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PDF--Public Access (1.693Mb) <'.~'l/Pt>.. ~y ... b..o ~<,~ #>~:r e oe~ '{]-.....~ "'c-...,e~ 1~f't,~~ February 24, 1984 ~~ ~+# "_,s,~e "P' <'\,e?'.d> ~ ~o~<?P$~ CONTACT: Carol Floyd · ~e-tC:1.'1~ -"e? OfficE=>: 21_4/688-3404 ~~> ~;v~ Home: 214/724-8007 <'\,~ 9-t-d ~f't,~ ***UT researchers study medical impact of Stormie Jones's transplant. DALLAS--Stormie Jones, the six-year-old girl who underwent a historic heart and liver transplant, may well make a far more important contribution to medical science. Researchers at The University of Texas Health Science Center at Dallas who first discovered the genetic basis of Stormie's kind of high blood cholesterol more than a decade ago have been watching closely as the child has progressed from her Valentine's Day operation. The question they want answered is: Will Stormie's donated liver begin to remove the high levels of low density lipoprotein (LDL) cholesterol from her blood? There are implications for at least one in 500 Americans who suffer from a less serious -- but nevertheless devastating -- form of the disease. Stormie has "homozygous familial hypercholesterolemia'' (FH) , -- which could be translated as a double dose of an abnormal gene causing high blood cholesterol levels. Drs. Joseph Goldstein and Michael Brown first traced out the genetics and biochemistry of this disease in the early 1970s at The UT Health Science Center. Since that time they and Drs. David Bilheimer and Scott Grundy have been working to understand and treat the disease. One in 500 Americans has "heterozygous familial hypercholesterolemia" -- that is, they inherited a mutant gene from one of their parents that produce higher-than-normal blood cholesterol levels from birth and heart attacks in early middle age. Patients like Stormie, who inherit mutant genes from both parents, have much higher cholesterol levels and develop heart attacks from atherosclerosis often during the first decade of life. Stormie's situation meant that none of her body's cells contained sophisticated mechanisms called "LDL recep~ors." In a normal person, these receptors recognize a form of cholesterol known as LDL and efficiently clear it from the blood. The receptors bond with the LDL and take it inside the cell so it can be used in manufacturing substances including cell walls and hormones. At the same time, the cell's own internal mechanism is told not to make cholesterol. Without any receptors, Stormie had no way to remove cholesterol from her blood. Her cholesterol levels were about six to eight times normal for a child her age. Work by Dr. John Dietschy, professor of Internal Medicine, has shown that the liver is vital in cholesterol removal, taking up 50 percent or more of the LDL cholesterol from blood each day. Therefore, doctors predicted a normal donated liver containing receptors (Over) could save her life. "With a normal liver, at the very least, we could get her to behave like a heterozygote. And we might even get her close to normal," says Bilheimer, professor of Internal Medicine UT researchers have shown the combination of mevinolin and colestipol was effective in lowering the cholesterol level in patients with heterozygous FH by stimulating the single normal gene to make more receptors. But their effectiveness in homozygous patients had not been studied extensively. Researchers may eventually be able to supply the missing LDL receptors through gene therapy to patients like Stormie. Bilheimer recalls hearing about Stormie's case last July when a dermatologist notified him of the cholesterol deposits on her skin. While Stormie's mother noticed yellow plaques on her buttocks and skin creases and various sites of her body when she was just three months old, her condition wasn't diagnosed until Bilheimer evaluated her. "I knew right away she was homozygous because of her age, her plasma cholesterol and the cutaneous xanthomas (plaques) on her skin." She had no history of a heart condition and no symptoms of angina (pain) or other complications with her heart at that time. She was admitted to the General Clinical Research Center (a research ward operated by the health science center) last September. A baseline evaluation was performed, and she was placed on a low-cholesterol diet. Her impaired ability to metabolize lipoprotein showed she was typical of the eight or nine other homozygous FH patients Bilheimer has studied in the past 10 years. He decided to give Stormie the experimental drug, mevinolin, to attempt to reduce her cholesterol level. In the past year, Bilheimer says he and Goldstein, professor and chairman of Molecular Genetics and professor of Internal Medicine, and Brown, professor of Molecular Genetics and Internal Medicine and director of the Center for Genetic Diseases, and Grundy, professor of Internal Medicine and Biochemistry, have learned that certain experimental drugs reduce