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How to cite this article: Monroy-Teniza ZA, Flores-Calderón J, Villasís-Keever MÁ. Prognostic factors related to mortality of children with atresia of bile ducts. Rev Med Inst Mex Seguro Soc. 2015;53 Suppl 3:S270-83.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26509303

ORIGINAL CONTRIBUTIONS

Received: August 14^th 2014

Accepted: September 1^st 2015

Prognostic factors related to mortality of children with atresia of bile ducts

Zuhy Arlette Monroy-Teniza,^a Judith Flores-Calderón,^b Miguel Ángel Villasís-Keever^c

^aServicio de Gastroenterología y Nutrición

^bJefatura de Gastroenterología

^cUnidad de Investigación en Epidemiología Clínica

Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Zuhy Arlette Monroy-Teniza

Telephone: (55) 3928 6658

Email: zuhy12@gmail.com

Background: The biliary atresia (BA) is the end result of a destructive and idiopathic inflammatory process affecting the intrahepatic and extrahepatic bile ducts, leading to fibrosis and biliary cirrhosis. The objective was to identify factors associated with mortality in children with BA.

Methods: Observational, longitudinal, analytical and retrospective study carried out in patients with biliary atresia treated between 2008 and 2012 in a tertiary care hospital from the Instituto Mexicano del Seguro Social.

Results: A total of 66 patients with BA; 49 were girls (74.2 %), 47 underwent hepatic portoenterostomy (or Kasai procedure: KP), the age at delivery was 4.5 months. When comparing the groups with and without KP, the lower age at the time of delivery, the age of diagnosis, a lower score on the PELD score and the Child-Pugh for the group with Kasai were statistically significant. Patients who died had a PELD score statistically higher (median 20) than those who lived (median 13), p = 0.004. The factor directly related with the mortality was the history of KP with an OR of 0.17 (95 % CI 0.04-0.71, p = 0.016).

Conclusions: The prognosis of children with BA remains gloomy because they are diagnosed in late stages. The most important factor associated with mortality in these patients is to perform KP.

Keywords: Biliary atresia, Mortality, Prognosis, Hepatic portoenterostomy.

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Background

Biliary atresia (BA) is the end result of an idiopathic, destructive, inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis, obliteration of the biliary tract, and the eventual development of biliary cirrhosis.¹ Fibrous obliteration may involve the entire extrahepatic biliary system or only parts of it, with concomitant damage and intrahepatic biliary fibrosis, so the term extrahepatic has fallen into disuse.² BA is one of the most common causes of cholestatic jaundice in the first months of life and, together with neonatal hepatitis, it represents the majority of cases, making early diagnosis crucial.

BA affects 1 in 10,000-19,000 live births, predominantly in females.³ The report of BA incidence shows some regional variations and it is higher in Asia than in the rest of the world; for example, the disease is diagnosed in about 5-6 out of every 100,000 live births in Europe and the United States, while in Japan 10.6 out of every 100,000 are diagnosed.^4,5 In Mexico we do not have hard data regarding the incidence of this disease. Some studies have documented seasonal variations and association with different races,⁶ but no genetic pattern of transmission has been determined.^7,8

BA is classified into two groups: the fetal or embryonic form, also called "early" or syndromic form, representing between 10 and 20% of cases and associated with birth defects such as asplenia, polysplenia, cardiovasculsar defects, situs inversus, intestinal malrotation, small intestine atresia, abnormal pancreaticobiliary junction, and abnormalities of the portal vein or hepatic artery. In this group, between 5 and 10% of patients have cystic dilatation of the biliary remnants, known as cystic biliary atresia. The other form is perinatal or postnatal, also known as late or nonsyndromic, which represents 80 to 90% of all cases and usually occurs as an isolated anomaly.^9,10

The Japanese Society of Pediatric Surgeons proposed an anatomical classification of BA by location of the atresia (Figure 1). In type I, atresia is at the level of the common bile duct (approximately 12% of cases), in type II it is at the level of the common hepatic duct (2.5% of cases), and in type III, the most frequent type (about 85%), the atresia is located in the porta hepatis.¹¹

As for its etiology, BA is the phenotypic response of neonatal liver and bile ducts to a variety of prenatal and perinatal factors that disrupt the normal development and maturation of the biliary tree, occurring during a specific period of time (prenatal or before three months), in an environment of genetic or immunologic susceptibility to this disease (Figure 2).^12,13

