Approaches to Biliary Atresia Care at Cincinnati Children’s - Alex Miethke, MD - Advances in establishing an early diagnosis
With Dr. Alex Miethke
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What the experts said
Biliary atresia incidence is far higher in the Far East than North America, occurring in 1 in 20,000 live births in North America.
At Cincinnati Children's, 42% of biliary atresia transplant recipients (53 total, data from 2000s) were unpalliated—never underwent Kasai—representing a failure to diagnose early enough.
The targeted age for Kasai should be less than 45 days of life, based on the French study outcomes.
Acholic stool is a major red flag for biliary atresia.
GGT levels are as predictive of biliary atresia as many more sophisticated tests.
MMP-7 is a matrix metalloproteinase important in degrading macromolecules, directly related to fibrosis.
In MMP-7 validation studies, the intrahepatic cholestasis comparator group was primarily idiopathic cholestasis, not Alagille or alpha-1 antitrypsin deficiency.
Cincinnati integrates MMP-7 into first-line outpatient workup for cholestasis, alongside liver function tests, GGT, and CMV testing, with the goal of completing workup by 35 days of life to enable Kasai by 45 days.
The combination of non-invasive tests (GGT, family history, MMP-7) may be as good as liver biopsy for diagnosing biliary atresia, potentially allowing direct progression to intraoperative cholangiogram.
MMP-7 values are surprisingly homogeneous across biliary atresia subtypes (splenic malformation, viral, genetic).
The composition of the non-biliary atresia intrahepatic cholestasis comparator group affects MMP-7 test performance; alpha-1 antitrypsin deficiency can cause bile plugs and confound diagnosis even on liver biopsy.
MMP-7 is validated for outpatient differentiation of biliary atresia from idiopathic neonatal cholestasis, not for separating from Alagille syndrome, so additional workup is still required.
In NICU settings, MMP-7 separates biliary atresia from TPN cholestasis and Alagille, but studies showing very high sensitivity/specificity excluded rare genetic causes.
Congenital heart disease patients tend to have elevated MMP-7 levels, making the test less specific in that population.
MMP-7 on dried blood spots could improve newborn screening specificity beyond direct bilirubin alone, reducing the number of false positives requiring workup.
MMP-7 is only clinically useful if turnaround time is 2-3 days; longer turnaround negates its value for timely diagnosis.
Studies that failed to reproduce high MMP-7 sensitivity/specificity used different ELISA assays; the test is highly dependent on the right assay and sufficient case volume to establish robust cutoffs.
Liver biopsy performed before 30 days of life can show an incomplete histologic picture (e.g., missing bile plugs, only stromal edema present), making diagnosis harder and requiring expert pathology review.
The most critical diagnostic challenge is avoiding Kasai in Alagille syndrome patients, as surgery precipitates a higher likelihood of transplant.
Intraoperative cholangiogram in Alagille patients can be very difficult to interpret because the ducts are so hypoplastic.
Genetic testing for Alagille syndrome takes several weeks, underscoring the need for early referral to reduce OR uncertainty.
In Kasai's 1968 series of 24 patients, 5 were classified as cured, all of whom underwent surgery between 2 and 3 months of life; none who had surgery at 4-5 months survived.
In the Childhood Liver Disease Research Network prospective study of 136 biliary atresia patients, 46% survived the first 2 years without death or transplant after Kasai.
Undergoing Kasai after 75 days of life carries a 1.73 hazard ratio for requiring transplant within the first two years, compared to earlier surgery.
A French retrospective study of 740 biliary atresia patients (1986-2002) showed that those who underwent Kasai before 30 days or between 31-45 days had 50% 12-year native liver survival, significantly better than those operated at 75-90 days or not operated.
Taiwan's stool card screening program decreased the age at biliary atresia diagnosis.
A Texas screening program measured direct bilirubin in 120,000 infants within the first 60 hours of life, with confirmation at two-week well-child check, identifying 7 biliary atresia patients and reducing age of referral to a specialist from 56 to 36 days.
Meta-analysis of stool card screening in Taiwan, China, and Japan showed reduction in average age at Kasai from 60-70 days to less than 60 days, with several studies showing significant pre/post differences.
Screening for biliary atresia is effective but remains very expensive, requiring more research on cost-effectiveness.
NASPGHAN guideline states that any direct bilirubin >1 mg/dL (not >20% of total, not >2, not >1.5) should trigger workup for cholestatic liver disease including biliary atresia.
In an Iranian study of 64 patients (half with biliary atresia, half with intrahepatic neonatal cholestasis), ultrasound had only 50% sensitivity for diagnosing biliary atresia.
A Chinese AI deep learning system trained on ultrasound images from 330 biliary atresia and 800 non-biliary atresia patients achieved 0.95 area under ROC curve in prospective validation (102 biliary atresia, 196 non-biliary atresia), outperforming expert radiologists.
MMP-7 (matrix metalloproteinase 7) was identified as a biliary atresia biomarker in early transcriptomic studies by Bezerra's group 20 years ago.
Using SOMA scan proteomics on Childhood Liver Disease Research Network serum samples (obtained at ~2 months of life), MMP-7 and ENPP-7 were the most sensitive biomarkers for biliary atresia.
A large Chinese validation study showed high MMP-7 sensitivity and specificity, but the comparator was primarily CMV and idiopathic cholestasis, not Alagille or alpha-1 antitrypsin deficiency.
UK and Iran studies did not show high MMP-7 sensitivity and specificity for biliary atresia.
A Taiwan study showed that MMP-7 level >10 at 6 months after Kasai predicts poor outcome (transplant requirement within first 2 years).
UT Southwestern/Cook Children's lab is working to run MMP-7 tests daily with next-day results.