This is a 4 week old female who presents to the office with parental reports of 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 changed her from breast-feeding to a commercial formula. Since the jaundice appears 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.
She was born by spontaneous vaginal delivery to a G2P1 A+ mother at 39 weeks with Apgar scores of 9 and 9 and 1 and 5 minutes. There were no complications noted at birth, the nursery, or at discharge home. The patient was not jaundiced at discharge or when seen at initial office visits. Her highest bilirubin previously was 12.0 and her blood type is A+.
Exam: VS Normal. Weight and height are at the 60th percentile. She is awake, alert, in no acute distress and is easily comforted by her mother during the exam. Her skin is jaundiced, most notably in the cephalic and truncal areas, with scleral icterus. Her liver is slightly enlarged without nodularity. No splenomegaly is noted. The remainder of her exam is normal.
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 DISIDA scan after 5 days of phenobarbital therapy. The scan showed 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 laparotomy with intraoperative cholangiogram, wedge liver biopsy and possible Kasai procedure.
Biliary atresia (BA) is a serious cause of infantile cholestasis and the most common cause of orthotopic liver transplantation in children. BA was originally thought of as the progressive fibrosis and obliteration of the extrahepatic biliary system. However, it is now known that the intrahepatic bile ducts are also affected by the disease process (1,2). The incidence of BA is not well known with individual studies reporting an incidence ranging from 1 in 8,000 live births to 1 in 25,000 (1-5).
There are 2 types of BA that are currently recognized and described: a fetal or embryonic type and a perinatal type. The fetal type occurs in 15-35% of cases and is characterized by an earlier onset of cholestasis (1). There is an association between the fetal type and other congenital anomalies such as situs inversus, polysplenia, cardiac malformations, and other manifestations (1,2). There also tends to be a lack of bile duct remnants at the porta hepatis with the fetal form of BA. The more common form of BA is the perinatal form which occurs in 65-85% of cases and is not associated with congenital anomalies (1).
As the names imply, the initiating event of the two types are theorized to occur at different times in development with probably very different etiologies. Research has focused on the possible etiology of the perinatal form with causes including viral infections, auto-immune disease, and immune mediated damage (1,4). The viruses that are under question include CMV, reovirus, rotavirus, HPV, and retroviruses (4). Theories of the etiology of the fetal type of BA center around a possible morphogenesis defect, known as the ductal plate malformation, due to defective gene expression leading to the associated congenital anomalies (1,4). While there are possible candidates for the defective gene there has been no definitive identification. Therefore the etiology of both forms of BA remains unknown at this point.
The signs and symptoms of biliary atresia will be dependent upon the time of presentation. Usually, the patient is born at term with a normal birth weight. Jaundice can be present at birth or it can present as late as 3 to 5 weeks of life. Other than jaundice, another common complaint is acholic stools, which are highly suggestive of cholestasis. 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 (3). Since the bile pigments are no longer released into the stool, they will be deposited in the urine leading to darker urine.
On physical exam the patient will usually have an enlarged firm liver (normal averaging 4.5-5 cm at 1 week and 6-7 cm during early adolescence) (3). The presence of splenomegaly is variable and more common with later presentations as part of the constellation of portal hypertension. Patients may also present with the findings associated with the fetal form of BA including polysplenia, situs inversus, and cardiac malformations (1).
The undiagnosed infant with BA will present with a much different picture. This is due to the progressive nature of the disease. Later presentations are associated with the progression of the disease to biliary cirrhosis and the development of portal hypertension with failure to thrive (2). The clinical picture at this point will be dominated with findings suggestive of cirrhosis and portal hypertension such as jaundice, hepatosplenomegaly, a nodular liver, varices, ascites, and hepatic vascular bruits (1,3).
Laboratory examination will show an elevated total bilirubin with an increased direct (conjugated) portion. The serum aminotransferases levels will tend to be normal or mildly elevated. Alkaline phosphatase will be highly elevated reaching levels higher then 5 times normal (2). Early in the disease process there are usually no changes in coagulation studies.
