haematinic physiology and pharmacology Flashcards
3 basic components needed for a mature functioning RBC
- iron;
- amino acids (make globin chains);
- blasts (DNA synthesis, diving cells etc.)
how much iron is in an average man + woman and what forms is it in
around 4g in men and 30-45% less in women (around 2.5g);
65% stored as haemoglobin, 20-30% as ferritin (some as haemosiderin), remainder in myoglobin, catalase and other enzymes
what is the iron status in the body regulated by
absorption
how is iron excreted from the body
passively through the gut, skin, faeces
iron intake requirements for men, women, growing children and pregnant people
men: 0.5-1.0mg/d
women: 1.0-2.0mg/d
growing children: 1.1-2.0mg/d
pregnancy: 1.5-3.0mg/d
8 key players in iron metabolism and what they do
- DMT-1 (divalent metal transporter) - involved in enterocyte uptake of Fe2+;
- Ferritin - intracellular storage;
- transferrin - ferric-ion delivery to the organs;
- transferrin receptor - uptake into target cells;
- haemosiderin - an iron-storage complex that is composed of partially digested ferritin and lysosomes;
- ferroportin - transfers Fe2+ out of enterocyte;
- hepcidin - regulates iron levels, acts as a feedback signal;
- HFE - regulates hepcidin production this controlling uptake into immature enterocytes
consumption -> store -> tissue iron pathway (draw this out! see lect)
consumption -> non haem iron (if haem-iron then goes straight into cell) -> Fe3+ –(ferric reductase)–> Fe2+ -> DMT-1 allows it to enter the enterocyte -> can be stored as ferritin (Fe3+) in the cell -> otherwise binds to binding protein -> transported out of the cell via ferroportin 1 -> Fe2+ –[o]–> Fe3+ -> transferrin -> target tissue
what causes increased absorption of iron (8)
Fe2+; haem iron; acids; absorbate; soulubilizing agents (sugars, amino acids etc.); pregnancy; increased erythroppoiesis; haemochromatosis; increased DMT-1 and ferroportin
how does hepcidin work
binds to ferraportin and causes its removal/destruction from enterocytes -> this means that iron is trapped in the storage cells and cant be removed (usually seen in anaemia of chronic disease)
what causes decreased absorption of iron (11)
Hepcidin; Fe3+; non-organic iron; alkalis; phytates/phosphates; tea; tetracyclines; high-iron diet; infections; high body iron stores
4 causes of iron deficency
inadequate diet; increased requirements (pregnancy, growth); malabsorption; blood loss (menstrual, GO, lung, Urinary)
who should GI investigations be considered in initially (if presenting with iron deficency anaemia)
all men; post menopausal women
what GI investigations should be done for IDA (5)
take drug Hx; tissue transglutaminase antibody (tTg); imaging of upper + lower GI tracts; check stools for paracites; faecal haemoglobin (not yet in practice)
what are some GI causes of iron deficency anaemia
hookworm infection; oesophago-gastric cancer; coeliac disease; crohn’s disease; gastritis; peptic ulceration; oesophagitis; gastrectomy; NSAID enteritis; meckel’s diverticulum; colon cancer; colitis etc.
with what frequency should iron supplements be given for max absorption
once a day
what are the typical iron replacement therapies
ferrous sulphate (3 month post Hb-normalisation); ferrous gluconate; sodium ironedetate; ferric maltol
what is given if parenteral iron is required (2)
ferric carboxymaltose; ferric derisomaltose
where is folic acid found naturally
green vegetables; offal
what is folic acid synthesized by
bacteria
what does folic acid require for biological activity
B12
what kind of molecule is biologically active folic acid
polyglutamate
why is folic acid non-absorpable in the GI tract
due to its polar nature (carboxyl group) it cannot pass through the lipid membranes of the cells
how is folic acid absorbed into the body
the polyglutamate molecule is deconjugated in the jejenum into monoglutamate -> these are smaller, less polar molecules and so can be absorbed
folic acid metabolism pathway (consumption -> liver)
consumed in polyglutamte form -> broken into monoglutamate form -> absorbed by jejenum -> converted into tetrahydrofolic acid (THF) -> methylated into methyl-THF -> enters blood stream -> either stored in liver or metabolised in tissue
what is the main role of folic acid in the body + pathway for this (CH3-TFH -> thymidine)
Folic acid is used to synthesize DNA precursors, which is essential for DNA replication and cell division
