Lecture 14 - Absorption and What Goes Wrong Flashcards
What are vitamins?
organic compounds that are required in small quantities for a variety of biochemical functions
water soluble vitamins?
B complexes (B12 & B9)
c or ascorbic acid
Fat soluble vitamins?
A or retinol
D or cholecalciferol
E or tocopherol
K
What is B12 known as?
cobalamin
where is B12 synthesised?
solely by microorganisms
Where do ruminants obtain B12 from?
the foregut
Human source of B12?
animal origin e.g. meat, fish, diary products
What are free from B12?
vegetables, fruits and other non-animal foods unless contaminated by bacteria
Who are more at risk of developing B12 deficiency?
vegetarians and vegans
RDA of B12?
1.-2.5 mcg/day
How much B12 does a western diet contain?
5-30 mcg
what are the body stores of B12?
2-5 mg
how much B12 a day does an adult lose?
1-3mcg (~0.1% of body stored)
how is B12 lost from the body?
in urine and faeces
How much B12 is stored if the supply is cut off?
enough for 2-5 years
two mechanisms for B12 absorption?
passive absorption and active transport
Passive absorption of B12?
through buccal, duodenal and ileal mucosa
rapid but insufficient
How much of an oral dose of B12 is passively absorbed?
<1%
active transport of B12?
normal physiological mechanism
Where does active transport of B12 occur?
through the ileum
What mediates active transport of B12?
gastric intrinsic factor
How much B12 is absorbed by active transport?
~70% of ingested amount
where is haptocorrin produced?
salivary glands
where is intrinsic factor produced?
secreted by parietal cells, secretion parallels that of gastric acid
it is a glycoprotein
how is B12 transported in the plasma?
bound to transcobalamin I, II, III
What is B12 mainly bound to in the plasma?
transcobalamin II
Where is vitamin B12 stored?
in the liver
What % of the transcobalamin is II?
~10%
What is a cellular role of B12?
it is an essential co-enzyme for 2 enzymes in the body
What is B12 an essential co-enzyme for?
the conversion of homocysteine to methionine
the conversion of methylmalonyl-coA to succinyl-CoA
What happens in the absence of intrinsic factor?
inadequate amounts of B12 are absorbed
what does inadequate absorption of B12 result in?
megaloblastic anaemia
What is pernicious anaemia classed as?
when megaloblastic anaemia is due to the absense of intrinsic factor
What is B12 essential for?
normal formation of red blood cells
What is megaloblastic anaemia characterised by?
insufficient/usually large and irregular shaped RBC due to the defective erythrocyte production due to lack of B12
What causes the unusually shaped RBC?
The inhibition of DNA synthesis during RBC production, the cell cycle cannot progress and this leads continuing cell growth without division resulting in macrocytosis
What is pernicious anaemia?
autoimmune atrophic gastritis - main cause severe vitamin B12 deficiency
What causes pernicious anaemia?
destruction of gastric parietal cells and the associated lack of intrinsic factor
immune response is directed against H+/K+ATPase
What does pernicious anaemia cause?
achlorhydria (production of gastric acid is low or absent)
What else can cause pernicious anaemia?
antibodies directed against intrinsic factor itself
Aetiology of B12 deficiency?
inadequate dietary intake (rare)
loss of gastric parietal cells or intrinsic factor
functionally abnormal intrinsic factor
bacterial overgrowth in intestine
disorders of ileal mucosa
disorders of plasma transport
dysfunctional uptake and use of B12 by cells
bacteria overgrowth causing B12 deficiency?
stagnant loop syndrome
bacteria that are present will compete with the body for the vitamin
Disorders of ileal mucosa causing B12 deficiency?
resection, absence of cubam receptor on ileal cells
Disorders of plasma transport causing B12 deficiency?
transcobalamin II deficiency
Drug induced B12 deficiency?
PPI and H2 antagonists
oral contraceptives and hormone replacement therapy
metformin
cholchicine
PPI and H2 antagonist B12 deficiency?
reduction in stomach acid reduces separation of B12 from food
can cause gastric hypochlorhydria (reduced acid)
oral replacement therapy may be used
Oral contraceptives and hormone replacement B12 deficiency?
thought to be due to a reduction in B12 carrier transcobalamin
Metformin B12 deficiency?
reduces B12 absorption
mechanism unknown
Cholchicine B12 deficiency?
used to treat gout
impairs or inhibits receptors on terminal ileum (cubam receptors)
What is the normal serum B12 levels?
115-1000pmol/L
What is the hallmark of symptomatic B12 deficiency?
megaloblastic anaemia
What happens in advanced, severe cases?
anaemia may be severe, with haematocrit as low as 10-15%
what are normal haematocrit values?
40% for women and 45% for men
What might megaloblastic anaemia be accompanied by?
leucopaenia, thrombocytopaenua and hypersegmented neutrophils
What are hypersegmented neutrophils?
normally the nucleus of neutrophils have 1-2 segments but these have 5 or 6
What is the haematocrit?
pack cell volume, % volume of RBC in blood
What do RBC look like in megaloblastic anaemia?
erythrocytes are not uniform biconcave disc shape, they are large and have unusual shape
What are the neurological symptoms of B12 deficiency?
paresthesia (pins and needles) in hands and feet
sensory loss
gait ataxia
weakness in legs
subacute combined degeneration of the spinal cord
What is B12 necessary for in the CNS?
development and initial myelination of the CNS and maintenance of its normal function
What can occur in the CNS with B12 deficiency?
demyelination of the spinal cord and peripheral nerves
at first the covering of the myelin sheath is damaged but then the entire nerve cel is affected
What is subacute combined degeneration of the spinal cord?
mentioned previously
affects the brain and peripheral nerves
serious condition and recovery is more likely is treated early
Digestive consequences of B12 deficiency?
hunters glossitis - tongue is smooth, red and shiny
can be sore
CV consequences of B12 deficiency?
angina
venous thromboembolic disease
Gynaecological consequences of B12 deficiency?
infertility
% of cyanocobalamin in human serum?
