Neonatal Congenital Biliary Atresia

　　1. Etiology

　　The etiology of biliary atresia is relatively complex and still not fully understood, including theories such as congenital maldevelopment of bile ducts, viral infection, abnormal convergence of pancreaticobiliary ducts, and bile acid metabolism disorders.

　　1. Congenital Developmental Abnormality

　　This disease was previously considered to be a congenital abnormality of bile duct development, but recent pathological and clinical studies believe that this theory is not entirely reliable. Common congenital malformations in clinical practice, such as anal atresia, intestinal atresia, and esophageal atresia, often accompany other malformations, while biliary atresia is rarely associated with malformations; no biliary atresia malformation has ever been found in fetal autopsies. The clinical symptoms of this disease sometimes appear several weeks after birth, or reappear after the physiological jaundice subsides. Some people, when performing biliary atresia surgery, can see tiny strands of bile duct remnants at the hilum of the liver, even in so-called 'unsurgical types', and tissue sections can show bile duct lumen, bile duct epithelium, residual bile pigment, and inflammatory cell infiltration, etc. Further explaining that biliary atresia is not a congenital developmental malformation, but a disease that appears before and after birth.

　　2. Infection factors

　　Some propose that biliary atresia, neonatal hepatitis, and choledochal cyst are all caused by viral infection, belonging to the same lesion, but the location of the lesion is different. After the liver and bile ducts are infected by the virus, the liver presents with giant cell changes, the bile duct epithelium is damaged, leading to lumen obstruction, resulting in biliary atresia or choledochal cyst. Inflammation can also cause periductal fibrosis and progressive bile duct obstruction. Currently, there are many reports suggesting a close relationship between cytomegalovirus infection and the occurrence of biliary atresia and choledochal cyst.

　　3. Congenital pancreatico-biliary union abnormality

　　Abnormal pancreatico-biliary union refers to a congenital malformation where the pancreatic duct and bile duct do not converge within the duodenal wall during embryogenesis but converge outside the wall. It is not only one of the important etiologies of congenital choledochal cyst, bile duct stones, pancreatic stones, pancreatitis, bile duct cancer, and pancreatic cancer, but also there are reports that abnormal pancreatico-biliary union can also lead to biliary atresia.

　　2. Pathogenesis

　　It is divided into two types: intraportal and extraportal types. The former is rare in incidence and has not been reported in China; the extraportal type is further divided into 6 types. Generally, types I, II, and III are called 'non-anastomotic types' or 'unsatisfactory surgical outcomes', accounting for 80% to 90%, with limited treatment options and poor prognosis; while types IV, V, and VI are called 'anastomotic types', accounting for 10% to 20%. Among the 6 types of biliary atresia, types I and II are considered to be maldevelopment of the bile ducts, where inflammatory damage to the bile duct epithelium leads to fibrosis, the lumen gradually narrows, but is not completely occluded. If the condition improves gradually, there is a possibility of recovery. If the inflammation continues to develop, the entire bile duct will be completely occluded. Type III is true biliary atresia, with severe involvement of the extrahepatic bile ducts, complete damage to the epithelium, and complete fibrosis of all structures. Due to the complete disappearance of bile ducts, there are no visible cavities in the hepatic, duodenal ligament, and hilum. Occasionally, small amounts of mucosal tissue can be seen in tissue sections, and anastomotic surgery cannot be performed. Types IV, V, and VI are bile duct interruptions, where the extrahepatic bile duct ends at a blind-ended part. The blind pouch contains bile that communicates with the liver, so anastomotic surgery can be performed. The liver of this disease presents with biliary cirrhosis, with hyperplasia of intrahepatic bile ducts, severe bile thrombi in the ducts, and sometimes rupture of small bile ducts, resulting in bile leakage. The liver cells and capillary bile ducts are also severely cholestatic. The liver cells may have giant cell changes, and there is fibrosis in the portal area.

　　It can be complicated with liver cirrhosis, portal hypertension, massive gastrointestinal bleeding, hepatic coma, sepsis, and other conditions; it can lead to growth disorders, malnutrition, anemia, and other symptoms in children.

