Cholestasis of the newborn

Cholestasis is a disorder of bilirubin excretion that results in elevated direct bilirubin levels and jaundice. There are many known causes of cholestasis, which are identified by laboratory testing, liver and biliary tract imaging, and sometimes liver biopsy and surgery. Treatment of cholestasis depends on the cause.

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Causes of neonatal cholestasis

Cholestasis may result from extrahepatic or intrahepatic disorders or a combination of both. The most common extrahepatic cause is biliary atresia. A large number of intrahepatic disorders are known, which are united by the collective term "neonatal hepatitis syndrome".

Biliary atresia is an obstruction of the bile ducts due to progressive sclerosis of the extrahepatic bile ducts. In most cases, biliary atresia develops several weeks after birth, probably following inflammation and scarring of the extrahepatic (and sometimes intrahepatic) bile ducts. This condition is rare in premature infants or in children immediately after birth. The cause of the inflammatory response is unknown, but infectious causes are thought to be involved.

Neonatal hepatitis syndrome (giant cell hepatitis) is an inflammatory process in the liver of a newborn. A large number of metabolic, infectious, and genetic causes are known; some cases are idiopathic. Metabolic diseases include alpha1-antitrypsin deficiency, cystic fibrosis, neonatal hemochromatosis, respiratory chain defects, and fatty acid oxidation defects. Infectious causes include congenital syphilis, ECHO viruses, and some herpesviruses (herpes simplex virus, cytomegalovirus); hepatitis viruses are less common. Less common genetic defects include Allagille syndrome and progressive familial intrahepatic cholestasis.

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Pathophysiology of neonatal cholestasis

In cholestasis, the primary cause is insufficient excretion of bilirubin, which leads to an increase in conjugated bilirubin in the blood and a decrease in bile acids in the gastrointestinal tract. As a result of the low content of bile acids in the gastrointestinal tract, a syndrome of malabsorption of fats and fat-soluble vitamins (A, D, E, K) develops, which leads to hypovitaminosis, malnutrition, and growth retardation.

Symptoms of neonatal cholestasis

Symptoms of cholestasis are detected during the first two weeks of life. Children have jaundice and often dark urine (conjugated bilirubin), acholic stools, and hepatomegaly. If cholestasis continues, persistent itching develops, as well as symptoms of fat-soluble vitamin deficiency; the growth curve may decline. If the causative disease leads to the development of liver fibrosis and cirrhosis, portal hypertension may develop, followed by ascites and gastrointestinal bleeding from esophageal varices.

Diagnosis of neonatal cholestasis

Any infant with jaundice after 2 weeks of age should be evaluated for cholestasis with measurement of total and direct bilirubin, liver enzymes, and other liver function tests including albumin, PT, and PTT. Cholestasis is diagnosed by an increase in total and direct bilirubin; when the diagnosis of cholestasis is confirmed, further investigations are needed to determine the cause. This investigation includes tests for infectious agents (eg, toxoplasmosis, rubella, cytomegalovirus, herpesvirus, UTI, hepatitis B and C viruses) and metabolic disorders including urine organic acids, serum amino acids, alpha1 antitrypsin, sweat tests for cystic fibrosis, urine reducing substances, and tests for galactosemia. A liver scan should also be performed; Contrast excretion into the intestine excludes biliary atresia, but inadequate excretion may be seen in both biliary atresia and severe neonatal hepatitis. Abdominal ultrasound may be helpful in assessing liver size and visualizing the gallbladder and common bile duct, but these findings are nonspecific.

If the diagnosis has not been made, a liver biopsy is usually performed relatively early. Patients with biliary atresia typically have enlarged portal triads, proliferation of bile ducts, and increased fibrosis. Neonatal hepatitis is characterized by abnormal lobular structure with multinucleated giant cells. Sometimes the diagnosis remains unclear, and then surgical intervention with operative cholangiography is required.

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Treatment of neonatal cholestasis

Initial treatment of neonatal cholestasis is conservative and consists of providing adequate nutrition with vitamins A, D, E, and K. Formulas with a high content of medium-chain triglycerides should be used in formula-fed infants, as they are better absorbed in conditions of bile acid deficiency. Sufficient calories should be provided; infants may require more than 130 kcal/(kg x day). In infants who retain a small amount of bile secretion, ursodeoxycholic acid 10-15 mg/kg once or twice daily may reduce pruritus.

There is no specific treatment for neonatal hepatitis. Children with suspected biliary atresia require surgical evaluation with intraoperative cholangiography. If the diagnosis is confirmed, a Kasai portoenterostomy is performed. Ideally, this should be done within the first two weeks of life. After this time, the prognosis is significantly worse. After surgery, many patients have serious chronic problems, including persistent cholestasis, recurrent ascending cholangitis, and failure to thrive. Even with optimal treatment, many children develop cirrhosis and require a liver transplant.

What is the prognosis for neonatal cholestasis?

Biliary atresia is progressive and, if untreated, leads to liver failure, cirrhosis with portal hypertension within a few months, and death in the infant before one year of age. Neonatal cholestasis associated with neonatal hepatitis syndrome (especially idiopathic) usually resolves slowly, but liver tissue damage and death may occur.