Multiple prenatal or perinatal factors have been postulated to explain the pathogenesis of the disease (Table I).¹³

It is thought that a cause may be altered immune system, when a large number of CD8 + T cells and NK lymphocytes (related to biliary obstruction) is detected, which is not present in other neonatal cholestatic diseases.¹⁴

Clinical signs of patients with BA

Affected children are usually term infants with normal birthweight, with apparently normal weight gain during the first weeks of life, so high suspicion is required for early diagnosis. There is no reliable screening test; however, monitoring the color of evacuations using colorimetric cards to detect hypocholia or acholia during the first days of life has proved useful for an earlier diagnosis.¹⁵

Laboratory tests are nonspecific; levels of bilirubin, transaminases, gamma glutamyl transpeptidase (GGT), and alkaline phosphatase are similar to other forms of neonatal cholestasis. In the early stage, tests of hepatic synthesis (such as albumin and clotting times) are normal, but will progressively alter as the disease progresses, especially in cases where bile flow is not restored after the Kasai procedure.¹ Probe testing is a technique that allows direct visualization of the presence of bile in the intestine. It involves the placement of a probe open to drainage for 24 hours in the second portion of the duodenum; BA diagnosis is suspected if bile is not found. This test has fallen into disuse, yet it is easy to perform and useful especially when there are no other diagnostic resources.¹⁶ On the other hand, using abdominal ultrasound, a finding of no gall bladder, traces of it, or the "triangular cord" sign may suggest BA. This test is useful to intentionally look for polysplenia associated with BA.¹⁷ The hepatobiliary excretion scan has a specificity between 50 and 74% and a sensitivity of 95%; it is useful if it is seen that the isotope does not reach the small intestine, which can support the diagnosis of BA.¹⁸ In cases where laboratory and biochemical studies have been inconclusive, it is advisable to do an exploratory laparotomy with intraoperative cholangiogram to not delay diagnosis. Liver biopsy allows a correct diagnosis in 90% of cases; the classic histological findings are the presence of edema and inflammatory changes in the portal tracts, bile duct proliferation, and bile plugs.¹⁹ If the biopsy is inconclusive and acholia persists, endoscopic retrograde cholangiopancreatography is indicated.²⁰

Treatment of patients with BA

BA is a surgical emergency. The Kasai procedure (portoenterostomy of Roux-en-Y) is the standard initial technique for the treatment of BA. The surgery involves a complete excision of the extrahepatic biliary tree with a transection of the fibrous portal plate near the hepatic hilum, in order to establish biliary-enteric continuity with the jejunal Roux-en-Y and allow bile drainage.^21,22 The age at which the surgery is performed is the most important prognostic factor for survival; about 60% of bile flow is reported to be re-established at 90 days of extrauterine life.²³  

Postoperative medical treatment should include nutritional support with supplemental lipid-soluble vitamins and semi-elemental formula containing medium-chain triglycerides.²⁴ Use of choleretic drugs such as ursodeoxycholic acid has been recommended at a dose of 15-30 mg/kg/day. It has been shown that the use of prophylactic antibiotics decreases the rate of signs of postoperative cholangitis, which occurs in up to 50% of cases during the first two years of life. Long-term prophylaxis is indicated when there is recurrence of cholangitis.²⁵ Steroids have also been used after the Kasai procedure to increase bile flow for their anti-inflammatory, immune, and choleretic effect; however, there are not enough studies to prove their usefulness.²⁶

When the disease progresses to cirrhosis, management focuses on the complications of this disease, such as portal hypertension, ascites, bleeding, infections, and encephalopathy. For ascites, sodium restriction, diuretics, and, in some cases, paracentesis for evacuation and portosystemic shunts are used. As for hepatic encephalopathy, its precipitating factors are to be identified and eliminated, such as bleeding in the digestive tract, infections, and hemorrhages, so protein intake should be restricted and antimonial measures administered (e.g., oral antibiotics and lactulose). For coagulopathy, vitamin K and fresh frozen plasma transfusions are administered.

