INTRODUCTION — Neonatal cholestasis is generally defined as conjugated hyperbilirubinemia that occurs in the newborn period or shortly thereafter. Cholestasis results from diminished bile formation and/or excretion, which can be caused by a number of disorders. Neonatal cholestasis lasting more than two weeks affects approximately 1 in 2500 births (excluding infants with intestinal failure-associated liver disease), but estimates vary depending on the definition used to define cholestasis [1,2].
This topic review provides a diagnostic approach to patients with neonatal cholestasis. Related material can be found in the following topic reviews:
●(See "Causes of cholestasis in neonates and young infants".)
●(See "Biliary atresia".)
●(See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia".)
●(See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)
DEFINITIONS
●Cholestasis – Cholestasis is defined as an impairment in the excretion of bile, which can be caused by defects in intrahepatic production of bile, transmembrane transport of bile, or mechanical obstruction to bile flow. The biochemical features of cholestasis reflect the retention of components of bile in the serum (eg, bilirubin, bile acids, and/or cholesterol). The pattern and severity of each of these abnormalities vary with the underlying disorder. Elevated conjugated bilirubin is the predominant characteristic in most of the causes of neonatal cholestasis.
●Conjugated hyperbilirubinemia – In a young infant, a threshold for initiating a clinical evaluation for cholestatic liver disease is conjugated or direct bilirubin >1.0 mg/dL (17.1 micromol/L) [3]. During the neonatal period, milder elevation of conjugated bilirubin is abnormal and warrants close follow-up. (See "Biliary atresia", section on 'Laboratory studies'.)
The threshold is somewhat higher, usually a serum direct bilirubin greater than 2.0 mg/dL (34.2 micromol/L), for defining clinically significant hyperbilirubinemia in infants with intestinal failure-associated liver disease (also known as parenteral nutrition-associated liver disease). (See "Intestinal failure-associated liver disease in infants", section on 'Definitions'.)
The terms "conjugated bilirubin" and "direct bilirubin" are often used interchangeably because conjugated bilirubin can be estimated by the "direct" reaction with a diazo reagent (van den Bergh reaction). However, direct-reacting bilirubin includes both the conjugated bilirubin and the delta fraction, which represents bilirubin covalently bound to albumin [4]. (See "Clinical aspects of serum bilirubin determination", section on 'Measurement of serum bilirubin'.)
●Neonatal cholestasis – The term "neonatal cholestasis" is often used to refer to cholestatic liver disease that is present at birth and/or develops within the first few months of life, rather than referring strictly to the neonatal period (the first 28 days of life). In clinical practice, these disorders usually become apparent within the first two months of life, which is the critical period for identifying infants with biliary atresia (table 1). However, similar diagnostic considerations apply for infants whose cholestasis is identified after two to three months of age. Although the cholestasis caused by these disorders is persistent, infants should be evaluated as soon as the conjugated hyperbilirubinemia is identified to avoid delay in diagnosis.
OVERVIEW
Indications for evaluation
●Jaundice – Any infant noted to be jaundiced at the two-week well-child visit should be evaluated for cholestasis (ie, conjugated hyperbilirubinemia) [3]. This is because physiologic jaundice (characterized by unconjugated hyperbilirubinemia) resolves by 14 days of age in at least 85 percent of infants [5,6]. Although most infants who are still jaundiced at two weeks of age have benign causes (breastfeeding, breast milk, or hemolytic jaundice), a few will have biliary atresia or other diseases that require prompt diagnosis and treatment to optimize outcomes. Initiating evaluation at the two-week visit is important because some of these infants may not have another health care visit until they are two months old. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Biliary atresia", section on 'Evaluation'.)
This approach results in screening between 60 and 375 healthy infants to detect one case of neonatal cholestasis [3]. To reduce the screening burden, the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) suggests the following approach in jaundiced infants who are most likely to have breast milk jaundice because they are exclusively or near-exclusively breastfed: The evaluation for cholestasis may be delayed until three weeks of age in such infants if they have a normal physical examination, no history of dark urine or light stools, and can be reliably monitored [3].
