Pathophysiology

The porphyrias are caused by inherited deficiencies of enzymes involved in heme synthesis.75 Heme is used in the bone marrow to make hemoglobin and in the liver to make cytochrome P-450 enzymes. The hepatic synthesis of heme is largely regulated by d-aminolevulinic acid (ALA) synthase, an inducible enzyme.

The symptoms and signs of the porphyrias result from the accumulation of toxic metabolites. They are classified either as erythropoietic and hepatic or on the basis of the specific enzyme deficiency.

Seizures and other neurologic manifestations only occur in the hepatic group, in which the porphyrin precursors ALA and porphobilinogen (PBG) accumulate.76 Both compounds have been implicated as directly neurotoxic.77

Three acute hepatic porphyrias, all autosomal dominant, are associated with seizures:78

  • acute intermittent porphyria (AIP)
  • hereditary coproporphyria (HCP)
  • variegate porphyria (VP)

HCP and VP are much less common than AIP. They present similarly except that HCP and VP are also associated with cutaneous photosensitivity.

Patients with AIP have approximately 50% reduction of PBG deaminase activity.75 This condition is particularly prevalent in Northern Europe, especially Finland.79 When the demand for hepatic heme synthesis is increased, the reduced PBG deaminase activity leads to the accumulation of ALA and PBG in the liver, plasma, and urine.78 Some of the PBG and ALA is converted to porphyrin.

AIP can be precipitated by:80

  • drugs that induce hepatic ALA synthase (e.g., enzyme-inducing antiepileptic drugs)
  • drugs that inhibit PBG deaminase (e.g., sulfonamide antibiotics)
  • hormones (e.g., estrogen, progesterone and its metabolites, and oral contraceptives)
  • alcohol
  • reduced caloric intake
  • intercurrent infections
  • major surgery

Clinical presentation

Clinical manifestations can persist for days to weeks and may be preceded by nonspecific symptoms.76 The most common acute symptom is abdominal pain, often severe enough to require narcotic analgesia. The pain is sometimes accompanied by nausea, vomiting, ileus, and constipation.

Sympathetically mediated signs include tachycardia, hypertension, sweating, and tremors. Sleep disturbance, anxiety, delirium, hallucinations, depressed mood, and paranoid delusions may be present.81,82 Lethargy and coma occur rarely. Peripheral motor neuropathies may lead to foot or wrist drops.

Seizures associated with AIP occur either as a direct neurologic manifestation of the condition or from hyponatremia, which may result from SIADH, vomiting, diarrhea, or poor oral intake. Some studies suggest that focal and generalized seizures occur in nearly one-third of pediatric cases and up to 20% of adult cases.83-85 By contrast, a study of patients registered at the National Porphyria Center in Sweden found that the lifetime prevalence of AIP-associated seizures was 2.2% of all those with known AIP and 5.1% of all those with manifest AIP.86

Evaluation

The diagnosis may be suspected based on the clinical presentation and may be confirmed by the presence of photosensitive porphyrins in the urine and reduced monopyrrole PBG deaminase in red blood cells.81,87

 

Treatment

After a definitive diagnosis, treatment of acute attacks consists of

  • narcotic analgesia for pain (see below)
  • symptomatic therapy of nausea, anxiety, and restlessness
  • oral or intravenous glucose
  • Intravenous hematin or heme arginate (to reverse the induction of ALA synthase and thereby reduce the production and accumulation of ALA and PBG78,88,89)

Drugs known to precipitate AIP must be avoided,78,90 particularly when treating seizures, pain, and acute anxiety attacks. Hahn et al. used a cell-culture model of primary chicken embryo liver cells, which maintain intact heme synthesis and regulation, to study the effects of several of the more recently approved antiepileptic drugs on porphyrin accumulation.91 Based on the results, they recommended vigabatrin or gabapentin, for which success was reported anecdotally,92 but not felbamate, lamotrigine, or tiagabine, as possible treatments for seizures in patients with porphyria.

Similar animal studies have suggested that patients with acute porphyrias may be at greater risk for developing porphyric attacks when treated with certain medications:

Greater risk Less risk
tramadol hydrocodone, oxycodone, morphine93
bupropion, nefazodone fluoxetine, paroxetine
diazepam, midazolam, triazolam low doses of lorazepam, oxazepam94

Complete recovery from attacks is the rule, although neuropathic deficits may take months to resolve.

Adapted from: Schachter SC and Lopez MR. Metabolic disorders. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;195-208. 
With permission from Elsevier (www.elsevier.com). 

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Reviewed By: 
Steven C. Schachter, MD
on: 
Wednesday, March 31, 2004