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ChemPath: Porphyrias Flashcards

1
Q

What is porphyria?

A

Disorders caused by deficiencies in enzymes of the haem synthesis pathway

  • This leads to the accumulation of toxic haem precursors
  • Deficiency of enzymes range for partial to complete
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2
Q

What are the two ways in which porphyria can manifest?

A
  • Acute neuro-visceral attacks
  • Acute or chronic cutaneous symptoms
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3
Q

List some key features of haem.

A
  • Organic heterocyclic compound
  • Fe2+ in the centre
  • There is a pyrolic (tetrapyrole) ring around the iron
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4
Q

What are the 2 major functions of haem?

A
  • Carry oxygen
  • Faciliate redox reactions
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5
Q

Where is haem found?

A

Made in all cells

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6
Q

Which 2 cell types to porphyrias typically affect?

A

Erythroid and hepatic

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7
Q

Draw the haem synthesis pathway.

A
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8
Q

Which intermediate of the haem biosynthesis pathway is neurotoxic?

A

Aminolevulinic acid (ALA)

Causes neuro-visceral symptoms

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9
Q

What types of porphyrin may be produced in the absence of iron?

A
  • Metal-free protoporphyrins
  • Zinc protoporphyrin
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10
Q

How can porphyrias be classified?

A

Principle site of enzyme deficiency:

  • Erythroid
  • Hepatic

Clinical presentation:

  • Acute or non-acute
  • Neurovisceral or skin lesions
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11
Q

Outline the pathophysiology of skin lesions in porphyria

A

Photosensitivity - porphyrinogens are oxidised and then activated by UV light into activated porphyrins. Activate porphyrins damage skin cells and trigger inflammatory pathways

NOTE: porphyrinogens do NOT oxidise cells

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12
Q

What is a key difference between porphyrinogens and porphyrins?

A

Porphyrinogens

  • Colourless
  • Unstable and readily oxidised to corresponding porphyrin

Porphyrins
- Highly coloured

porphyrinogen = precursor to porphyrins

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13
Q

Which porphyrins appears in the urine and which appear in faeces?

A
  • Porphyrins near start of the pathway are water soluble – urine (uro-)
  • Porphyrins near end less soluble – faeces (copro-)

NOTE: someone with AIP will have dark red/brown urine due to porphyrin accumulation

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14
Q

List four types of acute porphyria and the enzymes involved.

A

Plumboporphyria - PBG synthase

Acute intermittent porphyria - HMB synthase

Hereditary coproporphyria - coproporphyrinogen oxidase

Variegate porphyria - protoporphyrinogen oxidase

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15
Q

List three types of non-acute porphyria and the enzymes involved.

A

Congenital erythropoietic porphyria - uroporphyrinogen III synthase

Porphyria cutanea tarda - uroporphyinogen decarboxylase

Erythropoietic protoporphyria - ferrochelatase

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16
Q

What is the most common type of porphyria?

A

Porphyria cutanea tarda

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17
Q

What is the most common type of porphyria in children?

A

Erythropoietic protoporphyria (EPP)

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18
Q

What does ALA synthase deficiency cause?

A

X-linked sideroblastic anaemia

NOT a porphyria!

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19
Q

How can a mutation in ALA synthase lead to porphyria?

A

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.

Similar clinical picture to EPP

20
Q

What are the main features of PBG synthase deficiency?

A
  • Causes acute porphyria
  • Extremely rare
  • Leads to accumulation of ALA
  • Abdominal pain (most important feature)
  • Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
21
Q

Which deficiency causes acute intermittent porphyria? What is its inheritance pattern?

A

HMB synthase (aka PBG deaminase)
Autosomal dominant

22
Q

Outline the clinical features of acute intermittent porphyria (AIP)

A

Neurovisceral attacks:

  • GI symptoms - abdominal pain, vomiting, constipation
  • Neurological - polyneuropathy (paresthesia, weakness), seizures
  • GU symptoms - bladder dysfunction, red/brown urine
  • Autonomic dysfunction - tachycardia and hypertension
  • Psychiatric - hallucinations, anxiety, insomnia

Important: there are NO skin symptoms (because no porphyrinogens are produced)

NOTE: 90% will be asymptomatic

23
Q

What is the mechanism behind the symptoms in AIP?