●Other – Other indications for evaluation include acholic (pale-colored stools) or conjugated hyperbilirubinemia (regardless of other signs or symptoms).
Total and conjugated bilirubin — The first step in evaluating a jaundiced infant for possible cholestasis is to measure the serum concentrations of both total and conjugated bilirubin.
●If the infant has unconjugated hyperbilirubinemia (total bilirubin >2 mg/dL [34.2 micromol/L] at two weeks of age with normal conjugated bilirubin), this is often caused by breast milk jaundice, but other causes also should be considered, particularly if the total bilirubin is markedly elevated. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children".)
●If the infant has conjugated hyperbilirubinemia, causes of cholestatic jaundice should be investigated promptly, as discussed in the remainder of this topic. Conjugated hyperbilirubinemia is defined as a serum conjugated bilirubin concentration greater than 1.0 mg/dL (17.1 micromol/L) irrespective of the total bilirubin concentration.
In addition, infants with mildly elevated conjugated or direct bilirubin levels in the perinatal period (eg, >0.3 or levels above the normal laboratory limit) should be followed closely with repeat laboratory measurements and further evaluation if the abnormality worsens [7]. However, routine screening of asymptomatic neonates for conjugated hyperbilirubinemia is not currently recommended. (See "Biliary atresia", section on 'Laboratory studies'.)
Subsequent stages of evaluation — The evaluation of an infant with conjugated hyperbilirubinemia is complex because many disorders can present with neonatal cholestasis (table 1), and distinguishing among these disorders is difficult because of the lack of specific diagnostic tests. However, relatively few diagnoses account for the majority of cases (table 2) [8]. In term infants, the most common causes of neonatal cholestasis are biliary atresia (25 to 40 percent) and an array of rare genetic disorders (25 percent collectively) [3]. In premature infants, cholestasis more frequently results from total parenteral nutrition or sepsis. Measurement of total and conjugated bilirubin concentrations prior to initiation of total parenteral nutrition can help differentiate etiologies of neonatal cholestasis. The causes of neonatal cholestasis are discussed elsewhere. (See "Causes of cholestasis in neonates and young infants" and "Biliary atresia".)
Evaluation should be undertaken in a staged approach [9]:
●The initial step is rapid diagnosis and early initiation of therapy of treatable disorders:
•Biliary atresia must be identified early and differentiated from other causes of neonatal cholestasis because early surgical intervention (ie, before two months of age) results in a better outcome. Important steps in making this diagnosis are performing ultrasonography and liver biopsy; if these studies suggest obstruction, we proceed to cholangiogram. (See "Biliary atresia", section on 'Evaluation'.)
•Conditions such as sepsis, hypothyroidism, panhypopituitarism, and inborn errors of metabolism (eg, galactosemia, tyrosinemia) must be recognized and treated promptly to avoid significant progression of the illness. For infants in whom these disorders are excluded, consultation with a pediatric gastroenterologist is warranted [3]. (See 'Laboratory studies' below.)
●Additional testing is directed at the diagnosis of specific conditions, such as PI typing for alpha-1 antitrypsin deficiency and sweat and/or genetic testing for cystic fibrosis, and at potential complications of liver disease such as coagulopathy, hyperammonemia, and hypoglycemia.
HISTORY — A wide variety of disorders may cause neonatal cholestasis, as outlined in the table (table 1) and detailed in a separate topic review. (See "Causes of cholestasis in neonates and young infants".)
Aspects of the history that may be helpful in narrowing the differential diagnosis are summarized in the table (table 3) [3].
PHYSICAL EXAMINATION — Specific components of the physical examination may be useful in narrowing the differential diagnosis and are outlined in the table (table 4). Key features include [3]:
●Infants with biliary atresia are generally well-appearing, except for jaundice, and stools are often acholic (examples of stool colors here). Infants who present late (>90 days of age) with biliary atresia may have features of advanced liver disease including failure to thrive, ascites, and hepatosplenomegaly.
