January 4, 2001 – University of Utah School of Medicine researchers successfully have bred mutant mice with a disorder that blisters and scars the skin of human patients who are exposed to sunlight.

Above: Blistered skin on the hand of a patient with porphyria cutanea tarda. Click on this thumbnail image to access a high-resolution version for downloading. Save the graphic by placing the pointer within the image and holding down the mouse button (Macintosh), or by clicking the right mouse button (PC).

Scientists hope the mice will help them learn why some susceptible people develop porphyria cutanea tarda (PCT) and others do not. That eventually could lead to better ways to diagnose and treat PCT, which afflicts roughly one of every 5,000 people.

The mice - which develop some PCT symptoms but not skin blistering - were bred by molecular biologist John D. Phillips, hematologist James P. Kushner and other University of Utah scientists. Their research, funded by the National Institutes of Health, was published Jan. 2 in the journal Proceedings of the National Academy of Sciences.

Porphyria cutanea tarda (pronounced “pore-fear-ee-uh Q-tay-knee-uh tar-duh”) is the most common of a group of blood disorders known as the porphyrias. Each type of porphyria is caused by a deficiency of a different enzyme. The body uses eight enzymes in a multi-step process to make heme - the chemical that makes blood red and allows hemoglobin to carry oxygen through the bloodstream.

When one of the enzymes is lacking, other substances involved in heme production build up in the urine, liver, skin and other tissues to cause symptoms. Patients with PCT suffer liver damage, a possible increase in facial hair growth, and fragile skin and fluid-filled blisters on the face, arms, hands and other skin exposed to sun.

Many people who get PCT inherit one copy of a mutant gene that leaves them with half the normal level of URO-D, which is one of the enzymes used to make heme. But most people with a mutant URO-D gene do not develop symptoms. Those who suffer the skin blisters usually have a mutant URO-D gene and other risk factors. Known risk factors include:

• Alcohol abuse. Many PCT patients are alcoholics and suffer cirrhosis or other liver damage from alcohol and from PCT.
• Hepatitis C. About 80 percent of PCT patients also are infected with the liver-damaging hepatitis C virus, which is contracted most commonly by using dirty needles when injecting illicit drugs.
• Estrogen use. Some women develop PCT after using birth control pills or pills for estrogen replacement therapy after the menopause.
• A second mutant gene, named HFE, which causes hemochromatosis, a condition in which too much iron is absorbed from food, then builds up in the bloodstream and organs. It can damage the liver, heart, pancreas, hormone system and joints.

The PCT mice should help them do so. The scientists crossbred mice with the mutant URO-D gene and mice with the mutant hemochromatosis gene. After 14 weeks, the mice suffered signs of PCT, including very low activity by the URO-D enzyme and a buildup of other substances that can cause liver damage. The mice did not suffer skin blisters because they live indoors and are covered with fur, so they are not exposed to sunlight. But a buildup of toxins in their urine makes it glow orange under ultraviolet light.

Because the mice get PCT without complicating factors such as alcoholism or hepatitis C, the rodents should help researchers understand exactly how the mutant URO-D gene, excess iron and perhaps other mutant genes lead to production of the inhibitor and the appearance of PCT symptoms.

Understanding the detailed molecular causes of PCT could lead to development of a new test, perhaps in five to 10 years, to predict exactly which people will develop PCT symptoms. The test might make it possible to avoid the use of liver biopsies - removal of a small piece of liver - to diagnose PCT in people who already suffer liver damage.

PCT now is treated by 10 to 20 bloodlettings, called phlebotomies, to remove excess iron from the body. But if scientists can learn exactly how the disease happens at the molecular level, they might be able to develop treatments to interfere with that process, stopping the disease at an early stage, Phillips said.

In another study, published in December in a different journal, Kushner, Phillips and colleagues found preliminary evidence that women prone to PCT might be able to take birth control and hormone replacement therapy safely if the estrogen is applied by a patch on the skin instead of consumed in pill form.

A controversy over porphyrias began in 1985 when a University of British Columbia chemist, David Dolphin, proposed that patients with porphyria may have inspired werewolf and vampire legends centuries ago. He noted that people with PCT developed facial hair, those with several forms of porphyria had to avoid sunlight to prevent skin blistering, and that some porphyrias are treated by giving patients heme, a component of blood. Medical experts have discounted Dolphin’s theory, and porphyria patients were outraged that it placed a stigma on them.

One form of porphyria, acute intermittent porphyria, afflicted Britain’s King George III (1738-1820) with nervous system damage, purple-tinged urine and other symptoms, as depicted in the 1995 film “The Madness of King George.”

University of Utah researchers who conducted the PCT study with Phillips and Kushner were technician Laurie Jackson, now a graduate student in Texas; Michaeline Bunting, a postdoctoral fellow in genetics; Michael Franklin, a professor of pharmacology; and molecular biologist Kirk Thomas, an associate professor of medicine. They were aided by Joanne Levy and Nancy Andrews at Harvard Medical School in Massachusetts.