So Scared I Saw That Frequent Flyer – Acute Porphyria

In the spirit of Halloween, let’s delve into some our biggest fears as clinical monsters. Firstly, we have that ongoing fear of missing a diagnosis, because it makes us feel like we’re not smart or thorough enough. Secondly, we fear the return of the crazy frequent flyer that terrorizes our shifts with the same vague chief complaints that we’ve never been able to put together other than the fact that he or she has been labeled with having history of “psych.” Lastly, we fear the vampire or werewolf that may show up to our emergency department on Halloween night.

But have no fear, because there is a spectrum of disease that can help provide some explanation. Porphyrias refer to a group of 7 rare metabolic diseases that result from defects in one of the steps of heme biosynthesis. The diseases have been grouped as acute porphyrias (primarily neurovisceral) and photocutaneous porphyrias (primarily dermatologic).

Cutaneous porphyrias are due to overproduction of photosensitizing porphyrins by the liver or bone marrow. The most common form is porphyria cutanea tarda (PCT), which has been implicated as the medical explanation for the existence of vampires and werewolves. The hallmark of PCT is photosensitivity, which causes chronic blistering and burns on sun-exposed areas. This is a possible explanation for why everyone’s favorite vampire, Edward Cullen, sparkles when exposed to sun in the movie Twilight.

But of course, Hollywood glamourizes everything because cutaneous porphyrias look more like this:

Source: http://dxline.info/diseases/porphyria

The blisters and burns heal very slowly and are often associated with hirsutism. The hair growth can give the appearance of a werewolf.

Although seeing vampires and werewolves in our emergency department may be terrifying, the cutaneous porphyrias are less likely to present to the acute setting. The acute porphyrias are more frequently encountered in clinical practice, especially within the emergency setting. As result, the remainder of this post will focus on the acute porphyrias.

 

What is 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.

Who suffers from acute porphyria?

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).

What triggers an attack of acute porphyria?

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)

What are the clinical manifestations of acute porphyria?

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.

How is acute porphyria diagnosed?

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.

What is the immediate management of acute porphyria?

  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.

What is the definitive treatment and disposition of the patient with acute porphyria?

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.

 

 

 

Sources

Anderson, Karl E., et al. “Recommendations for the diagnosis and treatment of the acute porphyrias.” Annals of internal medicine142.6 (2005): 439-450.

Bissell, D. Montgomery, Karl E. Anderson, and Herbert L. Bonkovsky. “Porphyria.” New England Journal of Medicine 377.9 (2017): 862-872.

Ventura, Paolo, Maria Domenica Cappellini, and Emilio Rocchi. “The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine.” Internal and emergency medicine 4.4 (2009): 297-308.

American Porphyria Foundation – www.porphyriafoundation.com

 

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Derick

PGY-2 Emergency Medicine Resident at SUNY Downstate Medical Center/King's County Hospital Center
Clinical Monster in Training @DrAlfonsoEM

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