Acute porphyria

  • Porphyrias are a heterogenous group of heme biosynthesis disorders that result in accumulation of porphyrins
  • Neuropathy is only seen in the hepatic porphyrias:
    1. Acute intermitent porphyria (AIP, autosomal dominant)
    2. Variegate porphyria (VP, autosomal dominant)
    3. Hereditary coproporphyria (HCP, autosomal dominant)
    4. Aminolevulinic acid (ALA) dehydrase deficiency (autosomal recessive, extremely rare)
  • Estimated prevalence in Western countries is between 1-2 per 100,000 except Sweden where it is 1 per 10,000. Most cases are AIP.
  • Exact mechanism of neuropathy is unclear. Excess ALA may be neurotoxic or heme deficiency could decrease levels of cytochromes with detrimental effects for nervous tissue.
  • Acute attacks may be precipitated by stress, hormones and drugs and are characterized by abdominal manifestations, CNS manifestations and neuropathy.
  • Abdominal pain is usually severe and may mimic acute abdomen, accompanied by nausea, vomiting, constipation, ileus and distetion or diarrhea.
  • 5% of patients present without abdominal symptoms.
  • CNS involvement may manifest as almost any acute psychiatric symptom from agitation and nightmares to florid psychosis and may progress to seizures and coma.
  • Peripheral neuropathy usually manifests a few days after symptom onset. It is predominantly motor, axonal, rapid onset, diffuse, often asymmetric, typically ascending and rapidly progressing, resembling Guillain-Barré syndrome.
  • Isolated or multiple mononeuropathies may occur.
  • 40% of patients with porphyria develop neuropathy even between attacks.
  • Cranial nerves and autonomic nervous system are often involved.
  • Bulbar symptoms may be severe and compromise airway. Respiratory muscles may also be severely affected necessitating mechanical ventilation.
  • Urine appears reddish-brown during acute attacks.
  • Bullous skin lesions may appear in VP and HCP.
  • Acute attacs are 5 times more common in women, possibly due to hormonal influences.
  • Menstruation-related attacks can be difficult to manage.
  • Treatment of confusion and seizures may be difficult due to the limited number of drugs that are safe.
  • Mortality with proper treatment is <10%.
  • Recovery from neuropathy may be incomplete.
  • Repeated attacks may lead to chronic renal failure.

Diagnosis

  1. Detecton of urinary porphobilinogen using the Watson-Schwartz test.
  2. If positive: confirm by quantitative assay of urinary PBG and measurement of fecal and plasma porphyrins (PBG and ALA). This will also characterize the type of acute porphyria.
  3. Electrophysiological studies reveal a predominantly motor, axonal polyneuropathy.
  4. Genetic testing should be undertaken and family members should also be tested.

Management

  • Withdraw potentially exacerbating drugs.
  • Provide analgesia and antiemetics.
  • Hydration and IV glucose may be adequate treatment for mild cases.
  • For more severe attacks, administer heme arginate or hematin.
  • Respiratory management and mechanical ventilation may be necessary in severe cases.
  • Some studies with recombinant human porphobilinogen deaminase in patients with AIP suggest this treatment to be safe and effective.

The mainstay of porphyria management is the prevention of attacks.


Triggers of acute porphyria

  • Drugs that induce cytochrome P450 (eg. barbiturates, most anticonvulsants, sulfonamides, contraceptives)
  • Alcohol
  • Fasting
  • Stress
  • Infection
  • Premenstrual hormone changes in women


Anticonvulsants and acute porphyria

Use

  • Clobazam
  • Clonazepam
  • Lorazepam
  • Gabapentin
  • Acetazolamide
  • Vigabatrin

Use with caution

  • Valproate
  • Diazepam
  • Lamotrigine

Avoid

  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Primidone
  • Ethosuximide
  • Tiagabine
  • Felbamate
  • Topiramate
  • Oxcarbazepine

No data

  • Levetiracetam



References

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  • Effects of antidepressants and benzodiazepine-type anxiolytic agents on hepatic porphyrin accumulation in primary cultures of chick embryo liver cells. J.Pharmacol Exp Ther 1999;291:1150-5.
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  • Effects of sodium valproate on haem biosynthesis in man: implications for seizure management in the porphyric patient. Eur J Clin Invest 1988;18:29-32. doi: 10.1111/j.1365-2362.1988.tb01161.x
  • The effects of chronic carbamazepine treatment of haem biosynthesis in man and rat. Eur J Clin Pharmacol 1988;35:241-7. doi: 10.1007/BF00558260
  • Safety of anticonvulsants in hepatic porphyrias. Neurology 1981;31:480-4. doi: 10.1212/wnl.31.4.480
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