appropriate normal range; NB: Children are lower than adults and neonate are higher than all other times of life, lower in women than men
What causes pseudopolycythaemia?
High Hb, RBC and PCV/Hct which result from decrease in plasma volume
What causes true polycythaemia?
Increase in circulating red cells -> Blood doping in professional cyclists, medical negligence, appropriately elevated levels of erythropoietin due to hypoxia or due to inappropriate administration in haematologically normal subjects or when renal/other tumour inappropriately secretes eryhtropoietin, inappropriately increased independent eryhtropoiesis which is called polycythaemia vera (myeloproliferative neoplasm
What is polycythaemia vera?
Intrinsic bone marrow disorder which leads to inappropriately increased eryhtropoiesis - Can lead to hyperviscosity, leading to vascular obstruction
How can polycythaemia be treated?
If no need for high Hb or hyperviscosity is extreme, blood can be removed to thin the blood - if intrinsic bone marrow disease then drugs can be used to reduce bone marrow production of RBC
In which clinical situations would you think polycythaemia is due to which symptoms: young healthy athlete, breathless cyanosed patient, abdominal mass, splenomegaly?
Young healthy athlete - suspicious, breathless cyanosed patient - due to hypoxia, abdominal mass - carcinoma of kidney, splenomegaly - pointer to polycythaemia vera
What is anaemia?
Reduction in amount of Hb in a given volume of blood below what would be expected in comparison with a healthy subject of same age and gender -> Hb reduced and so is RBC, PCT/Hct usually
What causes anaemia?
Reduction of absolute amount of Hb in blood stream -> occasionally results from increase in volume of plasma rather than decrease in amount of Hb but this can't persist as excess fluid in circulation is excreted
What are the mechanisms of anaemia?
Reduced production of RBC/Hb in bone marrow, loss of blood from body, reduced survival of RBC in circulation, pooling of RBC in very large spleen
What is the mechanism of anaemia?
Reduced synthesis of Hb in bone marrow
What is the cause of anaemia?
Either condition causing reduced synthesis of haem or causing reduced synth of globin
How can you determine the cause of anaemia?
Classification based on cell size can help to suggest specific cause
How do you classify anaemia?
Microcytic (hypochromic), macrocytic (normochromic), normocytic (normochromic)
What are the common causes of microcytic anaemia?
Defect in haem synthesis due to iron deficiency and anaemia of chronic disease OR defect in globin (thalassaemia) due to defect in alpha chain synth (alpha thalassaemia) or beta chain synth defect (beta thalassaemia)
What is a cause of macrocytic anaemia?
Usually results from abnormal haemopoiesis so RBC precursors continue to synthesise Hb and other cellular proteins but fail to divide normally, so RBC appear larger than normal (megaloblastic erythropoiesis)
What is megaloblastic erythropoiesis?
Specifically referring to delay in maturation of nucleus while cytoplasm continues to mature and cell continues to grow
What is a megaloblast?
Abnormal bone marrow erythroblast -> larger than normal and shows nucleocytoplasmic dissociation; needs bone marrow examination to be sure of megaloblastic anaemia
What is an alternative mechanism of macrocytosis?
Premature release of cells from bone marrow - young RBC are 20% larger than mature RBC so if increased proportion of reticulocytes in circulation, MCV is increased
What are the common causes of macrocytic anaemia?
MEgaloblastic anaemia as a result of lack of vit B12 or folic acid; use of drugs interfering with DNA synthesis, liver disease and ethanol toxicity, recent major blood loss with adequate iron stores (reticulocytes increased), haemolytic anaemia (reticulocytes increased)
What are the mechanisms for normocytic, normochromic anaemia?
Recent blood loss, failure of production of RBC, pooling of RBC in spleen
What are the causes of normocytic, normochromic anaemia?
Peptic ulcer, oesophageal varices, trauma, failure of production of red cells -> early stages of iron deficiency or anaemia of chronic disease, renal failure, bone marrow failure/suppression/infiltration; hypersplenism (portal cirrhosis)
What is haemolytic anaemia?
Anaemia resulting from shorteneed survival of RBC in circulation -> haemolysis resulting from intrinsic abnormality of RBC or from extrinsic factors acting on normal RBC
What does inherited haemolytic anaemia result from?