A

Rise in PBG and ALA

24
Q

List some precipitating factors for acute intermittent porphyria.

A
  • ALA synthase inducers e.g. steroids, ethanol, anticonvulsants (CYP450 inducers), barbiturates
  • Stress (infection, surgery)
  • Starvation/reduced caloric intake
  • Endocrine factors - sex hormones
25
Q

Describe how acute intermittent porphyria is diagnosed.

A

Urinary PBG and ALA - raised in both

26
Q

How is acute intermittent porphyria acute attack managed?

A
  • IV haem arginate (switches off haem synthesis through negative feedback)
  • IV carbohydrate loading (inhibits ALA synthase) - second line if haem arignate not avaliable

Avoid attacks (adequate nutrition, avoid precipitant drug, prompt treatment of other illnesses)

27
Q

Name two acute porphyrias that have skin manifestations. State the enzymes affected.

A
  • Hereditary coproporphyria - coproporphyrinogen oxidase
  • Variegate porphyria - protoporphyrinogen oxidase

NOTE: Generally speaking the acute porphyrias are neurovisceral and the chronic porphyrias are cutaneous

28
Q

What is the negative consequence of accumulation of coproporphyrinogen III and protoporphyrinogen IX?

A
  • They are potent inhibitors of HMB synthase
  • Results in the accumulation of PBG and ALA - hence neurovisceral symptoms
29
Q

What are the main clinical features of hereditary coproporphyria?

A
  • Autosomal dominant
  • Acute neurovisceral attacks
  • Photosensitivity skin lesions (blistering, skin fragility, classically on the backs of the hands that tend to appear hours/days after sun exposure)
30
Q

What are the features of variegate porphyria?

A
  • Autosomal dominant
  • Acute attacks with skin lesions
31
Q

How can acute porphyrias be differentiated symtpoms-wise?

A
  • AIP - no skin lesions
  • Hereditary coproporphyria and variegate porphyria - skin lesions
32
Q

Which marker is raised in both AIP plus HCP and VP

A

Urine PBG

33
Q

How can hereditary coproporphyria and variegate porphyria be differentiated from acute intermittent porphyria biochemically?

A

Urine and stool porphyrins - raised in HCP and VP, but not in AIP

NOTE: DNA analysis offers a definitive diagnosis

34
Q

What is a common feature of non-acute porphyria?

A

Only present with skin lesions with NO neurovisceral manifestations

35
Q

List the enzymes associated with non-acute porphyria.

A
  • Uroporphyrinogen III synthase - congenital erythropoietic porphyria
  • Uroporphyrinogen decarboxylase - porphyria cutanea tarda
  • Ferrochetolase - erythropoietic protoporphyria
36
Q

What is the main clinical feature of non-acute porphyria?

A
  • Skin blisters, fragility, pigmentations and erosions
  • Occuring hours to days after sun exposure
37
Q

What are the key features of erythropoietic protoporphyria? Which key symptom is different to the rest of the non-acute porphyrias?

A

NON-BLISTERING and presents with photosensitivity, burning, itching, oedema following sun exposure

38
Q

What is a key investigation for erythropoietic protoporphyria?

A

Erythrocyte protoporphyrin

NOTE: only RBCs are affected

39
Q

Which enzyme is deficient in porphyria cutanea tarda?

A

Uroporphyrinogen decarboxylase

Leads to the accumulation of uroporphyrinogen III which is converted into uroporphyrin in the skin by UV

(Enzyme deficiency can be inherited or acquired)

40
Q

What are the clinical features of porphyria cutanea tarda?

A

Formation of vesicles on sun-exposed areas of skin crusting, superficial scarring and pigmentation

41
Q

How is PCT diagnosed biochemically?

A
  • Raised urine/serum uroporphyrins
  • Ferritin is often increased
42
Q

Which drug can cause acquired porphyria cutanea tarda?

A

Hexachlorobenzene

43
Q

What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?

A

Myelodysplastic syndromes

44
Q

During acute porphyria, what is the most useful sample to send?

A

Urine (for PBG and ALA levels)

45
Q

What clincial implication of porphyrias is important for doctors?

A

Have to be careful prescribing drugs as they could preciptate an attack

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