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a path 3 > CHEMPATH: Porphyrias > Flashcards

CHEMPATH: Porphyrias Flashcards

1
Q

Define porphyria.

A

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

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2
Q

What are the 3 presentations of porphyrias?

A
  1. Acute neuro-visceral attacks and/or;
  2. Acute or chronic cutaneous symptoms
    1. Blistering
    2. Non-blistering
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3
Q

Describe the structure of haem. What is its function?

A
  • Organic heterocyclic compound
  • Fe2+in centre
  • 4 pyrrolic (tetrapyrrole; x4 pyrole which is nitrogen with 4 carbons around it) rings around the iron
  • Have double bonds which are not presnet in the precursor porphyrinogens

Functions:

  • Carries oxygen
  • Invovles redox reactions
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4
Q

Porphyrias affect haem synthesis in which parts of the body?

A

Liver cytochrome

Erythroid cells (BM)

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5
Q

Haem formation begins with which enzyme? Where does this reaction occur?

A

ALA synthase in the mitochondria

succinyl coA + glycine –ALA synthase–> 5-ALA (aminolaevulinic acid)

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6
Q

List the 8 enzymes invovled in haem synthesis pathways.

A
  1. ALA synthase
  2. PBG synthase AKA ALA dehydratase
  3. HMB synthase
  4. Uroporphyrinogen III synthase
  5. Uroporiphyrinogen decarboxylase
  6. Coproporphyrinogen oxidase
  7. Protoporphyrinogen oxidase
  8. Ferrochetalase

ALA - aminolaevulinic acid

PBG - porphobilinogen

HMB - hydroxymethylbilane

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7
Q

Summarise the haem biosynthesis pathway.

A
  • ALA is generated within the mitochondrion
  • 2 ALAs leave the mitochondrion to be converted to PBG by PBG synthase which removes water (aka ALA dehydratase)
  • PBG converted to HMB, catalysed by HMB synthase (AKA PDG deaminase)
  • HMB –> either uroporphyrinogen III or uroporphyrinogen I
    • Uroporphyrinogen III synthase present –>Uroporphyrinogen III produced
    • Uroporphyrinogen III synthase ABSENT –> Uroporphyrinogen I produced
  • Uroporphyrinogen III –> coproporphyrinogen III (via uroporphyrinogen decarboxylase)
  • Coproporphyrinogen III goes into mitochondria and converted –> protoporphyrinogen IX (coproporphyrinogen oxidase)
  • Protoporphyrinogen IX –> protoporphyrin IX (via protoporphyrinogen oxidase) in mitochondria
  • If iron present in abundance, you get iron incorporated into the protoporphyrin IX and you gene haem (via ferrochetalase)
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8
Q

In which step of the haem biosynthesis pathway does the reaction return to being in mitochondria?

A

Coproporphyrinogen III –coproporphyrinogen oxidase–> protoporphyrinogen IX

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9
Q

What is produced in the absence of uroporphyrinogen III synthase?

A

uroporphyrinogen I

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10
Q

If there is a deficiency of iron for the haem biosynthesis, what happens to protoporphyrin IX?

A

If there is a deficiency of iron, you end up with metal-free protoporphyrins or zinc protoporphyrin

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11
Q

Briefly what happens when enzymes in this pathway are absent?

A

Intermediaries build up and may start to react with other enzymes to give new products

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12
Q

What 2 ways are used for classifying porphyrias?

A

By principal site of enzyme deficiency:

  • Erythroid
  • Hepatic

Clinical presentation:

  • Acute or non-acute
  • Neurovisceral or skin lesions
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13
Q

What is the cause of neurovisceral symptoms in porphyrias?

A

5-ALA build up which is neurotoxic

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14
Q

What is the cause of skin lesions in porphyrias?

A
  • Occur due to accumulation of porphyrin precursors in the skin
  • These are oxidised and converted by UV light into active porphyrins which are toxic

Porphyrinogens do NOT oxidise in cells because cells have a low oxygen environment BUT as soon as they enter the circulation, they are less stable and have more exposure to oxygen

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15
Q

What is the difference between the appearance of porphyrinogens and porphyrins?

A

Porphyrinogens are RAISED in porphyria and COLOURLESS (no double bonds)

  • Water-soluble (near start of pathway) and excreted in the urine (uroporphyrins)
  • Unstable and readily oxidised to corresponding porphyrin by the time the urine/faeces sample reaches the lab –> colourless/yellow to red or deep purple colour change

Porphyrins are HIGHLY COLOURED

  • Porphyrins near the end of the pathway are less soluble and are excreted in the faeces (coproporphyrins)
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16
Q

List 4 types of acute porphyrias and the enzyme affected. Which is the most common acute porphyria?

