Chem path 8s - Porphyrias

Question 1

What is the first step in the haem biosynthesis pathway?

Answer 1

Succinyl CoA + glycine —> 5-ALA (aminolaevulinic acid), catalysed by ALA synthase (rate-limiting step)

Question 2

Which substrate is the main cause of neurotoxicity in porphyrias?

Answer 2

ALA is neurotoxic

Question 3

Why are skin lesions seen in porphyrias?

Answer 3

Porphyrin precursors accumulate in skin which are oxidised and converted by UV light in to active porphyrins which are toxic

Question 4

What is seen in the urine of someone with porphyria?

Answer 4

The urine will start off colourless/yellow and then turns red/yellow as the porphyrinogens are oxidised in to porphyrins

Question 5

What is the most common type of porphyria?

Answer 5

Porphyria cutanea tarda

Question 6

What is the most common porphyria in childrne?

Answer 6

Erythropoietic protoporphyria

Question 7

What does ALA synthase deficiency cause?

Answer 7

Sideroblastic anaemia (not a porphyria)

Question 8

Deficiency of which enzyme causes acute intermittent porphyria?

Answer 8

HMBS (porphobilinogen deaminase)

Question 9

What does AIP lead to a rise of?

Answer 9

ALA and PBG

Question 10

Inheritance pattern of AIP

Answer 10

Autosomal dominant

Question 11

Presentation of AIP

Answer 11

90% are asymptomatic, certain triggers can result in an AIP attack.

4 P’s

• Painful abdomen
• Polyneuropathy
• Psych disturbances
• Port-wine urine

Neurovisceral attacks

• Hyponatraemia (SIADH) +/- seizures
• Tachycardia and hypertension

NO SKIN SYMPTOMS as no productino of porphryinogens

Question 12

What are some precipitating factors of an AIP attack?

Answer 12

Most commonly seen in pre-menstrual women
ALA synthase inducers e.g. CYP450 inducing drugs, barbiturates, steroids, ethanol, anti-convulsants
Starvation
Stress

Question 13

How is AIP diagnosed?

Answer 13

Urinary PBG and ALA levels

Diagnostic: erythrocyte hMBS activity

Question 14

Treatment of AIP?

Answer 14

Avoid precipitating factors
High carb diet
IV Haem-arginate (turns off haem synthesis through -ve feedback)

Question 15

Name two examples of acute porphyrias with skin lesions

Answer 15

Hereditary coproporphyria, variegate porphyria

Question 16

What is hereditary coproporphyria due to?

Answer 16

Deficiency in coproporphyrinogen oxidase

Question 17

What is variegate porphyria due to?

Answer 17

Deficiency in protoporphyrinogen oxidase

Question 18

In acute porphyrias with skin lesions, why are the porphyrinogens detectable in the stool?

Answer 18

stool because the defect is towards the end of the pathway and, hence, the molecules are not as soluble (this is NOT seen in AIP)

Question 19

Why do you get both neurovisceral and cutaneous presentation in acute porphyrias with skin lesions?

Answer 19

Because coproporphyrinogen III and protoporphyrinogen IX are potent inhibitors of HMBS which leads to build up of ALA and pBG

Question 20

Where is the enzyme deficiency in erythropoietic protoporphyria (non-blistering, most common in paeds)

Answer 20

Ferrochetalase

Question 21

Where is the enzyme deficiency in porphyria cutanea tarda?

Answer 21

Uroporphyrinogen III decarboxylase

Question 22

What are the symptoms of PCT and its biochemistry?

Answer 22

Skin lesions, blistering

Raised urinary uroporphyrinogens
Raised ferritin

Question 23

what is the management of pCT?

Answer 23

Avoid precipitants (alcohol, hepatic compromise), phlebotomy, hydroxychloroquine

Question 24

What is the cardinal feature of erythropoietic protoporphyria?

Answer 24

Photosensitivity only with NO blisters! (as only RBCs are affected need to measure RBC protoporphyrin)