cholesterol levels to about normal in the heterozygous form of the disease. "By manipulating regulatory processes in the body, we can actually stimulate the single remaining normal gene to make more receptors than it does in the baseline. And by giving the proper kinds of medications, we can actually induce more receptors to appear on the liver cells. That coincides with an enhanced rate of clearance of LDL from the plasma and a lower plasma cholesterol level. That is the main objective of therapy in the heterozygous patients who still have one normal LDL receptor gene," Bilheimer explains. "I told her family the experimental medication may or may not work. We agreed to try it but if it failed to work we planned to do a portacaval shunt," Bilheimer says. This operation was shown by Dr. Thomas Starzl (the Pittsburgh surgeon who performed Stormie's liver transplant) in the early '70s to lower cholesterol levels. The shunt diverts the venous blood supply from the intestine through the portal vein to the general circulation. ~ "The reason I didn't think about a liver transplant initially is because we didn't know the latest status of the operation and still considered it a relatively heroic procedure," (More) said Bilheimer. Yet after consulting with Dr. Burton Combes, chief of the Liver Unit at the health science center, he began considering a transplant. Shortly after Bilheimer's conversation with Combes, Starzl came to Dallas and described several improvements with liver transplants during the previous year. First of all, side effects such as hemorrhaging, were beginning to show up in portacaval shunt patients. Secondly, cyclosporin was improving chances for preventing rejection of transplanted organs. Also, mortality from the actual transplant itself had been reduced as surgical techniques became more sophisticated. Even with the improvements in liver transplants, there remained a 20 to 30 percent mortality rate in the first year. Yet doctors feared they were running out of options for Stormie. The disease had already ravaged her heart. Following massive damage to her heart caused by one heart attack and two subsequent coronary bypass open heart surgeries, doctors here feared Stormie's heart was too weak to withstand a liver transplant. Last October cardiologist Dr. Brian Firth and a specialist in pediatric intensive care medicine, Dr. Gary Turner performed an emergency cardiac catheterization and discovered she had a dominant left coronary artery. This meant most of her heart was being supplied by one artery instead of two. Known as stenosis, the abnormality occurs in about 10 percent of Caucasians. "I think that's why she got so sick so fast. I have seen other homozygous patients who had heart attacks but they didn't have a dominant left coronary artery. So they had a more balanced blood supply to the heart; therefore if you closed off part of one artery, enough of the heart wouln be supplied by the other to get through it. In her case, most of her heart was endangered when she developed pain," Bilheimer explains. Following the catheterization, Stormie was transferred to Presbyterian Hospital where she had a double coronary artery bypass graft operation. Afterwards, she seemed to be improving and returned to the General Clinical Research Center to begin experimental drug trials. Shortly after she began the medication, however, she developed problems and the medication was discontinued until her condition could be stabilized. She was sent to Children's Medical Center at Dallas briefly and then home to Cumby, Texas. One night in early December she developed severe chest pain and was rushed to Hopkins County Memorial Hospital in Sulphur Springs near Cumby. Dr. Robert Stenberg, a second-year Parkland medicine resident who was familiar with Stormie's case, was working in the emergency room that night. "Not only was it lucky that one of our medical residents was there, but it also happened to be one of our residents who had worked with me on Parkland wards in September and October, and I had been telling him about Stormie Jones, this little six-year-old girl with coronary heart disease. And here she was brought in with severe angina, and he immediately put two and two together and knew what he was faced with. So he didn't have to sit there struggling with a rare disease. It was just dumb luck that he happened to be there," Bilheimer recalls. Stenberg says he knew instantly who Stormy was. "It's not too many six-year-olds who have a scar on their (Over) chest from an open-heart operation." He adds: "It was unbelievable. It wasn't like it was common knowledge around Parkland who Stormie Jones was. It was a stroke of luck that I had worked with Dr. Bilheimer those two months." Stormie suffered a seizure -- doctors think she had a cardiac arrest -- in the ER before making the 80-mile trip to Children's intensive care unit.
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