ChemPath: Porphyrias

Question 1

What is porphyria?

Answer 1

• Disorders caused by deficiencies in enzymes of the haem synthesis pathway
• This leads to the accumulation of toxic haem precursors

Question 2

What are the two ways in which porphyria can manifest?

Answer 2

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

Question 3

List some key features of haem.

Answer 3

• Organic heterocyclic compound with Fe2+ in the centre
• 4 tetrapyrrole rings around the iron

tetrapyrrole ring - nitrogen with 4 carbons arounud it in ring

Question 4

Where is haem made?

What is its importance

Answer 4

made in every single cell –> by ALA synthase

haem then used to make cytochrome –> needed for electron transport in aerobic respiration

without it we would die

Question 5

what cells do porphyrias affect

Answer 5

haem synthesesis in eythroid cells and liver cytochrome

Question 6

Draw the haem synthesis pathway.

Answer 6

Grey box is mitochondria

Question 7

Which component of the haem biosynthesis pathway is neurotoxic?

Clinical Relevance of this?

Answer 7

5-ALA
Accumulation –> neuro-visceral symptoms

Question 8

What types of porphyrin may be produced in the absence of iron?

Answer 8

• Metal-free protoporphyrins
• Zinc protoporphyrin

Question 9

How can porphyrias be classified?

Answer 9

Principle site of enzyme deficiency:

• Erythroid
• Hepatic

Clinical presentation:

• Acute or non-acute
• Neurovisceral or skin lesions

Question 10

Outline the relationships between UV light and skin lesions.

Answer 10

Porphyrinogens are oxidised and then activated by UV light into activated porphyrins —> blistering/non blistering cutaenous presentations

NOTE: porphyrinogens do NOT oxidise in cells, it occurs in circulation

Question 11

What is a key difference between porphyrinogens and porphyrins?

Answer 11

Porphrinogens are pre-cursors to porphyrin

• Porphyrinogens - colourless, unstable and readily oxidised to porphyrin (no double bonds)
• Porphyrins - highly coloured (have double bonds)

Question 12

Which porphyrins appears in the urine and faeces?

Answer 12

• Urine - uroporphyrins are water soluble
• Faeces - coproporphyrins are less soluble and near the end of the pathway

NOTE: someone with porphyria will have colourless/yellow urine which turns red/dark red/purple as the porphyrinogens are oxidised and activated into porphyrins

NOTE: haem synthessis pathway –> early porphyrins are water soluble, later are less soluble

Question 13

List four types of acute porphyria and the enzymes involved.

Answer 13

• Plumboporphyria - PBG synthase
• Acute intermittent porphyria - HMB synthase / PBG deaminase
• Hereditary coproporphyria - coproporphyrinogen oxidase
• Variegate porphyria - protoporphyrinogen oxidase

Question 14

What are the most common porphyrias

Answer 14

1. Porphyria cutanea tarda
2. Acute intermittent porphyria –> these patients very sick in A&E
3. Erythropeoitic protoporphyria –> most common porphyria in children

Question 15

List three types of non-acute porphyria and the enzymes involved.

Answer 15

• Congenital erythropoietic porphyria - uroporphyrinogen III synthase
• Porphyria cutanea tarda - uroporphyginogen decarboxylase
• Erythropoietic protoporphyria - ferrochetolase

Question 16

What is the most common type of porphyria?

Answer 16

Porphyria cutanea tarda

Question 17

What is the most common type of porphyria in children?

Answer 17

Erythropoietic protoporphyria

Question 18

What does ALA synthase deficiency cause?

Answer 18

X-linked sideroblastic anaemia

Question 19

How can a mutation in ALA synthase lead to porphyria?

Answer 19

A gain-of-function mutation –> increased activity of ALA synthase

Increased throughput through the pathway –> ferrochetolase is overwhelmed –> build up of protoporphyrin IX

very rare, dont focus on it

Question 20

What are the main features of PBG synthase deficiency?

Answer 20

• Causes plumboporphyria
• Leads to accumulation of ALA

Acute neuro-visceral symptoms:
* Abdominal pain (most presenting important feature)
* Neurological symptoms (e.g. coma, bulbar palsy, motor neuropathy)

Extrememly rare

Question 21

Which deficiency causes acute intermittent porphyria?

Answer 21

HMB synthase (aka PBG deaminase)

Question 22

Outline the clinical features of acute intermittent porphyria.

Answer 22

• Rise in PBG and ALA
• Autosomal dominant
• Neurovisceral attacks (due to ALA accumulation)
  
  • Abdominal pain
  • Tachycardia and hypertension
  • Constipation, urinary incontinence
  • Hyponatraemia and seizures
  • Sensory loss/muscle weakness
  • Arrythmias/cardiac arrest

Important: there are NO skin symptoms (because no porphyrinogens are produced)

NOTE: 90% will be asymptomatic

Question 23

List some precipitating factors for acute intermittent porphyria.

