Chemical Pathology - Porphyrias

Question 1

What is haem?

Answer 1

tetrapyrole rings surrounding a central iron

Question 2

Roughly summarise the pathway of haem production

Answer 2

ALA is generated in mitochondria
ALA leaves mitochondria to be converted to PBG (aminolevulinic acid and porphobilinogen) under PBG synthase
PBG –> HMB (hydroxymethylbilane) under HMB synthase
HMB –> EITHER uroporphyrinogen 1 or 3 (uroporphyriogen 3 synthase present makes 3, absent makes 1)
Uroporphyrinogen 3 –> coproporphyrinogen 3 by uroprophyrinogrn decarboxylase
coproporphyrinogen
copro 3 does to proto IX - this is step that transitions into mitochondria again

penultimate step = inside mitochondrion make protoporphyrin IX by protoporphyrinogen oxidase

protoporphyrin under ferrochetalase this makes Haem in mitochondria

Question 3

by what 3 factors are porphyrias classified?

Answer 3

Site of enzyme deficiency - hepatic or erythroid
Acute/ non-acute
Neurovisceral or cutaneous

Question 4

What is the cause of cutaneous symptoms in some porphyrias?

Answer 4

porphyrin precursors build up under the skin and react with UV light which turns them into active porphyrins which are toxic

Question 5

Which toxic product leads to neurovisceral symptoms in porphyria?

Answer 5

5-ALA

Question 6

What is the most common porphyria? What enzyme is deficient?

Answer 6

Porphyria cutanea tarda (80%)
Uroporphyrinogen decarboxylase deficiency

Question 7

What is the most common porphyria in children? What enzyme is deficient?

Answer 7

Erythropoietic protoporphyria
Ferrochetalase deficiency

Question 8

What are the symptoms of ALA synthase deficiency?

Answer 8

Weirdly, doesn’t cause porphyria!
Instead, causes an X-linked sideroblastic anaemia

Question 9

What are the 2 types of acute neurovisceral porphyria, which enzyme deficiency causes each, and how can they be clinically differentiated?

Answer 9

1. Acute intermittent porphyria (most common) = HMB synthase deficiency - causes ATTACKS
2. plumboporphyria = PBG synthase deficiency - more one acute episode than numerous attacks

Question 10

What are the symptoms of the acute neurovisceral porphyrias?

Answer 10

Motor neuropathy
Psychiatric symptoms
Severe abdominal pain

Question 11

What is the most likely cause of an acute intermittent porphyria ‘attack’?

Answer 11

drugs such as barbiturates, steroids, ethanol & anticonvulsants.

Question 12

How can AIP be diagnosed (3)?

Answer 12

o Increased urinary PBG (and ALA)
o PBG oxidised = porphobilin, urine goes dark in light
o Decreased HMBS activity in erythrocytes

Question 13

How should acute intermittent porphyria be managed (2)?

Answer 13

avoid attacks (adequate nutrition, precipitant drugs, prompt treatment)
high carb diet - inhibits ALA synthase
IV haem arginate - micmicks haem so turns off synthesis

Question 14

recall 2 forms of acute porphyria that have skin symptoms. what are their inheritance?

Answer 14

Hereditary coproporphyria (due to a deficiency of coproporphyrinogen oxidase) 
Variegate porphyria (due to a deficiency of protoporphyrinogen oxidase) 

both autosomal dominant

Question 15

How do the cutaneous effects of porphyrias usually present and why?

Answer 15

blistering on back of hands (most exposed to UV)
also pigmentation, skin fragility

Question 16

Recall the 3 forms of non-acute porphyria, and which of these conditions causes blistering, and what the inheritance

Answer 16

Congenital eryhtropoietic porphyria (blistering) & recessive
Porphyria cutanea tarda (blistering) dominant
Erythropoietic protoporphyria dominant

Question 17

How can erythropoietic protoporphyria be diagnosed?

Answer 17

measure RBC protoporphyrin

Question 18

What is the most common cause of porphyria cutanea tarda?

Answer 18

Liver disease

Question 19

where is ALA generated?

Answer 19

mitochondria

Question 20

what is the immediate precursor to haem?

Answer 20

protoporphyrin IX is essentially the haem molecule without the iron core
• If iron present in abundance, you get iron in the protoporphyrin IX and make haem (via ferrochetalase)

Question 21

are porphyrinogens raised or lowered in porphyria?

Answer 21

raised

Question 22

are porphyrinogens coloured or colourless?

Answer 22

colourless until oxidised into porphyrins which are highly coloured

Question 23

what’s the inheritance of AIP

Answer 23

Autosomal Dominant
90% asymptotic

Question 24

does Acute Intermittent Porphyria cause skin lesions?

Answer 24

no

Question 25

what sodium unbalance is seen in acute intermittent porphyria and what’s the underlying diagnosis?

Answer 25

Hyponatraemia (SIADH) w/w out seizures

Question 26

main symptoms of EPP?

Answer 26

photosensitivity only - burning & iitching
no blisters

Question 27

what should you measure in EPP?

Answer 27

measure RBC protoporphyrin

Question 28

give 2 treatments of PCT?

Answer 28

regularly scheduled phlebotomies to reduce iron and porphyrin levels in the liver
hydroxychloroquine

Question 29

urine samples during an acute attack for diagnosis should be…

Answer 29

protected from light

Question 30

during an acute porphyria what test is best?

Answer 30

urine PBG (porphobilinogen) 
if urine PBG is normal this excludes attack 
if raised, check enzyme activity, stool,

Question 31

outline 5 difference between AIP & PCT?

Answer 31

AIP = HMBS deficiency, PCT = uroporphyrinogen decarboxylase
AIP = AD, PCT = mainly acquired
AIP = acute presentation, PCT = chronic
AIP = neurovisceral attacks, PCT = blistering in sun
AIP = F > M, PCT = M > F
AIP treatment = high CHO diet and haem arginate, PCT treatment =phlebotomy & hydroxychloroquine

Question 32

define porphyria

Answer 32

deficiency (partial/complete) of enzymes in haem biosynthesis = overproduction of toxic haem precursors

Question 33

what enzyme is involved in the rate limiting step of haem biosynthesis?

Answer 33

ALA synthase
Aminolevulinic acid synthase is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of 5-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes.

Question 34

summarise the porphyries into acute, non-acute, skin lesions & no skin lesions?

Answer 34

Acute:
o Acute, no skin lesions = ALAD, AIP
o Acute, skin lesions = Hereditary coproporphyria, Variegate porphyria

Chronic:
o Chronic, skin lesions = Porphyria cutanea tarda, Congenital erythropoietic porphyria
o Chronic, skin photosensitivity = Erythropoietic protoporphyria