Abnormalities in cell membrane, the Hb or enzymes in red cell
What does acquired haemolytic anaemia result from?
Extrinsic factors such as MOs, chemicals and drugs that damage RBC
What are the classes of haemolytic anaemia?
Inherited, acquired and extrinsic factors; intravascular, extravascular
How do extrinsic factors cause haemolytic anaemia?
Interact with RBC that have intrinsic abnormality
What causes intravascular haemolysis?
Occurs if very acute damage to RBC
What causes extravascular haemolysis?
Defective red cells removed by the spleen
Summary of inherited vs acquired haemolytic anaemia defects and damage
When should you suspect haemolytic anaemia?
Otherwise unexplained anaemia which is normochromic and normocytic/macrocytic; evidence of morphologically abnormal RBC, increased RBC breakdown (unconjugated bilirubin), increased bone marrow activity (increased reticulocyte count)
Why do you get gall stones and jaundice in haemolytic anaemia?
RBC are being broken down at a very high rate so liver can't cope and gall stones are made of bilirubin as they cannot be broken down quick enough
What are some examples of inherited haemolytic anaemia?
Membrane defect = hereditary spherocytes; Hb = Sickle cell anaemia; glycolytic pathway = pyruvate kinase deficiency; pentose shunt = glucose-6-phosphate dehydrogenase deficiency
What are some examples of acquired haemolytic anaemia?
Membrane (immune) - AI haemolytic anaemia; whole red cell (mechanical) - microangiopathic HA; whole red cell (oxidant) - drugs and chemicals; whole red cell (microbiological) - malaria
When are spherocytes more prone to haemolyse?
When osmotic pressure is reduced - not often needed
How do you treat hereditary spherocytosis?
Only effective treatment is splenectomy but has risks so done in severe cases -> 5mg of folic acid every day with good diet bieng important so secondary folic acid deficiency doesn't occur
What is the use of the G6PDH?
Important enzyme in pentose-phosphate shunt, with essential protection of red cell from oxidant damage -> some oxidants may be generated in blood stream
What leads to haemolysis in G6PD?
Extrinsic oxidants such as food stuffs (broad beans), chemicals (napthalene), drugs (dapsone, primaquine)
Who is affected by G6PD deficiency?
Gene is on X chromosome, so affected individuals are usually hemizygous males but sometimes homozygous females
What are the symptoms of G6PD deficiency?
Intermittent, severe intravascular haemolysis as a result of infection/exposure to exogenous oxidant
What does acute haemolysis require?
Blood transfusion, and prevention is important
What causes autoimmune haemolytic anaemia?.
Production of AutoAb directed at RBC antigens; with immunoglobulin bound to RBC is recognised by splenic macrophages which removes parts of RBC membrane, leading to spherocytosis
What is the mechanism of autoimmune haemolytic anaemia?
Spherocytes are less flexible than normal RBC, which combines with recognition of Ab and complement on RBC surface by splenic macrophages leading to removal of cells from circulation by spleen
A microcytic anaemia is likely to be due to Vitamin B12 deficiency Folic acid deficiency Iron deficiency Haemolysis Acute blood loss
Iron deficiency
Polycythaemia in a patient seeing his general practitioner in London because of he has noticed his urine is red is most likely to be due to Chronic renal failure Living at high altitude Hypoxia from chronic obstructive pulmonary disease Haemolysis Renal carcinoma
Renal carcinoma
How do you diagnose AI haemolytic anaemia?
Finding spherocytes and increased reticulocyte count, detecting immunoglobulin on red surface, detecting Ab to red cell Ag or other autoAb in the plasma
How do you treat AI haemolytic anaemia?
Use of corticosteroids and other immunosuppressive agents, splenectomy for severe cases
What are 3 episodes of intravascular haemolysis associated with in G6PD deficiency?
Appearance of considerable numbers of irregularly contracted cells
What happens to Hb in G6PD deficiency?
Denatured and forms round inclusions known as Heinz bodies, which can be detected by a specific test
What are Heinz bodies removed by?
The spleen, leaving defect in cell
What is hereditary spherocytosis?
Haemolytic anaemia or chronic compensated haemolysis resulting from inherited intrinsic defect of the red cell membrane - after entering circulation the cells lose membrane in spleen and become spherocytotic
What is extravascular haemolysis?
