Pernicious anaemia Flashcards
What are the different types of antibodies that cause pernicious anaemia?
2 types:
- intrinsic factor antibodies (IFAb) either blocking or binding
-> blocking: bind to vit K binding site of IF
-> binding: bind to ileal receptors, preventing B12-IF binding
-Gastric parietal cell (GPC) antibodies
What is macrocytic anaemia?
MCV: >100
Fail to produce DNA quick enough - large RBCs
Cells are fragile and easily destroyed
Mostly megaloblastic: impaired DNA synthesis
Non-megaloblastic: ne effect on DNA synthesis
What is normocytic anaemia?
MCV: 80-100
RBC size is normal, but decrease in haemoglobin
Causes: haemolysis or underproduction
What is microcytic anaemia?
MCV: <80
Lack of haemoglobin -> extra divisions of RBCs to compensate for insufficiency -> smaller, paler RBCs
Common cause: iron deficiency
What are the classes of anaemia?
Microcytic, macrocytic and normocytic
How are the classes of anaemia differentiated?
By the MCV - size of RBCs
What is MCV?
Mean corpuscular volume: measures the size and volume of RBCs
How does the immune system attack the self in autoimmune gastritis?
During the normal turnover, DCs sees H+/K+ ATPase pump as foreign
DCs express H+/K+ ATPase antigens on MHCII, presents to naive CD4 T cells in lymph nodes
CD4 cells differentiate into T helpers: Th1 and Th17
- Th1 release INFy, IL-2, TNFa - attracts macrophages, activates CD8 - attacks gastric mucosa
- Th17 release TGF-B - class switching of B cells - release antibodies against IF and gastric parietal cells
What type of anaemia is pernicious anaemia?
Megaloblastic anaemia - presence of large RBC precursors = megaloblasts
What occurs in pernicious anaemia?
Inability to produce IF, B12-IF complex cannot be formed -> B12 cannot bind to receptors on ileum -> cannot be absorbed by ileum
B12 acts as a cofactor for enzymes that produce amino acids in DNA synthesis > RBCs enlarge > megaloblasts - less functional, shorter lifespan
What are the clinical consequences of autoimmune gastritis?
Vitamin B12 deficiency - pernicious anaemia
Hypochlorhydria - reduced stomach acid due to damaged parietal cells
Gastric cancer - damage to mucosa lead to metaplastic changes
What drives autoimmune gastritis?
Self-sensitised T-lymphocytes and production of autoantibodies that target parietal cells in the stomach and intrinsic factor
Parietal cells produce HCl and intrinsic factor
> reduction in gastric acid > hypochlorhydria
> reduction of intrinsic factor > reduces vit B12 absorption > pernicious anaemia
Autoimmune attack causes gastric mucosa atrophy > thinning > metaplastic changes
What is the life cycle of a RBC?
IN BONE MARROW
haemoblast - stem cell in red bone marrow
Proerythroblast - high N:C, basophilic
Early erythroblast - high N:C, no nucleoli
Late erythroblast - cell division ceases, round nucleus
Normoblast - ejection of nucleus
Reticulocyte - between nucleated RBC, and mature RBC
IN BLOODSTREAM
Erythrocyte - central pallor, no nucleus
Digestion and absorption of vitamin B12
Vit B bound to proteins in food, released when mixed with saliva and stomach acid
B12 is freed from protein by pepsin in the stomach
Haptocorrin (R binder) from the saliva enter stomach and binds to B12 to form B12-R binder complex
Intrinsic factor from parietal cells is released and moves with the B12-R binder complex into the duodenum
Pancreatic proteases in the duodenum cleave off the R binder from the B12
B12 is free to bind to IF, forming B12-IF complex.
B12-IF complex binds to IF receptors in the ileum
B12 absorbed into the bloodstream, binds to transcobalamin
The taken up by cells by receptor mediated endocytosis
What is the role of vitamin B12 in the body? 4
- Development of myelination
- Function of the CNS
- Healthy RBC formation
- DNA synthesis
- B12 and folate are involved in DNA and RNA synthesis, role in folate cycle and methionine cycle
- Is a co-factor for two enzymes (presence essential for function)
> Methionine synthase (formation of 100 different substrates e.g. DNA, RNA) in methionine cycle and folate cycle
> L-methylmalonyl CoA mutase (converts enzymes for Krebs cycle = energy)
Vitamin B12 - solubility, what it contains, where it is stored
Water soluble vitamin
Contains mineral cobalt, so compounds are called cobalamins
B12 stored in the liver to serve as a reservoir, if dietary intake fluctuates
What are the clinical complications of pernicious anaemia if left diagnosed and untreated?
Permanent neurological damage -> memory loss, fatigue, depression
Increases risk of gastric cancer - damage to mucosa > metaplastic changes
Peripheral neuropathy -> B12 coenzyme for synthesis of NT and myelin
What are the tests for pernicious anaemia?
FBC - determines type and degree - measures MCV
Reticulocyte count - tests if bone marrow can make new RBCs
LDH levels - enzyme - high may indicate PA
Serum bilirubin levels
U&E
MMA (serum methylmalonic acid) - high = B12 deficiency
Homocysteine level - presence of IF and GPA antibodies - high = vit B12 deficiency
Endoscopy - look for degeneration of stomach lining
How is PPI use a risk factor for pernicious anaemia?
PPIs increase gastric pH, prevent pepsinogen > pepsin conversion, required to free vitamin B12 from protein
How is a strict diet a risk factor for pernicious anaemia?
Vitamin B12 is obtained from the diet
Deficiencies can occur from the lack of ingestion through the diet
How are tapeworm infections a risk factor for pernicious anaemia?
Tapeworms feed on vitamin B12, reduces levels in the body
How is type 1 diabetes a risk factor for pernicious anaemia?
More likely to express IF or gastric parietal cell antibodies
How is age a risk factor for pernicious anaemia?
Ability to absorb vitamin B12 reduces with age
How is a gastrectomy or bowel resection a risk factor for pernicious anaemia?
Gastrectomy: fewer parietal cells to produce IF
Small bowel resection: vit B12 no longer able to be absorbed in terminal ileum
How is family history a risk factor for pernicious anaemia?
Q5R gene codes for the IF
Mutation in this gene can lead to reduced production
What are the risk factors for pernicious anaemia?
Family history, gastrectomy, part of the SI removed, age, type 1 diabetes, tapeworm infection, strict diet, PPIs
What are the symptoms of pernicious anaemia? How are they caused?
Weakness, fatigue, shortness of breath: decreased erythrocytes, decreased oxygen
Tachycardia: heart works harder to deliver oxygenated blood around
Muscle weakness, numbness/tingling: vit B12 essential for myelin synthesis, which increases speed of electrical impulses along neurons
Nausea, vomiting and appetite loss: decreased erythrocytes and oxygen to gut
Jaundice: increased destruction of erythrocytes of RBCs in bone marrow, increases bilirubin
Heartburn: vit B12 needs to interact with acid to be available > indigestion
Why is hydroxocobalamin given more frequently in the first two weeks?
Boost levels of vit B12 and reduce symptoms quickly
Starts to work immediately
Stored for several months
After initial two weeks, given every two months (two weeks if neurological symptoms present) for life
How is hydroxocobalamin given?
Given IM, as absorption is rapid and efficient
Avoids GI tract where B12 absorption is blocked by autoantibodies
Not IV, as more side effects
What treatment can be given to manage pernicious anaemia?
Hydroxocobalamin - manufactured version of vitamin B12
