Congenital biliary atresia

　　One, Etiology

　　The etiology has not yet reached a clear conclusion. Early theories suggested that the disease is congenital bile duct developmental abnormality, related to the stasis or disorder of the bile duct system during the 4th to 10th weeks of embryonic development. However, anatomical studies of the bile duct systems of a large number of miscarried or premature infants did not find biliary atresia, on the contrary, recent research has provided more evidence supporting the idea that the disease is acquired postnatally. Some children with the disease have normal yellow stools at birth, but develop grayish-white stools and jaundice after a few weeks, which also suggests that the biliary obstruction occurs after birth. In addition, pathological examination found inflammatory changes in liver tissue, infiltration of inflammatory cells around the porta hepatis and bile ducts, and the occurrence of small abscesses or focal necrosis in the liver lobules. The formation of granulation tissue at the site of bile duct obstruction. Comparative pathological studies of extrahepatic biliary atresia and neonatal hepatitis found that the liver tissue lesions of the two are similar, only with different degrees. Extrahepatic biliary atresia is mainly manifested by bile duct thrombosis and inflammatory lesions, while neonatal hepatitis is characterized by more prominent liver cell necrosis. Therefore, it is now believed that biliary atresia may be an acquired disease similar to the pathological process of neonatal hepatitis. The biliary atresia observed after birth is the terminal stage and outcome of the inflammatory process, with inflammation causing the fibrosis and obstruction of bile ducts. The causes of inflammation are mainly viral infections, such as hepatitis B virus, cytomegalovirus, and may also include rubella virus, hepatitis A virus, or herpes virus. Some scholars propose that abnormal pancreatobiliary junction may also be a congenital factor in the occurrence of biliary atresia.

　　Although the etiology of this disease is diverse, the ultimate result is the obstruction of the bile excretion pathway, leading to obstructive jaundice. Recent studies have shown that the development of intrahepatic and extrahepatic bile ducts originates from two sources, thus explaining why the bile ducts below the gallbladder in patients with bile duct atresia can remain patent, while the upper bile ducts above the hepatic ducts become fibrotic and occluded.

　　2. Pathogenesis

　　This disease is caused by bile duct obstruction and bile stasis, leading to damage to the liver parenchyma. In the early stage, the liver may slightly enlarge and can develop into severe cholestatic liver cirrhosis within a few months, with the liver becoming明显肿大, hard in texture, appearing brown-green, with a granular or nodular appearance. The cross-section shows the proliferation of network-like gray-white connective tissue. Under the microscope, the liver lobules are deformed and separated by proliferative fibrous tissue strips, with varying sizes and shapes, central veins displaced or unclear, hepatic cords arranged in disorder, and sinusoids dilated or narrowed. Hepatocytes have bile deposition, appearing uniformly yellowish, granular, or coarse-grained. All cases show vacuolar degeneration of hepatocytes, hepatocyte swelling, hepatocyte proliferation, and Kupffer cell mobilization. The pathological changes in the intrahepatic type can manifest as bile stasis and liver cirrhosis within 2 to 3 months after birth, with most interlobular bile ducts destroyed and disappeared by 5 to 6 months, with small bile ducts arranged irregularly, narrowed, or occluded, and significantly reduced new bile ducts, with almost no bile ducts visible in the portal areas. In the extrahepatic type of bile duct atresia, the intrahepatic bile ducts are open, while the extrahepatic part or the whole is occluded. Due to the varying locations and extents of obstruction, the pathological changes of bile duct atresia also differ. The atretic bile ducts are histologically consistent with inflammatory changes, with a little cellular infiltration in the connective tissue that covers the inside, and in the granulation tissue, many round cell infiltrations and tissue cells phagocytizing bile pigments can be seen. However, the common bile duct with an inner lumen does not show the above pathological changes, with a normal histological structure and lined with cylindrical epithelium. Some researchers have found that more than 2/3 of the children with bile duct atresia have giant hepatocytes, similar to neonatal giant cell hepatitis, and thus, it is believed that there is a close relationship between these two diseases. Hitch listed 8 indicators for the changes in liver tissue structure: ① changes in liver lobule structure; ② swelling of hepatocyte cytoplasm; ③ inflammation in the portal area; ④ bile stasis; ⑤ fibrosis; ⑥ bile duct proliferation; ⑦ giant cell transformation; ⑧ extramedullary hematopoiesis. The last five indicators are significantly different between bile duct atresia and neonatal hepatitis. Electron microscopy examination shows that there are more morphologically diverse, unevenly sized, and dense high-electron-density materials (electrondense material, EDM) within hepatocytes, and also within the Kupffer cell cytoplasm. Some cells near the capillaries have their cell membrane connections destroyed, causing localized irregular expansion of the intercellular space. Microvilli are not abnormal. Compared with bile duct atresia, patients with neonatal hepatitis have fewer EDM within the liver tissue, slightly fewer capillaries, slightly smaller diameters, and no destruction, with more microvilli. Currently, scholars have different interpretations of the electron microscopy findings in bile duct atresia, and further research is needed.