methyl-THF -> enters targets cells via FAT receptors -> methyl-THF transfers its methyl group to vitamin B12 -> forms methylcobalamin and free THF -> serine provides a methylene group to THF -> methylene group quickly transfered to the nucleotide d-UMP -> d-UMP becomes d-TMP -> converted to thymidine (DNA nucleotide)
secondary role of folic acid + pathway (intracellular CH3-THF -> methionie)
lowering the levels of homocysteine in the body, too much of which can be harmful
methyl-THF transfers its methyl group to vitamin B12 -> forms methylcobalamin and free THF -> methylcobalamin transfers its methyl group to homocysteine -> converted into an essential amino acid called methionine
what is the consequence of a folate/B12 deficency
new DNA cannot be made (Hb can be made but not the cells!); build up of homocystien
what can folic acid easily be degraded by
cooking for too long
structure of B12
corrin ring (similar to haem) with a colablt complex centre
role of folic acid in foetal development
needed for the closure of the anterior neuropore of the neural tube during the 23rd day, and posterior neuropore during the 26th day of gestation - This is a crucial step in the development of the central nervous system
where is B12 stored
liver
what reaction is vit B12 involved in
co-enzyme for methyltransferase reactions (homocysteine ->methionine) i.e. essential to folate metabolism
what are some key players in B12 metabolism
R-binders; gastric parietal cell; gastric acid; intrinsic factor; pancreatic secretion; ileal receptor; Transcobalamin-I/II/III
where is B12 naturally obtained from in the diet
meat
vit B12 absorption pathway
B12 consumed -> R factors (haptocorrin) in saliva + gastric juice bind -> intrinsic factor secreted from parietal cells -> HCO3- secreted by pancreas as move towards ileum (increasing pH) -> B12-R split by IF -> B12-IF absorbed when reaches terminal ileum
why can B12 only be absorbed in the terminal ileum
this is the only place receptors where expressed
what cells are most vulnerable to folate/B12 deficency
rapidly dividing cells e.g. bone marrow precursors, gut epithelium
all cells are affected tho
what are 2 specific signs of B12 deficeincy
neuropathy and optic atrophy
what may folate/B12 deficiency cause in elders
confusion
what investigations should be done for suspected magaloblatic anaemia (4)
- blood film (unusually large, structurally abnormal, immature red blood cells- megaloblasts);
- B12/red cell folate levels;
- bone marrow biopsy;
- check methylmalonic acid and homocysteine levels
what does megaloblastic anaemia indicate
there is a bone marrow problem
6 causes of megaloblastic anaemia
- B12 deficiency;
- folate deficiency;
- combined deficiency;
- abnormal folate metabolism (e.g. due to Mtx);
- abnormal DNA synthesis;
- myelodysplasia
why does cell size increase in non-megaloblastic macrocytic anaemia
cells get bigger due to lipid deposits
causes of non-megaloblastic macrocytic anaemia (8)
- just macrocytosis;
- pregnancy;
- liver disease;
- alcoholism (classic example);
- reticulocytosis;
- hypothyroidism;
- drugs;
- marrow infiltration;
what is given to treat B12 deficiency
hydroxycobalamin
what does parenteral mean
administered or occurring elsewhere in the body than the mouth and alimentary canal
when might B12 prophylaxis be given
after a total gastrectomy/ileal resection -> given parenterally (IM usually), oral replacement can be given if absorption intact
when are folic acid supplements given as prophylaxis (3)
pregnancy + preconception (reduced risk of neural tube defects); haemolyis; Mtx therapy
5 causes of folate deficiency
- diet - anorexia, children, alcoholic, elderly;
- increased utilisation - physiological (growth, pregancy), pathological (cancers, haemolysis, inflammation);
- malabsorption - small bowel disease;
- urinary loss (haemodialysis);
- drugs (Mtx, sulfasalazine etc.)
what can cause a B12 deficiency (6)
- diet -vegans;
- gastric disease - autoimmune gastritis, major gastrectomy;
- ileal disease - resection, inflammation;
- infections - small bowel, fish tapeworm;
- pancreatic disease;
- transcobalamin-II deficiency;
- B12 destruction (NO)
how to test for B12 absorption
57/58Co labelled-B12 tracking; can be +/- intrinsic factor; urinary excretion sampled
what autoantibodies can be tested for in B12/folate deficiencies
B12 - anti parietal cell, anti intrisic factor;
folate - anti gliadin, anti endomysial
what is addisonian pernicious anaemia
a relatively rare autoimmune disorder that causes diminishment in dietary vitamin B12 (cobalamin) absorption due to destruction of specialise gastric body mucosa (mucosal atrophy), resulting in B12 deficiency and subsequent megaloblastic anemia