●By contrast, infants who are ill-appearing or failing to thrive are more likely to have an infection or metabolic disease.
LABORATORY STUDIES — Laboratory studies can help assess the extent of hepatobiliary dysfunction and may identify an etiology. Staged laboratory evaluation is presented in the table (table 5). These tests usually should be performed simultaneously with the imaging evaluation described below.
Initial panel of tests — The initial laboratory evaluation should include:
●Comprehensive metabolic panel:
•Total and conjugated bilirubin – To evaluate for conjugated hyperbilirubinemia (cholestasis) versus unconjugated hyperbilirubinemia.
•Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) – To assess liver cell injury.
•Serum alkaline phosphatase and gamma-glutamyl transpeptidase (GGTP) – These tests may provide supportive evidence for biliary obstruction. Furthermore, several genetic/metabolic disorders can be divided into high- and low-GGTP categories. For example, GGTP is typically elevated in biliary atresia and Alagille syndrome, while a normal to low GGTP is seen in most forms of progressive familial intrahepatic cholestasis, bile acid synthetic disorders, and arthrogryposis-renal dysfunction-cholestasis syndrome. (See "Causes of cholestasis in neonates and young infants".)
•Total protein and albumin.
•The comprehensive metabolic panel includes electrolytes, bicarbonate, and glucose, as an initial screen for metabolic disease.
●Complete blood count with differential.
●Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) – To further evaluate hepatocellular function and/or vitamin K deficiency.
Other laboratory tests — Additional tests may be appropriate to evaluate for systemic illness or specific causes of liver disease. Selection of these tests will vary based on the clinical presentation (table 5).
If genetic testing targeting neonatal cholestatic disorders is readily available, it should be considered early in the evaluation of neonatal cholestasis while simultaneously evaluating for biliary atresia and other treatable causes of neonatal cholestasis. Monogenic defects cause neonatal cholestasis in 25 to 50 percent of cases, and some (eg, Alagille syndrome, progressive familial intrahepatic cholestasis type 3, neonatal sclerosing cholangitis, cystic fibrosis) can present with features of biliary obstruction on liver biopsy pathology that can be difficult to distinguish from biliary atresia. Early identification of a genetic cause guides medical therapy and, sometimes, informs decisions about referral for liver transplant [10]. In one study in which genetic testing was performed on infants after excluding biliary atresia, the diagnostic yield was 60 percent [11]. Available next-generation sequencing techniques include targeted gene panels, whole-exome sequencing, and whole-genome sequencing [12]. Interpreting the results can be challenging because the implications of heterozygous variants may be unclear, knowledge about genotype-phenotype associations continues to evolve, and sequencing methods do not identify all types of genetic variation [13]. If genetic testing is undertaken, partnering with geneticists to aid in interpretation of results is recommended.
Matrix metalloproteinase-7 (MMP-7), a protease responsible for tissue remodeling, has been associated with liver fibrosis in biliary atresia. Multiple studies have shown that serum levels of MMP-7 are higher in cholestatic infants with biliary atresia compared with other causes of neonatal cholestasis, but further studies are needed before this test can be incorporated into a diagnostic algorithm. (See "Biliary atresia", section on 'Laboratory testing'.)
IMAGING STUDIES — Several imaging studies can assist in establishing the cause of the neonatal cholestasis. Most patients should be evaluated with abdominal ultrasonography. Hepatobiliary scintigraphy may be of use in some cases. It is important to complete these studies expeditiously since outcomes after Kasai portoenterostomy are improved with earlier intervention. Many patients will also require liver biopsy to establish the diagnosis. (See 'Additional tests' below and "Biliary atresia", section on 'Evaluation'.)
Ultrasonography — We suggest abdominal ultrasonography as the initial test because it is noninvasive, easily available, and can identify structural abnormalities of the hepatobiliary tract and abdominal organs [3]. The main utility of this test is to exclude other anatomic causes of cholestasis (ie, choledochal cyst). However, certain findings may suggest the diagnosis of biliary atresia, including absent (or nonvisualized) gallbladder and the presence of the triangular cord sign (triangular or band-like periportal echogenic density >3 mm in thickness) [14,15]. Ultrasound may also identify situs abnormalities, polysplenia, or vascular anomalies that could be associated with biliary atresia.