Red cells become less flexible and are removed prematurely by the spleen
How does the bone marrow respond to haemolysis?
Increased output of red cells leading to polychromasia and reticulocytosis
What does haemolysis lead to?
Increased bilirubin production, jaundice and gallstones
What are spherocytes more prone to?
Haemolyse when osmotic pressure is reduced -> osmotic fragility test is not often needed
Which proteins in the body contain iron?
Ribonucleotide reductase, Hb, myoglobin, cyclo-oxygenase, succinate DH, cytochrome a,b,c, P450, catalase
Why is iron essential in the body?
Due to its ability to gain and lose electrons easily and also ability to bind to oxygen
What is the role of iron in Hb?
Critical role of holding onto oxygen and most obvious consequences of iron deficiency are seen in blood
How is iron homeostasis maintained?
Red cells live for 120d but iron is recycled so no need to ingest a lot of iron BUT due to desquamated cells of skin and gut and bleeding (menstruation, pathological) leads to iron requirement
How much iron do men and women need daily?
1mg/day for men; women 2mg/day
Where does iron naturally occur in the diet?
Human diet provides 12-15mg iron/day in most natural foods -> meat, fish, vegetables, whole grain cereal, chocolate
What is a downside of dietary iron?
Most is not absorbed as we can only absorb Fe2+ (orange juice helps)
Which factors affect absorption?
Diet -> increase in haem iron, ferrous iron; intestine -> acid (duodenum), ligand (meat); systemic -> iron deficiency (anaemia/hypoxia, pregnancy)
Why is absorption of iron important?
No regulatory mechanisms for iron excretion
How does the gut cell alter iron absorption?
Ferroportin is controlled by hormone hepcidin which binds to and induces degradation of ferroportin, causing the iron to be stuck inside the enterocyte, which then means the iron is lost when the cell is shed
Where is ferroportin found?
Enterocytes of duodenum, macrophages if spleen which extract iron from RBC (old/damaged), hepatocytes
What occurs when hepcidin is high?
Leads to reduced iron entering the blood from the duodenum, macrophages and hepatocytes
What does transferrin form?
Stable complexes with iron and more than 40 other metal ions
What can't transferrin do?
Transport iron inside the cells where it is needed
What does transferrin-iron interact with?
Transferrin receptor and is internalised -> as pH drops iron is released and transferrin receptors are recycled
Why is iron removal/absorption so complex?
Iron is toxic and insoluble -> with binding proteins and transport systems maintaining iron in a soluble and non-toxic form
What is the mechanism to correct anaemia?
Tissue hypoxia occurs -> increase in erythropoietin -> red cell precursors: survive, grow and differentiate
How does anaemia of chronic disease (ACD) present in a patient?
No obvious cause except for illness of the patient -> no bleeding, marrow infiltration or iron/B12/folate deficiency
What are the signs in the lab of ACD?
C-reactive protein, erythrocyte sedimentation rate and acute phase response -> increases in ferritin, FVIII, fibrinogen, immunoglobulins
What are associated conditions of ACD?
Chronic infections (TB/HIV), chronic inflammation (RhA/SLE), malignancy, miscellaneous (cardiac failure)
What do cytokines do to iron?
Prevent usual flow of iron from duodenum to red cells -> block iron utilisation; stop erythropoietin increasing, stop iron flowing out of cells, increase production of ferritin, increase death of RBC -> make less RBC, so more die so less availability of iron
What are the causes of iron deficiency?
Bleeding (menstrual/GI), increased use (growht/pregnancy), dietary deficiency (vegetarian), malabsorption (coeliac)
When is a full GI investigation carried out?
Male, woomen over 40, post menopausal women and women with scanty menstrual loss
Which full GI investigations are carried out?
Upper GI endoscopy (oesophagus, stomach and duodenum), take duodenal biopsy, colonoscopy -> if nothing then small bowel meal followed through
What other investigations can be carried out?
Mestruating woman <40 if heavy period/multiple pregnancies and no GI symptoms then do nothing; urinary blood loss; antibodies for coeliac disease
What are the lab parameters?
MCV, serum iron, ferritin, transferrin (total iron binding capacity), transferrin saturation
What are the causes of low MCV?
