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Introduction
Biliary atresia is a fibro-inflammatory condition of the biliary tract that manifests within the first weeks of life with jaundice and acholic stools. In the absence of treatment, it will evolve with progressive hepatic fibrosis, cirrhosis, end-stage liver failure and death in the first years of life(1). It is one of the most important causes of neonatal and infant cholestasis, and it represents the most common indication for liver transplant in children(2). The current treatment for biliary atresia is the Kasai hepato-portoenterostomy (KPE), which attempts to restore the bile flow and preserve the native liver(3). KPE should be performed before 60 days of life, for a better prognosis(4). Therefore, the diagnosis of biliary atresia is crucial and must not be delayed. Infants who did not undergo the KPE (that were diagnosed late) or if the surgery was unsuccessful will need liver transplant(5). The diagnosis of biliary atresia remains a challenge for many pediatricians(6).
Case reports
We report two cases of infants with biliary atresia who were addressed to our clinic in recent years, with different outcomes.
The first patient (L.K.), a 7-day-old newborn male, with no significative familial or personal history, was referred to our hospital for evaluation of a neonatal cholestasis. Starting from the second day of life, the patient developed generalised jaundice. The laboratory tests performed in the neonatology unit revealed direct hyperbilirubinemia and an inflammatory syndrome. The case was interpreted as early-onset neonatal sepsis, and the patient received empiric antibiotic therapy with ampicillin and gentamicin, with good evolution. However, after the treatment was finished, the jaundice intensified, and the patient associated hyperchromic urine with progressively increasing values of direct hyperbilirubinemia and gamma-glutamyl transferase. Therefore, he was sent to our department for further investigations. On clinical exam, he had generalised jaundice, hyperchromic urine and pale stools. The laboratory tests showed elevation of serum transaminases (aspartate-aminotransferase [ASAT] 101 U/L, alanine-aminotransferase [ALAT] 49 U/L), cholestasis (gamma-glutamyl transpeptidase [GGT] 1244 U/L), and direct hyperbilirubinemia (total bilirubin 14.56 mg/dl, direct bilirubin 8.51 mg/dL). The abdominal ultrasound revealed “gallbladder ghost triad” (atretic gallbladder, with irregular contour and lack of smooth echogenic mucosal lining with an indistinct wall). Therefore, the diagnosis of biliary atresia was highly suggestive. Other possible causes of neonatal cholestasis were excluded: infectious (B and C hepatitis viruses, cytomegalovirus, Epstein-Barr virus, toxoplasmosis, syphilis), alpha1-antitrypsin deficiency, and hypothyroidism. The patient was transferred to the pediatric surgery clinic, where he had undergone the KPE at the age of 43 days. After that, he continued treatment with methylprednisolone (after surgeon recommendations), ursodeoxycholic acid, prophylactic antibiotherapy with co-trimoxazole, and a special formula for children with neonatal cholestasis. The KPE was successful: two months later, the patient presented with signs of bile flow restoration (jaundice cleared, the stools became yellow/brown, the bilirubin and cholestasis enzymes normalized). The patient is now 3.5 years old. He is periodically monitored in our clinic, and he has not had any episodes of infectious cholangitis.
The second patient (L.A.), a 37-day-old infant girl, was also transferred to our hospital from a local hospital. The patient came from a low-income family, had a teenage mother, and lived in poor conditions. She presented with prolonged jaundice (5 weeks) that started in the first week of life. The laboratory tests performed in the local hospital revealed a cholestatic hepatitis; after that, she was transferred to our hospital for evaluation and specialized treatment. There was no significative personal history besides the prolonged jaundice. On clinical examination, she had generalized jaundice and acholic stools (Figure 1).
The laboratory tests revealed increased transaminases (ASAT 197 U/L, ALAT 135 U/L), cholestasis (GGT 268 U/L), alkaline phosphatase (ALP) 552 U/l, and direct hyperbilirubinemia (total bilirubin 15.12 mg/dl, direct bilirubin 9.87 mg/dL). As for the first patient presented, ultrasonography was highly suggestive of biliary atresia (atrophic gallbladder and the absence of common bile duct), and she was transferred to the pediatric surgery hospital. KPE was performed at the age of 48 days, and quickly after the procedure, she developed the first episode of cholangitis. She was treated with extended-spectrum antibiotherapy, albumin infusion and diuretics, being transferred to our clinic for follow-up. We recommended treatment with ursodeoxycholic acid, prophylactic co-trimoxazole, diuretics (spironolactone and furosemide), and dietary management. The KPE was unsuccessful in this case; the jaundice never cleared, and the stools remained acholic. During the postoperative period, the evolution was very poor, and the parents did not follow the needed appointments: the patient had multiple infections (several episodes of cholangitis, a persistent cytomegalovirus infection, rotavirus infection, and Klebsiella pneumoniae infection), all of them requiring prolonged hospitalizations. Unfortunately, the outcome was unfavorable; she developed portal hypertension, ascites, significant growth failure, and she died at the age of 10 months after a cerebral hemorrhage while waiting for liver transplant procedures (that were difficult due to her social status).
