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
- 4 tetrapyrrole rings around the iron
tetrapyrrole ring - nitrogen with 4 carbons arounud it in ring
Where is haem made?
What is its importance
made in every single cell –> by ALA synthase
haem then used to make cytochrome –> needed for electron transport in aerobic respiration
without it we would die
what cells do porphyrias affect
haem synthesesis in eythroid cells and liver cytochrome
Draw the haem synthesis pathway.
Grey box is mitochondria
Which component of the haem biosynthesis pathway is neurotoxic?
Clinical Relevance of this?
5-ALA
Accumulation –> 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 relationships between UV light and skin lesions.
Porphyrinogens are oxidised and then activated by UV light into activated porphyrins —> blistering/non blistering cutaenous presentations
NOTE: porphyrinogens do NOT oxidise in cells, it occurs in circulation
What is a key difference between porphyrinogens and porphyrins?
Porphrinogens are pre-cursors to porphyrin
- Porphyrinogens - colourless, unstable and readily oxidised to porphyrin (no double bonds)
- Porphyrins - highly coloured (have double bonds)
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
NOTE: haem synthessis pathway –> early porphyrins are water soluble, later are less soluble
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
What are the most common porphyrias
- Porphyria cutanea tarda
- Acute intermittent porphyria –> these patients very sick in A&E
- Erythropeoitic protoporphyria –> most common porphyria in children
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 –> increased activity of ALA synthase
Increased throughput through the pathway –> ferrochetolase is overwhelmed –> build up of protoporphyrin IX
very rare, dont focus on it
What are the main features of PBG synthase deficiency?
- Causes plumboporphyria
- Leads to accumulation of ALA
Acute neuro-visceral symptoms:
* Abdominal pain (most presenting important feature)
* Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
Extrememly rare
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 (due to ALA accumulation)
- 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 by light - goes from yellow to purple
- Decreased HMB synthase activity in erythrocytes
shield urine from light!!
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)
NOTE: adequate carbs important, as low carb can trigger attack
Name two acute porphyrias that have skin manifestations. State the enzymes affected.
How would they be diagnosed
- Hereditary coproporphyria - coproporphyrinogen oxidase
- Variegate porphyria - protoporphyrinogen oxidase
Stool samples –> excess coproporphyrinogen II and protophorphoryinogen IX in stool (they’re less water soluble)
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 –> acute neuro-visceral attacks
skin manifestations due to porphyrinogen buiild up as well
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)
blisters on back of hand due to sun exposure
What are the main clinical features of variegate porphyria?
- Autosomal dominant
- Acute attacks with skin lesions
less severe than hereditary coproporphyria
diagnosis of acute porphyrias
send off urine in acute attack (protected from light) –> urine PBG raised in all 3 (not in Plumboporphyria (PBG synthase deficiency) as pathway doesn’t get that far)
- AIP - normal - no porphyrins in urine/feces (pathway doesn’t get that way)
- HCP and VP - high porphyrin in urine/feces
Clinically:
AIP –> no skin lesions, but HCP and VP do have skin lesions
NOTE: DNA analysis offers a definitive diagnosis
what are the acute porphyrias
Acute intermittent porphyria - neurovisceral attacks
Hereditary coproporphyria - neurovisceral attacks + blistering skin lesions
Variegate porphyria - neurovisceral attacks + blistering skin lesions
Plumboporphyria - PBG synthase
What is a common feature of non-acute porphyria?
Only present with skin lesions with NO neurovisceral manifestations
What are the non-acute porphyrias
- Uroporphyrinogen III synthase - congenital erythropoietic porphyria
- Uroporphyrinogen decarboxylase - porphyria cutanea tarda
- Ferrochetolase - erythropoietic protoporphyria
What is the main flinical feature of non-acute porphyria?
- Only skin affected!!
- Blisters in Porphyria cutanea tarda, Congenital erythropoietic porphyria
- No blisters in erythropoietic protoporphyria
- Skin fragility, pigmentations and erosions
- Occuring hours to days after sun exposure
What are the key features of erythropoietic protoporphyria?
How is it managed
NON-blistering and presents with photosensitivity, burning, itching, oedema minutes following sun exposure
Sun avoidance
What is a key investigation for erythropoietic protoporphyria?
RBC protoporphyrin
NOTE: only RBCs are affected
i.e. porphyrins won’t be high in urine/feces
What are the key features of porphyria cutanea tarda?
- Can be inherited or acquired (liver disease, HIV, drugs)
- Leads to formation of blisters 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 (fungicide for seeds)
What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?
Myelodysplastic syndromes
During acute porphyria, what is the most uesful sample to send?
Urine
