Anaemia

Question 1

Definition of anaemia

Answer 1

Low haemoglobin concentration

Question 2

What is anaemia classification based on?

Answer 2

Red cell size

Question 3

What are the classifications of anaemia?

Answer 3

• Microcytic= small (MCV <78fL)
• Normocytic= normal (MCV 78-98 fL)
• Macrocytic= large (MCV >98fL)

Question 4

Why is microcytic anaemia an issue?

Answer 4

-Not enough haemoglobin
-Haemoglobin= haem (iron) + globin chains

Question 5

What are the causes of microcytic anaemia?

Answer 5

• Iron deficient anaemia
  -Thalassaemia
  -AOCD (sometimes)
  -Lead poisoning
  -Congenital sideroblastic anaemia
  -Normal haemoglobin, microcytosis: thalassaemia polycythaemia rubra vera causing IDA secondary to bleeding

- Haemoglobinopathy/ thalassaemia (genetic defect in haemoglobin)

Question 6

What biochemistry is involved in iron studies?

Answer 6

• Ferritin= stores iron (tissue macrophages)
• Serum iron= free iron (fluctuates in inflammation)
• Transferrin= transports iron

Question 7

What are the biochemistry results in iron deficiency anaemia?

Answer 7

• Ferritin= low (main test)
• Serum iron= low
• Transferrin= high

In ACUTE Phase response (such as infection/inflammation):

• Ferritin= may rise
• Serum iron= low
• Transferrin= low (so used to confirm IDA)

Question 8

Presentation of iron deficiency anaemia

Answer 8

Fatigue
Shortness of breath on exertion
Palpitations
Pallor
Nail changes: this includes koilonychia (spoon-shaped nails)
Hair loss
Atrophic glossitis
Post-cricoid webs
Angular stomatitis

Question 9

Investigation of IDA

Answer 9

-Taking a history is the most important step in looking for potential causes of iron deficiency. It is useful to inquire about: changes in diet, medication history, menstrual history, weight loss, change in bowel habit

-Full blood count (FBC) demonstrates hypochromic microcytic anaemia
-Serum ferritin this will likely be low, as serum ferritin correlates with iron stores. However, it is important to recognise that ferritin can be raised during states of inflammation; so a raised ferritin does not necessarily rule out iron deficiency anaemia if the is co-occurring inflammation. For patients with co-occurring inflammatory disease, other iron studies can be performed.
-Total iron-binding capacity (TIBC)/transferrin this will be high. A high TIBC reflects low iron stores. . Note that the transferrin saturation will however be low

-Blood film anisopoikilocytosis (red blood cells of different sizes and shapes) , target cells, ‘pencil’ poikilocytes

-Endoscopy to rule out malignancy, males and post-menopausal females who present with unexplained iron-deficiency anaemia should be considered for further gastrointestinal investigations. Post-menopausal women with a haemoglobin level ≤10 and men with a haemoglobin level ≤11 should be referred to a gastroenterologist within 2 weeks.

Question 10

How do you treat and manage IDA?

Answer 10

-Ferrous sulphate 200mg tds until FBC normal and 3/12 (replenish stores)

-Find source- blood loss?
=Menstruation
=GI loss (Upper GI endoscopy and colonoscopy), malignancy
=Non absorption (coeliac screen)
=Other bleeding (nosebleeds, renal cancer…)
=Poor dietary intake (vegan)
=Increased requirement (growing children, pregnancy)

Question 11

Describe thalassaemia

Answer 11

• Common worldwide mostly with Africa and South Asia as protective against Malaria, genetic disorder
• Insufficient globin chains in haemoglobin, autosomal recessive
• MCV often much lower than Hb
  -Special testing- electrophoresis, HPLC, raised ferritin
  -In patients with thalassaemia, the red blood cells are more fragile and break down easily, causing haemolytic anaemia. The spleen acts as a sieve, filtering the blood and removing older cells. The spleen collects all the destroyed red blood cells, resulting in splenomegaly

Question 12

Features of thalassaemia

Answer 12

Microcytic anaemia (low mean corpuscular volume)
Fatigue
Pallor
Jaundice
Gallstones
Splenomegaly
Poor growth and development

Question 13

Alpha thalassaemia

Answer 13

Alpha:
=2 separate alpha-globulin genes are located on each chromosome 16
=If 1 or 2 alpha globulin alleles are affected then the blood picture would be hypochromic and microcytic, but the Hb level would be typically normal
=If are 3 alpha globulin alleles are affected results in a hypochromic microcytic anaemia with splenomegaly. This is known as Hb H disease
=If all 4 alpha globulin alleles are affected (i.e. homozygote) then death in utero (hydrops fetalis, Bart’s hydrops)

-Management
=Monitoring
=Blood transfusions
=Splenectomy
=Bone marrow transplant

Question 14

Beta thalassaemia

Answer 14

-Beta:
=Beta minor/trait: mild hypochromic, microcytic anaemia. It is usually asymptomatic (mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia). One abnormal one normal gene
=Beta intermedia: 2 abnormal copies (defective/deletion), more significant microcytic anaemia, blood transfusions, iron chelation to prevent overload
=Beta-thalassaemia major: absence of beta globulin chain chromosome 11 (2 deletions), presents first year of life with failure to thrive and hepatosplenomegaly, microcytic anaemia, HbA2 and HbF raised. Repeated transfusion leads to iron overload (organ failure) so desferrioxamine. Frontal bossing, enlarged maxilla, depressed nasal bridge, protruding upper teeth

Question 15

What are the main causes of normocytic anaemia?

