Porphyria

Question 1

What is a prophyria?

Answer 1

Deficiencies in enzymes of the haem biosynthetic pathway.

Deficiency of enzymes ranges from partial to complete.

Question 2

What do porphyrias cause?

Answer 2

•Overproduction of toxic haem precursors

–Acute neuro-visceral attacks and/or

–Acute or chronic cutaneous symptoms.

Question 3

What is Haem?

Answer 3

• Organic heterocyclic compounds
• Fe2+in centre
• 4 pyrrolic (tetrapyrrole) rings around the iron
• Carries oxygen
• Redox reactions
• Erythroid cells and liver cytochrome
• Made in all cells

Question 4

Draw this out: (x5)

Answer 4

:)

Question 5

Draw out the haem biosynthesis pathway x3

Answer 5

Question 6

What may enzyme deficiencies do?

Answer 6

Build-up ALA, PBG or one of the -porphyrinogens

Question 7

What can porphyrias be classed as?

Answer 7

Erythroid or hepatic

Acute or non acute

Neurovisceral or skin lesions

Question 8

Why do acute/ neurovisceral S/S happen?

Answer 8

–5-aminolaevulinic acid is neurotoxic

Question 9

Why do skin lesions happen?

Answer 9

Porphyrinogens

\/ oxidised

Porphyrins

\/ light

Activated porphyrins & O2

Question 10

What is Porphyrinogens vs. porphyrins?

Answer 10

•Porphyrinogens are raised in porphyria

–Colourless compounds

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

•Porphyrins are highly coloured

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

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

Question 11

What are the types of porphyrias?

Answer 11

Question 12

What is ALA synthase deficiency?

Answer 12

• Not a porphyria
• X-linked sideroblastic anaemia

Question 13

What is PBG synthase deficiency?

Answer 13

• ‘ALA Dehydratase or Plumboporphyria’
• Extremely rare form of porphyria
• Build-up of ALA, but not PBG
• Diagnostic implications

Question 14

What are the symptoms of HMB synthase deficiency?

Answer 14

Acute Intermittent Porphyria: Autosomal dominant

Neurovisceral attacks!

GI: Abdo pain, vomiting, constipation

Cardiovascular: Tachycardia, Hypertension, arrhythmias, cardiac arrest

Neurological: Seizures (hyponatraemia), sensory loss, weakness, psych symptoms

NO SKIN INVOLVEMENT BECAUSE NO PORPHYRINOGENS MADE!

Question 15

What may cause symptomatic ‘attacks’ of acute intermittent porphyria?

Answer 15

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

Precipitating factors for attacks:

ALA synthase inducers: Barbiturates, steroids, ethanol, anticonvulsants

Stress: Infection, surgery

Reduced caloric intake

Endocrine factors: More common in women and premenstrual

Question 16

How do you diagnose porphyria?

Answer 16

• Increased urinary PBG (and ALA)
• PBG gets oxidised to porphobilin
• Decreased HMBS activity in erythrocytes

Question 17

How do you treat porphyria?

Answer 17

Conservative: Avoid attacks, Adequate nutritional intake, Avoid precipitant drugs, Prompt treatment infection/illness

Medical: iv carbohydrate, iv haem arginate

Question 18

What are the •Acute porphyrias with skin lesions?

Answer 18

Hereditary coproporphyria

Variegate porphyria

Question 19

What does Coproporphyrinogen oxidase cause?

Answer 19

•Hereditary Coproporphyria (HCP)

–Autodomal dominant

–Acute neurovisceral attack

–Skin lesions

• Blistering
• Skin fragility

Question 20

What is Variegate Porphyria (VP)?

Answer 20

•Variegate Porphyria (VP)

–Autosomal dominant

–Acute attacks

–Skin lesions

Question 21

How can we differentiate the acute porhyrias?

Answer 21

• 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 22

What are Non-Acute porphyrias?

Answer 22

• Only present with skin lesions
• No neuro-visceral manifestations

Question 23

What are the types of non acute porphyrias?

Answer 23

• Congenital Erythopoietic porphyria
• Porphyria Cutanea Tarda
• Erythropoietic protoporphyria
• Skin affected only e.g. blisters, fagility, pigmentation, erosions etc. delay following sun exposure
• EPP: photosensitivity, burning, itching oedema following sun exposure

Question 24

What is PCT?

Answer 24

• 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 25

What is EPP?

Answer 25

Photosensitivity only, no blisters Only erythroid cells affected, therefore need to measure RBC protoporphyrin

Question 26

What are acquired porphyrias?

Answer 26

•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

Question 27

What is the diagnostic approach to porphyrias?

Answer 27

Question 28

Q1: During acute porphyria, the most useful sample to send is…? ## Footnote 1. Blood 2. CSF 3. Urine 4. Muscle biopsy 5. Stool 6. Skin biopsy

Answer 28

Urine

Question 29

Q2 Cutaneous erythema without blisters or bullae, most likely indicates...?

Answer 29

EPP

Question 30

Q3: Hyponatraemia associated with AIP is due to....

Answer 30

SIADH

Question 31

Q4 Urine samples taken during an acute attack for diagnosis should be… ## Footnote 1. Taken in an acidified container 2. Protected from light 3. Alkalinised 4. Interpreted with a paired serum sample

Answer 31

Protected from light