Cholestatic jaundice in infants is jaundice caused by elevated conjugated bilirubin, which has potential risk factors and implies abnormal hepatobiliary function. Early detection of cholestatic jaundice and early and correct diagnosis of the cause of jaundice are important for the treatment and prognosis of the disease.
I. Etiology
Cholestatic jaundice requires prompt diagnosis and treatment. It is important to distinguish between cholestatic jaundice and non-cholestatic jaundice in children.
The most common causes of cholestatic jaundice at 1 month of age are biliary atresia and infantile hepatitis. Other causes include: a1 antitrypsin deficiency, extrahepatic biliary obstruction, such as common bile duct stones and cystic duct cysts; metabolic abnormalities, such as tyrosinemia, galactosemia, hypothyroidism; congenital defects in bile acid metabolism; Alagille syndrome; Citrin defects, infections; and other rare diseases.
Among them, jaundice caused by bacterial sepsis, galactosemia, hypopituitarism, or stones is of acute onset and easily alerts physicians and parents for early diagnosis and treatment. It is worth noting that a proportion of children with cholestatic jaundice are often considered to have physiological jaundice or breast milk jaundice because they are well behaved and growing normally. These children can improve their condition and avoid complications if they are seen promptly and receive early treatment. In particular, children with biliary atresia can have their bile flow reestablished and achieve the longest-term survival of the liver if surgery is performed within 45-60 days.
II. Initial assessment of the jaundiced child
1. Jaundice with white stools and/or dark urine suggesting possible cholestatic jaundice
Infants passing white stools suggest the possible presence of cholestasis, especially persistent white stools are highly specific. It is worth noting that a few newborns have been reported in the literature to pass white stools but with less than 3 white stools, and on examination, these newborns do not have liver disease. Due to the dynamic nature of the disease, some children may not have abnormal stool color early in the disease, such as children with biliary atresia who have incomplete atresia early in life and may have normal stool color. Also, the stool color varies depending on the cause of the jaundice.
Dark urine is also a nonspecific sign of elevated conjugated bilirubin.
If a healthy full-term newborn has jaundice with white stools or if jaundice persists beyond 3 weeks of age, he should be further tested for elevated conjugated bilirubin.
Measurement of total bilirubin and direct bilirubin
Both combined or unconjugated bilirubin elevation can lead to jaundice in infants, so the detection and analysis of serum bilirubin plays an important role in distinguishing the cause of jaundice.
Total bilirubin (TB) and direct bilirubin (DB) should be measured for clinical evaluation in infants found to be jaundiced at 2 weeks of age. Breastfed children with no other medical history (absence of dark urine and light colored stools), normal physical examination, and the ability to be monitored with certainty can be reviewed at 3 weeks of age. If jaundice persists, total bilirubin and direct bilirubin will be measured; TB<5mg/dL with DB>1.0mg/dL; or TB>5mg/dL with DB to TB ratio >20% are considered abnormal.
Initial evaluation of infants with elevated conjugated bilirubin
Elevated conjugated bilirubin indicates the presence of cholestasis and requires a complete diagnostic evaluation of the etiology. The goal of the evaluation is to determine the etiology of the cholestasis and, at a minimum, to be able to rule out biliary atresia.
1. Children with galactosemia and hypothyroidism should be evaluated or have repeat newborn screening, and these conditions need to be managed as soon as possible to avoid sequelae. In addition, it should be noted that children with cholestasis, despite a confirmed diagnosis, still have the potential for other disorders. If the jaundice does not resolve with appropriate treatment according to the initial diagnosis, further evaluation with other methods should be considered.
2. Ultrasonography, which helps to identify anatomical abnormalities such as common bile duct cysts. Ultrasound examination reveals a small gallbladder or an extrahepatic biliary tract obstruction, but the sensitivity of ultrasound examination is only 73%, so extrahepatic biliary tract obstruction cannot be ruled out based on ultrasound results alone. Ultrasound findings of the “triangular sign” (fibrous mass in the porta hepatis) can help diagnose extrahepatic biliary atresia. However, this technique is also dependent on the skill and experience of the operator.
For cholestasis of unknown etiology, ultrasound is recommended to evaluate and assist in the diagnosis.
3.GGT (gamma-glutamyl transpeptidase)
GGT has been used to identify biliary atresia and infantile liver, especially in older infants with cholestasis Low GGT is helpful to help rule out obstruction; low GGT with elevated AKP suggests intrahepatic cholestasis due to hereditary or metabolic disease The degree of GGT elevation is not helpful in distinguishing the etiology of cholestasis.
IV. Further evaluation of the child with cholestatic jaundice
Cholestatic jaundice should be differentiated between hepatocellular and obstructive cholestasis; whether the cholestasis is physiological or due to anatomical abnormalities; and whether it needs to be treated medically or surgically.
Valuable detection methods include: percutaneous liver aspiration biopsy, nuclear scan, duodenal aspirate analysis, etc.
1.Percutaneous liver aspiration biopsy
Percutaneous hepatic aspiration biopsy is safe and rapid, and is useful in providing a specific diagnosis. 50%-99% of patients with biliary atresia are correctly diagnosed by hepatic aspiration biopsy. The sensitivity of liver biopsy for the diagnosis of biliary atresia (BA) is 99%, the specificity is 92%, and the specificity for the diagnosis of infantile liver is slightly lower. It is important to note that liver biopsy is affected by the dynamic nature of the disease in the diagnosis of cholestasis in newborns, as the presentation of the disease varies over time. Liver biopsy performed early in the course of biliary atresia may be difficult to differentiate from infantile liver.