0-10%
% of hydroxocobalamin in human serum?
8-15%
% of deoxyadenosylcobalamin in human serum?
22-39%
% of methylcobalamin in human serum?
36-62%
What is cyanocobalamin?
synthetic vitamin B12
What are the active forms of vitamin B12?
deoxyadenosylcobalamin and methylcobalamin
Treatment of vitamin B12 deficiency?
oral (cyanocobalamin)
parenteral (hydroxocobalamin)
When must treatment be parenteral?
in the case of gastric intrinsic factor deficiency (pernicious anaemia) or total gastrectomy
How long is treatment for B12 deficiency?
lifelong for patients with permanently decreases ability to absorb B12
Why is hydroxocobalamin given?
it has a longer half life than cyanocobalamin
Dose of parenteral hydroxocobalamin?
1mg three times per week for 2 weeks, then 1mg every 3 months thereafter
intramuscularly
What is vitamin B9 known as?
folate, folic acid
Sources of B9?
dark green leafy veg (broccoli, lettuce, brussel sprouts and spinach) and dried legumes (beans, lentils, chickpeas)
fruits and fruit juices
meat, seafood, poultry and eggs
fortified cereals and breas
RDA of B9?
200mcg/day
RDA of B9 in pregnancy?
400mcg/day supplement
How is folate destroyed?
Easily by heating, particularly in large volumes of water - leaching into cooking water when boiling
Why do we need folic acid from diet everyday?
it cannot be stored in the body
When is supplement needed in pregnancy?
From before conception till 12th week
What are natural folates conjugated to?
polyglutamyl chain - containing a different number of glutamic acids (1-7)
How are folates absorbed?
in the monoglutamate form
What is folic acid composed of?
pteridine ring
paramino benzoic acid
glutamic acid
What is glutamic acid?
an amino acid that can synthesise itself
What are the polyglutamates hydrolysed by?
folypoly-gamma-glutamate carboxypeptidase (folate conjugase)
What is the number of glutamic acid residues dependent on?
the type of food, can range from 1-7
Where is the polyglutamate chain removed?
in the apical brush borders of the mucosal cells (folate conjugase)
Where is folate conjugase found?
widely distributed in the mucosa of the small intestine
what does loss of activity of folate conjugase cause?
impaired folate absorption
What is the main dietary folate?
N5-methyltetrahydrofolate (5-MTHF)
Where are folates absorbed?
duodenum or jejunum
What is the proton-coupled folate transporter?
transport by this is pH dependent and uses energy generated by downhill movement of protons
What is the reduced folate carrier?
an anionic exchanger, mediating the cellular uptake of folate in exchange for anions
What does the reduced folate carrier have affinity for?
for the reduced folates e.g. 5methyltetrafolate and 5-tetrahydrofolate but not folic acid
What do enterocytes have?
folate receptors which bind folate and internalise it by receptor mediated endocytosis
How is folate exported from enterocyte?
by an organic anion transporter (OAT)
How is most folate transported?
as mono-glutamyl dertivative
How does folate circulate?
free in the blood, some (~1/3) is bound to albumin
What is normal folate plasma concentration?
10-30nmol/L
How is folate taken up into cells?
same as into enterocytes (PCFT, RFC, folate receptor)
How do folates exist inside cells?
as poly-glutamate conjugates (75%)
What happens to monoglutamates in a cell?
they leak out at a fairly rapid rate
What are the cell requirements for folate?
folate is crucial for the transfer of one-carbon units to amino acids, nucleotides and other biomolecules
What is dietary folic acid the starting material for?
the fundamental molecule, tetrahydrofolate
What reduces folate and what is it reduced to?
Dihydrofolate reductase
reduced partially to dihydrofolate or completely to tetrahydrofolate
Aetiology of folate deficiency?
inadequate dietary intake
congenital defects in the uptake system (PCFT)
intestinal disease (coeliac disease, IBD, tropical sprue)
drug interactions
chronic alcohol use
increased cellular requirement (pregnancy)
What drugs can affect folate deficiency?
cholestyramine, sulfasalazine, trimethoprim, methotrexate, metformin
How does alcohol affect folate?
accelerates folate breakdown
When do mutations in PCFT occur?
in patients with hereditary folate malabsorption syndrome
How does cholestyramine affect folate?
binds to folate in the GI tract and prevents its absorption
Why is more folate needed during pregnancy?
deficiency can impair foetal development
Symptoms of folate deficiency?
sore tongue and pain swallowing
GI symptoms (especially after meals)
neurologic (cognitive impairment, dementia, depression)
What can severe folate deficiency result in?
megaloblastic anaemia
What else should be looked for when considering folate deficiency?
marked weight loss
What are consequences of folate deficiency?
neural tube defects such as spina bifida and anencephaly
When do neural tube defects occur?
first month of pregnancy
What is the neural tube?
the embryonic precursor of the brain and spinal cord
What is spina bifida?
the spinal column does not close completely
What is anencephaly?
most of the brain and skull do not develop
How can oral folic acid prevent neural tube defects?
When taken before and during pregnancy it can prevent about 75%
Treatment of folate deficiency?
Oral folic acid for 1-4 months, 5mg daily
oral route is sufficient even when there is malabsorption
When is folate deficiency treated until?
Until haematological recovery occurs
What must be excluded before giving folic acid?
Vitamin B12 deficiency - symptoms are similar but folic acid may worsen the neurological complications
