The Porphyrias

Question 1

What is porphyria?

Answer 1

Deficiencies in enzymes of the haem biosynthetic pathway.

Overproduction of toxic haem precursors:

• Acute neuro-visceral attacks.
• Acute or chronic cutaneous symptoms.

Deficiency of enzymes ranges from partial to complete.

Question 2

What is haem?

Answer 2

Organic heterocyclic compounds with Fe2+in centre.

4 pyrrolic (tetrapyrrole) rings around the iron.

Carries oxygen

Made in all cells

Question 3

What are the classifications of porphyrias?

Answer 3

Principle site of enzyme deficiency:

• Erythroid or hepatic

Clinical presentation:

• Acute or Non-acute
• Neurovisceral or skin lesions

Question 4

Why can porphyria cause neurovisceral or acute signs?

Answer 4

5-aminolaevulinic (5-ALA) acid is neurotoxic

Question 5

Why can porphyria cause skin lesions?

Answer 5

Porphyrinogens are oxidised to porphyrins. When exposed to light, the porphyrins are activated and produce O2.

Question 6

What are porphyrinogens?

Answer 6

Raised in porphyria

Colourless compounds

Unstable and readily oxidised to the corresponding porphyrin by the time urine/faeces reaches lab.

Question 7

What are porphyrins?

Answer 7

Highly coloured.

Porphyrins near start of the pathway are water soluble – urine (uro-).

Porphyrins near end less soluble – faeces (copro-).

Question 8

What are the acute porphyrias and which enzymes are deficient?

Answer 8

ALA Dehydratase/Plumboporphyria - PBG Synthase

Acute Intermittent Porphyria - HMB Synthase

Hereditary Coproporphyria - Coproporphyrinogen oxidase

Variegate Porphyria - Protoporphyrinogen oxidase

Question 9

What are the non-acute porphyrias and which enzymes are deficient?

Answer 9

Congenital eryrthopoietic porphyria - Uroporphyrinogen III synthase

Porphyria cutanea tarda - Uroporphyrinogen decarboxylase

Erythorpoietic protoporphyria - Ferrochetolase

Question 10

What does an ALA synthase deficiency result in?

Answer 10

Not a porphyria

X-linked sideroblastic anaemia

Question 11

What does a PBG synthase deficiency result in?

Answer 11

‘ALA Dehydratase or Plumboporphyria’.

Extremely rare form of porphyria.

Build-up of ALA, but not PBG.

Diagnostic implications.

Question 12

What is HMB synthase deficiency?

Answer 12

Acute Intermittent Porphyria –Autosomal dominant

Question 13

What are signs and symptoms of HMB synthase deficiency?

Answer 13

Neurovisceral attacks:

• Abdo pain and vomiting
• Tachycardia and hypertension
• Constipation, urinary incontinence
• Hyponatraemia +/- seizures
• Psychological symptoms
• Sensory loss/muscle weakness
• Arrythmias/cardiac arrest

No skin symptoms: No production of porphyrinogens

Question 14

What is Acute Intermittent Porphyria?

Answer 14

Enzyme activity usually 50% of normal, 90% have no symptoms at all.

Precipitating factors:

• ALA synthase inducers: Barbiturates, steroids, ethanol, anticonvulsants.
• Stress: Infection, surgery
• Reduced caloric intake
• Endocrine factors

More common in women and premenstrual.

Question 15

How is acute intermittent porphyria diagnosed?

Answer 15

Increased urinary PBG (and ALA)

PBG gets oxidised to porphobilin

Decreased HMBS activity in erythrocytes

Question 16

What is the treatment of acute intermittent porphyria?

Answer 16

Avoid attacks:

• Adequate nutritional intake
• Precipitant drugs
• Prompt treatment infection/illness

IV Carbohydrate

IV Haem arginate

Question 17

Which acute porphyrias cause skin lesions?

Answer 17

Hereditary coproporphyria

Variegate porphyria

Question 18

What is Hereditary Coproporphyria (HCP)?

Answer 18

Autodomal dominant

Acute neurovisceral attack

• Blistering skin lesions
• Skin fragility

Question 19

What is Variegate Porphyria (VP)?

Answer 19

Autosomal dominant

Acute attacks

Skin lesions

Question 20

How are the acute porphyrias differentiated?

Answer 20

AIP – No skin lesions

HCP & VP – Skin lesions

Urine PBG: Raised in all three

Urine and faeces for porphyrins: Raised HCP or VP, but not AIP

Enzyme activity variable

DNA definitive but large number of mutations

Question 21

What are features of non-acute porphyrias?

Answer 21

Only present with skin lesions

No neuro-visceral manifestations

Question 22

What are the signs of non-acute porphyrias?

Answer 22

Skin affected only e.g. blisters, fagility, pigmentation, erosions etc. delay following sun exposure.

EPP: Photosensitivity, burning, itching oedema following sun exposure.

Question 23

What is Porphyria Cutanea Tarda (PCT)?

Answer 23

Inherited or acquired.

Uroporphyrinogen decarboxylase deficiency.

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

Biochemistry:

• Urinary (& plasma) uroporphyrins & coproporphyrins increased.
• Ferritin often increased

Avoid precipitants (alcohol, hepatic compromise).

Question 24

What is Erythropoietic protoporphyria (EPP)?

Answer 24

Photosensitivity only, no blisters

Only erythroid cells affected, therefore need to measure RBC protoporphyrin

Question 25

What is acquired porphyria?

Answer 25

PCT most cases sporadic without family history: Formation of specific inhibitor of uroporphyrinogen decarboxylase.

PCT-like syndrome hexachlorobenzene

EPP and CEP a/w myelodysplastic syndromes