porphyria Flashcards
definition of porphyria
Deficiencies in enzymes of the haem biosynthetic pathway
deficiency ranges from partial to complete
consequence of Deficiencies in enzymes of the haem biosynthetic pathway (ie porphyria)
->
Overproduction of toxic haem precursors
->
- Acute neuro-visceral attacks and/or
- Acute or chronic cutaneous symptoms.
what is haem
Organic heterocyclic compounds
Fe2+in centre
4 pyrrolic (tetrapyrrole - N with 4 carbons around it in an aromatic structure) rings around the iron
between them have covalent bridges with double bonds - not present in precursers iw porphorinogens
Carries oxygen
Redox reactions
Erythroid cells and liver cytochrome
Made in all cells - ALA synthase in every cell makes haem -> make cytochrome for the electron transport chain
summarise haem biosynthesis
Blue rectangle – processes in mitochondria
PBG synthase is also called ALA dehydratase – brings together 2 ALAS -> PBG
HMB synthase also called PBG deaminase
Protoporphyrin IX is haem w/o iron or metal core
If iron is present – get haem. If iron not present – get a different metal involved
classifications of porphyrias
Principle site of enzyme deficiency
* Erythroid or hepatic
Clinical presentation
* Acute or Non-acute
* Neurovisceral (acute) or skin lesions (non-acute)
NB - there are exceptions to all of these
pathology of the neurovisceral sx in porphyrias
deficiency in ALA synthase
-> 5-aminolaevulinic acid build up
this is neurotoxic
pathology of the skin lesions in porphyrias
due to porphyrinogens accumulating in skin
they are oxidised by UV light around
-> skin lesions
Prophyrinogens cant oxidise in cells because cells have a low oxygen pressure environment – need to get in circulation
what is the difference between porphyrinogens and porphyrins
porphyrinogens:
* no double bond = colourless
* unstable and readily oxidised -> porphyrin in lab
porphyrins
* double bond -> coloured (dark red/purple)
* near start of the pathway are water soluble because of carboxyl groups – urine (uro-) – see in plasma and urine because soluble
* near end less soluble – faeces (copro-) see in stool
common porphyrias
- Porphyria cutanea tarda – most common
- AIP = Acute Intermittent Porphyria
- most common in children Erythorpoietic protoporphyria – non-blistering cutaneous
effect of ALA synthase deficiency
doesnt cause a porphyria
causes an X linked sideroblastic anaemia
effect of gain of function ALA synthase mutation
in bone marrow
increases the throughput through the pathway
increase protoporphyrin 9 –
overwhelm ferrochetalase
picture similar to EPP
summarise PBG synthase deficiency
‘ALA Dehydratase or Plumboporphyria’
Extremely rare form of porphyria
Build-up of ALA, but not PBG
Diagnostic implications
features:
- Get neurovisceral sx - coma, ?palsy, motor neuropathy
- psych sx
- Abdominal pain – most common presenting complaint
features of HMB synthase deficiency
Acute Intermittent Porphyria
enzyme works 50%
Autosomal dominant
sx 90% have no Sx:
Neurovisceral attacks
* Abdo pain and vomiting
* Tachycardia and hypertension
* Constipation, urinary incontinence
* Hyponatraemia +/- seizures
* Psychological symptoms
* Sensory loss / muscle weakness
* Arrythmias / cardiac arrest
No skin symptoms: No production of porphyrinogens
precipitating features of acute intermittent porphyria
ALA synthase inducers
* Barbiturates,
* steroids,
* ethanol,
* anticonvulsants
All the drugs are cytopchrome p450 inducers
Overwhelm activity of HMB synthase
= accumulate ALA
Stress - Infection, surgery
Reduced caloric intake
Endocrine factors - More common in women and premenstrual
diagnosis of Acute intermittent porphyria
Increased urinary PBG (and ALA)
PBG gets oxidised to porphobilin
Decreased HMBS activity in erythrocytes
Urine – keep away from light
If keep in light it will go deep purple
Need to get to lab soon
what is Hereditary coproporphyria
Coproporphyrinogen oxidase deficiency
-> increased copro III and can detect in stool
inhibitors of HMB synthase – associated accumulaton of PGB and ALA = neurovisceral sx
Autosomal dominant
Acute neurovisceral attack
Skin lesions - back of hand and neck ie sun exposed - comes on hours/days after sun
* Blistering
* Skin fragility
* scarring
skin lesions in hereditory coproporphyria
what is variegate porphyria
Protophorphyrinogen oxidase deficiency – increase in protoporphringen IX – can see in stool – because less soluble
inhibitors of HMB synthase – associated accumulaton of PGB and ALA = neurovisceral sx
Autosomal dominant
- Acute attacks – neurovisceral attack
- Skin lesions
skin lesions in viriegate porphyria
summarise Porphyria cutanea tarda
Inherited or acquired - liver disease (Hep B, HIV, cirrhosis, drugs)
Uroporphyrinogen decarboxylase deficiency
Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring, pigmentation
Biochemistry:
- Urinary (& plasma) uroporphyrins & coproporphyrins increased
- Ferritin often increased
skin in erythropoietic protoporphyria
what is the approach to diagnosis of porphyrias
