By Allison Proffitt
August 11, 2016 | Doctors at Baylor College of Medicine and Texas Children’s Hospital
report a way to detect biliary atresia and other neonatal liver diseases
in newborns with a blood test. Their research appears in a letter
published in the current issue of the New England Journal of Medicine (DOI: 10.1056/NEJMc1605166).
Biliary
atresia is a life threatening and hard-to-detect disease of the liver
and bile ducts in which bile accumulates in the liver instead of
draining into the intestines. Newborns with biliary atresia appear
normal at birth, but damage to the liver is severe and rapid.
"If
you look at a biliary atresia child's liver at three weeks of life, it
has more fibrosis than most liver diseases known to man," Sanjiv
Harpavat, assistant professor of pediatrics, gastroenterology,
hepatology and nutrition at Baylor and Texas Children’s, told
Diagnostics World. "The fact that the liver can't excrete the bile
properly leads to really, really severe problems really fast."
The
disease accounted for about 60% of liver transplants in infants less
than one year of age from 2005 to 2014. "This is a field that already
has a shortage of livers, and kids actually die on the waiting list.
Biliary atresia accounts for most of those transplants," Harpavat said.
If
the disease is caught early enough, a Kasai hepatoportoenterostomy, a
surgery developed in the 1950s, can connect the liver directly to the
small intestine to help bile drain. The success of the Kasai procedure
is varied, but a good outcome is more likely if the operation is
performed before 30 to 45 days of life. Unfortunately, in the United
States, infants with biliary atresia are usually identified later and
the average age at surgery is 60 to 70 days.
Harpavat
was looking for a way to get ahead of the disease. "What we're
presenting here is a way to catch children really at the time of birth
and give them a diagnosis and treatment before 30 days of life," he
said.
Harpavat and his colleagues looked to a
bilirubin test that all newborns in the United States already get within
the first 48 hours after birth. All newborns are screened for total
bilirubin, a measure linked to jaundice that determines whether babies
need phototherapy.
"But every machine returns a
direct bilirubin results in addition," Harpavat explained. Direct
bilirubin is a measure of liver disease, and yet there are no published
guidelines on how to use that test result in newborns. "Oftentimes it's
just overlooked."
Harpavat and his colleagues
were curious about how early they could find evidence of disease, so
they called the birth hospitals for all of their biliary atresia
patients and asked if the direct bilirubin scores had been recorded.
"Our
hypothesis was, if that direct bilirubin was normal, then they didn't
have disease [at birth], and they'd developed disease in the next few
days," Harpavat said. "What we found was that every single child without
exception had high direct bilis [bilirubin scores] at birth."
To
determine if a direct bilirubin test could help early diagnosis of
biliary atresia, the researchers screened over 11,000 infants born in
four hospitals around Houston during a 15-month period. All of the
infants in the study were screened at birth, and those identified as
having direct bilirubin scores exceeding the 95th percentile were
rescreened at or before their first well-child visit.
A
total of 11 infants retested positive at the median age of 14 days.
Eight of those children had what Harpavat called "slight" elevations in
the direct bilirubin levels, levels "not consistent with liver disease,"
he said.
The three remaining children had
significant rises between the two tests, and visited pediatric
hepatologists for liver biopsy. Two were found to have biliary atresia,
and the third had a different liver condition.
"One
you can call a false positive," Harpavat said. "It's not biliary
atresia, but it's still a liver condition we needed to know about."
Only
one of the biliary atresia patients was well enough for surgery. (The
second child had a congenital heart defect that precluded the
procedure.) The child underwent the Kasai hepatoportoenterostomy at 26
days, and now, two years later, is still transplant free.
The
sample size was very small, but Harpavat is enthusiastic that the
screen will enable much earlier diagnosis of biliary artresia—without
additional tests—and could lay the groundwork for a national newborn
screening recommendation.
"The data was before
us all along. With a brand new screening test we'd have to think about
cost and we'd have to think about acceptability. The beauty of this test
is everything is already here. Everything is already in place,"
Harpavat said.
The pilot program has been
expanded to 10 hospitals in Houston and South Texas, but doctors are
already taking note of the findings for their patients.
Researchers
worked closely with primary care pediatricians throughout the city
during the pilot study, offering guidance and education when a patient
tested positive initially, Harpavat said, and physicians have been
incorporating what they've learned into their own practice to identify
infants with biliary atresia earlier who were not part of the screening
protocol.
"This is a great side story,"
Harpavat said. "It's totally not scientific research, but doctors are
starting to pay attention to the direct bilirubin and if it's high they
are actually calling us and we're able to pick up kids that way and
deliver early care to children throughout Houston, even if they aren't
on the pilot... These kids are getting tremendous benefit."