This is a 4-week-old female who presents to the office with increasing jaundice over the last week. Her parents report that 2 weeks ago, she began to have yellowing of her eyes with subsequent yellowing of her skin when she was diagnosed with physiologic jaundice. After persistent jaundice for 5 days, her parents switched her from breast-feeding to a commercial formula. Since the jaundice appeared to be worsening, her parents decided to bring her in for re-evaluation. Her stools have been pale in color for the past 10 days along with darker urine.
The patient was born by spontaneous vaginal delivery to a G2P1 A+ mother at 39 weeks. There were no complications noted at birth, in the nursery, or after discharge home. The patient was not jaundiced at discharge or at the initial office visit.
Exam: VS are normal. Weight and height are at the 60th percentile. She is awake, alert, in no acute distress. Her skin is jaundiced, most notably in the cephalic and truncal areas. Scleral icterus is noted. Her liver is slightly enlarged but without nodularity. No splenomegaly is noted. The remainder of her exam is unremarkable.
Laboratory examinations reveal a total bilirubin of 15 mg/dL, direct bilirubin of 12.3 mg/dL, ALT 45 U/L, AST 52 U/L, and an alkaline phosphatase of 2007 U/L. The patient undergoes a HIDA scan after 5 days of phenobarbital therapy. The scan shows normal uptake by the liver but no excretion of the isotope (i.e., no bile flow) into the bowel even after 24 hours. She is referred to the surgical service for evaluation. She is then scheduled for a percutaneous liver biopsy, laparotomy with intraoperative cholangiogram, and possible Kasai procedure.
Biliary atresia (BA) is a serious cause of infantile cholestasis and the most common cause of liver transplantation in children. BA is characterized by progressive fibrosis and obliteration of the extrahepatic biliary system with involvement of the intrahepatic bile ducts. The incidence of BA is approximately 1 in 10,000 to 15,000 live births in the United States with a slight female predominance. Incidence appears to be higher among Asians, African Americans, and preterm infants (1,2,3).
According to one classification system, there are 4 major types of BA that are described: isolated BA (80% of cases), cystic BA (5% to 10% of cases), cytomegalovirus (CMV)-associated BA (variable incidence based on geographic location), and BA splenic malformation (BASM) syndrome associated with congenital malformations such as laterality defects, polysplenia, or congenital cardiovascular, gastrointestinal, or genitourinary disease (5% to 10%). Other variants such as BA without laterality defects also exist (4).
The etiology of BA likely involves multiple factors, including viral infection, environmental exposures, toxins, genetic predisposition, and autoimmune responses. The viruses of relevant clinical significance include CMV, reovirus, and rotavirus. Additionally, the presence of immunoglobulins against CMV has been linked to poor hepatoportoenterostomy (Kasai procedure) outcomes, and the largest body of evidence supporting a viral etiology pertains to CMV (3). Developmental abnormalities of the hepatobiliary system may lead to increased susceptibility to bile duct injury and potential for a fibrotic inflammatory response after birth. Studies to identify specific gene defects remain ongoing. There is also growing evidence that suggests autoimmunity and involvement of the innate immune system in disease onset (5,6).
The signs and symptoms of biliary atresia will be dependent upon the time of presentation. Typically, the patient is born at term with a normal birth weight. On physical exam, the patient may have an enlarged, firm liver (palpable 2 to 6 cm below the right costal margin). Jaundice can be present at birth or present as late as 3 to 5 weeks of life. Other than jaundice, another common finding is acholic stools, which are highly suggestive of cholestasis but may not be present early in the disease course (6). There can be some pigment in the stool due to sloughing of cells that contain pigments. However, this pigment is only present superficially with the core of the stool remaining pale. Since bile pigments are no longer released into the stool, they deposit in the urine leading to a darkened color. Fat malabsorption may put infants at risk for failure to thrive. Signs of portal hypertension such as ascites, variceal bleeding, and splenomegaly may develop within the first year of life or later (2).
Laboratory examination will show an elevated total bilirubin with an increased direct (conjugated) bilirubin. Serum aminotransferase levels will tend to be mildly or moderately elevated. Alkaline phosphatase and serum gamma-glutamyl transpeptidase will also be elevated (6). Serum albumin and blood coagulation studies are typically normal early in the disease process. However, none of these findings are specific for BA (2).
There are many conditions that can cause cholestasis in the neonate that lead to jaundice. These include hepatitis (viral and other causes), sepsis, endocrinopathies, metabolic derangements such as galactosemia, and parenteral nutritional hepatotoxicities. Other diseases to consider in the differential diagnosis are idiopathic neonatal hepatitis, alpha-1-antitrypsin deficiency, cystic fibrosis, and persistent intrahepatic cholestasis disorders (1,7).