Finally, liver transplantation is the last resort to be used when the Kasai procedure fails, as manifested by progressive hepatocellular decompensation, impaired hepatic synthesis, and development of coagulopathy and intractable portal hypertension with recurrent gastrointestinal hemorrhage or hypersplenism. Transplant patients require combination immunosuppressive therapy based on steroids, tacrolimus, cyclosporine, antimetabolites, and immunomodulators.¹

Survival of patients with BA

If Kasai portoenterostomy is not done, BA is an invariably fatal disease in early life, because 50-80% of patients will die of biliary cirrhosis by the age of one, and 90 to 100% will die by three years of age. These children develop cirrhosis and succumb to failure of hepatic synthesis or to complications of portal hypertension.^27,28

Kasai portoenterostomy seems to have the greatest likelihood of restoring bile flow and increased long-term survival with the child’s native liver. Five-year survival is reported at 40.8% if the surgery is performed before 45 days old, whereas after this age survival is 31.2%; at 10 years it can be 40.8 and 25.7%, respectively.^29,30

Other studies have reported that children who have had a successful portoenterostomy can survive more than 10 years with their native liver and achieve a good quality of life. Their survival without liver transplantation is approximately 55.8% at two years,³¹ 46% at 5 years, 40% at 10 years,³² and up to 15-44% at 20 years. Adult patients have even been observed with their native livers (although with portal hypertension, biliary cirrhosis, and cholangitis), who even have children of their own.³³

In a review of 30 children with BA in the Hospital de Pediatría of the Centro Médico Nacional, treated between January 2005 and June 2007, in describing the survival rate, it was found that 85% who underwent Kasai before 12 weeks of life had a survival with native liver of 46% at five years.³⁴ In Centro Médico La Raza, 31 cases of BA were reported from 1999 to 2004 and 21 patients underwent Kasai surgery, of whom 14 died at an average age of 2.9 years.³⁵ Factors related to prognosis were not analyzed in these two reports, but it should be noted that the information in these two studies was obtained from abstracts at conferences.   

Liver transplantation is the treatment of choice for patients who experience a failure of the Kasai procedure. Survival reported in transplant patients is variable, according to the publication; for example, in a cohort of 41 Dutch patients transplanted between 1998 and 2008, four-year survival was 80% (95% CI: 67-93),²⁸ while in the United States the five-year survival of 1549 liver transplantation patients between 1987 and 1995 was 82.1%,³⁶ and it was 76% at five years in 1293 patients according to the European Liver Transplant Registry.³⁷ In a cohort of French patients, 10-year survival was described at 67.6%.²⁹

Survival factors in children with BA

Patients with BA who do not undergo Kasai surgery or liver transplant, progress to end-stage liver disease during the first year of life and die of these complications, worsened by significant malnutrition, progressive liver failure, and associated infectious processes.^1,38

Furthermore, the prognostic factors for patients to still have cholestasis, despite undergoing the Kasai procedure, include the anatomical type of biliary atresia (type III) and its histology (absent or small bile ducts in portal plate), the characteristics of the remains of the extrahepatic bile ducts, the age of completion of the Kasai procedure, the number and severity of episodes of postoperative cholangitis, the degree of fibrosis at the time of procedure, experience of the surgical center in management of these patients, and the failure to establish bile flow.²⁹ It has been mentioned that levels of total bilirubin > 2 mg/dL three months after portoenterostomy can predict a poor outcome, so alternative treatment should be proposed for these children, such as liver transplant.³¹ In addition, in Mexico, male gender, hepatic encephalopathy, infection with cytomegalovirus (CMV), and biopsy findings at the time of surgery have been mentioned as factors associated with poor prognosis.^34,35 Other factors that may influence survival are the presence of postoperative complications such as ascending cholangitis or complications related to biliary cirrhosis and liver failure. The impact of postoperative medications (steroid therapy, ursodeoxycholic acid, antibiotic prophylaxis for cholangitis) is still under discussion and there are not enough solid data for clear recommendations.³⁹ Patients with splenic malformation syndrome are diagnosed earlier on, but the results are worse than for those without these associated defects.³¹

