Chemical Pathology 7 - Porphyrias Flashcards
(36 cards)
Define porphyria
deficiency (partial/complete) of enzymes in haem biosynthesis → overproduction of toxic haem precursors
Acute neuro-visceral attacks and/or;
Acute or chronic cutaneous symptoms
generally acute = neuro-visceral and chronic = cutaneous (some conditions overlap)
Describe the structure of haem
Fe2+ centre + 4 pyrrolic (tetrapyrrole) rings around iron
What is the rate limiting step of haem synthesis?
ALA synthase
Roughly summarise the pathway of haem production
ALA + ALA –> PBG
PBG –> HMB
HMB –> EITHER uroporphyriogen 1 or 3
Uroporphyrinogen 3 –> haem
blue = within mitochondria
By what 2 factors are porphyrias classified?
Acute/ non-acute
Neurovisceral or cutaneous
What is the cause of cutaneous symptoms in some porphyrias?
porphyrins precursors in skin → activated by UV light → active porphyrin → toxic
do NOT oxidise in cells - low oxygen environment
circulation - less stable + ↑ exposure to oxygen
Which toxic product leads to neurovisceral symptoms in porphyria?
5-ALA
porphyrinogens in porphyria
RAISED in porphyria
Colourless
Unstable + readily oxidised to corresponding porphyrin by the time the urine/faeces sample reaches lab
porphyrins in porphyria
HIGHLY coloured
start of pathway:
- water-soluble → excreted urine (uroporphyrins)
- colourless/yellow urine sample → red or deep purple (oxidation → porphyrins)
near end of pathway
- less soluble → faeces (coproporphyrins)
What is the most common porphyria?
Porphyria cutanea tarda
What is the most common porphyria in children?
Erythropoietic protoporphyria
What are the symptoms of ALA synthase deficiency?
Weirdly, doesn’t cause porphyria!
Instead, causes an X-linked sideroblastic anaemia
ALA synthase gain-of-function mutation → throughput through pathway → ↑ protoporphyrin IX → overwhelms ferrochetalase conversion → haem → accumulation of protoporphyrin IX (similar to erythropoietic protoporphyria)
What are the 2 types of acute neurovisceral porphyria, which enzyme deficiency causes each, and how can they be clinically differentiated?
Acute intermittent porphyria (most common)
HMB synthase deficiency - causes ATTACKS
↑PBG and ALA; ↑ALA → neurovisceral symptoms
ALA dehydratase porphyria/Plumbopophyria
PBG synthase deficiency - more one acute episode than numerous attacks
causes ALA accumulation
No skin symptoms (as no production of porphyrinogens)
What are the symptoms of the acute neurovisceral porphyrias?
Motor neuropathy
Severe abdominal pain
Psychiatric symptoms
Hyponatraemia (SIADH) ± seizures
tachy,HTN
What is the most likely cause of an acute intermittent porphyria ‘attack’?
Drug that is CYP450 inducer
ALA synthase inducers – barbiturates, steroids, ethanol, anti-convulsants (CYP450 inducers)
Stress – infection, surgery
Reduced caloric intake
Endocrine factors – F>M, pre-menstrual
How can acute porphyria be diagnosed?
Urine left in light changes colour
↑ urinary PBG (and ALA)
PBG oxidised → porphobilin
↓ HMBS activity in erythrocytes
How should acute intermittent porphyria be managed?
Avoid attacks (adequate nutrition, precipitant drugs, prompt treatment)
High carbohydrate diet/IV carbs → inhibit ALA synthase
IV haem-arginate → mimic natural haem and so turns off haem synthesis through -ve feedback
Recall 2 forms of porphyria that have acute neurovisceral AND cutaneous symptoms
Hereditary coproporphyria
Variegate porphyria
what are HCP and VP deficiencies of?
- HCP - coproporphyrinogen oxidase
- VP - protoporphyrinogen oxidase
How do the cutaneous effects of porphyrias usually present and why?
blistering, skin fragility [back of hands, sun exposure]
Why do HCP and VP cause neuro-visceral attacks in addition to cutaneous?
Coproporphyrinogen III and protoporphyrinogen IX = potent inhibitors of HMB synthase
= accumulation of PBG and, consequently, ALA
How to differentiate between the different acute porphyrias?
Recall the 3 forms of non-acute porphyria
Congenital eryhtropoietic porphyria
Porphyria cutanea tarda (PCT)
Erythropoietic protoporphyria (EPP)
What is the presentation of non acute porphyrias?
only SKIN lesions (☀️), no neuro-visceral manifestations
blisters, fagility, pigmentation, erosions etc
EPP - photosensitivity, burning, itching oedema (no blistering)