Iron deficiency, thalassaemia trait, anaemia of chronic disease
What are the causes of low serum iron?
Iron deficiency and anemia of chronic disease
How do we confirm thalassaemia trait?
Hb electrophoresis, confirming additional Hb present
In which conditions is ferritin high and low?
Low in iron deficiency and high in chronic disease -> but if iron deficiency and underlying chronic disease then ferritin can be normal
How can you tell that the ferritin value is not ideal?
Raised CRP and ESR
What is the transferrin saturation in iron deficiency and chronic disease?
Iron deficiency = low saturation; chronic disease= normal
Which further investigations after determining iron deficiency can you carry out?
Endoscopy/colonoscopy, duodenal biopsy, anti-helicobacter Ab, anti-coeliac Ab -> abdo US to look at kidneys, dipstick urine, pelvic US to exclude fibroids
What if a man of any age presents with low ferritin?
Iron deficiency suggested and needs to have upper and lower GI endoscopies to look for source of bleeding
How do the following present in classic iron deficiency: Hb, MCV, serum iron, ferritin, transferrin, transferrin saturation?
Hb-> LOW. MCV -> LOW. Serum iron -> LOW. Ferritin -> LOW. Transferrin -> HIGH. Transferrin sat -> LOW
How do the following present in ACD: Hb, MCV, serum iron, ferritin, transferrin, transferrin saturation?
Hb-> LOW. MCV -> LOW/NORMAL. Serum iron -> LOW. Ferritin -> HIGH/N Transferrin -> N/L. Transferrin sat -> N
How do the following present in thalassaemia traits: Hb, MCV, serum iron, ferritin, transferrin, transferrin saturation?
Hb-> LOW. MCV -> LOW. Serum iron -> NORMAL. Ferritin -> N Transferrin -> N. Transferrin sat -> N
How do the following present when RhA with bleeding ulcer occurs: Hb, MCV, serum iron, ferritin, transferrin, transferrin saturation?
Hb-> LOW. MCV -> LOW. Serum iron -> LOW. Ferritin -> N. Transferrin sat -> LOW
What are the roles of vit B12 and folate?
Required for DNA synthesis, absence leads to severe anaemia which can be fatal
What is B12 required for?
DNA synthesis, Integrity of NS
What is Folic acid required for?
DNA synthesis and homocystine metabolism
Which cells are affected in B12/folate deficiency?
All rapidly dividing cells are affected -> bone marrow, epithelial cells on surface of mouth and gut, gonads, embryo
What are the clinical features of B12/folate deficiency?
Anaemia (weak, tired, short of breath), Jaundice, glossitis and angular cheilosis, weight loss, change of bowel habit, sterility
What are the types of anaemia in B12/folate deficiency?
Macrocytic and megaloblastic
What is the definition of macrocytic?
Average RBC size is above normal range
What are the causes of macrocytic anaemia?
Vit B12/folate deficiency, liver disease/alcohol, hypothyroid, drugs (azathioprine), haematological disorders (Myelodysplasia, aplastic anaemia, reticulocytosis -> chronic haemolytic anaemia)
What is megaloblastic?
Morphological change in red cell precursors within bone marrow
How does a normal red cell mature?
Erythroblast -> normoblast (early/intermediate/late) -> reticulocyte -> circulating RBC
What is megaloblastic anaemia?
Asynchronous maturation of nucleus and cytoplasm in the erythroid series with maturing red cells seen in bone marrow
What are the features of the peripheral blood in megaloblastic anaemia?
Anisocytosis, large red cells, hypersegmented neutrophils, giant metamyelocytes
Can thyroid disease be a cause of megaloblastic RBC?
x
What 3 tests would you do if someone had macrocytosis?
x
Where does dietary folate come from?
Fresh leafy vegetables -> destroyed by overcooking/canning/processing
What could cause a decrease in folate intake?
Ignorance, poverty, apathy
Which physiological conditions have an increased demand of folate?
Pregnancy, adolescence, premature babies
Which pathological conditions have an increased demand of folate?
Malignancy, erythoderma, haemolytic anaemia
How do you diagnose folate deficiency in the lab?
FBC and film, folate levels in the blood
How would you assess cause of decreased folate?
History (diet/alcohol/illness), examination (skin disease/alcoholic liver disease)
What are the consequences of folate deficiency?
