porphyria

[TFC2:p148-p149; RDM6:p1098]

@Unfinished

Porphyrin metabolism

• Porphyrins are cyclic structures formed by linkage of four pyrrole rings through methene bridges
• Haem is the most important porphyrins in human physiology

Biosynthesis of haem

• Start with formation of delta-aminolaevulinic acid (ALA)
  * By condensation and subsequent decarboxylation of succinyl CoA and glycine
  * Catalysed by ALA synthetase
  * Take place in the mitochondria
  * ALA synthetase is the rate-limiting factor in porphyrin biosynthesis

ALA synthetase

• Control of haem production is primarily through ALA synthetase
• Haem provides a negative feedback on the formation of ALA synthetase
• ALA synthetase is readily inducible
• In porphyria, there is a partial block in the synthetic pathway
• Therefore in porphyria, increase in ALA synthetase
  --> Increase in the intermediate products before the block

Classifications of porphyria

• 5 major syndromes in adults
  --> All autosomal dominant
• Hepatic Porphyria
  * Acute intermittent porphyria (AIP)
  * Variegate porphyria (VP)
  * Porphyria cutanea tarda
  * Hereditary coproporphyria (very rare)
• Erythropoietic Porphyria
  * Erythropoietic protoporphyria

Hepatic porphyria

Acute intermittent porphyria (AIP)

Defect

• Partial deficiency of porphobilinogen deaminase

Clinical features

Clinical signs and symptoms are similar to lead poisoning

• Abdominal pain, vomiting, constipation
• Peripheral neuropathy (lower motor neuron lesion) --> Can progress to bulbar paralysis
• Psychiatric disorders
• Skin is NEVER affected
• Triggers include
  * Certain drugs can induce the enzyme ALA synthetase
  * Infection, fasting, menstruation

Drugs which may trigger attacks of AIP

Sensitising drugs include:

• Barbiturates
• Diazepam
• Phenytoin
• Pentazocine
• Birth control pills
• Ethyl alcohol
• Sulfonamides
• Ergotamine preparation
• Others: (not found in textbook but in Prof Kam's lecture notes include)
  * Cephalosporin
  * Sulphonylurea
  * Steroids

Drugs which are SAFE in AIP

[RDM6:p1098]

Safe drugs include:

• Neostigmine, atropine
• Suxamethonium, pancuronium
• N2O
• Procaine
• Propofol, etomidate
• Morphine, pethidine, fentanyl
• Droperidol, promethazine, chlorpromazine, promazine

NB:

• Etomidate is NOT safe according to [PHW2:p92]

Investigation

• Acute attacks
  * Increased urinary porphobilinogen and delta-aminolevulinic acid (ALA) --> dark urine
  * Faecal porphyrins normal
• Remission
  * Same findings

Variegate porphyria (VP)

Defect

• Protoporphyrinogen oxidase deficiency

Clinical features

• Acute attacks = similar to AIP, except also affects skin
• Skin is photosensitised --> fragility, pigmentation, and hypertrichosis in light-exposed areas

Investigations

• Acute attacks
  * Increased urinary porphobilinogen and delta-aminolevulinic acid (ALA) --> same as AIP
  * Faeces contain excess coproporphyrins and protoporphyrins
• Remission
  * Urine may be normal

Porphyria cutanea tarda

Defect

• Uroporphyrinogen decarboxylase deficiency

Clinical features

• No acute attacks and are not usually drug-related
• Skin = bullae and hyperpigmentation on exposed area (like VP)
• Underlying alcoholic liver disease or hepatitis C common
• May have a history of exposure to toxins e.g. hexachlorobenzene

Investigations

• Normal porphobilinogen (PBG) and ALA in urine
• Normal porphyrins in stools
• Greatly increased uroporphyrin in urine
  --> Red urine

Hereditary coproporphyria

• Very rare
• Clinically like variegate porphyria
• With raised faecal and sometimes urinary coproporphyrin

Erythropoietic porphyria

Erythropoietic protoporphyria

• Defect = Ferrochelatase deficiency
• Clinical features = skin photosensitivity
• Investigations = Free protoporphyrin in RBC, normal urine