There are many conditions that can cause cholestasis in the neonate and lead to jaundice. These include hepatitis (viral and other causes), sepsis, endocrinopathies, metabolic derangements, and nutritional hepatotoxicities (6). The most common disorders in decreasing incidence are idiopathic neonatal hepatitis, BA, alpha-1-antitrypsin deficiency, and persistent intrahepatic cholestasis disorders (2). The greatest challenge is the differentiation of BA from idiopathic neonatal hepatitis and the intrahepatic cholestasis disorders.
Idiopathic neonatal hepatitis is not the same entity as neonatal viral hepatitis. As its name implies, the cause is unknown. There have been diseases that are now described that were once under the heading of idiopathic neonatal hepatitis such as alpha-1-antitrypsin deficiency. These patients tend to present with low birth weight, early onset of jaundice, and usually have pigmented stools (2). Associated malformations are usually not found with this disease and if present should prompt the search for an alternate diagnosis. Laboratory findings include elevations in the serum aminotransferases and bilirubin. Alkaline phosphatase can be elevated but is not always. Coagulation studies may also be abnormal. A diagnosis of idiopathic neonatal hepatitis should only made when other causes of cholestasis (including BA and alpha-1-antitrypsin deficiency) are ruled out. Histologic findings include disruption of the lobular architecture with hepatocellular swelling, focal necrosis, and the presence of multi-nucleated giant cells (2,7). However, the presence of hepatocellular swelling giant cells can also be seen in BA (7). The largest portion of the workup for idiopathic neonatal hepatitis is to rule out any metabolic, infectious, genetic, or other described conditions.
Under the heading of persistent intrahepatic cholestasis disorders is intrahepatic bile duct paucity which includes 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 in the triad. Intrahepatic bile duct paucity was previously referred to as "intrahepatic bile duct atresia" or "intrahepatic biliary atresia" (6, 8). This was a misleading term that is no longer used since by definition BA is the fibrosis and obliteration of the extrahepatic biliary system, not the intrahepatic system. These diseases are diagnosed by the presence of cholestasis and bile duct paucity on liver biopsy. The non-syndromic form describes a common pathology with various etiologies, which are still poorly understood. With the syndromic forms there are characteristic findings associated with the bile duct paucity (8). For example in Alagille syndrome, or arteriohepatic dysplasia, there are characteristic facies along with ocular, cardiovascular, vertebral, and kidney pathology.
Efforts must be made to diagnose BA early since the success of intervention is dependent upon the time frame. When a child presents with jaundice, the first step is to evaluate the total and fractionated bilirubin in each patient with jaundice. If the elevation is isolated to the unconjugated (indirect) fraction of bilirubin then significant liver pathology is unlikely (3). However, if the elevation is in the conjugated (direct) fraction or it is 20% or greater of an elevated total bilirubin then cholestasis more likely (6). If the presence of cholestasis is established, then the etiology must be found in a timely fashion. Panels of testing can quickly rule out or diagnose entities such as hypothyroidism, galactosemia, tyrosinemia, alpha-1-antitrypsin deficiency, and infectious diseases. Once these items are ruled out, the challenge is to differentiate between idiopathic neonatal hepatitis and BA.