The greatest challenge is the differentiation of BA from idiopathic neonatal hepatitis and the intrahepatic cholestasis disorders. Persistent intrahepatic cholestasis disorders include intrahepatic bile duct paucity, which comprises both non-syndromic bile duct paucity and syndromic forms such as Alagille syndrome. These are characterized by the absence or marked decrease in the number of intrahepatic interlobular bile ducts with normal sized arteries and portal veins. These diseases are diagnosed by the presence of cholestasis and bile duct paucity on liver biopsy. In Alagille syndrome, or arteriohepatic dysplasia, there are characteristic facies along with ocular, cardiovascular, vertebral, and renal pathologies (1).
Efforts must be made to diagnose BA early since the success of intervention is time dependent (earlier the better). When a child presents with jaundice, the first step is to evaluate the total and fractionated bilirubin. In contrast to elevated unconjugated bilirubin, if the elevation is in the conjugated (direct) fraction, or the direct fraction is 20% or greater of an elevated total bilirubin, then cholestasis is significant (1). If the presence of cholestasis is established, the etiology must be determined promptly. Panels of testing can quickly rule out or diagnose entities such as hypothyroidism, galactosemia, tyrosinemia, alpha-1-antitrypsin deficiency, and infectious diseases. Once these diseases are ruled out, the challenge is to determine if the patient has idiopathic neonatal hepatitis or BA (1,6).
Ultrasound is a somewhat useful imaging modality since it is noninvasive. BA findings may show a small, atrophic gallbladder. The triangular cord sign (a triangular or cone-shaped fibrotic mass just proximal to the portal vein bifurcation) might be seen in some cases (1,7). However, the presence of a normal gallbladder on ultrasound does not rule out BA. BA could be extrahepatic, intrahepatic, or both. Even with extrahepatic BA, the ducts could be fibrosed with no bile flow which is why normal biliary anatomy on ultrasound does not rule out BA.
Other non-invasive testing for BA includes the use of hepatobiliary scintigraphy with the use of 99mTc DISIDA (diisopropyl iminodiacetic acid) scan, which is favored over the HIDA (hepatobiliary iminodiacetic acid) scan because DISIDA will visualize bile excretion at higher bilirubin levels. Images consistent with BA will show normal uptake by the liver with no excretion into the bowel even after 24 hours. The diagnostic yield of the DISIDA scan can be increased by pretreatment with phenobarbital (5mg/kg/24h PO for 5 days prior to study) to increase the excretion of isotope. If the DISIDA scan demonstrates bile flow from the liver to the duodenum and the biliary tree is visualized, then BA is ruled out and the work-up can stop (1).
A useful procedure for the diagnosis of BA is percutaneous liver biopsy. When handled by an experienced pathologist familiar with BA, biopsy is reported to have a diagnostic accuracy ranging from 90% to 95% (7). Findings include early preservation of hepatic architecture, edema of the portal tracts, presence of bile duct plugs, tortuous proliferation of bile ductules, fibrosis, and intracellular and canalicular cholestasis. There is also a mixed infiltration of inflammatory cells with possible giant cell formation (6). However, giant cell transformation can also be seen in children with idiopathic neonatal hepatitis. If the biopsy shows absence or reduction in the amount of interlobular bile ducts at the portal triad with an intact biliary tree on scintigraphy, then a diagnosis of intrahepatic bile duct paucity is established (1).
Management of all patients with suspected BA should include exploratory laparotomy with intraoperative cholangiography. If an intact biliary tree is visualized, then an intraoperative cholangiogram is performed in which the surgeon cannulates the bile duct and injects contrast to determine if the biliary ducts are patent. A normal cholangiogram shows contrast flowing into the intrahepatic ducts, common hepatic ducts, common bile duct, and duodenum. The presence of contrast in the duodenum rules out extrahepatic BA as an etiology. Non-patency indicates sclerosed ducts and extrahepatic biliary atresia (7). This diagnostic algorithm is summarized below.
Diagnostic algorithm of biliary atresia:
If BA is limited to fibrosis of the distal biliary tree with patency of the proximal biliary tree and the intrahepatic bile ducts, excision of the fibrotic area and direct drainage into the bowel is performed (1).
