Porphyria

Porphyrias are a group of diseases associated with enzyme deficiencies associated with the production of heme. These diseases may be due to inborn errors of metabolism, environmental toxins of infectious agents. Historically, the porphyrias have been described by distinguishing between hepatic or erythroid forms. Porphyrias can also be divided into acute or cutaneous categories. The acute porphyrias usually cause abdominal pain, neuropathy, autonomic instability, and psychosis. These include aminolevulinic acid dehydratase (ALAD) deficiency and acute intermittent porphyria (AIP). The cutaneous porphyrias are associated with photosensitive lesions of the skin, which include congenital erythropoietic porphyria (CEP), [Page 1403]porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). A third group of porphyrias have both acute and cutaneous characteristics. These porphyrias are hereditary coproporphyria (HCP) and variegate porphyria (VP). The porphyrias are either autosomal dominant or autosomal recessive.

The porphyrias have a storied past throughout history. It is believed that the myths about Dracula stem from individuals with porphyria. Furthermore, one of the most famous cases of suspected porphyria was King George III of England. It is believed that he was a victim of variegate porphyria, from which he suffered abdominal pain, constipation, rashes, confusion, and limb weakness. It has been suggested that his mental and physical impairments may have played a role in Britain losing the American Revolution. Later in history, an epidemic of porphyria cutanea tarda occurred in southeastern Turkey between 1956 and 1961. It is believed that the Turkish government distributed fungicide-containing wheat. This was the first time that acquired porphyrias were associated with environmental toxins in humans.

Heme plays a critical role in many physiologic processes. It is essential for binding and transporting oxygen and is involved in the cytochrome P-450 pathway. Furthermore, it is necessary for the production of cyclic guanine monophosphate (cGMP) and regulating hydrogen peroxide. It also is involved in oxidation of tryptophan and prostaglandins. The heme biosynthesis pathway is a process that spans the mitochondria and cytosol of the blood cell. There are eight enzymes in the pathway. Delta-aminolevulinic acid (ALA) synthase is the rate-limiting enzyme. A defect at any point in the cycle may lead to a buildup of neurotoxic metabolites, including aminolevulinic acid (ALA) or porphobilinogen (PBG). These metabolites are thought to cause damage via oxidative stress or chronic renal failure. Nervous system damage may manifest itself as seizures that worsen with typical anticonvulsant medication. The patient may also note abdominal pain and absent peritoneal signs. Other neurologic sequelae include a Guillain-Barré– like syndrome, paresthesias, or weakness. Psychiatric symptoms, such as anxiety, confusion, insomnia, hallucinations, or paranoia, may also occur. The patient may also suffer from bladder dysfunction, tremors, or excessive sweating. Secondary cardiovascular disease or hepatocellular carcinoma is possible as well.

While the frequency of this set of diseases is currently unknown, there do seem to be certain ethnic groups that have a higher prevalence of particular porphyrias. For example, AIP has been found in individuals of Swedish and Finnish descent at a higher rate. South Africans of Danish descent are known to have a higher rate of VP. In terms of gender frequency, women are more likely to be afflicted with any type of porphyria.

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