Unfortunately BA is a progressive disease with which, even with a successful portoenterostomy, all children develop progressive inflammation, portal fibrosis, and fibrosis of the intrahepatic bile ducts in various degrees, which lead to biliary cirrhosis, portal hypertension to greater or lesser degrees, and the need for liver transplantation in 70-80% of patients,²⁹ so these patients account for nearly half of liver transplants performed in children. The PELD scale (Pediatric End-Stage Liver Disease) is a scale containing five variables (patient age, albumin, total bilirubin, INR, and degree of failure to thrive) that is currently used to identify patients with increased hepatic dysfunction, in order to prioritize liver transplantation for those at increased risk of death; subjects with higher scores (up 40 points) are those with a greater degree of severity.⁴⁰   

High mortality prior to transplantation has been associated with a long wait on the transplant list, the lack of donors, and late referral, so patients die from causes related directly or indirectly to advanced liver disease, such as sepsis (mainly), liver failure, gastrointestinal bleeding, and severe malnutrition.³⁸

Liver transplant can save the lives of patients with BA and, as already mentioned, it is indicated in patients with decompensated cirrhosis and end-stage liver disease when portoenterostomy was not performed due to late diagnosis, or in whom portoenterostomy failed to restore hepatointestinal bile flow, despite a "successful" initial portoenterostomy.¹ The results may vary significantly according to the surgical experience of the liver transplant centers; however, the patient’s preoperative conditions that have an impact on results are primarily their nutritional status and advanced liver failure.²⁹ Other mortality risk factors associated with liver transplantation are related to the preoperative condition of the patient (such as malnutrition, renal failure or portal hypertension, support treatment), the age at completion of Kasai surgery or transplantation, factors related to surgical technique, PELD score, graft quality, and type of immunosuppressive therapy.^{28,32,39,41,42}

As such, the objective of this study was to identify factors related to mortality in children diagnosed with BA.

Methods

Observational, longitudinal, analytical, and retrospective study (retrospective cohort) with the participation of all newborns and infants diagnosed with biliary atresia, treated between 2008 and 2012 in the Servicio de Gastroenterología Pediátrica of the Hospital de Pediatría of the Centro Médico Nacional Siglo XXI of the Instituto Mexicano del Seguro Social. The sampling was done by consecutive cases. It included patients with diagnosis of biliary atresia (clinical, surgical, and histopathologic data of certainty), of both sexes, weighing more than 1500 g, with diagnosis of cholestasis (defined as conjugated bilirubin > 20% of the total or ≥ 2 mg/dL), and with follow-up for at least two months after the first assessment in this hospital.

The study excluded patients with acute liver failure without accurate diagnosis, those diagnosed with cancer, and those with a history of drug use (e.g., anticonvulsants) or TPN associated with cholestasis.

Patients were excluded who, during follow-up, received another diagnosis involving cholestasis (e.g. choledochal cyst).

Results

During the period from January 2008 to December 2012, only 66 patients with biliary atresia (BA) met the selection criteria. Table II shows general characteristics of the 66 patients. It can be seen that the median age of patients at time of referral was 4.5 months, with patients from one month to 13 years and 1 month old. Most were female (74.2%). While, in general, the reason for referral was complementary diagnosis due to initial signs of cholestasis, patients with already confirmed diagnoses of BA were also referred to enter the liver transplant program, or patients requiring care for complications, especially related to portal hypertension. The place of origin of most children was states other than the Distrito Federal, with no clear predominance of northern or southern Mexico.

Overall, patients in at first evaluation already had significant clinical histories, with signs of hepatic encephalopathy in four (6%), cholangitis in 12 (18.1%), 16 (24%) with upper gastrointestinal bleeding, 52 (78.7%) with portal hypertension, 18 (27.2%) with some degree of malnutrition, 11 (16.6%) with Child-Pugh A, 47 (71.2%) with Child-Pugh B, and 8 (12.1%) with Child-Pugh C. Seventeen patients (25.7%) had a PELD score > 20.

Time of monitoring of patients starting at the first date of assessment is variable, with a median of eight months, a minimum of two months, and a maximum of nearly 17 years. Generally, monthly, bimonthly, or annual evaluations were given depending on the case of each patient. Of the total enrolled patients, the median was five outpatient evaluations, but there were cases with two and others with up to 16 evaluations.

During follow-up 10 patients were able to receive transplants. At the time of the last evaluation, 55 patients (83.3%) were alive and 11 (16.6%) had died.