Transient elastography — In one study, transient elastography revealed greater liver stiffness in cholestatic infants with biliary atresia compared with those without [16]. Thus, elevated liver stiffness measurement provides some support for a diagnosis of biliary atresia and expedites evaluation. While these initial results are promising, further research is needed before this technique is routinely included in the evaluation of neonatal cholestasis.
Scintigraphy — Hepatobiliary scintigraphy (sometimes known as a "HIDA scan") is an optional second step performed at institutions where this test is readily available, provided that it does not delay subsequent diagnostic steps. It may provide useful information about biliary obstruction. However, the test is associated with substantial numbers of false-positive results and occasional false-negative results (ie, excretion of tracer into the bowel despite biliary atresia) [3,17]. As a result, scintigraphy should be used only for supportive information and not to independently confirm or exclude the diagnosis of biliary atresia.
The test is performed by administering a technetium-labeled iminodiacetic acid analog intravenously and monitoring uptake by the liver and subsequent excretion into the biliary tree and intestine. Infants with biliary atresia usually have normal uptake of the isotope but absent excretion into the bile and intestine, whereas those with neonatal hepatitis typically have delayed uptake but appropriate excretion [9]. Thus, if scintigraphy demonstrates patency of the biliary tract, biliary atresia is unlikely, except in very young infants [3]. However, nonvisualization of the gallbladder or lack of excretion can occur in patients without biliary atresia [18]. The test depends upon adequate hepatocellular function, and pretreatment for five days with phenobarbital (5 mg/kg per day) increases the accuracy of this test by enhancing isotope excretion [19]. However, in most cases, we do not use phenobarbital, because it will delay diagnosis and does not obviate the need for liver biopsy. (See "Biliary atresia", section on 'Hepatobiliary scintigraphy'.)
The sensitivity of scintigraphy in detecting biliary obstruction is approximately 99 percent, and the specificity ranges from 69 to 72 percent [20]. This range reflects variations in use by different centers [3].
Magnetic resonance cholangiopancreatography — Magnetic resonance cholangiopancreatography (MRCP) has limited usefulness in the evaluation of neonatal cholestasis [21]. If it is performed, lack of visualization of the cystic duct or common hepatic duct supports a diagnosis of biliary atresia [22]. However, MRCP is not reliable for making the diagnosis, because the normal biliary tract is not consistently visualized in infants under three months of age, which leads to false-negative results. Moreover, young infants would likely require general anesthesia to perform this test.
ADDITIONAL TESTS
Liver biopsy — If the initial laboratory evaluation and imaging does not identify a specific diagnosis, we recommend performing a percutaneous liver biopsy, particularly when there is a clinical suspicion of biliary atresia or other causes of biliary tract obstruction [3]. The results can help to support the diagnosis of biliary atresia before moving on to an open cholangiogram, or help to differentiate this disorder from intrahepatic causes of cholestasis that might not require surgical exploration [3,23]. The biopsy should be interpreted by a pathologist with expertise in pediatric liver disease. If the results are equivocal and biopsy was performed when the infant was <6 weeks of age, repeat biopsy may be necessary. (See "Biliary atresia", section on 'Liver biopsy'.)
Cholangiogram
Open cholangiogram — If the above steps in the evaluation support the diagnosis of biliary atresia, the infant should be taken to the operating room. The first step is an intraoperative cholangiogram, which is the gold standard in the diagnosis of biliary atresia. If the intraoperative cholangiogram demonstrates biliary obstruction (ie, if the contrast does not fill the biliary tree or reach the intestine), the surgeon should perform a hepatoportoenterostomy (Kasai procedure). (See "Biliary atresia", section on 'Cholangiogram'.)