Non-invasive testing for biliary atresia currently relies on the use of hepatobiliary scintigraphy with the use of 99mTc-iminodiacetic acid compounds or HIDA scans. The newer iminodiacetic compounds have greater concentrations in the bile then the original compounds. HIDA scans using older compounds will not visualize the biliary tract if the bilirubin is high, so the currently favored compound is 99m Tc-disofenin or DISIDA. Images consistent with BA will show normal uptake by the liver with no excretion into the bowel even after 24 hours. The specificity 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 the disofenin (6,9). If the DISIDA scan demonstrates bile flow from the liver to the duodenum (i.e., the biliary tree is visualized), then BA is ruled out and the work-up can stop. Patients who demonstrate an obstructive pattern on DISIDA will have BA in 80-85% of cases (10); however, neonatal hepatitis is still possible since it can cause severe cholestasis. In patients with idiopathic neonatal hepatitis, there is slow uptake of the compound with excretion into the bowel; however, in some instances, the cholestasis is so sluggish, it cannot be reliably distinguished from BA. DISIDA scanning is less reliable with higher levels of serum bilirubin, however bowel activity is still observed with hyperbilirubinemia as high as 20-30 mg/dL. If there is poor uptake by the liver without bowel activity it is indicative of severe hepatocyte damage that could be caused by either BA or idiopathic neonatal hepatitis (9).
Another method for the diagnosis of BA is the use of ultrasound guided liver biopsy. While there are no pathognomonic histological changes, the biopsy is reported to provide a diagnosis of BA ranging from 70% to 97% (3,7). Findings include edema of the portal tracts, tortuous proliferation of bile ductules, fibrosis, along with intracellular and canalicular cholestasis. There is also a mixed infiltration of neutrophils and lymphocytes with a mild non-specific cholangitis (7). Of note is that there can also be ballooning of the hepatocytes and multinucleated giant cell formation. This can cause some overlap between the histological picture presented by BA and by idiopathic neonatal hepatitis (2,7). 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 (formerly known as intrahepatic biliary atresia) is established and true or extrahepatic BA is ruled out (6). Also of note is that there should be no dilation of the intrahepatic bile ducts in BA as can happen with some other forms of extrahepatic cholestasis (11).
The gold standard for the diagnosis of BA is the laparotomy with intraoperative cholangiography. If an intact extrahepatic biliary system is not visible, then extrahepatic biliary atresia is evident. If an intact biliary tree is visible, then an intraoperative cholangiogram is done, in which the surgeon cannulates the bile duct and injects contrast to determine if the biliary ducts are patent. Non-patency indicates sclerosed ducts and extrahepatic biliary atresia. A patent biliary system visualized on the intraoperative cholangiogram rules out extrahepatic biliary atresia. At this point, a wedge liver biopsy is obtained. This biopsy is examined for the presence of intrahepatic bile ducts. If the intrahepatic bile ducts are obliterated or reduced in number, then bile duct paucity (formerly called intrahepatic biliary atresia), is present. An intact and patent extrahepatic biliary tree rules out extrahepatic biliary atresia and the presence of normal intrahepatic bile ducts rules out bile duct paucity. This diagnostic algorithm is summarized below.
Diagnostic algorithm of biliary atresia:
1) Direct hyperbilirubinemia prompts evaluation and lab work-up.
2) Look for evidence of bile excretion (DISIDA scan, pigmented stools): Any evidence of bile excretion, rules out BA. If cholestasis is present (i.e., no bile excretion is demonstrated), then proceed to next the step.
3) Laparotomy:
. . . . . a) Look for a visible biliary tree: If absent, then extrahepatic BA is present. If present, then proceed to next step.
. . . . . b) Perform an intraoperative cholangiogram: If non-patent, then extrahepatic BA is present. If cholangiogram demonstrates patents ducts, then proceed to next step.
. . . . . c) Perform a wedge liver biopsy: If intrahepatic bile ducts are obliterated or reduced in number, then bile duct paucity (formerly known as intrahepatic BA), is present. The biopsy can also be used to find an alternate diagnosis. If bile ducts are patent and present, then BA is not present, in which case the biopsy is likely to demonstrate an alternate diagnosis such as neonatal hepatitis.
Depending on the anatomic type of BA which is present, it can be classified as either a correctable lesion (20% of cases) or a non-correctable lesion (80% of cases) (2,10). A correctable lesion has fibrosis of the distal biliary tree with the proximal biliary tree and the intrahepatic bile ducts remaining patent. In these cases, excision of the fibrotic area and direct drainage into the bowel is possible.
