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Key Histopathologic Features of Liver Biopsies That Distinguish Biliary Atresia From Other Causes of Infantile Cholestasis and Their Correlation With Outcome

A Multicenter Study

Russo, Pierre MD; Magee, John C. MD; Anders, Robert A. MD, PhD; Bove, Kevin E. MD; Chung, Catherine MD; Cummings, Oscar W. MD; Finegold, Milton J. MD; Finn, Laura S. MD; Kim, Grace E. MD; Lovell, Mark A. MD; Magid, Margret S. MD; Melin-Aldana, Hector MD; Ranganathan, Sarangarajan MD; Shehata, Bahig M. MD; Wang, Larry L. MD, PhD; White, Frances V. MD; Chen, Zhen MS; Spino, Catherine ScD the Childhood Liver Disease Research Network (ChiLDReN)

The American Journal of Surgical Pathology: December 2016 - Volume 40 - Issue 12 - p 1601–1615
doi: 10.1097/PAS.0000000000000755
Original Articles

The liver biopsy guides diagnostic investigation and therapy in infants with undiagnosed cholestasis. Histologic features in the liver may also have prognostic value in the patient with biliary atresia (BA). We assessed the relative value of histologic features in 227 liver needle biopsies in discriminating between BA and other cholestatic disorders in infants enrolled in a prospective Childhood Liver Disease Research Network (ChiLDReN) cohort study by correlating histology with clinical findings in infants with and without BA. In addition, we reviewed 316 liver biopsies from clinically proven BA cases and correlated histologic features with total serum bilirubin 6 months after hepatoportoenterostomy (the Kasai procedure, HPE) and transplant-free survival up to 6 years. Review pathologists were blinded to clinical information except age. Semiquantitative scoring of 26 discrete histologic features was based on consensus. Bile plugs in portal bile ducts/ductules, moderate to marked ductular reaction, and portal stromal edema had the largest odds ratio for predicting BA versus non-BA by logistic regression analysis. The diagnostic accuracy of the needle biopsy was estimated to be 90.1% (95% confidence interval [CI]: 85.2%, 94.9%), whereas sensitivity and specificity for a diagnosis of BA are 88.4% (95% CI: 81.4, 93.5) and 92.7% (95% CI: 84.8, 97.3), respectively. No histologic features were associated with an elevated serum bilirubin 6 months after HPE, although it (an elevated serum bilirubin) was associated with an older age at HPE. Higher stages of fibrosis, a ductal plate configuration, moderate to marked bile duct injury, an older age at HPE, and an elevated international normalized ratio were independently associated with a higher risk of transplantation.

*Department of Pathology and Laboratory Medicine, the Children’s Hospital of Philadelphia, Philadelphia, PA

¶¶Department of Pathology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA

Departments of Surgery

§§§Biostatistics, University of Michigan, Ann Arbor, MI

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD

§Division of Pediatric Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Department of Pathology, Indiana University School of Medicine, Indianapolis, IN

#Department of Pathology, Texas Children’s Hospital, Houston, TX

**Department of Pathology, Seattle Children’s Hospital, Seattle, WA

††Department of Pathology, University of California San Francisco, San Francisco, CA

***Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, CA

‡‡Department of Pathology, Children’s Hospital Colorado, Aurora, CO

§§Department of Pathology, Kravis Children’s Hospital, Mount Sinai Health System, New York, NY

∥∥Department of Pathology, Ann & Robert H. Lurie Children's Hospital, Chicago, IL

##Department of Pathology, Children’s Healthcare of Atlanta, Atlanta, GA

†††Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO

‡‡‡Quest Diagnostics, Health Informatics, Madison, NJ

Division of Pathology, The Hospital of Sick Children, Toronto, ON, Canada

Conflicts of Interest and Source of Funding: Supported by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and from the National Center for Advancing Translational Sciences (NCATS) UL1 grants: DK 62445 [Mt Sinai School of Medicine], DK 62497 and UL1 TR000077 [Cincinnati Children’s Hospital Medical Center, University of Cincinnati], DK 62470 [Baylor College of Medicine], DK 62470 [Children’s Healthcare of Atlanta, Emory University], DK 62481 and UL1 TR000003 [The Children’s Hospital of Philadelphia, University of Pennsylvania], DK 62456 [University of Michigan], DK 84536 and UL1 TR000006 [Riley Hospital for Children, Indiana University], DK 84575 and UL1 TR000423 [Seattle Children’s Hospital, University of Washington], DK 62500 and UL1 TR000004 [UCSF Children’s Hospital, University of California San Francisco], DK 62503 and UL1 TR000424 [Johns Hopkins School of Medicine], DK 62466 and UL1 UL1 TR000005 [Children’s Hospital of Pittsburgh, University of Pittsburgh], DK 62453 and UL1 000154 [University of Colorado Denver, The Children’s Hospital Colorado], DK 62452 and UL1 TR000448 [Washington University School of Medicine, St Louis, St Louis Children’s Hospital], DK 84538 and UL1 TR000130 [Children’s Hospital Los Angeles, University of Southern California], DK 62436 and UL1 TR000150 [Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University. C.S. is employed by the University of Michigan, an entity that has received grant funds from Childhood Liver Disease Research Network (ChiLDReN). J.C.M. has received grant funding from NIDDK and Novartis. Z.C. provided data analysis for Saber. H.M.-A. received travel expenses from the NIDDK. F.V.W. received travel expenses through her PI’s NIDDK grant for this study (Dr Yumi Turmelle, Washington University School of Medicine). P.R. received grant funds. L.S.F. received travel reimbursement from NIDDK. B.M.S. has received travel expenses from NI. G.E.K. has received travel expenses from the NIDDK. For the remaining authors none were declared.

Correspondence: Pierre Russo, MD, Department of Pathology and Laboratory Medicine, the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, 324 South 34th Street, Philadelphia, PA 19104 (e-mail:

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