　　1. Liver cirrhosis (hepatic sclerosis):It is a common chronic progressive liver disease in clinical practice, a diffuse liver damage formed by the long-term or repeated action of one or more etiologies. Pathologically, there are extensive liver cell necrosis, nodular regeneration of residual liver cells, proliferation of connective tissue and formation of fibrous septa, leading to the destruction of the lobular structure and the formation of pseudo-lobules, gradual deformation and hardening of the liver, and the development of liver cirrhosis.

　　2. Portal hypertension (portalhypertension):It is a syndrome caused by persistent elevation of portal venous pressure, with the vast majority of patients caused by liver cirrhosis, a few patients secondary to obstruction of the main portal vein or hepatic vein, and some factors of unknown cause.

　　3. Hepatic encephalopathy (hepaticencephalopathy, HE):Also known as hepatic coma, it is a comprehensive syndrome of central nervous system dysfunction caused by severe liver disease, based on metabolic disorders. Its main clinical manifestations are disturbance of consciousness, abnormal behavior, and coma. There are acute and chronic encephalopathies.

　　4. Sepsis:It is a systemic infection caused by pathogenic bacteria entering the blood circulation and growing and reproducing there, producing toxins. It is prone to occur when the body's resistance is reduced. Clinically, it is mainly manifested as chills, high fever, toxicemia symptoms, rash, joint pain, enlargement of the liver and spleen, infectious shock, migratory foci, etc. The majority of cases present an acute course, with severe illness and poor prognosis. It is now further believed that sepsis is a series of cascading reactions caused by the activation and release of inflammatory mediators after pathogenic bacteria and their toxins and metabolites enter the blood flow.

　　5. Anemia:Hypochromia is defined as having a lower count of red blood cells, hemoglobin content, and hematocrit in a certain volume of circulating blood than the normal standard.

　　1. Jaundice

　　Jaundice is the initial symptom, generally beginning to appear gradually within 1 to 2 weeks after birth, with a few cases not starting until 3 to 4 weeks later. However, there are also cases with jaundice appearing within the first week. After the onset of jaundice, it usually does not subside and becomes increasingly severe, with the skin turning golden yellow or even brown, and the mucosa and sclera also becoming significantly yellow. In the late stage, even tears and saliva may turn yellow.

　　2. Change in stool color

　　For the first few days after birth, most infants show no abnormal symptoms, with normal stool color. The stool turns pale yellow at the same time as jaundice appears, gradually becoming more yellowish white, or turning into clay-like grayish white. However, during the course of the disease, it may also turn into yellowish white. It is reported that 15% of children with biliary atresia defecate white stools only one month after birth, and by the late stage, due to the increased concentration of bilirubin in the blood and other organs, a small amount of bilirubin can pass through the intestinal glands into the intestinal cavity, causing some stools to become pale yellow.

　　3. Change in urine color

　　The color of urine becomes darker with the severity of jaundice, resembling the color of black tea, and can stain diapers yellow.

　　4. Skin itching

　　The skin may have scratch marks due to itching.

　　5. Liver enlargement

　　The abdomen is abnormally distended, with a significant enlargement of the liver, which can be 1 to 2 times larger than normal. Especially the right lobe of the liver, its lower edge can exceed the umbilical level to reach the right iliac fossa. The longer the course of the disease (4 to 5 months or longer), the larger the liver becomes, with very clear edges. Palpation reveals a hard liver texture. Almost all cases show an enlargement of the spleen, with the edge at the level of the rib margin or a few centimeters below, and the abdominal wall veins are all visible. In the late stages, there may be a certain amount of ascites in the abdominal cavity, resulting in a shifting dullness on percussion.

　　6. General condition

　　The nutritional development of the patient is generally not much changed in the first 3 to 4 months, the feeding is good, without nausea, vomiting and other gastrointestinal symptoms, the height and weight are not much different from normal infants, occasionally the child is listless, the actions and reactions are slightly slower than healthy infants; by the time the course reaches 5 to 6 months, although the appearance may still be good, the physical development has begun to slow down, the spirit is low, and due to the decrease of prothrombin in the serum, some cases have shown a tendency to hemorrhage, skin petechiae, nosebleeds, etc. The symptoms of various fat-soluble vitamin deficiencies can be manifested; when vitamin A is deficient, it appears in ophthalmic diseases and other parts of the body's epithelial keratin changes; vitamin D deficiency can be accompanied by rickets or other sequelae, and most children with bile duct atresia die around the age of 1 due to liver cirrhosis, portal hypertension, and hepatic coma.