A

ALA dehydratase/plumboporphyria - PBG synthase

Acute intermittent porphyria - HMB synthase (MOST COMMON ACUTE PORPHYRIA)

Hereditary coproporphyria - coproporphyrinogen oxidase

Variegate porphyria - protoporphyrinogen oxidase

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17
Q

List 3 types of non-acute porphyrias and the enzymes affected in each.

A

Congenital erythropoietic porphyria - uroporphyrinogen III synthase

Porphyria cutanea tarda - uroporphyrinogen decarboxylase (MOST COMMON OVERALL)

Erythropoietic protoporphyria - ferrochetolase

18
Q

Which porphyrias are acute with skin lesions vs acute without skin lesions?

A

Acute, no skin lesions = Plumboporphyria, AIP

Acute, skin lesions = Hereditary coproporphyria, Variegate porphyria

19
Q

Which porphyrias are chronic with skin lesions vs with photosensitivity alone?

A
  • Chronic, skin lesions = porphyria cutanea tarda, congenital erythropoietic porphyria
  • Chronic, skin photosensitivity= erythropoietic protoporphyria
20
Q

What is the condition resulting from ALA-synthase deficiency?

A

NOT a porphyria but rather an X-linked sideroblastic anaemia

BUT ALA synthase gain-of-function mutation –> increased throughput of pathway –> build-up of protoporphyrin IX –> overwhelms ability of ferrochetalase to convert it to haem, resulting in an accumulation of protoporphyrin IX (similar to erythropoietic protoporphyria)

21
Q

What is the pathophysiology of PBG synthase deficiency? What is the presentation?

A
  • A lack of PBG synthase/ALA dehydratase –> ALA dehydratase deficiency porphyria (or Plumboporphyria)
  • –> accumulation of ALA (not PBG)
  • –> acute porphyria/plumboporphyria

It is an extremely RARE form of porphyria

Presentation:

  • Neurological (e.g. coma, bulbar palsy, motor neuropathy)
  • Abdominal pain (most important feature)
22
Q

What is the pathophysiology of HMB synthase/PBG deaminase deficiency? How is it acquired? What is its presentation?

A

1.Pathophysiology

  • Causes a rise in PBG and ALA;
  • ALA rise –> neurovisceral symptoms
  • = acute intermittent porphyria (AIP)

2. Autosomal dominant inheritance pattern

  1. Presentation: 90% remain asymptomatic, enzyme activity is 50% of normal but attacks are common although
  • Neurovisceral attacks:
    • Abdominal pain and vomiting
    • Tachycardia and hypertension
    • Constipation, urinary incontinence
    • Hyponatraemia (SIADH) ± seizures
    • Psychological symptoms
    • Sensory loss/muscle weakness
    • Arrhythmias/cardiac arrest
  • No skin symptoms (as no production of porphyrinogens)
23
Q

What are the precipitating factors for attacks in acute intermittent porphyria?

A

Precipitating factors (cytochrome inducers):

  • ALA synthase inducers – barbiturates, steroids, ethanol, anti-convulsants
  • Stress – infection, surgery
  • Reduced caloric intake
  • Endocrine factors – F>M, pre-menstrual
24
Q

How are acute porphyrias diagnosed?

A

Diagnosis:

  • Increased urinary PBG (and ALA) – send urine to lab quickly and keep in the dark otherwise it will turn purple.
    • PBG oxidised –> porphobilin
  • Decreased HMBS activity in erythrocytes
25
Q

How do you treat acute porphyrias?

A
  • Avoid attacks –
    • adequate nutritional intake,
    • avoid precipitating drugs,
    • prompt tx for infection
  • High carbohydrate diet –> inhibit ALA synthase (low carb intake can provide attack)
  • IV haem-arginate –> mimic natural haem and so turns off haem synthesis through -ve feedback
26
Q

Compare and contrast AIP with PCT.

A
27
Q

Generally speaking, acute porphyrias are neurovisceral and the chronic porphyrias are cutaneous, however, there are some exceptions, what are these?

A
  • Hereditary coproporphyria = deficiency of coproporphyrinogen oxidase
  • Variegate porphyria = deficiency of protoporphyrinogen oxidase
28
Q

Given that protoporphyrinogen oxidase and coporphyrinogen oxidase are much further down the pathway drom ALA and PBG, why do they still cause acute episodes?

