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YEAR 5: Chemical Pathology JK > ChemPath: Porphyrias > Flashcards

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
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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 with Fe2+ in the centre
  • There is a terapyrrole ring around the iron
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4
Q

Where is haem found?

A

Erythroid cells

Liver cytochrome

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5
Q

Draw the haem synthesis pathway.

A
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6
Q

Which component of the haem biosynthesis pathway is neurotoxic?

A

5-ALA

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7
Q

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

A
  • Metal-free protoporphyrins
  • Zinc protoporphyrin
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8
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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9
Q

Outline the relationships between UV light and skin lesions.

A

Porphyrinogens are oxidised and then activated by UV light into activated porphyrins.

NOTE: porphyrinogens do NOT oxidise cells

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10
Q

What is a key difference between porphyrinogens and porphyrins?

A
  • Porphyrinogens - colourless, unstable and readily oxidised to porphyrin
  • Porphyrins - highly coloured
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11
Q

Which porphyrins appears in the urine and faeces?

A
  • 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

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12
Q

List four types of acute porphyria and the enzymes involved.

A
  • Plumboporphyria - PBG synthase
  • Acute intermittent porphyria - HMB synthase / PBG deaminase
  • Hereditary coproporphyria - coproporphyrinogen oxidase
  • Variegate porphyria - protoporphyrinogen oxidase
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13
Q

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

A
  • Congenital erythropoietic porphyria - uroporphyrinogen III synthase
  • Porphyria cutanea tarda - uroporphyginogen decarboxylase
  • Erythropoietic protoporphyria - ferrochetolase
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14
Q

What is the most common type of porphyria?

A

Porphyria cutanea tarda

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15
Q

What is the most common type of porphyria in children?

A

Erythropoietic protoporphyria

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16
Q

What does ALA synthase deficiency cause?

A

X-linked sideroblastic anaemia

17
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.

18
Q

What are the main features of PBG synthase deficiency?

A
  • Causes acute porphyria
  • Leads to accumulation of ALA
  • Abdominal pain (most important feature)
  • Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)
19
Q

Which deficiency causes acute intermittent porphyria?

A

HMB synthase (aka PBG deaminase)

20
Q

Outline the clinical features of acute intermittent porphyria.

A
  • 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

21
Q

List some precipitating factors for acute intermittent porphyria.

A
  • ALA synthase inhibitors (e.g. steroids, ethanol, anticonvulsants (CYP450 inducers))
  • Stress (infection, surgery)
  • Reduced caloric intake
  • Endocrine factors
22
Q

Describe how acute intermittent porphyria is diagnosed.

A
  • increased urinary PBG (and ALA)
  • PBG gets oxidised to porphobilin
  • Decreased HMB synthase activity in erythrocytes
23
Q

How is acute intermittent porphyria managed?

A
  • 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)
24
Q

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

A
  • Hereditary coproporphyria - coproporphyrinogen oxidase
  • Variegate porphyria - protoporphyrinogen oxidase
25
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
26
Q

What are the main clinical features of hereditary coproporphyria?

A
  • 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)
27
Q

What are the main clinical features of variegate porphyria?

A
  • Autosomal dominant
  • Acute attacks with skin lesions
28
Q

How is the porphyrin level in the urine and faeces different in hereditary coproporphyria and variegate porphyria compared to acute intermittent porphyria?

A
  • AIP - normal
  • HCP and VP - high

NOTE: DNA analysis offers a definitive diagnosis

29
Q

What is a common feature of non-acute porphyria?

A

Only present with skin lesions with NO neurovisceral manifestations

30
Q

List the enzymes associated with non-acute porphyria.

A
  • Uroporphyrinogen III synthase - congenital erythropoietic porphyria
  • Uroporphyrinogen decarboxylase - porphyria cutanea tarda
  • Ferrochetolase - erythropoietic protoporphyria
31
Q

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

A
  • Skin blisters, fragility, pigmentations and erosions
  • Occuring hours to days after sun exposure
32
Q

What are the key features of erythropoietic protoporphyria?

A

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

33
Q

What is a key investigation for erythropoietic protoporphyria?

A

RBC protoporphyrin

NOTE: only RBCs are affected

34
Q

What are the key features of porphyria cutanea tarda?

A
  • Can be inherited or acquired
  • Leads to formation of vesicles on sun-exposed areas of skin crusting, superficial scarring and pigmentation
35
Q

Outline the biochemistry features of porphyria cutanea tarda.

A
  • Urine/plasma uroporphyrins and coproporphyrins are raised
  • Ferritin is often increased
36
Q

Which drug can trigger porphyria cutanea tarda?

A

Hexachlorobenzene

37
Q

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

A

Myelodysplastic syndromes

38
Q

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

A

Urine

YEAR 5: Chemical Pathology JK (26 decks)

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