More commonly, the biliary system is fibrotic to the level of the porta hepatis. These patients need to undergo the Kasai procedure to establish bile flow. The Kasai procedure is the Roux-en-Y hepatoportoenterostomy where the porta hepatis is attached to a loop of bowel after resection of the fibrotic biliary system. This procedure anastomoses the liver directly to the bowel so that, in theory, bile can flow from the liver into the bowel. At the porta hepatis, there are microscopic bile ductules that have proliferated which communicate with the intrahepatic ductule system. Examination of frozen tissue sections from the porta hepatis can be used to determine residual bile duct size and patency (1).
The success of the Kasai procedure depends largely on two factors: age at procedure and experience of the center it is performed at. To obtain maximum benefit from the Kasai procedure, it should be performed before the patient is 90 days of age, ideally less than 60 days. This is the major reason why the diagnostic determination of whether BA exists must be done expeditiously. Establishment of bile flow is achieved in 90% of the patients who are less than 2 months of age. Approximately one-third of patients will have failure to reestablish bile flow (2). The decrease in the success rate of the Kasai procedure with advancing age is due to progressive damage to the liver from untreated BA (i.e. further back-up of bile flow inflicts additional damage to the existing intrahepatic ducts). The other factor is the experience of the center performing the surgery. Outcomes of the procedure and post-procedure survival are improved when the hospital does more than 5 procedures a year (7).
If the child is diagnosed at an age greater than 12 weeks (3 months), the Kasai procedure has a lower probability of success. However, it is the general consensus that a patient should undergo the Kasai procedure even if he/she presents at an age greater than 3 months if it is possible that bile flow can be established. While a post-Kasai transplant is technically more difficult, there is no reported change in survival after transplantation in patients who underwent primary transplantation versus those who had a failed Kasai procedure prior to transplant. In patients who initially had successful bile flow post-Kasai, liver transplantation occurs at roughly 5 years of age (7).
Ascending cholangitis is the most common complication of the Kasai procedure (7). The etiology for this is both anatomic and bacterial. Bowel bacteria have access to the existing bile ducts and hepatic tissue. The normal anatomy of an intact bile duct prevents bowel contents from refluxing up towards the liver. In the Kasai procedure, bowel contents containing digestive enzymes have direct access to the existing bile ducts and hepatic tissue causing the cholangitis. Repeated episodes of cholangitis can thus lead to extensive liver damage and cirrhosis. An anti-refluxing valve can be surgically created within the duodenal segment anastomosed to the liver, but such alterations in the Kasai procedure and various medical regimens have not proven successful. The effectiveness of long-term antibiotic prophylaxis has not been fully determined (3).
Another common complication of BA is portal hypertension. This occurs due to the progressive inflammation and fibrosis of the intrahepatic biliary system and/or repeated episodes of cholangitis leading to cirrhosis. The portal hypertension that develops will have sequelae such as varices, ascites, hypertensive gastropathy, hypersplenism, and encephalopathy. Esophageal variceal hemorrhage develops in approximately 40% of patients. Treatment relies on the same methods employed in adults for other forms of portal hypertension (i.e. fluid resuscitation, octreotide, variceal band ligation or sclerotherapy, or surgery) (2). If left untreated, BA ultimately results in mortality by age 18 to 24 months secondary to hepatic failure and biliary cirrhosis (2).
After the Kasai procedure, patients can be stratified into 1 of 3 prognostic groups postoperatively (3,7). The first group includes the patients who produce adequate bile flow and are relieved of their jaundice. They will have long-term survival and possibly not need liver transplantation. The second group patients have moderate bile flow, but they remain jaundiced and will continue to survive post-Kasai. However, they will likely require liver transplantation later in life. The third group includes those who do not establish bile flow. These patients develop liver failure within months and require a liver transplant (7).
As mentioned above, the chance of establishing bile flow in BA patients with the Kasai procedure is dependent upon the age that the patient undergoes surgical intervention. However, it should be noted that the establishment of bile flow does not necessarily mean long-term cure since BA often results in intrahepatic inflammation that can lead to cirrhosis. Patients who undergo the Kasai procedure can survive with their native liver in about 50% of cases, but the remainder will eventually require liver transplantation (3,7). Five-year survival rates of patients with BA post intervention are expected to surpass 90%. Ten-year survival ranges from 30% to 70% depending on patient age at operation. Survival with one's native liver at 20 years is reported to be less than 50% (7).
BA is no longer a fatal disease in all who are diagnosed with it. The early diagnosis and treatment of BA can lead to long-term survival without the need for liver transplantation. This requires that surgery be performed in a timely manner at a high level center to increase the likelihood of success. Efforts to introduce screening methods for BA have been attempted with mixed results. Stool color cards are a simple method that can help detect acholic stools and have been used with some success internationally. These cards are printed with photographs of normal and abnormal stool colors and appearance and may be given to parents with information on what to do if they see a potentially abnormal stool (1,7). It is nevertheless important to maintain a high clinical suspicion in the jaundiced patient, especially if it is beyond the first two weeks of life.