　　Congenital bile duct atresia has various classification methods. According to the different range of bile duct atresia, the commonly used classification method currently divides it into the following types.

　　1. The intraportal type is rare.

　　2. The extrahepatic type can be divided into 3 types, and each type can be further divided into several subtypes, as follows.

　　Type Ⅰ: Common bile duct atresia, with 2 subtypes (Figure 1).

　　Type Ⅰa: Low atresia of the distal end of the common bile duct.

　　Type Ⅰb: High atresia of the common bile duct.

　　Type Ⅱ: Bile duct atresia, with 3 subtypes (Figure 2).

　　Type Ⅱa: The bile duct from the gallbladder to the duodenum is open, while the bile duct is completely absent or fibrous strand-like.

　　Type Ⅱb: Complete atresia of extrahepatic bile ducts.

　　Type Ⅱc: Bile duct atresia with absent common bile duct.

　　Type Ⅲ: Bile duct atresia in the porta hepatis, with 6 subtypes (Figure 3).

　　Type Ⅲa: Dilated bile duct type.

　　Type Ⅲb: Fine bile duct type.

　　Type Ⅲc: Bile lake-like bile duct type.

　　Type Ⅲd: Strand-like bile duct type.

　　Type Ⅲe: Mass-like connective tissue bile duct type.

　　In the past, what was called the

　　Postoperative complications often threaten life, the most common being postoperative cholangitis, with an incidence rate of 50%, even up to 100%. The pathogenesis is most likely ascending infection, but sepsis is rare. During an attack, liver tissue culture rarely shows bacterial growth. Some scholars believe that this is the result of portal吻合, which blocks the outflow of portal lymph, making it prone to infection and developing intrahepatic cholangitis. Unfortunately, each attack aggravates liver damage, thereby accelerating the progression of biliary cirrhosis. It is more common in the first year after surgery, gradually decreasing thereafter, from 4-5 times a year to 2-3 times. Using aminoglycoside antibiotics for 10-14 days can reduce fever and restore bile flow. Antibiotics and cholagogues are often used prophylactically in the first year. Another important complication is fibrosis at the anastomotic site, resulting in bile stasis. The hope of restoring bile flow through reoperation is 25%. In addition, the continued development of intrahepatic fibrosis leads to cirrhosis. In some cases, it progresses to portal hypertension, hypersplenism, and esophageal varices.

　　Gradual jaundice, with jaundice of the sclera as the earliest sign, can appear shortly after birth or within a month. In some cases, it may appear 1-2 weeks after the physiological jaundice subsides, when it should gradually fade but instead progressively worsens. As the jaundice intensifies, the stool changes from normal yellow to pale clay color, and sometimes from pale clay color to light yellow. This is due to the high concentration of bilirubin in the blood, which permeates through the intestinal wall into the intestinal cavity, coloring the stool and darkening the urine, resembling the color of strong tea.

　　In the first 3 months, there is no significant change in the child's nutrition and development, height, and weight. After 3 months, development slows down, nutrition is poor, and the child becomes listless, anemic. From 5 to 6 months, due to biliary obstruction, fat absorption disorders, and a lack of fat-soluble vitamins, the overall condition deteriorates rapidly. Vitamin A deficiency can cause dry eyes, nail deformities, dry and lackluster skin; vitamin D deficiency can cause rickets and convulsions; vitamin K deficiency leads to reduced serum thrombin, causing subcutaneous hemorrhage and nosebleeds, among other phenomena; it is prone to upper respiratory tract infections and diarrhea.