Endoscopic retrograde cholangiopancreatography — Endoscopic retrograde cholangiopancreatography (ERCP) is an alternative technique available at a few select tertiary care centers [3]. It involves endoscopic intubation of the biliary and pancreatic ducts through the ampulla of Vater with a small catheter and injection of contrast material to facilitate radiologic visualization of the ductal systems. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for biliary disease in children".)
ERCP appears to be a sensitive and specific means of detecting biliary obstruction [3,24-29]. However, its utility in neonates is limited by the availability of appropriately-sized endoscopes [29], the need for deep sedation or general anesthesia in most cases [3], and the lack of validation. In select circumstances, ERCP can clarify the etiology of neonatal cholestasis (eg, identify a biliary cyst (image 1)) and avoid the need for laparotomy.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric liver disease" and "Society guideline links: Neonatal jaundice".)
SUMMARY AND RECOMMENDATIONS
●Indications for evaluation – Any infant who is noted to be jaundiced at two weeks of age should be evaluated for cholestasis by measuring total serum bilirubin and conjugated (or direct) bilirubin. The laboratory evaluation of breastfed infants who have a normal physical examination, have normally colored stools and urine, and can be closely monitored may be delayed until they are three weeks of age. (See 'Indications for evaluation' above.)
●Initial screening – In a young infant, a reasonable threshold for initiating a clinical evaluation is conjugated (or direct) bilirubin >1.0 mg/dL (17.1 micromol/L). During the neonatal period, milder elevation of conjugated bilirubin is abnormal and warrants close follow-up. (See 'Definitions' above and 'Total and conjugated bilirubin' above.)
●Causes – Causes of cholestasis in neonates and young infants include several types of biliary obstruction, hepatic or systemic infection, metabolic diseases, and toxic or alloimmune insults (table 1). Biliary atresia and neonatal hepatitis account for most cases of cholestasis in term infants. In premature infants, cholestasis more frequently results from total parenteral nutrition or sepsis. (See 'Subsequent stages of evaluation' above and "Causes of cholestasis in neonates and young infants".)
●Evaluation – The evaluation of cholestatic jaundice in infants after two weeks of age should be undertaken in a staged approach, guided by a focused history (table 3), physical examination (table 4), and laboratory evaluation (table 5). (See 'Subsequent stages of evaluation' above.)
•The initial step is rapid diagnosis and early initiation of therapy of treatable disorders (eg, sepsis, hypothyroidism, inborn errors of metabolism). If genetic testing targeting neonatal cholestatic disorders is readily available, it should be considered early in the evaluation of neonatal cholestasis while simultaneously proceeding with the remainder of the workup. (See 'Laboratory studies' above.)
•The next step is to distinguish biliary atresia from other causes of neonatal cholestasis because early surgical intervention for biliary atresia before 60 days of age results in improved outcomes. Key steps are ultrasonography and liver biopsy. (See 'Imaging studies' above and 'Liver biopsy' above.)
•Hepatobiliary scintigraphy provides supportive information about biliary obstruction and can be performed if the test is readily available and does not delay subsequent diagnostic steps. However, the test is associated with substantial numbers of both false-positive and false-negative results, so it should not be used solely to either confirm or exclude the diagnosis of biliary atresia. (See 'Scintigraphy' above.)
●Additional tests
•Additional testing is directed at the diagnosis of specific conditions and evaluation of associated complications (eg, coagulopathy). If jaundice fails to resolve in an infant in whom a treatable condition is diagnosed (eg, urinary tract infection or galactosemia) and treated, further evaluation should be performed. Selection of these tests depends upon the clinical presentation (table 5). (See 'Other laboratory tests' above.)
•Endoscopic retrograde cholangiopancreatography (ERCP) is not routinely recommended. However, if expertise in neonatal ERCP is available, this procedure can be used to detect extrahepatic obstruction, including biliary atresia or cholelithiasis. (See 'Endoscopic retrograde cholangiopancreatography' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert J Shulman, MD, Stephanie H Abrams, MD, MS, and Jessi Erlichman, MPH, who contributed to earlier versions of this topic review.
