The Porphyrias Flashcards
What is porphyria?
Deficiencies in enzymes of the haem biosynthetic pathway.
Overproduction of toxic haem precursors:
- Acute neuro-visceral attacks.
- Acute or chronic cutaneous symptoms.
Deficiency of enzymes ranges from partial to complete.
What is haem?
Organic heterocyclic compounds with Fe2+in centre.
4 pyrrolic (tetrapyrrole) rings around the iron.
Carries oxygen
Made in all cells
What are the classifications of porphyrias?
Principle site of enzyme deficiency:
- Erythroid or hepatic
Clinical presentation:
- Acute or Non-acute
- Neurovisceral or skin lesions
Why can porphyria cause neurovisceral or acute signs?
5-aminolaevulinic (5-ALA) acid is neurotoxic
Why can porphyria cause skin lesions?
Porphyrinogens are oxidised to porphyrins. When exposed to light, the porphyrins are activated and produce O2.
What are porphyrinogens?
Raised in porphyria
Colourless compounds
Unstable and readily oxidised to the corresponding porphyrin by the time urine/faeces reaches lab.
What are porphyrins?
Highly coloured.
Porphyrins near start of the pathway are water soluble – urine (uro-).
Porphyrins near end less soluble – faeces (copro-).
What are the acute porphyrias and which enzymes are deficient?
ALA Dehydratase/Plumboporphyria - PBG Synthase
Acute Intermittent Porphyria - HMB Synthase
Hereditary Coproporphyria - Coproporphyrinogen oxidase
Variegate Porphyria - Protoporphyrinogen oxidase
What are the non-acute porphyrias and which enzymes are deficient?
Congenital eryrthopoietic porphyria - Uroporphyrinogen III synthase
Porphyria cutanea tarda - Uroporphyrinogen decarboxylase
Erythorpoietic protoporphyria - Ferrochetolase
What does an ALA synthase deficiency result in?
Not a porphyria
X-linked sideroblastic anaemia
What does a PBG synthase deficiency result in?
‘ALA Dehydratase or Plumboporphyria’.
Extremely rare form of porphyria.
Build-up of ALA, but not PBG.
Diagnostic implications.
What is HMB synthase deficiency?
Acute Intermittent Porphyria –Autosomal dominant
What are signs and symptoms of HMB synthase deficiency?
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
What is Acute Intermittent Porphyria?
Enzyme activity usually 50% of normal, 90% have no symptoms at all.
Precipitating factors:
- ALA synthase inducers: Barbiturates, steroids, ethanol, anticonvulsants.
- Stress: Infection, surgery
- Reduced caloric intake
- Endocrine factors
More common in women and premenstrual.
How is acute intermittent porphyria diagnosed?
Increased urinary PBG (and ALA)
PBG gets oxidised to porphobilin
Decreased HMBS activity in erythrocytes
What is the treatment of acute intermittent porphyria?
Avoid attacks:
- Adequate nutritional intake
- Precipitant drugs
- Prompt treatment infection/illness
IV Carbohydrate
IV Haem arginate
Which acute porphyrias cause skin lesions?
Hereditary coproporphyria
Variegate porphyria
What is Hereditary Coproporphyria (HCP)?
Autodomal dominant
Acute neurovisceral attack
- Blistering skin lesions
- Skin fragility
What is Variegate Porphyria (VP)?
Autosomal dominant
Acute attacks
Skin lesions
How are the acute porphyrias differentiated?
AIP – No skin lesions
HCP & VP – Skin lesions
Urine PBG: Raised in all three
Urine and faeces for porphyrins: Raised HCP or VP, but not AIP
Enzyme activity variable
DNA definitive but large number of mutations
What are features of non-acute porphyrias?
Only present with skin lesions
No neuro-visceral manifestations
What are the signs of non-acute porphyrias?
Skin affected only e.g. blisters, fagility, pigmentation, erosions etc. delay following sun exposure.
EPP: Photosensitivity, burning, itching oedema following sun exposure.
What is Porphyria Cutanea Tarda (PCT)?
Inherited or acquired.
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
Avoid precipitants (alcohol, hepatic compromise).
What is Erythropoietic protoporphyria (EPP)?
Photosensitivity only, no blisters
Only erythroid cells affected, therefore need to measure RBC protoporphyrin
What is acquired porphyria?
PCT most cases sporadic without family history: Formation of specific inhibitor of uroporphyrinogen decarboxylase.
PCT-like syndrome hexachlorobenzene
EPP and CEP a/w myelodysplastic syndromes
