ChemPath: Porphyrias Flashcards
What is porphyria?
- Disorders caused by deficiencies in enzymes of the haem synthesis pathway
- This leads to the accumulation of toxic haem precursors
What are the two ways in which porphyria can manifest?
- Acute neuro-visceral attacks
- Acute or chronic cutaneous symptoms
List some key features of haem.
- Organic heterocyclic compound with Fe2+ in the centre
- There is a terapyrrole ring around the iron
Where is haem found?
Erythroid cells
Liver cytochrome
Draw the haem synthesis pathway.
Which component of the haem biosynthesis pathway is neurotoxic?
5-ALA
What types of porphyrin may be produced in the absence of iron?
- Metal-free protoporphyrins
- Zinc protoporphyrin
How can porphyrias be classified?
Principle site of enzyme deficiency:
- Erythroid
- Hepatic
Clinical presentation:
- Acute or non-acute
- Neurovisceral or skin lesions
Outline the relationships between UV light and skin lesions.
Porphyrinogens are oxidised and then activated by UV light into activated porphyrins.
NOTE: porphyrinogens do NOT oxidise cells
What is a key difference between porphyrinogens and porphyrins?
- Porphyrinogens - colourless, unstable and readily oxidised to porphyrin
- Porphyrins - highly coloured
Which porphyrins appears in the urine and faeces?
- Urine - uroporphyrins are water soluble
- Faeces - coproporphyrins are less soluble and near the end of the pathway
NOTE: someone with porphyria will have colourless/yellow urine which turns red/dark red/purple as the porphyrinogens are oxidised and activated into porphyrins
List four types of acute porphyria and the enzymes involved.
- Plumboporphyria - PBG synthase
- Acute intermittent porphyria - HMB synthase / PBG deaminase
- Hereditary coproporphyria - coproporphyrinogen oxidase
- Variegate porphyria - protoporphyrinogen oxidase
List three types of non-acute porphyria and the enzymes involved.
- Congenital erythropoietic porphyria - uroporphyrinogen III synthase
- Porphyria cutanea tarda - uroporphyginogen decarboxylase
- Erythropoietic protoporphyria - ferrochetolase
What is the most common type of porphyria?
Porphyria cutanea tarda
What is the most common type of porphyria in children?
Erythropoietic protoporphyria
What does ALA synthase deficiency cause?
X-linked sideroblastic anaemia
How can a mutation in ALA synthase lead to porphyria?
A gain-of-function mutation will results in increased throughput through the pathway leading to a build-up in protoporphyrin IX as it overwhelms the ability of ferrochetolase to convert it into haem.
What are the main features of PBG synthase deficiency?
- Causes acute porphyria
- Leads to accumulation of ALA
- Abdominal pain (most important feature)
- Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
Which deficiency causes acute intermittent porphyria?
HMB synthase (aka PBG deaminase)
Outline the clinical features of acute intermittent porphyria.
- Rise in PBG and ALA
- Autosomal dominant
- Neurovisceral attacks
- Abdominal pain
- Tachycardia and hypertension
- Constipation, urinary incontinence
- Hyponatraemia and seizures
- Sensory loss/muscle weakness
- Arrythmias/cardiac arrest
Important: there are NO skin symptoms (because no porphyrinogens are produced)
NOTE: 90% will be asymptomatic
List some precipitating factors for acute intermittent porphyria.
- ALA synthase inhibitors (e.g. steroids, ethanol, anticonvulsants (CYP450 inducers))
- Stress (infection, surgery)
- Reduced caloric intake
- Endocrine factors
Describe how acute intermittent porphyria is diagnosed.
- increased urinary PBG (and ALA)
- PBG gets oxidised to porphobilin
- Decreased HMB synthase activity in erythrocytes
How is acute intermittent porphyria managed?
- Avoid attakcs (adequate nutrition, avoid precipitant drug, prompt treatment of other illnesses)
- IV carbohydrate (inhibits ALA synthase)
- IV haem arginate (switches off haem synthesis through negative feedback)
Name two acute porphyrias that have skin manifestations. State the enzymes affected.
- Hereditary coproporphyria - coproporphyrinogen oxidase
- Variegate porphyria - protoporphyrinogen oxidase
