As I listened to our fellow present the case of a 5-month-old infant referred for evaluation of persistent jaundice, painful memories of several similar cases flashed by, causing me to ask, "Is this another late diagnosis of biliary atresia?"
This infant was noted to be icteric at the standard 2-week well-child visit. His serum total bilirubin level was elevated (5.4 mg/dL). However, this and the yellow skin were dismissed by the primary care team as being typical for newborns. Despite the continued concerns expressed by his parents, the infant was not further evaluated. At 4.5 months of age, the distraught parents sought a second opinion. He was gaining weight poorly, his stools appeared pale, and his abdomen was distended. On exam, the liver was found to be enlarged.
It was at this point that the child was referred to us. However, by then, the delay in assessment had already decided his fate: He had developed cirrhosis. Our evaluation for jaundice was transformed into one for liver transplant.
The Consequences of Late Diagnosis
In contrast to newborns with physiologic unconjugated hyperbilirubinemia, which is common and benign, biliary atresia (conjugated hyperbilirubinemia) deserves great respect.
This disease results from a rapidly progressive inflammatory and fibrosing injury to the extrahepatic bile ducts, which interrupts bile flow and leads to severe liver injury. Progression of the disease occurs in the first weeks of life, with cirrhosis and portal hypertension uniformly noted at 8-12 weeks of life. It is for these reasons that, despite its relative rarity, biliary atresia is the leading indication for liver transplantation in children, accounting for > 40% of cases.
The initial approach to infants with biliary atresia is surgical palliation via Kasai portoenterostomy (also known as hepatoportoenterostomy), the goal of which is to restore bile flow and forestall progression of hepatic fibrosis. Successful bile drainage is possible in 70%-80% of cases if this procedure is performed before 60 days of age. This might be too optimistic, though, as many centers average approximately 50% owing to many late referrals. Unfortunately, widespread education programs conducted for the past several decades have not reduced the average age at which this procedure is performed in biliary atresia.
In our case, the late diagnosis could have been avoided with prompt recognition. Neonatal jaundice is often considered to be physiologic, or due to breast milk, and thus inconsequential. The problem is that further evaluation is often not pursued, despite the recommendation from the American Academy of Pediatrics to test serum total and fractionated (ie, direct or conjugated) bilirubin levels in all infants with jaundice that persists beyond the first 2 weeks of life. In addition, guidelines from the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition recommend completion of diagnostic evaluation, or at least exclusion of biliary atresia, by 45-60 days of age.
The Traditional Diagnostic Strategy
The first critical step is to recognize that a jaundiced infant has cholestasis (an elevated serum direct or conjugated bilirubin level). Granted, this is not without its challenges; early differentiation in clinical practice can be difficult, owing to the commonality of signs and symptoms among infants with cholestasis. However, the findings of persistent jaundice, hepatomegaly, acholic stools, and poor growth should strongly suggest biliary atresia.
Standard liver tests (ie, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase [GGT]) have low sensitivities and therefore do not aid in the differential diagnosis when used alone. Hepatobiliary iminodiacetic acid scans are frequently used to exclude biliary atresia, although misinterpreting these scans has been shown to delay diagnosis and subsequent surgical intervention.
Liver ultrasonography may reveal the absence of a gallbladder, which is suggestive of biliary atresia. Liver biopsy, however, remains the most diagnostically accurate tool. The characteristic biopsy findings include obstruction, bile duct proliferation, portal expansion or fibrosis, and bile duct plugging. These findings would inform surgical exploration with operative cholangiography and/or pathologic examination of the bile duct remnant to confirm the diagnosis of biliary atresia.
So, in practice, our objective is to minimize the number of infants referred for exploration — and avoiding unnecessary surgery — while precisely recognizing the infant with biliary atresia without delay.
Embracing New Screening Approaches
Infant stool color cards have proven valuable screening tools for biliary atresia since being introduced in Taiwan in 2004. These parent-empowered stool cards have now been successfully adopted in such countries as Canada, Switzerland, and Brazil, and evidence shows that their use significantly improves jaundice-free native liver survival from 32% (pre–screening era) to 57% (post–screening era). Although economic analysis has shown that screening with stool color cards would be highly cost-effective in the United States, this strategy has not yet been widely adopted.
There is also incredible promise in two minimally invasive, highly discriminatory strategies for screening: direct or conjugated bilirubin level and serum matrix metalloproteinase 7 (MMP-7) level.
Harpavat and colleagues reported the value of obtaining serum bilirubin levels measured early after birth, showing that 56% (34 of 61) of newborns with biliary atresia had elevated direct or conjugated levels within 17 hours of life.
In a 2020 cross-sectional screening study, investigators assessed 124,385 infants born at 14 Texas hospitals over 3 years, finding that 99% had conjugated or direct bilirubin tested within the first 60 hours of life. Newborn screening with direct or conjugated bilirubin measurements detected all known infants with biliary atresia in the study population. Also encouraging was the finding that the mean age at which infants underwent Kasai portoenterostomy was significantly younger after screening was implemented (36 vs 56 days, respectively). As a result, 1-year transplant-free survival after Kasai portoenterostomy was also higher after screening was put in place (95% vs 71%).
The serum MMP-7 level, which reflects the progressing severity of liver fibrosis, is another emerging diagnostic biomarker for biliary atresia, which may also serve as a therapeutic target.
Lertudomphonwanit and colleagues used proteomics to screen serum samples obtained from 35 infants at the time of diagnosis of biliary atresia and 35 age-matched infants diagnosed with intrahepatic cholestasis. The combination of serum levels of MMP7 and GGT differentiated between the two diseases with an area under the receiver-operating characteristic curve of 0.98, outperforming all other individual proteins or serum markers.
Subsequent studies further established the high sensitivity and specificity of MMP-7 for differentiating biliary atresia from other neonatal cholestasis, as well as its diagnostic accuracy in 100 infants with cholestasis and 288 with neonatal obstructive jaundice.
We Can Do Better
Although it is well established that age at diagnosis is the key factor associated with outcomes in infants with biliary atresia, the nonspecific clinical and biochemical features of this entity and other forms of neonatal cholestasis present a diagnostic challenge. The discovery of minimally invasive biomarkers highly predictive of biliary atresia may allow us to address those limitations through timely diagnosis and stratification of care.
Biliary atresia is a rare disorder that a clinician may see only a few times in practice, but its tragic consequences merit our keeping a vigilant watch for it in patients. Efforts to combat its effects would be greatly aided by a well-organized national newborn biliary atresia screening program.
Let's not waste any more time in our efforts to do better at identifying and treating biliary atresia.
William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; Director Emeritus, Pediatric Liver Care Center; Medical Director Emeritus, Liver Transplantation; and Professor, University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center. He has served as director of the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for Medscape. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.
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Cite this: Why Biliary Atresia Demands Our Respect - Medscape - Aug 19, 2020.