After evaluating this article, participants will be able to:
1. Identify the symptoms associated with porphyria to improve diagnostic accuracy in clinical practice.
2. Understand the pathophysiology of porphyria to better predict the clinical implications of this disease.
3. Incorporate treatment strategies for porphyria into clinical practice.
Porphyuria, the disease sometimes blamed for vampire mythology, has a spectrum of pathology that can easily go undiagnosed and under treated by emergency physicians.
The patient is a 46-year-old male who presents to the ED at night with agitation and delusional episodes lasting several hours. During these episodes, he has sensations of hair growth on his face, trunk, and arms. Occasionally, he becomes convinced that the hair growth is real. He also complains that he experiences structural facial malformations and lesions that take place within minutes and remain for hours. He thinks these changes will make him appear to be a wolf, and avoids seeing his face or body whenever possible. However, he does not believe that he truly is a wolf. He also reports auditory and visual hallucinations most pronounced at night when trying to sleep.
When placed in a small psychiatric room in the ED and told to dress into a patient gown, he becomes extremely agitated and violent toward the staff. The patient requires several security guards to physically restrain him after injections of haloperidol and lorazepam fail to sedate him.
This patient is suffering from a case of lycanthropy – the delusion that one is being transformed into a wolf.
Consider the description of the title character of Bram Stoker’s Dracula: “His eyebrows were very massive, almost meeting over the nose, and with bushy hair that seemed to curl in its own profusion. The mouth ... was fixed and rather cruel-looking, with peculiarly sharp white teeth; these protruded over the lips, whose remarkable ruddiness showed astonishing vitality in a man of his years ... The general effect was one of extraordinary pallor.”
According to genetic experts, the characteristics typically associated with vampires and werewolves are reminiscent of the symptoms and remedies associated with porphyria. In 1963, Illis published a paper “On Porphyria and the Aetiology of Werewolves” in the Proceedings of the Royal Society of Medicine. Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphin’s publication for the American Association for the Advancement of Science, “Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends”, gained widespread media coverage, thus popularizing the connection.
According to Dolphin: (1) Porphyria victims are extraordinarily sensitive to sunlight. Even mild exposure can cause severe disfigurement. Facial skin may scar, the nose and fingers may fall off, and the lips and gums may become so taut that the teeth project like fangs. (2) To avoid sunlight, people with serious cases of porphyria go out only at night.
(3) Currently, porphyria can be treated with injections of blood products. Centuries ago, porphyria victims might have sought to treat themselves by drinking blood. (4) Garlic contains a chemical that worsens porphyria symptoms, causing sufferers to avoid it – just like vampires.
Porphyria is named from the ancient Greek word porphura, meaning purple. The Greeks borrowed the term from the Phoenicians, who extracted a purple pigment from purpura mollusks to dye the garments of their royal families.
There are eight different types of porphyria, four of these variations can cause sensitivity to light: Erythropoietic Protoporphyria Protoporphyria (EPP), Congenital Erythropoietic Porphyria (CEP or Gunther’s Disease), Porphyria Cutanea Tarda (PCT) and Variegate Porphyria. The types of porphyria can vary substantially in their symptoms and severity. Historical victims of the worst, most disfiguring forms may have inspired tales of werewolves and vampires. Even today, the diagnosis and management of the disease can be challenging and elusive.
The physical features of “vampires” could have been caused by porphyria cutanea tarda (PCT). The disease results in abnormal production of pigments that are essential components of proteins such as hemoglobin. PCT primarily causes skin problems such as blisters that appear on sun-exposed areas of the body such as the hands and face. Even after minor trauma, the skin in these areas can desquamate or blister. In addition, people with PCT may also have darkening and thickening of the skin, as well as increased hair growth. In CEP, the teeth can be stained a reddish brown due to the buildup of pigments.
Symptoms of porphyria cutanea tarda can be alleviated by avoiding sunlight (direct exposure can allegedly destroy a vampire). The original Count Dracula, Vlad III the Impaler was also said to have suffered from acute porphyria, which may have started the notion that vampires were, “allergic to the light of day”. Julia Gnuse, regarded as the most tattooed woman in the world, received her dermal artwork to hide scars from PCT.
Healing is slow and is associated with scarring and hair growth, especially on the face. Most of the time the facial hairs are fine, so the hirsutism is barely noticeable. Sometimes, however, the hair growth can give the appearance of a werewolf, leading to speculations that these mythical creatures have a medical condition.
All the versions of porphyria have one trait in common: they each result from defects in the body’s heme synthesis. Heme is made in a sequence of eight steps where each step is catalyzed by a separate enzyme. If any of these eight steps fails because of an inherited genetic mutation or an environmental toxin, the porphyrin intermediates may build up to toxic levels. These porphyrins accumulate in the skin and other organs before being excreted in feces and urine (which may turn a port-wine color). When exposed to light, the porphyrins can turn caustic and destroy surrounding tissue.