A

Both diseases cause insoluble porphyrinogens from the end of the pathway to be deposited in stool as they are not as soluble but acute episodes also occur because…

  • …coproporphyrinogen III and protoporphyrinogen IX are potent inhibitors of HMB synthase –> accumulation of PBG and, consequently, ALA.
29
Q

How is hereditary coproporphyria and variegate porphyria acquired? What are the signs/symptoms in acute attacks?

A
  • Hereditary Coproporphyria (HCP)
    • Autosomal dominant
    • Acute neurovisceral attacks
    • Skin lesions – blistering, skin fragility [back of hands, after sun]
  • Variegate Porphyria (VP)
    • Autosomal dominant
    • Acute attacks
    • Skin lesions
30
Q

How can you differentiate between the different acute porphyrias?

A

DNA analysis offers a definitive diagnosis, but there are several mutations that can cause these conditions

31
Q

Compare and contrast the following in acute porphyrias:

  • Skin lesion presence
  • Urine PBG
  • Porphyrins in urine +/- faeces
  • Enzyme activity
A

Plumboporphyria (ALA dehydratase/PBG synthase deficiency) not given here as it is extremely rare with only a few cases resported worldwide

32
Q

List 3 non-acute porphyrias and the types of skin signs seen in each.

A

CEP and PCT are blistering

EPP is the only non-blistering

Skin signs tend to occur hours-days after sun exposure. There are no neuro-visceral manifestations with these porphyrias.

33
Q

What are the enzyme deficiencies in the 3 non-acute porphyrias? Which is the most common?

A
  • Congenital Erythropoietic Porphyria (CEP) - uroporphyrinogen III synthase deficiency
  • Porphyria Cutanea Tarda (PCT) - uroporphyrinogen decarboxylase deficiency
  • Erythropoietic Protoporphyria (EPP) - ferrochetalase deficiency

PCT is most common (1 in 25,000)

34
Q

How is PCT acquired? What is found on investigations?

A
  • Acquired (80%), inherited (20%)
  • Skin symptoms only – vesicles on sun-exposed areas with skin crusting, superficial scarring and pigmentation

Biochemistry:

  • Urine/plasma uroporphyrins + coproporphyrins are increased
  • Ferritin increased
35
Q

What are the precipitants of PCT? What is the treatment?

A

Avoid precipitants (e.g. alcohol, hepatic compromise)

Treatment:

  • Phlebotomy (reduce ferritin)
  • Hydroxychloroquine
36
Q

What are the symptoms of erythropoietic protoporphyria (EPP)? What is the pathophysiology? What investigation is key?

A
  • Photosensitivity only (no blisters)
    • burning,
    • itching
    • oedema following sun

Only erythroid cells are affected therefore important to measure RBC protoporphyrin

37
Q

Which chemical can trigger porphyrias? How are most acquired? Which porphyrias are associated with myelodysplastic syndromes?

A
  • Most cases of PCT are sporadic with no FHx
  • PCT-like syndromes can be triggered by hexachlorobenzene (fungicide added to wheat in Turkey in 1950s)
  • EPP and CEP are associated with myelodysplastic syndromes
38
Q

What are the most important diagnostic tests for:

  1. Acute porphyrias
  2. Porphyrias with skin features
  3. Photosensitivity porphyrias
A

In skin features total porphyrins need to be measured so ideally urine and faecal.

39
Q

22-year-old female

  • On holiday, drinking heavily –> abdominal pain, nausea and vomiting –> Paranoia
  • Returned to UK:
    • Tonic/clonic seizures
    • Blurred vision, flashing lights à admitted to DGH
  • Clinical deterioration:
    • Transferred to ITU
    • Developed ophthalmoplegia and quadriparesis
    • Respiratory failure –> intubated and ventilated
A
  • Biochemistry:
    • [Na+] = 118 mmol/L (135-145)
    • Urine ALA = 207 μmol/mmol creatinine(<3.8)
    • Urine PBG = 215 μmol/mmol creatinine(<1.5)
    • Hydroxymethylbilane synthase = 11nmol/mL RBCs(20-42)
  • Diagnoses:
    • Acute intermittent porphyria (seizures, quadriparesis, SIADH)
    • Pulmonary emboli
  • Treatment
    • Haem-arginate
    • High CHO diet

Abdominal pain + Neurological symptoms + Psychiatric symptoms = consider porphyrias with elevated ALA

40
Q

Which electrolyte abnormality is commonly seen in AIP?

A

SIADH (hyponatraemia)

41
Q
A
42
Q
A

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