　　Currently, due to the unclear etiology, there is no specific preventive measure. Preventive measures should run through from pre-pregnancy to prenatal care:

　　1. Pre-marital physical examination plays a positive role in preventing birth defects, the size of which depends on the items and content of the examination, mainly including serological tests (such as hepatitis B virus, syphilis spirochete, HIV), reproductive system examination (such as screening for cervical inflammation), general physical examination (such as blood pressure, electrocardiogram), and inquiring about the family history of diseases and personal past medical history, etc., and do a good job of genetic counseling work.

　　2. Pregnant women should try to avoid harmful factors, including staying away from smoke, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, toxic and harmful heavy metals, etc. During the process of prenatal care during pregnancy, systematic screening for birth defects should be carried out, including regular ultrasound examination, serological screening, etc., and chromosomal examination may be required if necessary.

　　Once abnormal results appear, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the womb; whether there are sequelae after birth, whether they can be treated, and what the prognosis is, etc. Take practical and feasible diagnostic and treatment measures.

　　1. Serum bilirubin tests

　　Serum bilirubin levels are elevated, especially the direct bilirubin, reaching 85-340μmol/L (5-20m/dl) in the serum, and the dynamic observation shows a continuous increase.

　　2. Liver function tests

　　At 3 months after birth, perform the zinc sulfate turbidity test (ZnTT) and thymol turbidity test (TTT), most of which are positive. The lecithin flocculation test is later than ZnTT and TTT and is positive. ALT and AST are mostly slightly or moderately elevated, rarely exceeding 500U. Lactate dehydrogenase and leucine aminopeptidase are mostly normal or slightly elevated. Alkaline phosphatase is elevated in all cases after 3 months of birth, usually above 20U (Kim's), and has diagnostic significance when exceeding 40U (Kim's), and increases with the increase of age.

　　3. Determination of urobilin and urobilinogen

　　The stool and urine bilirubin and coproporphyrin tests are negative, and no bilirubin or coproporphyrin is present in the urine. In the later stage, part of the serum bilirubin can渗透 through the intestinal wall into the intestinal lumen, and generate a small amount of urobilinogen and coproporphyrin, which oxidize to become urobilin and coproporphyrin.

　　4. Determination of serum 5-nucleotidease

　　The activity of 5-nucleotidease is significantly increased, and the bile duct atresia children are all higher than the upper limit of normal by 15U, 33.33% of the children are higher than 50U, and the neonatal hepatitis children are all lower than 50U. This result is also consistent with the pathological histological changes, that is, the bile duct hyperplasia in bile duct atresia is serious, and the difference is significant compared with neonatal hepatitis. The determination of 5-nucleotidease can help with the early diagnosis of bile duct atresia.

　　5. Determination of serum bile acid

　　The serum bile acid in children with bile duct atresia is significantly increased, and dynamic observation is helpful for differential diagnosis with neonatal hepatitis.

　　6. Determination of serum alpha-fetoprotein (AFP)

　　AFP is produced by the normal fetal liver and naturally regresses after one month of birth. Bile duct atresia is mainly due to bile duct epithelial hyperplasia, without hepatocyte hyperplasia, and cannot synthesize AFP. The qualitative test is negative, occasionally positive, with a very low average value. In neonatal hepatitis, there is hepatocyte hyperplasia, an increase in AFP synthesis, and an increase in AFP in the blood. By radioimmunoassay, continuous quantitative determination, a peak greater than 4mg/dl can be diagnosed as neonatal hepatitis.

　　7. Plasma low-density lipoprotein (LP-x) test

　　LP-x is a normal low-density lipoprotein in the serum of patients with obstructive jaundice. When there is bile duct atresia, bile stasis in the liver, and the LP-x in the serum is significantly increased.

　　8. Red blood cell hydrogen peroxide hemolysin test

　　When there is biliary obstruction, there is a lack of fat-soluble vitamin E, and the red blood cell membrane lacks vitamin E, losing the oxidative action of vitamin E, and unable to prevent hemolysis induced by H2O2. If the hemolysis rate increases, it indirectly proves the lack of vitamin E, indicating the degree of obstruction, normal hemolysis in infants.