Questions
1. True/False: A 2-week-old infant presents with persistent jaundice to the office. No further work up is necessary since this is physiologic jaundice.
2. A DISIDA scan report, for a patient in whom biliary atresia is suspected, comes back stating that there was poor uptake into the liver and no visualization of the isotope into the bowel. Can you diagnose biliary atresia in this patient?
3. A liver biopsy shows hepatocellular ballooning and the presence of multinucleated giant cells. Is this consistent with biliary atresia?
4. A patient presents to you with lightly colored stool. However, when the stool is broken up, it is noticed that the center is clay colored. What is this indicative of?
5. A 16-week-old patient is diagnosed with biliary atresia. Should the patient undergo a Kasai procedure if there are no contraindications, or should the patient simply wait for a liver transplant?
References
1. Abdel-Kader Hassan HH & Balistreri WF. Chapter 383. Cholestasis. In: Kliegman RM, St Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020. Elsevier, Philadelphia, PA. pp:2092-2101.
2. Sokol RJ, Mark JA, Mack CL, et al. Chapter 22. Liver & Pancreas. In: Bunik M, Hay WW, Levin MJ, Abzug MJ (eds). Current Diagnosis & Treatment: Pediatrics, 26th edition. 2022. McGraw Hill, New York. pp:648-694.
3. Hackam DJ, Upperman J, Grikscheit T, et al. Chapter 39. Pediatric Surgery. In: Brunicardi F, Andersen DK, Billiar TR, et al (eds). Schwartz's Principles of Surgery, 11th edition. 2019. McGraw Hill, New York. pp:1705-1758.
4. Bezerra JA, Wells RG, Mack CL, et al. Biliary Atresia: Clinical and Research Challenges for the Twenty-First Century. Hepatology. 2018;68(3):1163-1173. doi:10.1002/hep.29905
5. Yerina SE, Ekong UD. Biliary Atresia/Neonatal Cholestasis: What is in the Horizon? Pediatr Clin North Am. 2021;68(6):1333-1341. doi:10.1016/j.pcl.2021.08.002
6. Suchy, FJ & Mack CL. Chapter 62. Anatomy, Histology, Embryology, Developmental Anomalies, and Pediatric Disorders of the Biliary Tract. In: Feldman M, Friedman LS, Brandt LJ (eds). Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 11th edition. 2020. Elsevier/Saunders, Philadelphia, PA. pp:973-994.
7. Sanchez-Valle A, Kassira N, Varela VC, et al. Biliary Atresia: Epidemiology, Genetics, Clinical Update, and Public Health Perspective. Adv Pediatr. 2017;64(1):285-305. doi:10.1016/j.yapd.2017.03.012
Answers to questions
1. False. Persistent jaundice needs to be worked up before permanent damage is done by any number of pathological conditions such as BA. Since there is little risk involved, the threshold to obtain a serum fractionated bilirubin should be low. If there is an elevation of conjugated bilirubin at 14 days of age or earlier, it is due to neonatal cholestasis or BA.
2. No. With poor uptake into the liver, you can only confirm that there is cholestasis. This may be transient cholestasis due to hepatitis, or it may be due to severe damage to the hepatocytes by several possible causes, including biliary atresia. It can be difficult to rule in BA with a DISIDA scan alone, but BA can be ruled out if normal bile excretion is confirmed.
3. Yes, this histopathology is consistent with the histopathology seen with biliary atresia. However, it is also consistent with idiopathic neonatal hepatitis, and therefore, a definitive diagnosis cannot be made on this biopsy result alone.
4. The presence of clay colored or acholic stools are indicative of cholestasis. The lack of bile flow into the bowel prevents the characteristic stool coloring. The superficial light coloring is due to the sloughing of pigmented cells during the transit in the bowel and does not affect the core of the stool. This stool is abnormal and could be due to BA or other causes of cholestasis.
5. While there is reduced chance of long-term survival with the patient's native liver in someone who undergoes the Kasai procedure after 3 months of age, there is some benefit. The Kasai procedure can lead to extended survival time with the native liver, allowing the patient to stabilize baseline health. There is also a benefit in that there will be longer period of time to find a donor and prepare the patient for transplantation. There is currently no cutoff age when a Kasai procedure is considered to be completely futile. However, each patient is different, and some may be better served by primary liver transplantation.