In the non-correctable lesions, 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 basically anastomoses the liver directly to the bowel so that in theory, bile can flow from the liver into the bowel. The reason that the procedure succeeds is that at the porta hepatis there are microscopic bile ductules that have proliferated which communicate with the intrahepatic system. Some groups use frozen section biopsy during the laparotomy to examine the tissue at the porta hepatis using the size of the vessels as a marker for the likelihood of successful re-establishment of bile flow. However, there have been variations in the size of vessels required and this theory is not universally accepted.
The success of the Kasai procedure depends largely on 2 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 3 months old, ideally less then 2 months. This is the major reason why the diagnostic determination of whether BA exists, must be done expeditiously. Establishment of bile flow is achieved in 80% of the patients who are less then 2 months, 50% between 2 and 3 months, and less then 10% if older then 3 months (12). 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 then 5 procedures a year (1,5,13).
If the child is diagnosed at an age greater then 3 months, the Kasai procedure has a low probability of success. Performing a Kasai procedure after this age is thus controversial, versus proceeding straight to liver transplantation, which is the treatment for a failed Kasai procedure. It is the general consensus that a patient should undergo the Kasai procedure even if they present at ages greater then 3 months if it is possible that bile flow can be established (12,14). While a post Kasai transplant is technically more difficult, there was no reported change in survival after transplantation in patients who underwent primary transplantation versus those who had a failed Kasai procedure prior to transplantation (11,13). The use of the Kasai procedure may not provide long term cure in the older BA patient but it may buy time for preparation for transplantation, finding a donor, and advancement of transplantation technology.
Ascending cholangitis is the most common complication, occurring in 40-60% of Kasai procedures (1). The etiology for this is 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 toward the liver. In the Kasai procedure, the bowel contents containing digestive enzymes have direct access to the existing bile ducts and hepatic tissue causing the cholangitis. 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. There does appear to be an increased risk in the patients with established bile flow, probably due to an intact pathway for ascending bacteria. Prophylactic antibiotics with trimethoprim-sulfamethoxazole is designed to reduce bowel bacterial counts. Repeated episodes of cholangitis can lead to extensive liver damage and cirrhosis.
Another common complication of BA is portal hypertension, which occurs in 35-75% of patients (1). 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 the sequelae of other forms of portal hypertension such as varices, ascites, hypertensive gastropathy, hypersplenism, and encephalopathy (1). The most common presentation is esophageal variceal hemorrhage occurring in 30-60% of patients (1). Treatment relies on the same methods employed in adults for other forms of portal hypertension.
BA is a chronic cholestatic disease if untreated can lead to complications as a result of the cholestasis. The end result is biliary/hepatic cirrhosis if BA is not treated with a life expectancy of 2 years (2). Mortality is a result of liver failure or portal hypertension. As mentioned before 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 also involves intrahepatic inflammation that can lead to cirrhosis.
After the Kasai procedure, the patient can be stratified into 1 of 3 prognostic groups at 4 to 6 weeks post operatively (10). The first group are 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 has moderate bile flow but they remain jaundiced and will continue to survive post-Kasai, however they will eventually need liver transplantation later in life. The third group are those who do not establish bile flow. This is considered a failure of the Kasai procedure and they will need liver transplantation in order to survive.
While the Kasai procedure establishes bile flow, it does not necessarily halt the intrahepatic inflammation and fibrosis. Patients who undergo the Kasai procedure can survive with their native liver in 20-30% of cases, but the remainder will eventually need liver transplantation (2,10). Overall survival rates of patients with BA post intervention in recent studies range from 70 to 85% (5,13). Ten year survival ranges from 33% in older studies to 68% in more recent studies (2,13). Survival with one's native liver at 5 years has been reported to be as high as 32% in recent studies and 27% at 10 years (5,13).
