U9C2 Pernicious Anemia Flashcards
Why would the patient be tired and breathless?
Tiredness is a result of less oxygen in the blood meaning tissues and cells can’t respire resulting in fatigue. Breathless Is a result of the body trying to increase the oxygen intake.
What is the life cycle of a RBC?
What can go wrong with red blood cell development to cause anaemia?
- Erythroblasts require folate and vitamin B12 for proliferation during their differentiation.
- Deficiency of folate or vitamin B12 inhibits purine and thymidylate syntheses, impairs DNA synthesis causes erythroblast apoptosis, resulting in anemia
What medications would be asked about and why?
- Proton Pump Inhibitors- Block H+/K+ ATPase, so stop the release of H+ which reduces the production of gastric acid. Gastric acid is required for activation of pepsinogen to pepsin. Pepsin is required to free vitamin B12 from protein
- Metformin- Used to treat type 2 diabetes and PCOS. Reduces ATP production and increases AMP production. Inhibits vitamin B12 absorption by inhibiting Ca2+ influenced IF-vitamin B12 binding to the receptor complex
- Nitrous Oxides- Oxidizes vitamin B12 = inactivating it. Cannot be used as co-factor for methionine synthase = demyelination of nerves = peripheral neuropathy
What test results would indicate PA and why?
Urea and electrolytes in normal rage
• Hb (low) -> which was due to impaired DNA synthesis in RBCs (during erythropoiesis) meaning fewer RBCs which contain Hb
• Haematocrit (low) - this means the % of BC in the blood vol
• RBC (low)
• MCH (high) - this means the mean corpuscular haemaglobin meaning the avg amount of Hb per RBC is higher -> because of macrocytosis (larger than normal
RBCs - contain more Hb) - but there are fewer of RBCs -> so this measurement does not account for lower overall no.s of RBCs as it is an avg -> so indicates a form of megaloblastic anemia
• MCV (high) - this means mean cell vol of RBCs -> due to macrocytosis (vol of RBCs is larger)
-> so indicates a form of megaloblastic anemia
• WBC (low) -> as B12/folate are needed to make WBCs too (haemopoiesis ) -> so indicates a form of megaloblastic anaemia
• Platelets (low) -> as B12/folate are needed to make platelets too (haemopoiesis ) -> so indicates a form of megaloblastic anaemia
• Ferritin (high) - ferritin is stores iron (is a storage protein) by binding to iron -> so high levels indicate less iron is being ‘used’ in RBCs in the haem group (Hb) - due to dvfunctional RBC erythropoiesis
• Folate (normal) - indicates the megaloblastic anaemia IS NOT folate deficiency anaemia (i.e., low folate is not causing impaired DNA synthesis in RBCs)
• B12 (low) - indicates the megaloblastic anemia IS pernicious anaemia (low B12 is causing impaired DNA synthesis in RBCs during erythropoiesis)
Anti-parietal cell antibody (APCA) test
- This test looks for antibodies against the parietal cells of the stomach
Anti-Intrinsic Factor Antibody (AIFA) Test
- This test looks for antibodies against intrinsic actor
What is intrinsic factor and what cells secrete it?
Glycoprotein which only acts on B12 in the second segment of the duodenum
Parietal into the stomach
Type 1 vs 2 intrinsic factor
type 1 binds to the vitamin B12 binding site while type 2 binds to an allosteric site and prevents the intrinsic factor-vitamin B12 complex from attaching to enterocytes in the small intestine
What are the risk factors for pernicious anaemia?
- Family Hx and genetics - intrinsic factor receptor deficiency (Imerslund-Gräsbeck syndrome) and transcobalamin Il deficiency
- Women
- Age >60
- HavIng an autoimmune disease such as crohn’s or type 1 diabetes
- Drugs - colchicine, PPIs, metformin, H2 receptor antagonists and nitrous oxide
- Diet
B12 absorption pathway
In saliva & the stomach
• B12 (colbalamin) binds to haptocorrin (or R- binder/transcobalamin I)
• Protein-bound B12 must be released by pepsin digestion
• If B12 is in the form of supplement in can bind to R-binder directly
In the duodenum
• R-binder is degraded by pancreatic and B12 is released
• B12 binds to intrinsic factor
In the ileum of small intestine
• The B12/intrinsic factor complex is taken up by enterocytes via pinocytosis
• Absorbed vitamin B12 then binds to transcobalamin II for delivery to tissues
What are the cell types in the gastric pit and what do they secrete?
How is a deficiency in B12 caused?
Proton pump on gastric parietal cells
• Prevents release of IF & HCl
Intrinsic factor B12 binding site
• prevents B12 binding to IF
B12-IF complex
• prevents the B12-IF complex from binding to its receptors on enterocytes in the ileum
Why is hydroxocobalamin given more frequently during the first two weeks thansubsequently? Why is it given by intramuscular injection rather than orally?
- Hydroxocobalamin is a man-made injectable form of vitamin B12 used to treat low levels (deficiency) of this vitamin
- Vitamin B12 helps your body use fat and carbohydrates for energy and make new protein.
BENEFICIAL FEATURES
- It is also important for normal blood, cells, and nerves.
DEFICIENCY
- DOSAGE: Initially 1 mg 3 times a week for 2 weeks, then 1 mg every 2-3 months
- This quickly builds up the body’s store of vitamin B12 and it is stored in the liver.
- Once a store of vitamin B12 has built up, this can supply the body’s needs for several months. An injection is then only usually needed every two to three months to ton up the sunniv
- Vitamin B2 replacement usually administered intramuscularly
- Usually absorbed via ileum in the presence of intrinsic factor
- Injecting hydroxocobalamin intramuscularly results in higher bioavailability compared to oral administration
What are different types of autoantibody that can lead to pernicious anaemia?
- Three types present in many but not all patients
- ~75% patients have type I antibody that prevent B12 binding to IF by blocking binding site. These are found in plasma and gastric juice
- Type Il antibodies prevent binding of IF-B12 complex to binding sites in ileum which is essential for B12 absorption
- Type III (Anti-gastric parietal cell) antibodies present in 85-90% of patients recognise the a & B subunits of gastric proton pump. These destroy parietal cells but this is not exclusive to just pernicious anemia. For suspected pernicious anemia, anti-GPC and IFAb are requested together. You only test IFAb in patients +ve for GPC antibodies
How does immune system produce antibodies against its own gastric parietal cells?and intrinsic factor?
- Autoimmune gastritis: loss of pareital cell in stomach (body and fundus)
- PA can be the result of autoimmune gastritis (or atrophic gastrits)
- Autoantibodies attack both IF and the gastric parietal cells producing IF (two Antibodies produced anti parietal and intrinsic)
- They may block either the vitamin B12 binding site or the ileal mucosal receptor
- The last stage of this disease is chronic atrophic gastritis (the chronic inflammation leads to atrophy of the mucosa)
- Dysrequlated immune system means a loss of tolerance to self antigen
- Dendritic cells clear apoptotic parietal cells produced during normal turnover of gastric mucosa
- DC presents the H+/K+ ATPase (from parietal cell) as it deems it as foreign to naive CD4+ T-cell in lymph node
- Dendritic cell activates CD4+ T-cells which then activates B cells - produce antibodies against the antigen
- The CD4 T cell will also attack gastric parietal cells