Clinical course of patients with BA with and without Kasai surgery

As it was observed that patients’ clinical conditions and courses were different, it was considered convenient to describe follow-up in two groups based on whether or not they underwent the Kasai procedure. As described in Table III, only 47 of 66 patients had the Kasai procedure, with a minimum age of one month at referral for this group, and a maximum of 157 months; this latter value corresponded to a 13-year-old patient sent from another unit for follow-up. In the other group without the Kasai procedure, the minimum age of referral was two months, with a maximum of 18 months. The median age of diagnosis in the group with Kasai was a month and a half old, with a minimum of one month and a maximum of five months. The median diagnostic for the group without Kasai procedure was four months, with a minimum of one month and a maximum of 10 months. Within the Kasai procedure group, 27.6% had some degree of malnutrition at admission, so the percentage of the group excluding that subgroup was 26.3%. 

Within the group with Kasai portoenterostomy, the minimum age at the surgery was 19 days and the maximum 154 days, with a median of 61 days. Over 60% of patients underwent surgery in a different unit of the Hospital de Pediatría de Centro Médico Nacional Siglo XXI.  

At the end of follow-up in 2012, mortality was higher for the group without Kasai surgery, with 15.7%, compared with 2.12%. Four patients without Kasai and six with Kasai had liver transplants. More than 78% of patients with Kasai survived to the end of follow-up with complications such as liver cirrhosis and portal hypertension.

As for their histories before the first evaluation, the group with Kasai procedure had already presented cholangitis in more than 25% of patients, and an episode of upper gastrointestinal bleeding (27.6%), whereas patients without Kasai frequently had encephalopathy (10.5%) and already had some degree of cirrhosis and portal hypertension (100 and 94.7%, respectively). No history of hepatopulmonary or hepatorenal syndrome was identified.

On admission to care at this hospital, 11 patients (23.4%) who underwent Kasai had Child A, 34 of them (72.3%) Child B, and the group without Kasai often had Child C, found in six patients (31.5%).

The PELD scale had the highest score in the group without Kasai, with a median of 27, a minimum of 8, and a maximum of 45 points.

Up to 73.6% (14 patients) in the group without Kasai procedure did not have liver biopsy. Of this group, two (10.5%) had a Metavir staging of F2, and three patients (15.7%) had F3. In the group with Kasai surgery, only one (2.12%) had F1, five (10.6%) F2, and 17 (36.1%) F3. We did not find F4 for any patient on their first biopsy.

In comparing the two groups with and without the Kasai procedure, there was a statistically significant lower age at diagnosis and referral in the group with the procedure, as well as a lower PELD scale and Child-Pugh scores for the same group.

In Figure 3 for Child-Pugh staging, one can see that the group with Kasai procedure (which had more patients) initially had more children with Child-Pugh B and, over the course of development, due to loss of patients, the number of children with Child-Pugh A increased. On the other hand, in the group without Kasai, at the start of follow-up there were no patients with Child-Pugh A, and at the end of follow-up, in addition to a greater loss of patients, most of those who remained had Child-Pugh C.

Figure 4, which shows PELD scores, demonstrates that the lowest values over time ​​were for the group with Kasai, and the highest were for those without. It is observed that all patients with Kasai on admission had a PELD score below 20, and in the opposite case, all patients without Kasai on admission had higher scores, which forced them to be placed on the liver transplant list.

Overall survival estimated by Kaplan-Meier curve was 5.6 years (95% CI 4.5-6.6).

Factors associated with mortality in children with BA

Table IV describes factors related to mortality. It is noted that the proportion of patients who had Kasai procedure and who died was statistically lower than those who lived (36.4% vs. 78.2%); however, the age at the procedure was similar between the two groups. Also, patients who died had a statistically higher PELD score (median 20) than those who lived (median 13), p = 0.04.

Another point to note is the fact that the frequency of gastrointestinal bleeding was higher in the group of survivors, which explains why these patients received interventions to treat and prevent this bleeding.

It is also worth noting that only 28 patients had liver biopsy taken; Table IV shows that there was no difference in the findings according to Metavir classification; however, only four of the 11 patients who died had undergone biopsy.

