Cholestasis in infants

by Diana Lerner, MD, Jonathan Ramprasad, MD, and Bernadette Vitola, MD, MPH

Diana Lerner, MD, is a pediatric gastroenterology fellow at The Medical College of Wisconsin.

Jonathan Ramprasad, MD, is a pediatric gastroenterology fellow at the Medical College of Wisconsin.

Bernadette Vitola, MD, MPH, is a pediatric gastroenterologist at Children's Hospital of Wisconsin. She also is an assistant professor of Pediatrics (Gastroenterology) at the Medical College and a member of Children's Specialty Group.

Introduction

Cholestasis is defined as reduced bile flow and abnormal accumulation of conjugated bilirubin, indicating impaired hepatobiliary function. Conjugated bilirubin is considered abnormal if it is 1 mg/dl or above when the total bilirubin is less than 5 mg/dl or more than 20 percent of the total bilirubin when the total is above 5 mg/dl.

Cholestasis occurs in approximately 1 in 2,500 births. Biliary atresia and neonatal hepatitis account for most cases. The other etiologies of cholestasis are numerous and include anatomic obstruction (such as bile sludging and choledochal cyst), infection (such as urinary tract infection and CMV), metabolic disorders (such as galactosemia and tyrosinemia), genetic disorders (such as alpha-1 antitrypsin deficiency, cystic fibrosis and Alagille syndrome), endocrine dysfunction (such as hypothyroidism and panhypopituitarism) and toxins (such as TPN). See Table 1.

Conjugated hyperbilirubinemia in the first month of life is pathologic and may be a serious or even life-threatening disease requiring urgent evaluation. Biliary atresia is the most time-sensitive with regard to treatment and outcomes. Surgical treatment of biliary atresia with the Kasai portoenterostomy has a statistically superior outcome when performed by 2 months of age. In addition, early diagnosis may allow for optimal nutritional and medical support, which can decrease the likelihood of complications of chronic liver disease.

The primary care physician is critically important in the evaluation of the jaundiced infant. It is recommended that all infants with persistent jaundice beyond 2 weeks old be assessed with a fractionated bilirubin. In healthy breast-fed infants with no signs of cholestasis, this investigation can be postponed until 3 weeks old. If conjugated hyperbilirubinemia is present, prompt referral to a pediatric gastroenterologist for further evaluation is imperative.

Clinical findings

Aside from jaundice, the clinical presentation of the cholestatic infant can vary widely depending on the etiology. Infants with biliary atresia often are healthy-appearing and asymptomatic until later in the disease course. Infants with cholestasis due to infection or a metabolic disease such as galactosemia or tyrosinemia often appear ill. Cholestasis as a result of a genetic mutation may have associated physical findings such as a heart murmur, vertebral anomalies, typical facial features and eye findings in Alagille syndrome.

The triad of jaundice, acholic stools and dark urine should alert the clinician to the possibility of cholestasis, especially biliary atresia. Parental reports of stool color often are misleading. Reportedly normal stools can falsely reassure the pediatrician. It is preferable for the provider to visualize the stool. It is not uncommon for the stool color to become acholic over several weeks as the extrahepatic biliary drainage system becomes progressively damaged in biliary atresia. Malnutrition and impaired absorption of fat-soluble vitamins (A, D, E and K) are significant long-term sequelae of cholestasis. Supplementation with calorically dense formula, primarily ones containing medium-chain triglycerides, and vitamin supplementation frequently are required.

Evaluation

  • Determine if the patient is acutely ill and requires urgent care.
  • Assess the presence of cholestasis by measuring total and conjugated serum bilirubin.
  • Review the results of the newborn screen specifically for galactosemia, tyrosinemia and hypothyroidism.
  • Evaluate the synthetic function of the liver by investigating for hypoglycemia, coagulopathy and hypoalbuminemia.
  • Immediately refer to a pediatric gastroenterologist for additional testing. The specialist will obtain critical laboratory tests and an abdominal ultrasound, preferably at a center with pediatric radiology.
  • Liver biopsy and intraoperative cholangiogram are the gold standard for differentiating biliary atresia from other causes of cholestasis and should be expedited in infants approaching 6-8 weeks old.
  • Scintigraphy (hepatobiliary iminodiacetic acid or HIDA scan) adds little value to the evaluation of the cholestatic infant given the significant false positive results. Referral to a pediatric gastroenterologist should not be delayed in order to obtain a HIDA scan.

Critical quick questions

  • How old is the child?
  • Are the stools acholic? (See image reference* below.)
  • Is this biliary atresia?
  • Is there evidence of liver disease: hypoglycemia or coagulopathy?

Critical tests

  • Fractionated bilirubin (total and conjugated).
  • AST, ALT, GGT, alkaline phosphatase, albumin.
  • Prothrombin time/INR.
  • CBC.
  • Glucose.
  • Newborn screen.
  • Abdominal ultrasound.

* For images of normal and abnormal infant stool color, visit the American Academy of Pediatrics website, aap.org. Search for Òinfant stool,Ó select Screening for Biliary Atresia by Infant Stool Color Card in Taiwan and see Page 3.

For outcomes from our Gastroenterology, Hepatology and Nutrition Center, visit chw.org/quality.

 
Jonathan Ramprasad, MD, Diana Lerner, MD, and Bernadette Vitola, MD, MPH, use a liver model to aid in discussion of a patient's care. The physicians are part of the Gastroenterology, Hepatology and Nutrition Center team. Children's Hospital of Wisconsin has one of the largest pediatric gastroenterology programs in the country, with leading experts in issues ranging from feeding and swallowing to cyclic vomiting.