Discussion
We chose to present these cases comparatively to emphasize the importance of early diagnosis in biliary atresia, as well as proper care following the KPE, in order to offer patients the best possible prognosis. Although both cases benefited from prompt diagnosis and timely intervention, the living conditions and the quality of care play an equally important role.
Biliary atresia represents an immune-mediated, obstructive cholangiopathy with neonatal onset. It is the most frequent cause of obstructive cholestasis, manifesting with prolonged jaundice (beyond the first two weeks of life), acholic pale stools, and hyperchromic urine(7). Although it is a rare disease, it is the most common indication for liver transplant in children(2). Biliary atresia affects multiple ethnicities, the incidence ranging from approximately 1:5000 newborns in Taiwan to 1:20,000 in Europe, Canada or the United States of America(8). The natural course of biliary atresia is characterized by an ongoing process of inflammation, fibrosis and obliteration of the biliary tract, leading to complete obstruction. Therefore, it is a severe liver disease of infancy, progressing from cholestasis to cirrhosis and end-stage liver disease in the first years of life, without treatment. The etiology of biliary atresia is complex and multifactorial, involving both prenatal and perinatal factors. Some viruses, including cytomegalovirus, reovirus or rotavirus(9), can initiate bile duct damage and produce alterations in the immune response, with release of modified “self” antigens that activate bile duct T-cells, continuing with chronic injury of the bile ducts(10). Exposure to environmental toxins can also be responsible for developing biliary atresia, recent studies showing that biliatresone toxin could induce biliary atresia in various species(11).
The clinical manifestations include prolonged jaundice, clay-coloured or acholic stools and dark urine. If left untreated, infants develop hepatomegaly, distended abdomen, failure of growth (due to malabsorption), pruritus, or coagulopathy(12). This condition leads to progressive liver fibrosis, cirrhosis and death by the age of 2 years old without proper treatment.
Diagnosing biliary atresia as fast as possible is critical, as early treatment is linked to improved outcomes and may lessen or postpone the need for liver transplantation(13). Liver ultrasound, cholangiogram and liver biopsy play an important role in the diagnosis of biliary atresia.
Infants diagnosed with this condition are treated surgically with KPE as soon as possible. This procedure connects a loop of the small intestine to the biliary system, enabling bile drainage and helping to delay the progression to liver cirrhosis, potentially postponing the need for liver transplantation(14).
According to Serinet et al.(4), a 12.1% difference in 15-year native liver survival was observed between patients who underwent the KPE before 46 days of age and in those who either underwent the procedure later, or did not undergo surgery despite the absence of contraindications, primarily due to delayed diagnosis. Surprisingly, a retrospective study performed by Wong et al.(15) concluded that performing the KPE after 60 days of age was not correlated with poorer outcomes, with a substantial proportion of patients up to 100 days of age still achieving effective bile drainage and normal postoperative bilirubin levels.
Even though the KPE is performed under 60 days of life and it seems to be successful, the regular follow-up of these patients plays another crucial role, because after the procedure, patients can develop complications. The most frequent complication after KPE is cholangitis. A systematic review performed by Decharun et al.(16) revealed that the incidence of cholangitis after KPE is between 40% and 93%. Over half of patients develop cholangitis within the first six months post-KPE, and approximately 90% experience an episode within the first year. Episodes of cholangitis occurring after two years are uncommon. Chen et al.(17) concluded that earlier cholangitis after KPE and the number of cholangitis episodes within two years post-KPE may serve as prognostic indicators for poor outcomes and the need for future liver transplant.
The clinical cases presented before aim to highlight the differences in the evolution of BA in two patients who were diagnosed in time and who underwent KPE. The first patient had a very good evolution after the intervention, with clearance of jaundice and normalization of bilirubin levels, and no episode of cholangitis. The second patient had poor outcomes, with cholangitis in the first weeks after the procedure, which was treated at that moment. After that, in evolution, she had multiple episodes of cholangitis and other infections, each of these infections having a negative impact on the liver function. She developed liver cirrhosis and, at the age of 10 months old, she died following a bacterial sepsis and cerebral hemorrhage.
What is known?
- Biliary atresia represents an important cause of neonatal cholestasis, and it is the leading indication for liver transplant in pediatrics.
- Rapid diagnosis is very important to allow early therapeutic intervention, with a high chance of survival.
What is new? Take-home messages
- Every infant with cholestasis must be evaluated for possible biliary atresia.
- The Kasai procedure must be performed (if possible) within 46 days of life.
- Cholangitis is the most frequent complication after the Kasai procedure.
- The follow-up of these patients plays an important role in order to give them a better prognosis, to prolong the survival with the native liver, and to postpone the need for liver transplantation.
Autor corespondent: Alina Grama E-mail: gramaalina16@yahoo.com
CONFLICT OF INTEREST: none declared.
FINANCIAL SUPPORT: none declared.
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