CHEMPATH: Porphyrias Flashcards
Define porphyria.
Porphyria = deficiency (partial/complete) of enzymes in haem biosynthesis –> overproduction of toxic haem precursors
What are the 3 presentations of porphyrias?
- Acute neuro-visceral attacks and/or;
- Acute or chronic cutaneous symptoms
- Blistering
- Non-blistering
Describe the structure of haem. What is its function?
- Organic heterocyclic compound
- Fe2+in centre
- 4 pyrrolic (tetrapyrrole; x4 pyrole which is nitrogen with 4 carbons around it) rings around the iron
- Have double bonds which are not presnet in the precursor porphyrinogens
Functions:
- Carries oxygen
- Invovles redox reactions
Porphyrias affect haem synthesis in which parts of the body?
Liver cytochrome
Erythroid cells (BM)
Haem formation begins with which enzyme? Where does this reaction occur?
ALA synthase in the mitochondria
succinyl coA + glycine –ALA synthase–> 5-ALA (aminolaevulinic acid)
List the 8 enzymes invovled in haem synthesis pathways.
- ALA synthase
- PBG synthase AKA ALA dehydratase
- HMB synthase
- Uroporphyrinogen III synthase
- Uroporiphyrinogen decarboxylase
- Coproporphyrinogen oxidase
- Protoporphyrinogen oxidase
- Ferrochetalase
ALA - aminolaevulinic acid
PBG - porphobilinogen
HMB - hydroxymethylbilane
Summarise the haem biosynthesis pathway.
- ALA is generated within the mitochondrion
- 2 ALAs leave the mitochondrion to be converted to PBG by PBG synthase which removes water (aka ALA dehydratase)
- PBG converted to HMB, catalysed by HMB synthase (AKA PDG deaminase)
- HMB –> either uroporphyrinogen III or uroporphyrinogen I
- Uroporphyrinogen III synthase present –>Uroporphyrinogen III produced
- Uroporphyrinogen III synthase ABSENT –> Uroporphyrinogen I produced
- Uroporphyrinogen III –> coproporphyrinogen III (via uroporphyrinogen decarboxylase)
- Coproporphyrinogen III goes into mitochondria and converted –> protoporphyrinogen IX (coproporphyrinogen oxidase)
- Protoporphyrinogen IX –> protoporphyrin IX (via protoporphyrinogen oxidase) in mitochondria
- If iron present in abundance, you get iron incorporated into the protoporphyrin IX and you gene haem (via ferrochetalase)
In which step of the haem biosynthesis pathway does the reaction return to being in mitochondria?
Coproporphyrinogen III –coproporphyrinogen oxidase–> protoporphyrinogen IX
What is produced in the absence of uroporphyrinogen III synthase?
uroporphyrinogen I
If there is a deficiency of iron for the haem biosynthesis, what happens to protoporphyrin IX?
If there is a deficiency of iron, you end up with metal-free protoporphyrins or zinc protoporphyrin
Briefly what happens when enzymes in this pathway are absent?
Intermediaries build up and may start to react with other enzymes to give new products
What 2 ways are used for classifying porphyrias?
By principal site of enzyme deficiency:
- Erythroid
- Hepatic
Clinical presentation:
- Acute or non-acute
- Neurovisceral or skin lesions
What is the cause of neurovisceral symptoms in porphyrias?
5-ALA build up which is neurotoxic
What is the cause of skin lesions in porphyrias?
- Occur due to accumulation of porphyrin precursors in the skin
- These are oxidised and converted by UV light into active porphyrins which are toxic
Porphyrinogens do NOT oxidise in cells because cells have a low oxygen environment BUT as soon as they enter the circulation, they are less stable and have more exposure to oxygen
What is the difference between the appearance of porphyrinogens and porphyrins?
Porphyrinogens are RAISED in porphyria and COLOURLESS (no double bonds)
- Water-soluble (near start of pathway) and excreted in the urine (uroporphyrins)
- Unstable and readily oxidised to corresponding porphyrin by the time the urine/faeces sample reaches the lab –> colourless/yellow to red or deep purple colour change
Porphyrins are HIGHLY COLOURED
- Porphyrins near the end of the pathway are less soluble and are excreted in the faeces (coproporphyrins)
List 4 types of acute porphyrias and the enzyme affected. Which is the most common acute porphyria?
ALA dehydratase/plumboporphyria - PBG synthase
Acute intermittent porphyria - HMB synthase (MOST COMMON ACUTE PORPHYRIA)
Hereditary coproporphyria - coproporphyrinogen oxidase
Variegate porphyria - protoporphyrinogen oxidase
List 3 types of non-acute porphyrias and the enzymes affected in each.
Congenital erythropoietic porphyria - uroporphyrinogen III synthase
Porphyria cutanea tarda - uroporphyrinogen decarboxylase (MOST COMMON OVERALL)
Erythropoietic protoporphyria - ferrochetolase
Which porphyrias are acute with skin lesions vs acute without skin lesions?
Acute, no skin lesions = Plumboporphyria, AIP
Acute, skin lesions = Hereditary coproporphyria, Variegate porphyria
Which porphyrias are chronic with skin lesions vs with photosensitivity alone?
- Chronic, skin lesions = porphyria cutanea tarda, congenital erythropoietic porphyria
- Chronic, skin photosensitivity= erythropoietic protoporphyria
What is the condition resulting from ALA-synthase deficiency?
NOT a porphyria but rather an X-linked sideroblastic anaemia
BUT ALA synthase gain-of-function mutation –> increased throughput of pathway –> build-up of protoporphyrin IX –> overwhelms ability of ferrochetalase to convert it to haem, resulting in an accumulation of protoporphyrin IX (similar to erythropoietic protoporphyria)
What is the pathophysiology of PBG synthase deficiency? What is the presentation?
- A lack of PBG synthase/ALA dehydratase –> ALA dehydratase deficiency porphyria (or Plumboporphyria)
- –> accumulation of ALA (not PBG)
- –> acute porphyria/plumboporphyria
It is an extremely RARE form of porphyria
Presentation:
- Neurological (e.g. coma, bulbar palsy, motor neuropathy)
- Abdominal pain (most important feature)
What is the pathophysiology of HMB synthase/PBG deaminase deficiency? How is it acquired? What is its presentation?
1.Pathophysiology
- Causes a rise in PBG and ALA;
- ALA rise –> neurovisceral symptoms
- = acute intermittent porphyria (AIP)
2. Autosomal dominant inheritance pattern
- Presentation: 90% remain asymptomatic, enzyme activity is 50% of normal but attacks are common although
-
Neurovisceral attacks:
- Abdominal pain and vomiting
- Tachycardia and hypertension
- Constipation, urinary incontinence
- Hyponatraemia (SIADH) ± seizures
- Psychological symptoms
- Sensory loss/muscle weakness
- Arrhythmias/cardiac arrest
- No skin symptoms (as no production of porphyrinogens)
What are the precipitating factors for attacks in acute intermittent porphyria?
Precipitating factors (cytochrome inducers):
- ALA synthase inducers – barbiturates, steroids, ethanol, anti-convulsants
- Stress – infection, surgery
- Reduced caloric intake
- Endocrine factors – F>M, pre-menstrual
How are acute porphyrias diagnosed?
Diagnosis:
-
Increased urinary PBG (and ALA) – send urine to lab quickly and keep in the dark otherwise it will turn purple.
- PBG oxidised –> porphobilin
- Decreased HMBS activity in erythrocytes
