Chem Path 8 - 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 tetrapyrrole ring around the iron
Where is haem found?
Erythroid cells
Liver cytochrome
Which component of this 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 in cells
What is a key difference between porphyrinogens and porphyrins?
Porphyrinogens – colourless, unstable and readily oxidised to porphyrin
Porphyrins – highly coloured
Which porphyrins appear in the urine and faeces
Urine – uroporphyrins are water soluble
Faeces – coproporphyrins are less soluble and near the end of the pathway
List four types of acute porphyria and the enzymes involved.
Plumboporphyria – PBG synthase
Acute intermittent porphyria – HMB synthase
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 result 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
· Arrhythmias/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 attacks (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
What is the negative consequence of accumulation of coproporphyrinogen III and protoporphyrinogen IX?
They are potent inhibitors of HMB synthase
Results in the accumulation of PBG and ALA
What are the main clinical features of hereditary coproporphyria?
Autosomal dominant
Acute neurovisceral attacks
Skin lesions (blistering, skin fragility, classically on the backs of the hands that tend to appear hours/days after sun exposure)
What are the main clinical features of variegate porphyria?
Autosomal dominant
Acute attacks with skin lesions
How is the porphyrin level in the urine and faeces different in hereditary coproporphyria and variegate porphyria compared to acute intermittent porphyria?
AIP - normal
HCP and VP – high
NOTE: DNA analysis offers a definitive diagnosis
What is a common feature of non-acute porphyria?
Only present with skin lesions with NO neurovisceral manifestations
List the enzymes associated with non-acute porphyria.
Uroporphyrinogen III synthase – congenital erythropoietic porphyria
Uroporphyrinogen decarboxylase – porphyria cutanea tarda
Ferrochetolase – erythropoietic protoporphyria
What is the main clinical feature of non-acute porphyria?
Skin blisters, fragility, pigmentations and erosions
Occurring hours to days after sun exposure
What are the key features of erythropoietic protoporphyria?
NON-blistering and presents with photosensitivity, burning, itching, oedema following sun exposure
What is a key investigation for erythropoietic protoporphyria?
RBC protoporphyrin
What are the key features of porphyria cutanea tarda?
Can be inherited or acquired
Leads to formation of vesicles on sun-exposed areas of skin crusting, superficial scarring and pigmentation
Outline the biochemistry features of porphyria cutanea tarda.
Urine/plasma uroporphyrins and coproporphyrins are raised
Ferritin is often increased
Which drug can trigger porphyria cutanea tarda?
Hexachlorobenzene
What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?
Myelodysplastic syndromes
During acute porphyria, what is the most useful sample to send?
Urine