　　9. Determination of bilirubin in duodenal drainage fluid

　　The principle of this method is that the bile of children with bile duct atresia cannot enter the digestive tract, and the duodenal fluid does not contain bile pigments. A newborn duodenal aspiration tube with a metallic tip is inserted into the stomach through the nasal cavity (or mouth), aspirated to empty the gastric juice, placed in the child's right lateral position with the hip slightly elevated, and 20ml of clear water is injected to stimulate gastric peristalsis. Under the X-ray fluorescence screen, the tube is continued to be inserted to make the metallic tip enter the second segment of the duodenum, aspirate the duodenal fluid, and after the first tube is finished (bile juice is placed in a test tube), 2-5ml/kg of 33% magnesium sulfate is injected from the drainage tube. Subsequently, duodenal fluid is aspirated every 15 minutes and separately placed in 'A', 'B', and 'C' tubes, and the pH value, white blood cells, and bilirubin are checked. In the 19 cases reported by Li Shuisheng where the duodenal fluid did not contain bilirubin, 18 were diagnosed with bile duct atresia, and in the 11 cases where the duodenal fluid contained bilirubin, 2 were diagnosed with bile duct atresia. These two cases were severe jaundice children, related to excessively high serum bilirubin, from the intestinal wall into the intestinal cavity. This method can achieve a 90% diagnostic rate and is helpful for the early diagnosis of bile duct atresia.

　　10. B-ultrasound

　　The extrahepatic bile ducts are often not palpable, and the gallbladder is often not visible or significantly shrunken. Dynamic observation of the changes in the gallbladder before and after eating is more helpful for diagnosis.

      Normal breastfeeding..

　　1. Try to keep the child calm, avoid excessive crying and shouting, and ensure adequate sleep.
　　2. Keep the air in the living room circulating. The child should avoid staying in crowded public places to reduce the chance of respiratory tract infections. Clothing should be added or subtracted in time according to the change of weather, and attention should be paid to prevent colds.
　　3. Keep the stool smooth. If the stool is dry and difficult to defecate, excessive force can increase abdominal pressure, increase the burden on the heart, and even cause serious consequences..

　　1. Treatment

　　1. Surgical Treatment

　　Once diagnosed with biliary atresia, surgery is the only treatment method. Any confirmed diagnosis or those who cannot rule out the disease should undergo surgical treatment as early as possible for biliary reconstruction. The first 60 days after birth are the appropriate time for biliary reconstruction surgery. After 3 months, secondary biliary cirrhosis occurs, leading to irreversible liver function damage, and the postoperative effect is poor.

　　(1) Surgical Indications:

　　① Direct bilirubin continuously elevated for more than 3 weeks.

　　② Excrement of kaolin or pale yellow for 2 weeks.

　　③ The liver is significantly harder than that of同龄 children.

　　(2) Surgical Methods: Anastomosis is the main surgical method, including:

　　① Hepaticoduodenal Anastomosis.

　　② Hepaticojejunostomy Roux-Y Anastomosis.

　　③ Hepaticocholedochal Anastomosis.

　　④ Liver Transplantation: When late-stage liver damage is irreversible, liver transplantation can be performed.

　　2. Postoperative Treatment

　　After the operation, bile secretion should be promoted, and postoperative cholangitis should be prevented. After the operation, it is advisable to drip cefazolin and aminoglycosides and other antibiotics. After the operation, bile promotion can be achieved with dehydrocholic acid and prednisolone, which is effective. There are also reports recommending prostaglandin E and glucagon. If jaundice does not subside or recurs after the operation, surgery should be redone within 2 months. Correct the postoperative amino acid metabolism abnormalities and ensure the supply of calories, essential fatty acids, amino acids, fat-soluble vitamins, and trace elements such as iron and zinc.

　　2. Prognosis

　　There are reports that the jaundice clearance rate of those operated within 60 days of birth is above 90%, while for those operated more than 90 to 120 days after birth, the clearance rate is below 30%. Even if the operation is done well with good bile drainage, it is inevitable to die of liver failure after the operation. Therefore, the best time for biliary atresia surgery is 6 to 10 weeks after birth, and it should not exceed 90 days after birth.