Answer 15

-Anaemia of chronic disease
-Bone Marrow Failure
(-Haemodilution by IV fluids
-EPO insufficiency like renal failure)

-CKD
-Aplastic anaemia
-Haemolytic anaemia
-Acute blood loss

Question 16

Describe the pathophysiology of anaemia of chronic disease

Answer 16

-Iron 'stuck' in stores (not mobilising)
=New red cells hard to make (iron not mobilised)
=Low transferrin
=MCV starts to fall over time
=Can be borderline microcytosis

Question 17

Examples of chronic disease

Answer 17

-Inflammatory
=Crohn’s, arthritis

-Infection
=Tuberculosis, osteomyelitis, persistent pneumonia

• Cancer (e.g. pancreatic)
• RAISED INFLAMMATORY MARKERS (CRP)
  -Rouleaux blood film results (inflammation)

Question 18

What would the biochemistry results show for anaemia of chronic disease?

Answer 18

• Ferritin (stores iron)= normal/high
• Serum iron (free iron)= low
• Transferrin (transport iron)=low

Question 19

What is required for diagnosis of ACD?

Answer 19

• Chronic disease
• Inflammatory markers
• Low transferrin

Question 20

How is ACD treated?

Answer 20

• Don’t prescribe iron
• Don’t transfuse
• Treat the cause

Question 21

IDA vs ACD

Answer 21

-IDA
=Low serum iron (<8)
=High TIBC
=Low transferrin
=Low ferritin

-ACD
=Low serum iron (<15)
=Low TIBC
=Low transferrin
=High ferritin

Question 22

Describe Bone Marrow Failure

Answer 22

-Bone marrow not able to function to produce normal blood cells
-Often several cytopenias in peripheral blood
=Pancytopenia (all): anaemia (failure of red blood cells), thrombocytopenia (failure of platelets), leukopenia (failure to produce white cells)

Question 23

Causes of Bone Marrow Failure

Answer 23

-Malignancy/ Clonal
=Blood and others- taking over marrow space to prevent production
-Drugs
=Chemotherapy
=Other cytotoxics (methotrexate)
=Antibiotics (idiosyncratic cytopenias)
-Infection (HIV)
-Nutritional
-Radiation (poisons)
-Congenital

Question 24

Causes of macrocytic anaemia

Answer 24

-Haematinic Deficiency (B12 and folate deficiency, megaloblastic, methotrexate)
-Haemolysis
-Altered lipid content
=Alcohol, liver disease, hypothyroidism, drugs

-Non megaloblastic
=Alcohol
=Liver disease
=Hypothyroid
=Aplastic
=Reticulocytotic
=Pregnancy
=Myelodysplasia

Question 25

Describe Haematinic deficiency

Answer 25

• B12 and folate involved in DNA synthesis

- Deficiency= ‘bad blueprints’, DNA defective

Question 26

Sources and stores of B12 and folate

Answer 26

-B12:
=animal protein, some yeast, supplements (vegans)
=Stores= years
=Also severe neurological effects (subacute combined degeneration of the spinal cord)

-Folate:
=Vegetables, nuts, yeast
=Stores= 6 weeks

Question 27

Describe B12 metabolism

Answer 27

• Dietary intake and digestion
• Intrinsic factor (protein) from gastric parietal cells
• Absorption in distal small bowel (ileum)

Question 28

What causes of B12 deficiency are related to metabolism of B12?

Answer 28

• Veganism= dietary intake
• Pernicious anaemia= intrinsic factor from gastric parietal cells
• Ileal disease like Crohn’s= absorption in distal small bowel
  -Atrophic gastritis secondary to H.pylori infection, gastrectomy, malnutrition (alcoholism)

Question 29

Describe pernicious anaemia

Answer 29

• Older patients
• Autoimmune disease affecting gastric mucosa
• Antibodies to intrinsic factor 50% (+/- gastric parietal cells).
  =vitamin B12 is important in both the production of blood cells and the myelination of nerves → megaloblastic anaemia and neuropathy
• Replace B12 (as hydroxocobalamin)

Question 30

Risk factors for pernicious anaemia

Answer 30

more common in females (F:M = 1.6:1) and typically develops in middle to old age
associated with other autoimmune disorders: thyroid disease, type 1 diabetes mellitus, Addison’s, rheumatoid and vitiligo
more common if blood group A