Liver biopsy reveals cholestasis and injury of the intrahepatic bile ducts and can provide a specific diagnostic basis. For example, a1 antitrypsin deficiency with positive PAS; Alagille syndrome with bile duct deficiency; sclerosing cholangitis with necrotizing bile duct damage; and other characteristic manifestations of metabolic and storage diseases may also be found.
For cholestasis of uncertain etiology, a percutaneous liver aspiration biopsy is performed and the pathological findings are described by a pathologist with expertise in pediatric liver disease. Liver puncture is performed early in the course of the disease (less than 6 weeks of age) and needs to be repeated if the pathologic findings are not sufficiently definitive.
2. Nuclear scan
Intravenous injection of radioactive material drains into the intestine within the expected time, and if there is no visualization in the area of the intestinal scan 24 hours after injection, it suggests biliary obstruction or hepatocellular dysfunction.
The sensitivity of the nuclide scan for the diagnosis of biliary atresia is high, and children with complete biliary obstruction do not excrete radioactive material at all. The specificity of a nuclide scan for biliary atresia or other obstructive disease is low, and some children with normal anatomy do not excrete tracers.
Despite its high sensitivity, nuclide scanning is time consuming, expensive, and has false-positive and false-negative results, so the Cholestasis Guidelines Committee believes that it is only of value if other methods cannot rule out biliary obstruction.
3.Duodenal fluid aspiration analysis
Duodenal fluid is collected by tube placement or provocation test and analyzed for bilirubin concentration; a positive result is obtained if the bilirubin concentration of the aspirate is lower than the serum bilirubin concentration. A small amount of literature considers the analysis of bilirubin concentration in duodenal aspirates for the diagnosis of biliary obstruction. The sensitivity of the duodenal aspirate analysis method is similar to that of the nuclear scan, and the technique is not very demanding and inexpensive. However, the technique is not widely used because it is time-consuming, invasive, and inconvenient.
The guidelines suggest that duodenal aspiration fluid analysis can be considered if other methods fail to detect bile duct obstruction.
4.Magnetic resonance cholangiopancreatography (MRCP)
MRCP requires deep sedation or general anesthesia as well as advanced techniques and extensive clinical experience to evaluate cholestasis, and the committee believes that this method is not used as a routine.
5. Endoscopic retrograde cholangiopancreatography (ERCP)
This technique is increasingly used in the analysis of cholestasis in smaller infants.ERCP involves endoscopic insertion of a tube into the biliary tract as well as into the hepatopancreatic jugular and injection of a contrast contrast agent to visualize the biliary system, and the patient requires general anesthesia. Small pediatric lateral view duodenoscopy has advanced the spread of this technique in small infants. It has a high sensitivity and specificity.
The cost of equipment and the expertise required to perform it have both limited the use of ERCP. Prior to performing ERCP, a liver puncture biopsy should be performed. Since ERCP can clarify the cause of cholestasis in newborns and avoid abdominal exploratory surgery, it can be performed in small infants when specialized personnel and equipment are available.
V. Summary
Identification of jaundice and detection of stool/urine abnormalities in children older than 2 weeks of age can help in early detection of the condition and timely diagnosis. If the condition does not improve after appropriate treatment according to the initial diagnosis, further complete evaluation should be done. Children should be evaluated promptly even if they appear well, as these children may have serious conditions that require urgent treatment, such as extrahepatic biliary obstruction. If diagnosed early and treated surgically, the patient’s liver can achieve longer-term survival.
Laboratory tests for cholestasis should include direct bilirubin. TB should be considered abnormal if it is <5 mg/dl and DB >1.0 mg/dl, or TB >5 mg/dl and DB >20%. 2-week-old infants found to be jaundiced should be tested for TB and DB for clinical evaluation, and in breastfed children with no other history (no dark urine or light stools) and a normal physical examination and able to confirm monitoring, they can be If jaundice persists, TB and DB should be tested.
Liver aspiration biopsy has the highest diagnostic accuracy. However, because of the progressive and dynamic nature of extrahepatic biliary atresia, percutaneous hepatic aspiration biopsy may also be missed.
Nuclear scan can rule out extrahepatic biliary obstruction.
Ultrasound is used to rule out anatomic abnormalities and may have additional uses as imaging studies are further developed and if the “triangular sign” (fibrous mass in the hilar region) can be confirmed
ERCP can be used in centers with good equipment and experienced pediatric gastroenterologists.
The use of MRCP has been less analyzed.
Duodenal aspirate analysis or provocation testing should be used in children in remote areas or when other tests are not available.
In conclusion, neonatal cholestasis needs to be diagnosed more quickly in order to achieve better treatment and improve patient prognosis. The guidelines help the clinician in the diagnosis. During the evaluation process, clinicians should not rely solely on a single test to determine the cause of cholestasis; remain alert to the patient, detect jaundice in a timely manner, choose an appropriate and time-saving diagnostic method in the context of the actual situation; and report the condition to a superior physician and make a timely referral for a definitive diagnosis and timely treatment. In addition, scientific research in this field needs to be further deepened and developed.