To determine which factors are directly related mortality, a multivariate logistic regression analysis was done with the variables that were statistically significant in univariate analysis. The results showed that undergoing Kasai was the only significant variable: OR 0.17 (95% CI: 0.04-0.71; p = 0.016). As shown in Table V, there was no statistically significant difference when comparing the groups with and without Kasai, whether living or dead, which is attributed to the groups not having a homogeneous distribution.

Discussion

The results of this study give us a broad overview of what is happening in our environment regarding the care process and outcome of children with BA. While overall the data are consistent with the statements of other authors in the world, this study shows us the need to continue with the strategies for early detection of this disease in order to provide appropriate treatment for this group of children.

It is advisable to make some observations on some points related to the variables analyzed. For example, most of the patients treated in our hospital were female, as has been reported around the world despite many differences in prevalence between countries. We cannot make a calculation of incidence in our country because of the bias that exists in our case, as this hospital only attends the population entitled to social security in the south of our country; however, a progressive increase was evident in the number of cases treated in our hospital, because this went from four cases in 2009 to 16 in 2012. Furthermore, when reviewing records, no cases of syndromic BA were found, as the presence of associated congenital malformations was not documented in any case, neither at cardiac nor digestive level. Despite the reports in the literature regarding the anatomical classification of BA found by surgeons in the intraoperative period, this is not done in our surgical records, so it is not possible to calculate the frequency of different existing anatomical types, although we assume that the most common type is III, as reported in some studies and from the macroscopic description of the porta hepatis, which, unfortunately for us, is the worst prognosis according to literature.

A point that could not be determined was the possible etiologic factor or the possible causes of this disease, regarding which, although not the aim of this study, we can mention that some patients presented CMV infection, maternal age varied widely, and that there were different unassociated infectious processes, et cetera.

As for the status of children at the time of first evaluation in this hospital, it is notable that most of them were term and had birth weight appropriate for gestational age. Later, when they reached this hospital, the majority had some degree of malnutrition. It was also possible to determine the variability of the biochemical data of the children, which in many cases were associated with a history of having undergone Kasai procedure, which was the most important protective factor for mortality.

BA patients treated at this hospital enter at a late age for Kasai procedure, as their median age is 4.5 months, so this operation is carried out at 75 days of life, with which, according to literature, survival will be about 31.2% at five years and 25.7% at 10. The cases with a successful portoenterostomy done at a younger age are patients who are alive, although they have clinical data of biliary cirrhosis and portal hypertension, for which they are currently receiving specific treatment for these complications. In fact, a number of these patients have been discharged from the hospital with their native liver due to being more than 17 years old but with some degree of cirrhosis. There is a big difference with the publications of other countries, such as Japan, where bypass surgery is performed at younger ages and their survival rates are higher.

An important point is the 10 cases who managed to get liver transplants. While survival was 30%, at present and after more than a year of follow-up, these three cases have generally good clinical conditions.

When comparing the groups with and without Kasai in the study, age at the time of referral, age at diagnosis, and PELD and Child-Pugh scores were all statistically significant, favoring longer survival and fewer complications, according to reports in the world literature. Bilirubin levels were not analyzed at a specific time after Kasai, due to lack of uniformity in measuring this variable in all children at the same time; however, decrease in this level was documented over the course of follow-up.

It is also important to recognize that the weaknesses of this study are due to biased sample from it being an institution for insurance beneficiaries not reliably representing the population. In addition, patients lost during follow-up certainly cause a loss of valuable information regarding their prognosis. The strengths of this study are that it was conducted over a considerable period of time, patient characteristics were deeply analyzed, and previous records were consulted from which all necessary information was taken. It is a work that had not been done in this institution and that helps give us an overview of the current status of patients with biliary atresia to take the necessary measures for diagnosis at younger ages, especially in places far from the Distrito Federal, where we can see that mortality was higher.

Conclusions

We can say that the prognosis of children with BA remains grim, since this condition is diagnosed at late stages, which leads to complications and death at an early age. The most important factor related to mortality is to do Kasai surgery. All patients with BA upon arriving at our hospital already have some degree of liver damage, and most have Child B and C (83%). At the time of the last assessment, the majority of patients in the group with Kasai had Child A (66%), and the other group Child C (66%).

Therefore, what remains is to insist on early recognition of children with this disease, for referral and treatment in order to reduce mortality and improve quality of life.

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