　　Physical examination may show abdominal distension, enlargement of the liver, smooth surface, hard texture, and rounded edges. In the late stage, there may be intrahepatic cholestasis, liver fibrosis, biliary cirrhosis, and symptoms of portal hypertension such as splenomegaly, varices of the abdominal wall, and ascites. Ultimately, this can lead to liver failure, and hepatic encephalopathy is often the direct cause of death in this disease. If the bile duct cannot be reconstructed surgically, the general survival period is 1 year.

　　The main symptoms of biliary atresia are persistent jaundice, clay-colored stools, tea-colored urine, and enlargement of the liver and spleen. In the late stage, it can manifest as biliary cirrhosis, ascites, varices of the abdominal wall, and severe coagulation disorders. Some children may develop cyanosis and clubbing fingers due to the formation of 'vasodilator substances' within the liver, which open up a short circuit between the pulmonary and systemic circulation.

　　Early diagnosis of biliary atresia remains very difficult. The diagnostic methods used are diverse in form and means, and require comprehensive analysis in combination with clinical and laboratory examinations. Supplemental radionuclide scans, cholangiography, and liver biopsy are recommended for those with difficult diagnoses, and early surgical exploration is advocated.

　　If biliary atresia is not treated surgically, only 1% of patients survive to the age of 4. However, surgery also requires a great deal of determination, which has a profound impact on both the infant and the family. There is early developmental delay, repeated hospitalizations in the first year, and there are also complex issues such as reoperation.

　　Surgery undoubtedly prolongs survival, with reported 3-year survival rates of 35% to 65%. The basis for long-term survival is: ① surgery before 10 to 12 weeks of age; ② a large bile duct in the portal area (>150 μm); ③ blood bilirubin concentration 3 months after surgery

　　For many years, it has been considered that Kasai surgery can be used as the first step in the treatment of biliary atresia. After the infant has developed and grown, liver transplantation can be performed to achieve permanent cure.

　　There are many experimental methods available, but they all have poor specificity. During biliary atresia, the total serum bilirubin level increases, and the proportion of bilirubin in one minute also increases accordingly. Abnormal high levels of alkaline phosphatase are of reference value for diagnosis. The peak value of gamma-glutamyl transferase is higher than 300 IU/L, showing a persistent high level or rapid increase. The level of 5'-nucleotidase is higher when bile duct hyperplasia is more significant, with a measured value greater than 25 IU/L. The method of red blood cell hydrogen peroxide hemolysis is relatively complex. If hemolysis is above 80%, it is considered positive. The peak value of alpha-fetoprotein is below 40 μg/ml. The results of other routine liver function tests have no differential significance.

　　The diet of patients with congenital biliary atresia should be light and easy to digest, with an emphasis on eating more vegetables and fruits, and a reasonable dietary arrangement, ensuring adequate nutrition. Patients should eat less high-fat foods such as oils, fats, and meat, eggs, and milk. Fish and chicken, which have less fat, can be eaten in moderation.

　　First, treatment

　　Surgery is the only treatment method for biliary atresia. According to the types of biliary atresia proposed by Kasai, they can be divided into 'reconstructible' or 'treatable' types, which have relatively normal or dilated extrahepatic bile ducts. Bile drainage can be restored through biliary-enteric anastomosis, with good results. Another type is 'non-reconstructible' or 'non-treatable', for which there are two treatment methods: portal enteric anastomosis (Kasai surgery) or liver transplantation. Since 1959 when Kasai performed the first portal jejunal anastomosis for biliary atresia in Japan, nearly 40 years of clinical practice have shown that a portion of children have been able to survive for a long time, including those whose quality of life is close to that of normal children. Literature reports that 40% to 50% of children with biliary atresia have good long-term outcomes after portal enteric anastomosis, with effective bile drainage. The remaining 50% to 60% often experience various late complications, most of which require liver transplantation before the age of 2. Currently, with the development of liver transplantation technology and the application of new immunosuppressive drugs such as cyclosporin and ganciclovir, biliary atresia has become a major indication for pediatric liver transplantation.

