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
- Deficiency of enzymes range for partial to complete
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
- Fe2+ in the centre
- There is a pyrolic (tetrapyrole) ring around the iron
What are the 2 major functions of haem?
- Carry oxygen
- Faciliate redox reactions
Where is haem found?
Made in all cells
Which 2 cell types do porphyrias typically affect?
Erythroid and hepatic
Draw the haem synthesis pathway.
Which intermediate of the haem biosynthesis pathway is neurotoxic?
Aminolevulinic acid (ALA)
Causes neuro-visceral symptoms
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 pathophysiology of skin lesions in porphyria
Photosensitivity - porphyrinogens are oxidised and then activated by UV light into activated porphyrins. Activated porphyrins damage skin cells and trigger inflammatory pathways
NOTE: porphyrinogens do NOT oxidise cells
What is a key difference between porphyrinogens and porphyrins?
Porphyrinogens
- Precursor to porphyrins
- Colourless
- Unstable and readily oxidised to corresponding porphyrin
Porphyrins
- Highly coloured
Which porphyrins appears in the urine and which appear in faeces?
- Porphyrins near start of the pathway are water soluble – urine (uro-)
- Porphyrins near end less soluble – faeces (copro-)
NOTE: someone with AIP will have dark red/brown urine due to porphyrin accumulation
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 - uroporphyinogen decarboxylase
- Erythropoietic protoporphyria - ferrochelatase
What is the most common type of porphyria?
Porphyria cutanea tarda
What is the most common type of porphyria in children?
Erythropoietic protoporphyria (EPP)
What does ALA synthase deficiency cause?
X-linked sideroblastic anaemia
NOT a porphyria!
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.
Similar clinical picture to EPP
What are the main features of PBG synthase deficiency?
- Causes acute porphyria
- Extremely rare
- 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? What is its inheritance pattern?
HMB synthase (aka PBG deaminase)
Autosomal dominant
Outline the clinical features of acute intermittent porphyria (AIP)
Neurovisceral attacks:
- GI symptoms - abdominal pain, vomiting, constipation
- Neurological - polyneuropathy (paresthesia, weakness), seizures
- GU symptoms - bladder dysfunction, red/brown urine
- Autonomic dysfunction - tachycardia and hypertension
- Psychiatric - hallucinations, anxiety, insomnia
Important: there are NO skin symptoms (because no porphyrinogens are produced)
NOTE: 90% will be asymptomatic
What is the mechanism behind the symptoms in AIP?
Rise in PBG and ALA
List some precipitating factors for acute intermittent porphyria.
- ALA synthase inducers e.g. steroids, ethanol, anticonvulsants (CYP450 inducers), barbiturates
- Stress (infection, surgery)
- Starvation/reduced caloric intake
- Endocrine factors - sex hormones
Describe how acute intermittent porphyria is diagnosed.
Urinary PBG and ALA - raised in both
How is acute intermittent porphyria acute attack managed?
- IV haem arginate (switches off haem synthesis through negative feedback)
- IV carbohydrate loading (inhibits ALA synthase) - second line if haem arignate not avaliable
Avoid attacks (adequate nutrition, avoid precipitant drug, prompt treatment of other illnesses)
Name two acute porphyrias that have skin manifestations. State the enzymes affected.
- Hereditary coproporphyria - coproporphyrinogen oxidase
- Variegate porphyria - protoporphyrinogen oxidase
NOTE: Generally speaking the acute porphyrias are neurovisceral and the chronic porphyrias are cutaneous
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 - hence neurovisceral symptoms
What are the main clinical features of hereditary coproporphyria?
- Autosomal dominant
- Acute neurovisceral attacks
- Photosensitivity skin lesions (blistering, skin fragility, classically on the backs of the hands that tend to appear hours/days after sun exposure)
What are the features of variegate porphyria?
- Autosomal dominant
- Acute attacks with skin lesions
How can acute porphyrias be differentiated symtpoms-wise?
- AIP - no skin lesions
- Hereditary coproporphyria and variegate porphyria - skin lesions
Which marker is raised in both AIP plus HCP and VP
Urine PBG
How can hereditary coproporphyria and variegate porphyria be differentiated from acute intermittent porphyria biochemically?
Urine and stool porphyrins - raised in HCP and VP, but not in AIP
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
- Ferrochelatase - erythropoietic protoporphyria
What is the main clinical feature of non-acute porphyria?
- Skin blisters, fragility, pigmentations and erosions
- Occuring 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?
Erythrocyte protoporphyrin
NOTE: only RBCs are affected
Which enzyme is deficient in porphyria cutanea tarda?
Uroporphyrinogen decarboxylase
Leads to the accumulation of uroporphyrinogen III which is converted into uroporphyrin in the skin by UV
(Enzyme deficiency can be inherited or acquired)
What are the clinical features of porphyria cutanea tarda?
Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring and pigmentation
How is PCT diagnosed biochemically?
- Raised urine/serum porphyrins
- Ferritin is often increased
Which drug can cause acquired 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 (for PBG and ALA levels)
What clincial implication of porphyrias is important for doctors?
Have to be careful prescribing drugs as they could preciptate an attack