Answer 23

• ALA synthase inhibitors (e.g. steroids, ethanol, anticonvulsants - CYP450 inducers
• Stress (infection, surgery)
• Reduced caloric intake
• Endocrine factors

Question 24

Describe how acute intermittent porphyria is diagnosed.

Answer 24

• increased urinary PBG (and ALA)
• PBG gets oxidised to porphobilin by light - goes from yellow to purple
• Decreased HMB synthase activity in erythrocytes

shield urine from light!!

Question 25

How is acute intermittent porphyria managed?

Answer 25

* Avoid attakcs (adequate nutrition, avoid precipitant drug, prompt treatment of other illnesses) * IV carbohydrate (inhibits ALA synthase) * **IV haem arginate** (switches off haem synthesis through negative feedback) NOTE: adequate carbs important, as low carb can trigger attack

Question 26

Name two acute porphyrias that have skin manifestations. State the enzymes affected. How would they be diagnosed

Answer 26

* Hereditary coproporphyria - coproporphyrinogen oxidase * Variegate porphyria - protoporphyrinogen oxidase Stool samples --> excess coproporphyrinogen II and protophorphoryinogen IX in stool (they're less water soluble)

Question 27

What is the negative consequence of accumulation of coproporphyrinogen III and protoporphyrinogen IX?

Answer 27

* They are potent inhibitors of HMB synthase * Results in the accumulation of PBG and ALA --> acute neuro-visceral attacks skin manifestations due to porphyrinogen buiild up as well

Question 28

What are the main clinical features of hereditary coproporphyria?

Answer 28

* Autosomal dominant * Acute neurovisceral attacks * Skin lesions (blistering, skin fragility, classically on the backs of the hands that tend to appear hours/days after sun exposure) | blisters on back of hand due to sun exposure

Question 29

What are the main clinical features of variegate porphyria?

Answer 29

* Autosomal dominant * Acute attacks with skin lesions | less severe than hereditary coproporphyria

Question 30

diagnosis of acute porphyrias

Answer 30

send off urine in acute attack (protected from light) --> urine PBG raised in all 3 (not in Plumboporphyria (PBG synthase deficiency) as pathway doesn't get that far) * AIP - normal - no porphyrins in urine/feces (pathway doesn't get that way) * HCP and VP - **high porphyrin in urine/feces** Clinically: AIP --> no skin lesions, but HCP and VP do have skin lesions NOTE: DNA analysis offers a definitive diagnosis

Question 31

what are the acute porphyrias

Answer 31

Acute intermittent porphyria - neurovisceral attacks Hereditary coproporphyria - neurovisceral attacks + blistering skin lesions Variegate porphyria - neurovisceral attacks + blistering skin lesions Plumboporphyria - PBG synthase

Question 32

What is a common feature of non-acute porphyria?

Answer 32

Only present with skin lesions with NO neurovisceral manifestations

Question 33

What are the non-acute porphyrias

Answer 33

* Uroporphyrinogen III synthase - congenital erythropoietic porphyria * Uroporphyrinogen decarboxylase - porphyria cutanea tarda * Ferrochetolase - erythropoietic protoporphyria

Question 34

What is the main flinical feature of non-acute porphyria?

Answer 34

* Only skin affected!! * Blisters in Porphyria cutanea tarda, Congenital erythropoietic porphyria * No blisters in erythropoietic protoporphyria * Skin fragility, pigmentations and erosions * Occuring hours to days after sun exposure

Question 35

What are the key features of erythropoietic protoporphyria? How is it managed

Answer 35

NON-blistering and presents with photosensitivity, burning, itching, oedema minutes following sun exposure Sun avoidance

Question 36

What is a key investigation for erythropoietic protoporphyria?

Answer 36

RBC protoporphyrin NOTE: only RBCs are affected i.e. porphyrins won't be high in urine/feces

Question 37

What are the key features of porphyria cutanea tarda?

Answer 37

* Can be inherited or acquired (liver disease, HIV, drugs) * Leads to formation of **blisters** on sun-exposed areas of skin crusting, superficial scarring and pigmentation

Question 38

Outline the biochemistry features of porphyria cutanea tarda.

Answer 38

* Urine/plasma **uroporphyrins** and coproporphyrins are raised * Ferritin is often increased

Question 39

Which drug can trigger porphyria cutanea tarda?

Answer 39

Hexachlorobenzene (fungicide for seeds)

Question 40

What haematological condition are erythropoietic protoporphyria and congenital erythropoietic porphyria associated with?

Answer 40

Myelodysplastic syndromes

Question 41

During acute porphyria, what is the most uesful sample to send?

Answer 41

Urine