　　As previously mentioned, due to the progressive development of biliary atresia into liver cirrhosis, it becomes irreversible after more than 3 months, so the operation should be completed within 60 days after diagnosis. If it is not possible to distinguish between biliary atresia and infantile liver syndrome, an exploratory laparotomy can also be performed within 6-8 weeks. Preoperative preparation: The liver function of newborns has not matured and there is a lack of normal bacterial flora in the intestines. The synthesis of vitamin K in the intestines is insufficient, resulting in low prothrombin levels and a tendency to bleed naturally. Vitamin K should be supplemented before surgery, along with glucose and vitamins B, C, and D. If anemia is present, blood transfusion should be given, and plasma should be administered to those with low serum protein levels. Antibiotics should be administered before surgery, and intraoperative cholangiography should be prepared.

　　1. Kasai surgical method This operation consists of two basic parts: the anatomy of the hilum and the reconstruction of the bile duct by the hilum-enteric anastomosis. After laparotomy, a re-exploration or intraoperative cholangiography should be performed again to confirm the diagnosis. Then, the gallbladder is separated, and the remaining bile duct and the fibrous strands of the common bile duct are separated along the cystic duct, and they are separated towards the hilum. The fibrous strands often continue into a triangular fibrous mass at the bifurcation of the portal vein. The liver lobe is pulled upwards at the hilum area, and the bifurcation of the portal vein is pulled downwards with a venous hook, fully exposing the fibrous mass at the hilum area. Careful dissection of the fibrous tissue at the hilum is performed at the left and right bifurcations of the portal vein, ligating 2-3 small veins entering the fibrous mass from the portal vein, and then removing the fibrous mass, its thickness reaching the surface of the liver parenchyma, where it is possible to see the fine opening of the hilum bile ducts that gradually secrete yellow bile juice. The main factor determining the efficacy of the hilum-enteric anastomosis is whether there is any residual bile duct at the hilum during surgery. The scope and level of the hilum anatomy are also very important, directly affecting the excretion of bile from the hilum. The venous ligament on the lateral side of the left portal vein can be cut to free the portal vein, which is more conducive to exposure and resection of the fibrous mass. The operation can be performed with the help of a surgical microscope to ensure more precise resection of the fibrous mass.

　　The reconstruction of bile ducts is mostly performed by lifting the jejunum through the posterior colon to the hilum of the liver to complete the anastomosis. Generally, the jejunum is cut about 15-20 cm from the Treitz ligament. The distal part of the intestinal tube is closed, and it is lifted to the hilum area through the mesentery of the transverse colon. The anastomosis is made on the opposite side of the mesentery of the intestinal wall, 1-2 cm long, and is adapted to the length of the fibrous mass at the base of the hilum. The elevated intestinal loop is retained for about 20 cm. Then, a jejuno-jejunal Y-shaped anastomosis is performed.

　　To prevent ascending cholangitis caused by reflux, Suruga improved the surgical technique by cutting the ascending branch to create a jejuno-cutaneous external fistula, and collecting bile juice daily for re-injection. The advantages of the Suruga operation are that it is convenient to observe the bile excretion volume and color after surgery, detect the bilirubin content, and perform bacterial culture, etc. The disadvantages are that postoperative management is difficult, the number of surgeries is increased, and there is severe peritoneal adhesion, which brings difficulties to the operation for liver transplantation in the future. The diagram of the type of surgery (Figure 4).

　　Postoperative treatment includes liver protection, bile promotion, and prevention of biliary tract inflammation. Bile promotion is very important, in addition to oral dehydrocholic acid, dinoprost (prostaglandin E2), and intramuscular injection of glucagon (glucagon), traditional Chinese medicine such as Yinzhui Huang intravenous infusion can also be used. Corticosteroids should be appropriately used after surgery, and antibiotics should be used for no less than 1 month.

　　2. Reoperation issues There are different opinions on whether reoperation is needed for cases of Kasai surgery with no bile excretion, low excretion volume, or once good excretion, but then interrupted. Some people believe that repeated abdominal surgery can exacerbate peritoneal adhesions, affecting future liver transplantation surgery and the prognosis of liver transplantation, so in countries where liver transplantation is widely practiced, this situation is a contraindication for liver transplantation.