Biliary atresia 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. However, the key is the early diagnosis of BA in order to ensure that surgery can be performed in a timely manner at a high level center to increase the likelihood of success. Despite this, there are still many children who are untreated at 3 months of age (as high as 14-19% in some studies) (1). Efforts to introduce screening methods for BA have been attempted with poor results. The best method so far, is to maintain a high clinical suspicion in the jaundiced patient. Direct hyperbilirubinemia deserves a prompt and thorough evaluation.
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 he/she undergo a Kasai procedure if there are no contraindications or should the patient just wait for a liver transplant?
References
1. Narkewicz M. Biliary Atresia: An Update on Our Understanding of the Disorder. Curr Opin Pediatr 2001;13:435-440.
2. Dellert S, Balistreri W. Chapter 52 - Neonatal Cholestasis. In: Walker W, Durie P, Hamilton J, et al (eds). Pediatric Gastrointestinal Disease, third edition. 2000, Lewiston, NY: B.C. Decker Inc., pp. 880-891.
3. D'agata I, Balistreri W. Evaluation of Liver Disease in the Pediatric Patient. Pediatr Rev 1999;20(11):376-388.
4. Sokol R, Mack C. Etiopathogenesis of Biliary Atresia. Seminars in Liver Disease 2001;21(4):517-524.
5. McKiernan P, Baker A, Kelly D. The Frequency and Outcome of Biliary Atresia in the UK and Ireland. Lancet 2000;355:25-29.
6. Balistreri W. Chapter 356 - Neonatal Cholestasis. In: Behrman R, Klieghman R, Jenson H (eds). Nelson Textbook of Pediatrics, sixteenth edition. 2000, Philadelphia: W.B. Saunders Co., pp. 1203-1207.
7. Perez-Atayde A. Chapter 71 - Liver Biopsy Interpretation. In: Walker W, Durie P, Hamilton J, et al (eds). Pediatric Gastrointestinal Disease, third edition. 2000, Lewiston, NY: B.C. Decker Inc., pp. 1440-1465.
8. Suchy F. Chapter 52 - Anatomy, Anomalies, and Pediatric Disorders of the Biliary Tract. In: Feldman M, Scharschmidt B, Sleisenger M, Klein S (eds). Sleisenger & Fordtran's Gastrointestinal and Liver Disease, sixth edition. 1998, Philadelphia: W.B. Saunders Co., pp. 905-928.
9. Gainey, M. Chapter 77 Part 5 - Radionuclide Diagnosis. In: Walker W, Durie P, Hamilton J, et al (eds). Pediatric Gastrointestinal Disease, third edition. 2000, Lewiston, NY: B.C. Decker Inc., pp. 1655-1675.
10. Guzzetta P, Anderson K, Altman P, et al. Chapter 37 - Pediatric Surgery. In: Schwartz S (ed). Principles of Surgery, seventh edition. 1999, New York: McGraw-Hill, pp. 1715-1754.
11. Engum S, Grosfeld J. Chapter 67 - Pediatric Surgery. In: Townsend C (ed). Sabiston Textbook of Surgery, sixteenth edition. 2001, Philadelphia: W.B. Saunders Co., pp. 1463-1517.
12. Sinatra F: Liver Transplantation for Biliary Atresia. Pediatrics in Review 2001;22(5):166-168.
13. Chardot C, Carton M, Spire-Bendelac N, et al. Prognosis of Biliary Atresia in the Era of Liver Transplantation: French National Study From 1986 to 1996. Hepatology 1999;30(3):606-611.
14. Chardot C, Carton M, Spire-Bendelac N, et al. Is the Kasai Operation Still Indicated in Children older then 3 months diagnosed with Biliary Atresia? J Pediatr 2001;138(2):224-228.
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 by definition neonatal cholestasis.
2. No. With poor uptake into the liver you can only state 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. To make a diagnosis, there needs to be normal uptake in the liver with no movement into the bowel, even after 24 hours. Pretreatment with phenobarbital improves the yield on the DISIDA scan.
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 can not 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.
5. While there is little 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. However, each patient is different and some may be better served by primary liver transplantation.