Chem Path: Porphyrias

Question 1

What is porphyrias?

Answer 1

Deficiencies in enzymes of the haem synthesis pathway, leading to an overproduction of haem intermediate toxic products

Question 2

What are the 2 ways porphyrias can present?

Answer 2

Acute neuro-visceral attacks

Cutaneous symptoms

Question 3

What is haem?

Answer 3

Fe core with 4 pyrrolic rings around it with double bonds

Carries oxygen

Good for redox reactions

Question 4

What is a key difference between haem and its precursors

Answer 4

Precursors do not have double bonds between the rings

Question 5

Which cells does porphyrias affect the most?

Answer 5

Erythroid cells and liver cytochromes

Question 6

Why is cytochrome crucial?

Answer 6

It is needed for the electron transport chain in the mitochondria

Question 7

What starts the haem synthesis pathway in the mitochondria?

Answer 7

Succinyl CoA + Glycine = 5 ALA by ALA synthase

Question 8

What is step 2 in the haem synthesis pathway?

Answer 8

5 ALA leaves the mitochondria and is converted to PBG via PBG synthase

Question 9

What is step 3 in the haem synthesis pathway?

Answer 9

PBG is converted to HMB by HMB synthase

Question 10

What is step 4 in the haem synthesis pathway?

Answer 10

HMB is converted to Uroporphyrinogen 3 if Uroporphyrinogen synthase is present. Otherwise it turns into Uroporphyrinogen 1

Question 11

What is step 5 in the haem synthesis pathway?

Answer 11

Uroporhyrinogen 3 is converted to coproporphyrinogen 3

Question 12

What is step 6 in the haem synthesis pathway?

Answer 12

coproporphyrinogen 3 enters the mitochondria and is converted to protoporphyrinogen 9

Question 13

What is step 7 in the haem synthesis pathway?

Answer 13

protoporphyrinogen 9 is converted to protoporhyrin 9

Question 14

What is step 8 in the haem synthesis pathway?

Answer 14

protoporhyrin 9 is converted to Haem by ferrochetalase

If no Fe present at this stage, you get metal free protoporhyrin or zinc protoporhyrin

Question 15

What are the 2 principle sites of enzyme deficiency?

Answer 15

Erythroid

Hepatic

Question 16

What are the 3 types of presentations

Answer 16

Neurovisceral
Blistering cutaneous
Non blistering cutaneous

Question 17

What gives neurovisceral/acute symptoms?

Answer 17

Accumulation of 5 ALA

Question 18

What gives skin lesions?

Answer 18

Accumulation of porphyrinogens, which is oxodised to active porphyrins in UV light

Question 19

What are porphyrinogens

Answer 19

Precursors to porphyrins

Question 20

What colour are porphyrinogens

Answer 20

Colourless

Question 21

What happens in porphyria

Answer 21

porphyrinogens are raised and are usually colourless / yellow. They rapidly oxidise to porphyrins and turn red or purple

Question 22

How are porphyrins excreted?

Answer 22

The ones near the start of the pathway are water soluble and are excreted via urine while the ones towards the end of the pathway are less soluble and excreted via faeces

Question 23

What is the most common type of porphyria?

Answer 23

porphyria cutenea tarda

Question 24

What most common porphyria in kids?

Answer 24

Erythropoietic protoporphyria - blistering porphyria

Question 25

What can cause acute porphyria

Answer 25

PBG synthase deficiency

Question 26

What happens in PBG synthase deficiency

Answer 26

Accumulation of ALA

Question 27

What does Accumulation of ALA cause

Answer 27

Neurovisceral symptoms - coma, bulbar palsy, motor neuropathy ABDO PAIN Psychiatric symptoms

Question 28

What causes acute intermittent porphyria (AIP)?