　　3. Postoperative complications and treatment

　　(1) Postoperative biliary tract inflammation: Unlike biliary tract inflammation caused by bile duct obstruction in adults, it only occurs in children with bile excretion after hepaticojejunal anastomosis, but not in cases without bile excretion after obstruction is relieved. The characteristics of biliary tract inflammation after biliary atresia surgery are that the degree of jaundice rapidly deepens even exceeds preoperative levels, but obstructive pyogenic cholangitis rarely occurs. In addition, biliary tract inflammation is often difficult to control, and postoperative biliary tract inflammation has an important impact on the prognosis, and it is the most common and most difficult to treat complication after Kasai surgery.

　　The main causes of biliary tract inflammation are reflux and abnormal development of intrapulmonary bile ducts. Without ascending stoma, there will definitely be food reflux and subsequent ascending infection of intestinal bacteria, causing ascending cholangitis. Ascending stoma can prevent biliary tract inflammation caused by food reflux, but at the same time, because the stoma is in communication with the outside world, it still has the conditions for the occurrence of biliary tract inflammation.

　　According to the time of occurrence of biliary tract inflammation after surgery, it can be divided into early biliary tract inflammation and late biliary tract inflammation. Early biliary tract inflammation occurs within 1 month after surgery, at this time, the bile duct epithelium has not yet healed with the intestinal mucosal epithelium, and after inflammation, the bile ducts that were originally open are prone to occlusion. If the recurrent biliary tract inflammation in children cannot be controlled, it often leads to death due to liver failure or sepsis. Late biliary tract inflammation occurs more than 1 month after surgery, with recurrent fever and jaundice in children, eventually leading to liver cirrhosis or liver failure. Chronic and irreversible biliary tract inflammation is a contraindication for liver transplantation.

　　(2) Liver fibrosis and portal hypertension: Literature reports that the incidence of esophageal varices in children who have had biliary tract inflammation is 7 times higher than that in children who have not had biliary tract inflammation. Recurrent biliary tract inflammation can lead to severe liver damage, and in the late stage, it can lead to liver cirrhosis and portal hypertension. Research also found that although the Kasia procedure can achieve good bile drainage, the liver function of the children can still progressively deteriorate, especially during adolescence. Since liver fibrosis after biliary atresia surgery is an important factor affecting the outcome of the surgery, some people propose to measure serum procollagen III peptide, type IV collagen, and plasma endothelin to reflect and observe the degree of liver fibrosis. The treatment for portal hypertension can be endoscopic injection of sclerosing agents into esophageal varices, and due to poor prognosis, the fundamental treatment is still liver transplantation.

　　(3) Intrahepatic bile duct dilatation: in children with long-term survival, intrahepatic bile ducts may appear cystic dilatation, clinical manifestations include fever, jaundice, and white feces. Diagnosis can be made by ultrasound. Isolated cystic cavities can be treated by percutaneous cyst puncture and drainage under ultrasound guidance or intraperitoneal cyst jejunostomy, while multiple cystic dilatations require liver transplantation.

　　II. Prognosis

　　Kasai reported in 1989 that if the correct surgical method is adopted within 60 days after birth, the postoperative effect is excellent and the 10-year survival rate is greater than 70%. However, the American Academy of Pediatrics reported only 25%, and the French large group case report only 24%. The recent report of a group of 163 cases by Okzaki of Japan shows that the 10-year survival rate is only 13%, and the survival rate of patients undergoing liver transplantation can reach 29%. In recent years, due to the progress of liver transplantation technology and perioperative management, liver transplantation for children under 1 year of age can also achieve a survival rate of 70% to 80%, so liver transplantation has become an effective method for treating biliary atresia. Some researchers propose that liver transplantation should be the first-line treatment for biliary atresia, but some other researchers believe that liver transplantation should be considered as an option after Kasai surgery fails. Currently, the standards for liver transplantation in biliary atresia are not sufficient, especially for the long-term survival of children reaching adolescence after biliary atresia surgery, and further research is needed. Inomata summarized the experience of Kasai surgery before and after liver transplantation in the treatment of biliary atresia and proposed a treatment strategy for biliary atresia: Kasai surgery should be the first choice for the treatment of biliary atresia, and liver transplantation should be performed if it fails; for children diagnosed with advanced disease and liver cirrhosis, liver transplantation should be considered first.