One of the more common types of the disease is acute intermittent porphyria (AIP), which allegedly afflicted King George III of Britain – the “mad king”. In AIP, the most notable symptoms are neurological attacks, such as trances, seizures and hallucinations, which often persist over days or weeks. Of note, King George was also treated with arsenic and antimony for his chronic ailments, which undoubtedly exacerbated his condition. Other historians have suggested that Vincent van Gogh may have suffered from AIP.
In congenital erythropoietic porphyria (CEP), one of the rarest forms, 18 different mutations in the gene encoding the enzyme uroporphyrinogen III cosynthase have been reported in different families. These mutations obstruct heme synthesis to varying degrees, giving a spectrum of severity. In advanced stages, CEP causes appalling photomutilations from the light-activated porphyrins, including loss of facial features and fingers, scarring of the cornea and blindness. The condition may have been less rare in the past, especially in isolated pockets where inbreeding could occur such as the valleys of Transylvania – perhaps giving rise to tales of vampires. To date, only a few hundred cases of this disease have been officially diagnosed.
While the accumulation of porphyrins is usually caused by a genetic mutation, toxins (such as chronic ethanol poisoning) and environmental contaminants can also perpetuate the disease. The most notorious environmental episode occurred in Turkey in the 1950s, when 4,000 people developed a form of porphyria after eating wheat seeds that had been sprayed with a fungicide, hexachlorobenzene. Hundreds died, and use of the fungicide was later banned around the world.
Since porphyrias are such rare conditions, most hospital laboratories typically do not have the expertise or technology to perform porphyria testing. In general, testing involves sending samples of blood, stool and urine to a reference laboratory.
Empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. A high-carbohydrate diet is typically recommended; in severe attacks, a 10% dextrose infusion is administered. Pain typically is severe, frequently out of proportion to physical signs and often requires high doses of opioids to reduce it to tolerable levels. Hot water baths or showers may temporarily lessen pain. Nausea and vomiting can be intractable and may respond to antiemetic agents. Despite popular belief, in reality, no one has ever proven that garlic actually exacerbates porphyria.
Although there exists no antidote or “silver bullet” for the treatment of porphyuria, Hematin (trade name Panhematin) and heme arginate (NormoSang) are the drugs of choice in acute porphyria. These drugs need to be given early in an attack to be effective and are patient variable in response. They are not curative drugs but can shorten the duration and reduce the intensity of an attack.
Seizures often accompany the disease. Some seizure medications such phenobarbital actually exacerbate this condition. Benzodiazepines are considered safe and can be efficacious when used in conjunction with newer anti-seizure medications such as gabapentin.
In most cases of porphyria, blood or heme transfusions can supply some relief from the symptoms, and remain the mainstay of treatment. Interestingly, the heme pigment may be robust enough to survive digestion, and is absorbed from the intestine (even though the protein parts of hemoglobin are broken down). In other words, it is theoretically possible to relieve the symptoms of porphyria by drinking blood – another possible link with the vampire stories.
Heme infusions help in the treatment of porphyria patients in two ways. First, they overcome the body’s shortage of heme, relieving the anemic state. Second, the extra heme suppresses further heme synthesis via a negative feedback loop, bringing an end to the production of toxic porphyrin intermediates. Phlebotomy can also remove porphyrin intermediates from the circulation. In most cases, some degree of normality can be restored within a few days of an attack.
In the more serious and rare forms of porphyria such as CEP, the treatments are less effective. A patient may require an emergent splenectomy to treat hemolytic anemia. In CEP, the genetic defect affects the stem cells in the bone marrow, which divide to produce new red blood cells. In principle, CEP can be cured by bone-marrow transplantation. Bone-marrow transplants have been carried out successfully in children with CEP, usually within the first few years of life. The treatment apparently cures the disease over a period of years. A future cure for porphyria may involve gene therapy, in which the impaired genes are replaced with functional ones using a virus as a vector.
Clinical Applications for Emergency Physicians:
As the adage goes in clinical emergency medicine, when you hear hoof beats, think of horses. However, if you never consider zebras, you may miss the diagnosis altogether. This is true for the clinical applications of porphyuria. Although rare, if you never entertain this in your differential, you’ll fail to fully appreciate its vast spectrum of pathology and will likely under treat the disease. Often, these patients get labeled with a moniker of “psych”, “chronic pain of unclear etiology” or as having “drug seeking behavior”. Don’t fall into that trap. This can be a life-threatening illness that often requires high doses of opioids, dextrose administration, and aggressive control of seizure activity.