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
How do you treat acute porphyrias?
-
Avoid attacks –
- adequate nutritional intake,
- avoid precipitating drugs,
- prompt tx for infection
- High carbohydrate diet –> inhibit ALA synthase (low carb intake can provide attack)
- IV haem-arginate –> mimic natural haem and so turns off haem synthesis through -ve feedback
Compare and contrast AIP with PCT.
Generally speaking, acute porphyrias are neurovisceral and the chronic porphyrias are cutaneous, however, there are some exceptions, what are these?
- Hereditary coproporphyria = deficiency of coproporphyrinogen oxidase
- Variegate porphyria = deficiency of protoporphyrinogen oxidase
Given that protoporphyrinogen oxidase and coporphyrinogen oxidase are much further down the pathway drom ALA and PBG, why do they still cause acute episodes?
Both diseases cause insoluble porphyrinogens from the end of the pathway to be deposited in stool as they are not as soluble but acute episodes also occur because…
- …coproporphyrinogen III and protoporphyrinogen IX are potent inhibitors of HMB synthase –> accumulation of PBG and, consequently, ALA.
How is hereditary coproporphyria and variegate porphyria acquired? What are the signs/symptoms in acute attacks?
-
Hereditary Coproporphyria (HCP)
- Autosomal dominant
- Acute neurovisceral attacks
- Skin lesions – blistering, skin fragility [back of hands, after sun]
-
Variegate Porphyria (VP)
- Autosomal dominant
- Acute attacks
- Skin lesions
How can you differentiate between the different acute porphyrias?
DNA analysis offers a definitive diagnosis, but there are several mutations that can cause these conditions
Compare and contrast the following in acute porphyrias:
- Skin lesion presence
- Urine PBG
- Porphyrins in urine +/- faeces
- Enzyme activity
Plumboporphyria (ALA dehydratase/PBG synthase deficiency) not given here as it is extremely rare with only a few cases resported worldwide
List 3 non-acute porphyrias and the types of skin signs seen in each.
CEP and PCT are blistering
EPP is the only non-blistering
Skin signs tend to occur hours-days after sun exposure. There are no neuro-visceral manifestations with these porphyrias.
What are the enzyme deficiencies in the 3 non-acute porphyrias? Which is the most common?
- Congenital Erythropoietic Porphyria (CEP) - uroporphyrinogen III synthase deficiency
- Porphyria Cutanea Tarda (PCT) - uroporphyrinogen decarboxylase deficiency
- Erythropoietic Protoporphyria (EPP) - ferrochetalase deficiency
PCT is most common (1 in 25,000)
How is PCT acquired? What is found on investigations?
- Acquired (80%), inherited (20%)
- Skin symptoms only – vesicles on sun-exposed areas with skin crusting, superficial scarring and pigmentation
Biochemistry:
- Urine/plasma uroporphyrins + coproporphyrins are increased
- Ferritin increased
What are the precipitants of PCT? What is the treatment?
Avoid precipitants (e.g. alcohol, hepatic compromise)
Treatment:
- Phlebotomy (reduce ferritin)
- Hydroxychloroquine
What are the symptoms of erythropoietic protoporphyria (EPP)? What is the pathophysiology? What investigation is key?
- Photosensitivity only (no blisters)
- burning,
- itching
- oedema following sun
Only erythroid cells are affected therefore important to measure RBC protoporphyrin
Which chemical can trigger porphyrias? How are most acquired? Which porphyrias are associated with myelodysplastic syndromes?
- Most cases of PCT are sporadic with no FHx
- PCT-like syndromes can be triggered by hexachlorobenzene (fungicide added to wheat in Turkey in 1950s)
- EPP and CEP are associated with myelodysplastic syndromes
What are the most important diagnostic tests for:
- Acute porphyrias
- Porphyrias with skin features
- Photosensitivity porphyrias
In skin features total porphyrins need to be measured so ideally urine and faecal.
22-year-old female
- On holiday, drinking heavily –> abdominal pain, nausea and vomiting –> Paranoia
- Returned to UK:
- Tonic/clonic seizures
- Blurred vision, flashing lights à admitted to DGH
- Clinical deterioration:
- Transferred to ITU
- Developed ophthalmoplegia and quadriparesis
- Respiratory failure –> intubated and ventilated
- Biochemistry:
- [Na+] = 118 mmol/L (135-145)
- Urine ALA = 207 μmol/mmol creatinine(<3.8)
- Urine PBG = 215 μmol/mmol creatinine(<1.5)
- Hydroxymethylbilane synthase = 11nmol/mL RBCs(20-42)
- Diagnoses:
- Acute intermittent porphyria (seizures, quadriparesis, SIADH)
- Pulmonary emboli
-
Treatment
- Haem-arginate
- High CHO diet
Abdominal pain + Neurological symptoms + Psychiatric symptoms = consider porphyrias with elevated ALA
Which electrolyte abnormality is commonly seen in AIP?
SIADH (hyponatraemia)
