In this age of five-day genetic test results and 18F-DOPA PET scans to guide treatment of congenital hyperinsulinism, it’s hard to imagine the multiple steps once required to diagnose HI, keep babies safe from severe low blood sugar and put them on a path toward a normal life.

CHOP endocrinologist Charles A. Stanley, MD, remembers those days well, but not particularly fondly.

There were children who had near-total pancreatectomies when they probably could have been medically managed, if medicines like diazoxide and octreotide had been available. Or they could have had a much smaller portion of their pancreas removed, if doctors had known the difference between focal and diffuse disease and had a way to diagnose the type.

Those not-so-good-old days serve as a reminder that much of the discovery about HI and many of the advances in treatments have come out of Children’s Hospital.

Early expertise

“In the 1950s, Dr. Koop started doing pancreatectomies at CHOP,” Stanley recalled, referencing then Surgeon-in-Chief C. Everett Koop, MD, ScD, who went on to become U.S. Surgeon General. “Dr. Lester Baker developed an interest in what was called ‘idiopathic hypoglycemia of infancy’ back then.”

While doctors could test for a baby’s sugar level to find hypoglycemia, it wasn’t until 1965 that a test was created to measure insulin. That was a big step forward in figuring out hyperinsulinism. In the ’60s, CHOP was instrumental in trials of diazoxide as Dr. Baker’s growing expertise drew more and more patients to CHOP. As an Endocrinology fellow, Dr. Stanley helped with the trial. Its Food and Drug Administration approval in 1973 was a huge advance as patients who responded to diazoxide could avoid surgery.

“Dr. Baker and I saw three or four cases a year for a long time and had gotten good at managing HI,” Dr. Stanley says.

Eventually, genetic testing became available, and while it did facilitate further research to identify genes that cause HI, it didn’t help guide treatment initially.

“It used to take three months to get results — not very helpful when you’re trying to plan a baby’s surgery,” Dr. Stanley says.

Key: diffuse or focal disease?

So Dr. Stanley adapted and refined the acute insulin response test helping him distinguish between focal and diffuse disease within a matter of days. This coincided with when N. Scott Adzick, MD, MMM, arrived at CHOP as Surgeon-in-Chief in 1995.

“We’d infuse the patient with a series of agents that stimulated insulin secretion and test the baby’s blood after each infusion,” Dr. Stanley says. “Those with potassium channel mutations would respond to calcium. There was a unique pattern. We could tell in advance if it was focal disease, and then Dr. Adzick could do an intensive search during surgery to find the focal lesion instead of taking out the whole pancreas.”

Dr. Adzick would start at the tail of the pancreas, take a slice of tissue, then Dr. Stanley and a pathologist would evaluate it in a lab right off the operating room. If no abnormal beta cells were visible, Dr. Adzick would take another biopsy.

“Sometimes we evaluated as many as 27 or 28 biopsies until we hit the lesion,” Dr. Stanley says. “Dr. Adzick was comfortable in sharing the decision-making. When we’d find the lesion, he’d remove it. We had a very tight team approach, and that allowed us to leave a lot of the normal pancreas in place so the child would not only be cured of HI, but also wouldn’t get diabetes later.

“We were the only place in the country that did that.”

Center’s launch brought breakthroughs to more patients

The urgency to offer this advanced, patient-specific treatment led CHOP to create the Congenital Hyperinsulinism Center in 1998.

“We began to actively recruit HI patients because we knew we had a better way to treat these children,” Dr. Stanley says. “The hospital committed funds so we could hire and train nurse practitioners to facilitate referrals from other pediatric hospitals. We went from three or four patients a year to 15 to 20.”

The next huge leap came when Dr. Stanley had another light-bulb moment. He had been reading about research from doctors in Finland who used 18F-DOPA PET scans to find focal lesions and concluded he could apply that theory to finding the location of a focal lesion in the pancreas, saving even more of each patient’s pancreas. Again, a team approach made it happen with Endocrinology, Pathology, Radiology, Surgery and Nuclear Medicine at Penn Medicine each adding expertise.

A research study for the 18F-DOPA PET scan began in December 2004 at CHOP, in collaboration with Radiology partners from Penn who already held an FDA Investigational New Drug application, allowing them to make and study this drug in humans. Patients receive an injection of the special radioactive compound that endocrine cells in the pancreas collect and store. If patients have focal lesions, these cells light up during the PET scan about 85 percent of the time. “It’s like a beacon for me,” Dr. Adzick says. “With that roadmap, I know where to look for the lesion.”

More than 240 Patients Cured

In the 15 percent of patients where the PET scan doesn’t identify the location, Dr. Adzick relies on his vast experience of more than 500 pancreatectomies (see related story below), to find and remove the lesion. Each year, Adzick operates on 30 to 40 babies with HI, and more than 240 children have been cured of focal HI by surgery since the center opened.

Currently, genetic testing labs screen for the 10 most common HI mutations, making diagnosis of focal or diffuse disease possible in 95 percent to 97 percent of cases within a week. Dr. Stanley’s research identified three of the dozen or so genes associated with HI, and he continues to actively search for more.

In all, the HI Center treats approximately 80 children with HI annually — more than anywhere else in the world.

“Now it goes on to the next generation,” says Dr. Stanley, who handed over leadership of the center to Diva De León-Crutchlow, MD, MSCE, in 2013. “Diva is developing newer and even better treatments.”


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