ChemPath: Porphyrias ✔️ Flashcards
What is porphyria?
- Disorders caused by deficiencies in enzymes of the haem synthesis pathway
- Deficiency can be partial or complete
- 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
Which cells produce haem?
Aminolevulinic acid synthase (ALA synthase) –> found in all cells to produce haem
Where is haem found?
Erythroid cells
Liver cytochrome
Draw the haem synthesis pathway.
Blue rectangle = processes within the mitochondria
* succinyl CoA + glycine produces 5-ALA using ALA synthase
* 5-ALA leaves mitochondria and two of them join together to make PBG using PBG synthase
* PBG is converted to HMB using HMB synthase
* HMB then produces 1 of 2 products (uroporphyrinogen I and III)
* Uroporphyrinogen III is important for haem synthesis: as uroporphyrinogen III is converted to coproporhyrinogen III and then taken up by the mitochondria to form protoporphyrinogen IX –>protoporphyrin IX –> HAEM
What can an enzyme deficiency in the haem pathway cause?
- 7 enzymes in the pathway, any of which can be affected to cause porphyria (build up of porphyrins). There are 3 porphyria presentations.
- Therefore, enzyme deficiencies can cause build up of 5-ALA, PBG, or any of the porphyrinogens
- This build up can cause them to go via alternative pathways and build up other toxic/waste products
Which component of the haem biosynthesis pathway is neurotoxic?
5-ALA –> CAUSES NEUROVISCERAL 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 VS non-acute
- Neurovisceral (acute) or cutaneous skin lesions (non-acute)
What are the enzyme deficiencies and consequent presentations of porphyria?
7 enzymes in the pathway, of which any 7 can be affected.
THREE presentations:
1. Neurovisceral
2. Blistering cutaneous symptoms
3. Non-blistering cutaneous symptoms
Outline the relationships between UV light and skin lesions.
Porphyrinogens are oxidised and then activated by UV light into activated porphyrins as double bonds are formed.
NOTE: porphyrinogens do NOT oxidise in cells due to low availability of O2 in cells
What is a key difference between porphyrinogens and porphyrins?
- Porphyrinogens - (PRECURSORS to porphyrins) colourless, unstable and readily oxidised to porphyrin
- Porphyrins - highly coloured
NOTE: porphúra means purple in Greek
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 (AIP) - HMB synthase / PBG deaminase (2nd most common)
- Hereditary coproporphyria (HCP) - coproporphyrinogen oxidase
- Variegate porphyria (VP) - protoporphyrinogen oxidase
List three types of NON-ACUTE porphyria and the enzymes involved.
- Congenital erythropoietic porphyria - uroporphyrinogen III synthase
- Porphyria cutanea tarda - uroporphyginogen decarboxylase –> MOST COMMON!
- Erythropoietic protoporphyria - ferrochetolase (3rd most common in general, most common in children)
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
Causes sideroblastic anaemia
Does NOT cause any 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.
What are the main features of PBG synthase deficiency (also called ALA dehydratase deficiency) ?
- Causes acute porphyria
- Leads to accumulation of ALA
Neurovisceral symptoms: - Abdominal pain (MOST IMPORTANT feature)
- Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
Which deficiency causes acute intermittent porphyria (AIP)?
HMB synthase (aka PBG deaminase)
Outline the clinical features of acute intermittent porphyria (AIP).
- 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
How do AIP attacks come about?
Normally, enzyme activity rests at 50% of normal
Therefore 90% remain asymptomatic
BUT, precipitating factors can then cause AIP attacks e.g.
* DRUGS (most common) –> ALA synthase inhibitors e.g. steroids, ethanol, anticonvulsants (AKA CYP450 inducers)
* Stress (infection, surgery)
* Reduced caloric intake
* Endocrine factors
List some precipitating factors for acute intermittent porphyria (AIP).
- 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 haem arginate –> IMMEDIATE treatment! (switches off haem synthesis through negative feedback)
- IV carbohydrate (inhibits ALA synthase)
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 as a result of hereditary coproporphyria (coproporphyrinogen oxidase) and variegate porphyria (protoporphyrinogen oxidase)?
- They are potent inhibitors of HMB synthase
- Results in the accumulation of PBG and ALA –> this will lead to neurovisceral symptoms!
What are the main clinical features of hereditary coproporphyria (HCP)?
- Autosomal dominant
- ACUTE neurovisceral attacks (due to coproporphyrinogen III build-up being potent inhibitors of HMB synthase = accumulation of PBG and ALA)
- 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 (VP)?
- Autosomal dominant
- ACUTE neurovisceral attacks (due toprotoporphyrinogen IX build-up being potent inhibitors of HMB synthase = accumulation of PBG and ALA)
- 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
Investigations to differentiate between the acute porphyrias:
- CLINICAL DIAGNOSIS:
AIP –> NO skin lesions
HCP + VP –> YES skin lesions (blistering, back of the hand) - URINE:
Urine PBG raised in all 3 (AIP, HCP + VP)
Urine porphyrins raised in HCP + VP only (but not AIP) - FAECES:
Faeces porphyrins raised in HCP + VP only (but not AIP)
Enzyme activity variable for all
DNA definitive but large number of mutations
How is the porphyrin level in the urine and faeces different in hereditary coproporphyria (HCP) and variegate porphyria (VP) compared to acute intermittent porphyria (AIP)?
- 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 (CEP)
- Uroporphyrinogen decarboxylase - porphyria cutanea tarda (PCT)
- Ferrochetolase - erythropoietic protoporphyria (EPP)
What is the main clinical feature of NON-ACUTE porphyria?
- Skin blisters, fragility, pigmentations and erosions in sun-exposed areas
- Occuring hours to days after sun exposure
What are the key features of erythropoietic protoporphyria EPP)?
- NON-blistering and presents with photosensitivity, burning, itching, oedema following sun exposure
- Seen in CHILDREN
- Photosensitivity lesions only, NO BLISTERING
- Management = sun avoidance
What is a key investigation for erythropoietic protoporphyria (EPP)?
RBC protoporphyrin
NOTE: only RBCs are affected THEREFORE only need to measure RBC protoporphyrin
What are the causes and key features of porphyria cutanea tarda (PCT)?
- Can be inherited or acquired
- Uroporphyrinogen decarboxylase deficiency
- Aquired causes = liver disease (Hep B, HIV, cirrhosis), drugs
- Leads to formation of vesicles on sun-exposed areas of skin crusting, superficial scarring and pigmentation
Outline the biochemistry features of porphyria cutanea tarda (PCT).
- Urine/plasma uroporphyrins and coproporphyrins are raised
- Ferritin is often increased
Which drug can trigger porphyria cutanea tarda (PCT)?
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!! –> detect PBG & porphyrins:
* Urine PBG raised in all 3 (AIP, HCP + VP)
* Urine porphyrins raised in HCP + VP only (but not AIP)
NOTE: protect urine sample from light as light break down the porphyrins leading to a false negative
Diagnostic approach diagram for porphyria:
- Is it acute –> then send urine sample
- Look for skin lesions
- Assess photosensitivity