Megaloblastic, macrocytic anaemia; neural tube defects in developing fetus; increased risk of thrombosis in association with variant enzymes involved in homocysteine metabolism
Which neural tube defects occur in folate deficiency in the fetus?
Spina bifida, anencephaly -> all pregnant women take folic acid 0.4mg before conception and for first 12 weeks
What are high levels of homocysteine associated with?
Atherosclerosis, premature vascular disease
What are mildly elevated levels of homcysteine levels associated with?
CVD (definitely), arterial thrombosis (probably) and venous thrombosis (possible)
What are the consequences of vit B12 deficiency?
Neurological problems - bilateral peripheral neuropathy, subacute combined degeneration of cord (posterior and pyramidal tracts of spinal cord), optic atrophy and dementia
What are some clinical signs of B12?
Paraesthesiae, muscle weakness, difficult walking, visual impairment, psychiatric disturbance
What would you discover upon examination of patient with B12 deficiency?
Absent reflexes and upgoing plantar responses
What are the causes of B12 deficiency?
Poor absorption, reduced dietary intake -> stores are large, last for 3/4y, present in animal produce and vegans are at risk; infections/infestations -> abnormal bacteria flora (stagnant loops), tropical sprue, fish tapeworm
How does normal B12 absorption occur?
In small intestine where B12 is stored and when stores are saturated, excess b12 is excreted in urine -> 2 methods of absorption: 1) slow and inefficient in duodenum and 2) where B12 combines with intrinsic factor (made in parietal cells) which then binds to ileal receptors
What are the 3 essential things needed for B12 absorption?
Intact stomach, intrinsic factor and functioning small intestine
What are the reasons for impaired B12 absorption?
Reduction in IF -> post gastrectomy, gastric atrophy, antibodies to IF/parietal cells; Diseases of small bowel (terminal ileum) -> crohns, coeliac disease and surgical resection
What is pernicious anaemia?
AI condition associated with severe lack of IF -> peak age of 60y and FHx - males have decreased life expectancy due to Ca stomach
Which antibodies occur in pernicious anaemia?
IF Ab which are occasionally found in other conditions and parietal cell antibodies in 9% of adults with PA and 16% of normal females over age of 60; increased in relative of patients with PA
Which infections can cause impaired B12 absorption?
H Pylori, Giardia, fish tapeworm, bacterial overgrowth
Which drugs are associated with low B12?
Metformin, proton pump inhibitors (omeprazole), oral contraceptive pill
How would you check for the cause of B12 deficiency in patients with low b12?
Ab to parietal cells and IF; Ab for coeliac disease; breath test for bacterial overgrowth; stool for H pylori; test for giardia (olden days: schilling test)
How is part 1 of the schilling test carried out?
Before test, replenish stores of B12; drink radiolabelled B12 and measure excretion in urine -> if no B12 in urine then there is something wrong
What is the reason for no B12 in the urine during the schilling test?
Not absorbing B12 -> PA or small bowel disease; or hadn't corrcted B12 deficiency before the test
How is part 1 of the schilling test carried out?
Repeat test with addition of IF and measure for excretion of B12 in urine
What is the meaning of results of schilling test being low in P1 and normal in P2?
x
What is the meaning of results of schilling test being low in P1 and low in P2?
x
What is the meaning of results of schilling test being normal in P1?
x
What should you do if patient comes in presenting with B12 deficiency symptoms but B12 levels are normal?
Measure methylmanolyl acid and homocysteine, look for anti-IF Ab; treat as B12 deficiency until all results are back
What is the treatment for B12 deficiency?
Injections of B112 of 1000micrograms 3x/week for 2 weeks and then every 3 months -> if neuro involvement then B12 injections alternate days until no further improvement (up to 3wks) and then every 2 months
A 49 y old man with grey hair and blue eyes presents with anaemia. His blood count is as follows: Hb 90g/l WBC 4 x 109/l platelets 160 x 109/l MCV 110fl Which would be the most appropriate set of investigations 1) Blood film, liver function, Shilling test 2) Folate, B12, thyroid function, liver function 3) Thyroid function, B12 and anti-intrinsic factor antibodies 4) Ferritin, shilling test, folate 5) Blood film, thyroid antibodies, anti-parietal cell antibodies
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