Answer 28

HMB synthase deficiency

Question 29

What happens in HMB synthase deficiency

Answer 29

Accumulation of ALA and PBG

Question 30

How is HMB synthase deficiency inherited

Answer 30

Autosomal dominant

Question 31

What are the symptoms of HMB synthase deficiency

Answer 31

Nuerovisceral symptoms due to accumulation of ALA Abdo pain, vomiting, tachycardia, hypertension, hyponatraemia, seizures, psyco symptoms, sensory loss, muscle weakness, arrythmias, cardiac arrest, NO CUTANEOUS SYMPTOMS

Question 32

Why are there no cutaneous symptoms in HMB synthase deficiency

Answer 32

As there is no production of porphyrinogen

Question 33

What can precipitate HMB synthase deficiency

Answer 33

ALA synthase inducers (barbiturates, steroids, ethanol, anti convulsants) Reduced caloric intake

Question 34

How is HMB synthase deficiency diagnosed

Answer 34

Increased urinary PBG and ALA - ensure urine not exposed to light as it will cause PBG to be oxidised to prophobilin Decreased HMB synthase activity in erythrocytes

Question 35

How to treat HMB synthase deficiency ?

Answer 35

Avoid precipitating factors IV carbohydrate to inhibit ALA synthase IV haem arginate

Question 36

What are the general symptoms of acute vs chronic porphyrias

Answer 36

Acute - Neurovisceral | Chronic - Cutaneous (Skin lesion)

Question 37

What are the 2 acute porphyrias that present with cutaneous symptoms?

Answer 37

``` Hereditary coproporphyria (HCP) - Due to coproporphyrinogen oxidase deficiency Variegate porphyria (VP) - Due to protoporphyrinogen oxidase deficiency ```

Question 38

Can you get neuro symptoms with HCP and VP and if so why?

Answer 38

Yes As the build up in pre products can inhibit HMG synthase, causing accumulation of PBG and ALA

Question 39

How to diagnose HCP ad VP?

Answer 39

Detect porhyrinogens in stool as these molecules are not very soluble

Question 40

How do HCP and VP present?

Answer 40

Nuero symptoms - acute Blistering On back of hands and neck Appear after sun exposure

Question 41

How are HCP and VP inherited?

Answer 41

Autosomal dominant

Question 42

How do you differentiate between the 3 acute porphyrias (HCP, VP and AIP)?

Answer 42

AIP - No cutaneous symptoms All 3 would have raised urine PBG and porphyrins AIP will NOT have raised faecal porphyrins DNA analysis

Question 43

How to non acute porphyrias present?

Answer 43

Only cutaneous symptoms

Question 44

What are the 3 enzyme deficiencies in non acute porphyrias and what are they commonly associated with?

Answer 44

Uroporphyrinogen III synthase - Congenital erythropoetic porphyria Uroporphyrinogen decarboxylase - porphyria cutanea tarda (most common porphyria) Ferrochetalase - Eryhtropoetic protoporphyria (most common in kids) The first 2 are blistering

Question 45

How does Eryhtropoetic protoporphyria present

Answer 45

``` NOT blistering Photosensitivity Burning Itching Oedema All following sun exposure ```

Question 46

How is Eryhtropoetic protoporphyria detected and treated

Answer 46

Measure RBC protoporphyrin concentration Cannot measure in urine Sun avoidance is the only treatment

Question 47

What types of PCT are there?

Answer 47

3 2 of them are familial 1 is acquired (mostly via liver disease)

Question 48

How does PCT present?

Answer 48

Vesicles on sun exposed areas Crusting Superficial scarring Pigmentation

Question 49

What can PCT like syndromes be triggered by?

Answer 49

Hexachlorobenzene

Question 50

What are Eryhtropoetic protoporphyria and congenital Eryhtropoetic porphyria usually associated with

Answer 50

Myelodysplastic syndromes

Question 51

Summarise the diagnostic approach to porphrias

Answer 51

If there are acute features, do urine PBG If urine PBG raised check urine/faecal porphyrins, enzyme activity and DNA If skin features present send off urine/faecal/plasma porphyrins If there is photosensitivity check RBC protoporhyrins

Question 52

Low Na associated with AIP is most likely due to what?

Answer 52

SIADH