Chemical Pathology Flashcards
(38 cards)
Describe the pathogenesis of Pyphoria.
Porphyrigens are self-oxidizing and form porphyrins that react with UV light, leading to oxygen radicals in the skin, blisters, scars, and hypertrichosis
An increase in PBG and dALA mimics neurotransmitters and leads to CNS dysfunction.
How does fasting lead to acute porphyric attacks?
An increase in FA oxidation requires upregulation of PGC-1. PGC-1 leads to the build-up of the haem precursor dALA, which causes the acute attack.
List factors that may cause an acute porphyrin attack.
Puberty- sex hormones
Fasting
inducing of cytochrome p450
What are the signs/symptoms of an APA?
Abdominal pain- acute similar to surgical pain
Sen and motor neuropathy- weakness, bulbar palsy, resp paralysis
Autonomic Neuropathy- Tachycardia, Hypertension, Tachyarrythmia
anxiety, convulsions, psychosis
Hypo Na+
How do you manage APA?
Measure PBG and dALA
do not operate
Increase glucose
slowly correct Na+
ICU-ventilator
Haematologist- Haem increase, decrease haemoxgenase.
Describe Pyphoria Variegata.
AD
Afrikaans population
R59W single mutation of PPOX
Decrease PPOX
1/300
What are the tests for PV?
Protoporphyrin > Coprophyrin in stool
Plasma Fluorescence screening of protein-bound Protoporphyrin
Why can PV lead to an acute porphyrin attack?
A decrease in PPOX, leads to an increase in the protoporphyrinogen, and as a result, there is an inhibition of PBG deaminase and as a result an increase in precursors PBG and dALA
How do you diagnose PV?
Mutation analysis and Fluorescence screening.
How do you treat PV?
Treat acute attack if present
Provide sunscreen.
How do you diagnose APA?
Test for PBG and dALA in urine.
Why is PPOX required, if Protoporphyrinogen can spontaneously oxidise to protoporphyrin?
The process takes place in the mitochondria, a highly reduced environment.
What is the role of folate?
It carries a 1-carbon/methyl fragment required for
synthesis of purines and pyrimidine required for DNA synthesis. Furthermore, it is required for the methylation of homocysteine to form methionine.
What is the function of Vit B12?
It is a co-factor for Methionine synthases and Methylmalonyl-mutase.
Describe the relationship between folate and Vit B 12.
folate is required for the conversion of homocysteine to methionine of which Vit B12 is also required.
What causes a folate deficiency?
Caused by:
poor dietary intake, Lack of leafy greens or folate supplements.
Malabsorption.
Anti-folate chemotherapeutics-methotrexate.
What happens in a folate deficiency?
It plays an essential role in DNA/RNA synthesis, hence rapidly dividing cells are affected first.
Mucosal cells- malabsorption
Neural tube defects in Foetus
Anaemia- Megaloblastic, this is because the body favours the SAM process over the DNA/RNA process, thus protecting the nervous system. As a result, insufficient RNA and DNA are synthesized, hence cell division stops and forms megaloblastic RBC.
Who gets B12 defiecient?
Poor dietary intake – elderly (tea and toast), alcoholics, and strict vegans who do not take vitamin supplements for years.
People who are unable to release B12 from proteins – achlorhydria: atrophic gastritis, gastrectomy, long-term PPi’s (omeprazole)
No production of Intrinsic factor: Pernicious anaemia (autoimmune disease against the parietal cell or intrinsic factor)
Damage to the distal Ileum; : Crohn’s disease, gut resections, celiac disease
Theft in the GIT: tapeworms, bacterial overgrowth (blind loops)
Rare congenital deficiencies of transcobalamin II or enzymes that activate B12 intracellularly
B12 deficiency generally takes years to develop and early symptoms are very non-specific. This is why GPs give B12 injections to many patients, – just in case
What happens in a Vit B12 Deficiency?
With B12 deficiency the same thing happens – all available folate gets trapped as 5-methyl-THF and this is how B12 deficiency indirectly causes megaloblastic anemia. The problem however is that SAM production also decreases resulting in neurological damage
Why would someone with Vit B12 Deficiency seem to have low Folate?
B12 reaction is prioritised, folate essentially becomes trapped as methyl THF, causing ‘functional’ folate deficiency – this is why B12 deficiency also causes megaloblastic
Anaemia – even if the patient is not folate deficient
Why is it not advised to give folate in a Vit b12 deficiency?
Both folate and vitamin B12 can cause megaloblastic anaemia. If your patient has B12 deficiency and you only give them folate YOU WILL WORSEN THE NEUROLOGICAL damage!
WHY – giving extra folate allows DNA/RNA synthesis and cell division in all body cells to resume. These growing cells are going to use up any available methionine and SAM (which is already in short supply) to make proteins and in other methylation reactions. Methionine gets “stolen” or diverted from the CNS and with even less SAM in the CNS myelin synthesis deteriorates even further.
What are the biochemical Test of folate and Vit B 12 deficiency?
B12- homocysteine and urinary methyl-malonic acid (earliest)
Megaloblastic anaemia and increased LDH 1 isoenzyme late.
How to tell if a patient is haemolysing intravascularly?
Unconjugated bilirubin goes up
Elevated urobilinogen on urine dipstix (increase flux through bili pathway)
Red cell enzymes go up in plasma – LDH 1 and AST
Free haemoglobin in plasma is rapidly bound by haptoglobin and cleared so haptoglobin levels go down
Red cell fragments – schistocytes visible on a peripheral blood smear
Haemoglobinuria – in really severe cases
How is Iron lost in the body?
GIT cells into the stool, desquamation
blood loss (menstruation)- most common
