Chemical Pathology - Porphyrias Flashcards
What is haem?
tetrapyrole rings surrounding a central iron
Roughly summarise the pathway of haem production
ALA is generated in mitochondria
ALA leaves mitochondria to be converted to PBG (aminolevulinic acid and porphobilinogen) under PBG synthase
PBG –> HMB (hydroxymethylbilane) under HMB synthase
HMB –> EITHER uroporphyrinogen 1 or 3 (uroporphyriogen 3 synthase present makes 3, absent makes 1)
Uroporphyrinogen 3 –> coproporphyrinogen 3 by uroprophyrinogrn decarboxylase
coproporphyrinogen
copro 3 does to proto IX - this is step that transitions into mitochondria again
penultimate step = inside mitochondrion make protoporphyrin IX by protoporphyrinogen oxidase
protoporphyrin under ferrochetalase this makes Haem in mitochondria
by what 3 factors are porphyrias classified?
Site of enzyme deficiency - hepatic or erythroid
Acute/ non-acute
Neurovisceral or cutaneous
What is the cause of cutaneous symptoms in some porphyrias?
porphyrin precursors build up under the skin and react with UV light which turns them into active porphyrins which are toxic
Which toxic product leads to neurovisceral symptoms in porphyria?
5-ALA
What is the most common porphyria? What enzyme is deficient?
Porphyria cutanea tarda (80%)
Uroporphyrinogen decarboxylase deficiency
What is the most common porphyria in children? What enzyme is deficient?
Erythropoietic protoporphyria
Ferrochetalase deficiency
What are the symptoms of ALA synthase deficiency?
Weirdly, doesn’t cause porphyria!
Instead, causes an X-linked sideroblastic anaemia
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
- plumboporphyria = PBG synthase deficiency - more one acute episode than numerous attacks
What are the symptoms of the acute neurovisceral porphyrias?
Motor neuropathy
Psychiatric symptoms
Severe abdominal pain
What is the most likely cause of an acute intermittent porphyria ‘attack’?
drugs such as barbiturates, steroids, ethanol & anticonvulsants.
How can AIP be diagnosed (3)?
o Increased urinary PBG (and ALA)
o PBG oxidised = porphobilin, urine goes dark in light
o Decreased HMBS activity in erythrocytes
How should acute intermittent porphyria be managed (2)?
avoid attacks (adequate nutrition, precipitant drugs, prompt treatment)
high carb diet - inhibits ALA synthase
IV haem arginate - micmicks haem so turns off synthesis
recall 2 forms of acute porphyria that have skin symptoms. what are their inheritance?
Hereditary coproporphyria (due to a deficiency of coproporphyrinogen oxidase) Variegate porphyria (due to a deficiency of protoporphyrinogen oxidase)
both autosomal dominant
How do the cutaneous effects of porphyrias usually present and why?
blistering on back of hands (most exposed to UV)
also pigmentation, skin fragility
Recall the 3 forms of non-acute porphyria, and which of these conditions causes blistering, and what the inheritance
Congenital eryhtropoietic porphyria (blistering) & recessive
Porphyria cutanea tarda (blistering) dominant
Erythropoietic protoporphyria dominant
How can erythropoietic protoporphyria be diagnosed?
measure RBC protoporphyrin
What is the most common cause of porphyria cutanea tarda?
Liver disease
where is ALA generated?
mitochondria
what is the immediate precursor to haem?
protoporphyrin IX is essentially the haem molecule without the iron core
• If iron present in abundance, you get iron in the protoporphyrin IX and make haem (via ferrochetalase)
are porphyrinogens raised or lowered in porphyria?
raised
are porphyrinogens coloured or colourless?
colourless until oxidised into porphyrins which are highly coloured
what’s the inheritance of AIP
Autosomal Dominant
90% asymptotic
does Acute Intermittent Porphyria cause skin lesions?
no
what sodium unbalance is seen in acute intermittent porphyria and what’s the underlying diagnosis?
Hyponatraemia (SIADH) w/w out seizures
main symptoms of EPP?
photosensitivity only - burning & iitching
no blisters
what should you measure in EPP?
measure RBC protoporphyrin
give 2 treatments of PCT?
regularly scheduled phlebotomies to reduce iron and porphyrin levels in the liver
hydroxychloroquine
urine samples during an acute attack for diagnosis should be…
protected from light
during an acute porphyria what test is best?
urine PBG (porphobilinogen) if urine PBG is normal this excludes attack if raised, check enzyme activity, stool,
outline 5 difference between AIP & PCT?
AIP = HMBS deficiency, PCT = uroporphyrinogen decarboxylase
AIP = AD, PCT = mainly acquired
AIP = acute presentation, PCT = chronic
AIP = neurovisceral attacks, PCT = blistering in sun
AIP = F > M, PCT = M > F
AIP treatment = high CHO diet and haem arginate, PCT treatment =phlebotomy & hydroxychloroquine
define porphyria
deficiency (partial/complete) of enzymes in haem biosynthesis = overproduction of toxic haem precursors
what enzyme is involved in the rate limiting step of haem biosynthesis?
ALA synthase
Aminolevulinic acid synthase is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of 5-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes.
summarise the porphyries into acute, non-acute, skin lesions & no skin lesions?
Acute:
o Acute, no skin lesions = ALAD, AIP
o Acute, skin lesions = Hereditary coproporphyria, Variegate porphyria
Chronic:
o Chronic, skin lesions = Porphyria cutanea tarda, Congenital erythropoietic porphyria
o Chronic, skin photosensitivity = Erythropoietic protoporphyria
