Acute Porphyria

The acute porphyrias are due to hepatic overproduction of the porphyrin precursors, and the symptoms are caused by injury to the nervous system. The cardinal symptom of acute porphyria is a porphyria attack, which manifests as neurovisceral symptoms.

Acute porphyria has a pan-ethnic distribution with a large amount of variability from region to region. The prevalence of the mutations for acute porphyria in Western populations is 1 carrier per 2000 persons (Bissell et. al.).

Since this is a genetic disease (mainly autosomal dominant), patients may endorse a family history, but up to a 1/3 of patients will be unaware due to incomplete penetrance. The disease may not manifest for several generations.

The peak age for acute porphyria is in the early 30s, but the age distribution is from 18 to 45 years. It is 4 to 5 times more common in women than men (likely due to effects of female hormones).

Attacks occur in less than 10% of patients with a genetic predisposition which suggests the importance of environmental factors and genetic modifiers. Drugs, hormones, and nutritional alterations are the common culprits for acute attacks.

Source: Adapted from the American Porphyria Foundation

The common theme among the triggers for acute porphyria is an increase in the demand for hepatic heme (particularly via the cytochrome P450 enzymes). Drugs, including many anticonvulsants, alcohol, and tobacco are some of the most common triggers. (For a full list of drugs, go to http://www.porphyriafoundation.com/drug-database )

Other causes include:

• Crash dieting
• Endogenous hormones (explains the predominance of attacks in women)
• Metabolic stress (i.e. infections, surgery)

Per a NEJM review on porphyria:

“The typical patient … is a previously healthy young woman who has had several days of severe fatigue and an inability to concentrate, followed by progressively worsening abdominal pain, nausea, vomiting, and subtle neurologic signs (weakness, dysesthesia, and altered affect). Analgesic agents, including opioids, have provided little or no relief. The patient’s medical record may reveal previous visits to the emergency department with the same symptoms and a non-diagnostic evaluation. The vital signs are notable for tachycardia and elevated systolic blood pressure. The abdominal examination is unexpectedly benign. Abdominal imaging may show changes consistent with ileus but otherwise is normal. The lack of objective findings and a poor response to analgesics often create an initial impression of psychosomatic pain or drug addiction. “

The neurovisceral symptoms of acute porphyria may seem extremely vague and nonspecific, making diagnosis difficult. It can consist of anything from abdominal pain to altered mental status, and in severe cases, respiratory failure. The most common emergency department presentation of acute porphyria is acute abdominal pain. Other features may include seizures, confusion, hallucinations, and a progressive polyaxonal motor neuropathy, which can progress to paralysis and respiratory failure requiring mechanical ventilation.

Although a single characteristic symptom may not lead to a diagnosis, additional features in a patient with abdominal pain might heighten the suspicion of acute porphyria. These may be dark or reddish urine, new-onset hypertension, hyponatremia, proximal muscle weakness, pain associated with the luteal phase of the menstrual cycle, recent use of medications known to exacerbate porphyria, and low calorie/low-carbohydrate diet.

In an acute attack, a rapid qualitative test for urinary porphobilinogen level can help screen for acute porphyria (positive when the level is 10 to 150 times the upper limit of normal). A quantitative porphobilinogen test can take 4 to 10 days. This often means a substantial delay in diagnosis, which can be costly in terms of misdirected medical care, progressive neurologic loss, respiratory paralysis, and even death.

1. Medications
   • Medications taken by the patient should be reviewed immediately.
   • Drugs that are potential causes should be discontinued if possible.
2. Fluid Resuscitation and Electrolyte Imbalances
   • Fluid resuscitation should be considered in all patient with acute porphyria since intractable nausea and vomiting can result in hypovolemia.
   • Careful correction of hyponatremia and hypomagnesemia is important, particularly when those conditions are associated with seizures.
3. Neurologic
   • Since acute porphyrias are primarily neurotoxic, progressive neuropathy is particularly concerning because it can lead to respiratory failure (similar to Guillain-Barré Syndrome).
   • Seizures are difficult to treat because almost all anticonvulsants drugs can further exacerbate an attack. Gabapentin can be given safely, and benzodiazepines are relatively safe.
4. Pain
   • Because the pain is often severe, unrelenting, and refractory to narcotic analgesia, the impression is that it is psychosomatic pain or opioid addiction.
   • The neurovisceral pain tends to only improve after definitive treatment.

The definitive treatment for acute porphyria is to stop or bypass the heme biosynthesis pathway in order to prevent further accumulation of porphyrin precursors. Sometimes this is as simple as removing the offending medication.

Some cases of acute porphyria require further treatment after the patients are admitted to the hospital and the diagnosis is confirmed. Glucose has been proven to decrease enzymatic activity within the biosynthesis pathway, thus decreasing the concentration of porphyrin precursors.

Severe or prolonged attacks should be treated with intravenous heme (i.e. Panhematin). It acts as negative feedback on the heme biosynthesis pathway, thus decreasing the toxic porphyrin precursors.

Source: Bissel et. al.

Although hospital pharmacies do not typically stock Panhematin, the supplier will send it by air express on request.