Classifications of Porphyria

Porphyrias are classified as being either hepatic or erythropoietic in origin. In both classes they are characterized by the overproduction of porphyrin or their precursors. Biosynthesis of heme is controlled differently in liver and bone marrow, with the rate-limiting enzyme in liver being aminolevulinic acid (ALA) synthase, whereas the biosynthesis of heme in the bone marrow is partly regulated by the uptake of iron.

Acute hepatic porphyrias are characterized by a rapid onset of symptoms that are largely neurologic; the erythropoietic variety manifests primarily in the skin, leading to cutaneous photosensitivity (Box 200-1).

Signs and Symptoms of Hepatic Porphyrias

Acute attacks are comprised of a wide variety of symptoms, ranging from skin lesions to abdominal pain to neurologic manifestations of varying intensity. Abdominal, back, or extremity pain grows in intensity over a 24- to 48-hour period, which may lead the clinician to consider appendicitis or an acute abdomen. Rebound tenderness is not usually present.

Nausea and vomiting are frequently seen, as are anxiety and restlessness. Often these patients have some degree of constipation that worsens as the condition develops. Tachycardia may also be present, suggesting an infectious process or increased bowel toxicity.

In general the severity of the symptom pattern seems to the clinician to be out of proportion to the manifesting signs. It is thought that the bowel symptoms are due to a neurologic disturbance of normal function.

Mental abnormalities can range from confusion to acute psychosis and may be the first presentations of an attack. With prolonged attacks, sensory and motor functions are impaired and can result in respiratory paralysis and death.⁵ Many patients are diagnosed with schizophrenia, and a considerable number confined to mental institutions are thought to be afflicted with one of the porphyrias.^6,7

The majority of carriers are usually asymptomatic except when they are exposed to drugs or chemicals that exacerbate the condition. Neurologic symptoms and the sequelae of an acute or prolonged attack can take months to clear, but eventual recovery occurs in the majority of cases.

Heme Formation

Final heme formation is regulated by the action of ferrochelatase in the mitochondria. Reducing substances such as ascorbic acid, cysteine, or glutathione are required. Iron must be in the ferrous rather than ferric form. Ferrochelatase activity is inhibited by high concentrations of heme. Thus, the feedback system prevents further formation. Heme concentration also feeds back on ALA synthase, the rate-limiting step in the biosynthetic pathway.

Because heme formation is essential for aerobic metabolism, its absence would be lethal. Therefore, multiple control systems have evolved to regulate the metabolic pathway, which has made it difficult to elucidate the exact mechanism of the deficit, be it genetic or acquired. Recent advances in identifying specific DNA encoding the heme biosynthetic enzymes, however, has resulted in a more precise diagnosis of the specific genetic deficit.

Red blood cell (RBC) incorporation of heme, iron, and glycine occurs in maturing cells up through and including reticulocytes but is eventually lost as the red cell ages. Hypoxia and erythropoietin will increase ALA synthase activity in RBCs but not the liver, whereas drugs and chemicals will affect the liver but not erythropoietic tissues. Figure 200-1 illustrates heme synthesis and porphyria.

FIGURE 200-1 The heme synthesis and porphyria.

(From Sassa S, Kappas A. The porphyrias. Scientific American medicine. New York: Scientific American, 2003:9:V:1-9.)

Etiologic Agents Triggering Porphyria

Numerous agents that trigger episodes of porphyria have been identified, and patients afflicted must be careful when taking prescription medications, estrogens, and some herbal medicines; they must also avoid environmental exposures to heavy metals, organophosphates, and any substance that places an excess burden on the cytochrome P-450 system. In particular, exogenous estrogens—whether from oral contraceptives, estrogen patches, or estrogen replacement therapy—are strong contributors to an underlying porphyria deficit.^13,14 This is one reason why acute attacks of porphyria are seen more often in women than men, especially premenstrually. Additionally, some studies have suggested that estrogens enhance the porphyrin-inducing activities of other agents, making women more vulnerable to environmental exposures than their male counterparts.^15,16

Herbicide-induced porphyria has been shown to decrease the activity of several enzymes involved in the porphyritic pathway as well as to increase the porphyrin content in nerve tissue.^16,17 A considerable number of chemicals have also been linked to porphyria or porphyrinuria in humans; these generally involve chronic industrial exposures or environmental exposures. An example of an epidemic of PCT produced by the accidental ingestion of wheat treated with the fungicide hexachlorobenzene occurred in Turkey in the 1950s.

Some researchers have hypothesized that several otherwise unexplained chemical-associated illnesses such as multiple chemical sensitivity syndrome (MCSS) may represent mild chronic cases of porphyria or other acquired abnormalities in heme synthesis.^18,19

According to William Morton, who has written extensively on porphyrias, MCSS as first described by Cullen in 1979 may, in fact, be porphyria. Morton speculates that exposures to porphyrogenic chemicals, medications, or severe infection overpower the already deficient enzyme system, resulting in an accumulation of the specific porphyrin because of diminished enzyme function. He proposed that the resultant symptoms are due to an increase of the porphyrinogen and not an accumulation of the toxin itself. Many diagnosticians have tried to expedite the distinction between “real” porphyria and secondary porphyrinopathies by requiring that a porphyria diagnosis be based on urinary or fecal porphyrin excretions or both 2 to 20 times the upper limit of normal. This classification would exclude individuals demonstrating lesser degrees of porphyrinogenic activity, possibly some of those whose conditions are in remission or not subject to environmental exposures.²⁰

The intensity of porphyria symptoms varies widely. About 10% of the cases present with acute severe attacks, whereas approximately 25% are seen with chronic symptomatology of varying degrees. The remaining percentage (65%) present with no symptoms but may become susceptible under the right circumstances.²¹

Not all researchers agree with Morton’s and others’ premise that environmental toxicities induce underlying genetic deficits leading to symptomatic porphyria. According to Hahn and Bonkovsky, “patients with multiple chemical sensitivity syndrome may, at times, have modest increases in urinary coproporphyrin excretion; this is a common finding found in many asymptomatic subjects or patients with diverse other conditions (e.g., diabetes mellitus, heavy alcohol use, liver disease, and many kinds of anemia). Such secondary coproporphyrinuria does not indicate the existence of coproporphyria.”²²

Regardless of which view is correct, an increasing number of cases are being diagnosed by clinicians. Certainly, with the increasing levels of pollutants in the environment, hormonal additives to the food chain, and the unmonitored multiple pharmacy prescriptions encountered by most humans, the potential for unmasking an underlying deficit increases.