Question 31

Features of pernicious anaemia

Answer 31

-Anaemia features
=lethargy
=pallor
=dyspnoea
-Neurological features
=peripheral neuropathy: ‘pins and needles’, numbness. Typically symmetrical and affects the legs more than the arms
=subacute combined degeneration of the spinal cord: progressive weakness, ataxia and paresthesias that may progress to spasticity and paraplegia
=neuropsychiatric features: memory loss, poor concentration, confusion, depression, irritabiltiy
-Other features
=mild jaundice: combined with pallor results in a ‘lemon tinge’
=glossitis → sore tongue

Question 32

Investigation of pernicious anaemia

Answer 32

-Full blood count
=macrocytic anaemia: macrocytosis may be absent in around of 30% of patients
=hypersegmented polymorphs on blood film
=low WCC and platelets may also be seen

-Vitamin B12 and folate levels
=a vitamin B12 level of >= 200 nh/L is generally considered to be normal

-Antibodies
=anti intrinsic factor antibodies: sensivity is only 50% but highly specific for pernicious anaemia (95-100%)
=anti gastric parietal cell antibodies in 90% but low specificity so often not useful clinically

-Schilling test is no longer routinely done
=radiolabelled B12 given on two occasions, firstly on its own, secondly with oral IF. Urine B12 levels are then measured

Question 33

Management of pernicious anaemia

Answer 33

Management
vitamin B12 replacement
usually given intramuscularly
no neurological features: 3 injections per week for 2 weeks followed by 3 monthly treatment of vitamin B12 injections
more frequent doses are given for patients with neurological features
there is some evidence that oral vitamin B12 may be effective for providing maintenance levels of vitamin B12 but it is not yet common practice
folic acid supplementation may also be required

Complications other than the haematological and neurological features detailed above
increased risk of gastric cancer

Question 34

How is Haematinic deficiency treated?

Answer 34

-Serum levels to diagnose
-Oral folate
-Intramuscular B12 (or oral)
-Find cause
-NEVER replace folate without knowing B12
=can precipitate cord disease (BeFore)

Question 35

Causes of haemolysis

Answer 35

-Shortened red cell survival
=Immune vs non-immune
=Intravascular vs extravascular
=Congenital vs Acquired

Question 36

Intrinsic problems relating to RBC survival and typical causes

Answer 36

```Heritdary
-Haemoglobin
=Sickle cell, thalassemia
-Enzymes
=G6PD deficiency
-Structural proteins
=Hereditary Spherocytosis
~~~

Haemolytic disease of new-born
Warm autoimmune haemolytic anaemia

Question 37

Extrinsic threats to the RBC and causes

Answer 37

-Antibodies
=Autoimmune haemolysis, haemolytic transfusion reaction
-Microangiopathy
=Disseminated intravascular coagulation, eclampsia, HUS, TTP, heart valves
-Toxins
-Infection
=Malaria

Question 38

How do you know if haemolysis is happening?

Answer 38

• Anaemia -> macrocytic over time
• Lots of reticulocytes
• Jaundice (haemoglobin metabolised resulting in unconjugated bilirubin)
• Dark urine (products)
• Chronic= splenomegaly (can produce blood)

Question 39

How can you SHOW haemolysis is happening?

Answer 39

-Red cells dying
=Macrocytic anaemia /normocytic
=Reticulocyte response
=Bilirubinaemia (unconjugated)
=Release of lactate dehydrogenase (released from red cells)
=Consumption of Haptoglobin (soaks up free haemoglobin)

-Cause?
=Blood film (morphology): schistocytes
=Coomb’s Test (immune): autoimmune haemolytic anaemia
=Haematologist

Question 40

Neonate anaemia

Answer 40

Anaemia plus jaundice= haemolysis (unconjugated bilirubin)
=FBC, cause

Question 41

Overview of haemolytic disease of new-born

Answer 41

-Haemolysis and jaundice in the neonate.
-It is caused by incompatibility between the rhesus antigens on the surface of the red blood cells of the mother and fetus. The rhesus antigens on the red blood cells vary between individual. This is different to the ABO blood group system.

When a woman that is rhesus D negative (does not have the rhesus D antigen) becomes pregnant, we have to consider the possibility that the fetus will be rhesus D positive (has the rhesus D antigen). It is likely at some point in the pregnancy the blood from the fetus will find a way into her bloodstream. When this happens, the fetal red blood cells display the rhesus D antigen. The mother’s immune system will recognise the rhesus D antigen as foreign and produce antibodies to the rhesus D antigen. The mother has then become sensitised to rhesus D antigens.

Usually, this sensitisation process does not cause problems during the first pregnancy (unless the sensitisation happens early on, such as during antepartum haemorrhage). During subsequent pregnancies, the mothers anti-D antibodies can cross the placenta into the fetus. If that fetus is rhesus positive, these antibodies attach themselves to the red blood cells of the fetus and causes the immune system of the fetus to attack its own red blood cells. This leads to haemolysis, causing anaemia and high bilirubin levels. This leads to a condition called haemolytic disease of the newborn.

A direct Coombs test (DCT) can be used to check for immune haemolytic anaemia. This will be positive in haemolytic disease of the newborn.