Historical estimates place the incidence of cholestasis among all neonates at 1 in 2500 live births.1 A recent retrospective data review found that among all infants cared for in a large hospital system in the United States who had at least 1 measured conjugated bilirubin level, 3 in 1000 had a peak conjugated (direct) bilirubin greater than 2.0 mg/dL2; however, in the majority of these patients a specific hepatobiliary disorder was not identified, and the peak bilirubin was relatively low (<5 mg/dL). The incidence of cholestasis in the neonatal intensive care unit (NICU) is significantly higher. In 1 series, cholestasis (defined as direct bilirubin > 1.0 mg/dL when total bilirubin is 5 mg or less or direct bilirubin > 20% of total bilirubin when the total bilirubin is above 5 mg/dL) was identified in 2% of all NICU patients.3 Risk factors that are common in this population include prematurity, low birth weight, sepsis, shock, surgery, and parenteral nutrition.4 Thus, although cholestatic liver disease is rare in general outpatient pediatrics, the neonatologist must be familiar with the initial triage and diagnostic evaluation, as well as supportive care, of the cholestatic infant.
Cholestasis refers to any impairment in the hepatic excretion of bile. Bile is an aqueous solution of bile acids, cholesterol, conjugated bilirubin, proteins, phospholipids, toxins and xenobiotic substances, and electrolytes. Biochemically, an increase in serum conjugated bilirubin is the most commonly identified marker of cholestasis. The usual rule of thumb is that a direct-reacting fraction of bilirubin greater than 2 mg/dL or greater than 15% of total bilirubin should be regarded as evidence of cholestasis. However, it is helpful to remember that direct and conjugated bilirubin are not identical. Unconjugated bilirubin is the product of heme breakdown, which in the liver is conjugated with glucuronic acid prior to secretion into bile. The traditional assay relies on the fact that conjugated bilirubin (the “direct-reacting fraction”) reacts much more readily with a diazo reagent than does unconjugated bilirubin (the “indirect-reacting fraction”), which is measured after the addition of an accelerating agent. Unconjugated bilirubin does participate, albeit more slowly, in the unaccelerated reaction, and when the concentration of unconjugated bilirubin is high, the direct bilirubin measurement will be spuriously elevated.5, 6 Laboratories that report conjugated and unconjugated fractions as such, rather than as direct and indirect fractions, are typically using a newer spectrophotometric method (Kodac BuBc), and some laboratories report measurements for both direct and conjugated bilirubin. The direct bilirubin measurement (ironically, an indirect estimate of the conjugated bilirubin concentration) is generally a higher number than the conjugated bilirubin measurement, and it also includes measuring the delta bilirubin or the bilirubin bound to albumin.
Physiology of Normal Bile Production and Excretion
Some understanding of bile acid physiology is necessary for an adequate description of cholestatic pathophysiology. The biochemistry and transport of bile acids is complex, and this discussion is restricted to the clinically salient points. Figure 39-1 provides a cartoon representation of the basic machinery of bile excretion.
Basic anatomy of the hepatocytes and cholangiocytes as it relates to bile formation and enterohepatic circulation. The specific transporters are discussed in the text. BSEP, bile salt excretory protein; FIC1, familial intrahepatic cholestasis 1.
Bile Acid Synthesis and Enterohepatic and Cholehepatic Circulation
Bile acids are synthesized from cholesterol within hepatocytes. Cholic acid and chenodeoxycholic acid are the bile acids synthesized by the liver and are referred to as “primary” bile acids. After conjugation with glycine or taurine, they are secreted with other normal bile constituents into the duodenum. Bacterial action within the small bowel converts cholic acid to deoxycholic acid and chenodeoxycholic acid to lithocholic acid, the “secondary” bile acids. The majority of intestinal bile acid is reabsorbed through an active transport mechanism in the ileum, transported to the liver via the portal vein, and again taken up by hepatocytes.7 This cycle is referred to as the enterohepatic circulation.
Bile acids perform myriad physiologic functions. Within the hepatocyte, they participate in the regulation of multiple genes by means of the farnesoid X receptor, a nuclear receptor also known as the bile acid receptor.8 In bile, they form the major osmotic force driving the secretion of water, increasing bile volume and flow rate (so-called bile-acid-dependent flow), and thus an adequate pool of bile acids is required for normal bile excretion.9 Fecal loss of bile acids provides a major route for the elimination of cholesterol in humans, and bile acids solubilize unmodified cholesterol in bile as well. Bile acids function within the intestine to promote diffusion and absorption of fatty acids and lipid-soluble vitamins (A, D, E, K). They have direct antimicrobial activity and appear to regulate other antimicrobial activity within the small intestine mediated by FXR receptors. In the colon, bile acids stimulate propulsive motility as well as modulate water and electrolyte transport. There is also intriguing evidence that bile acids act as endocrine factors via G protein-coupled receptors to modulate adipocyte thermogenesis and hepatic blood flow.7
Physiologic Cholestasis of the Neonate
The normal physiology of the neonatal liver differs from that of older children and adults in clinically important ways, particularly with regard to the processing and excretion of bile. Evidence collected from human and animal studies has led to the concept of a “physiologic cholestasis” of infancy.10 Compared to older infants and adults, the neonate possesses a decreased total-body pool of bile acid, and this pool is relatively concentrated in the hepatic and circulating compartments rather than within the bowel lumen. After birth, the rates of bile acid synthesis and uptake by hepatocytes increase rapidly, as does the intraluminal concentration of bile acids within the bowel. The concentrations of bile acids in serum decline more slowly to normal adult levels over the first 6–12 months of life.11, 12, and 13 These findings are thought to reflect immaturity in the uptake and synthesis of bile acids by hepatocytes and in the transport of bile acids across the ileal epithelium.
Consequences of Cholestasis
The result of cholestasis is retention of bile acids and bile products within the hepatocytes and liver. As the level of these products builds, damage to the hepatocytes results.
Hepatic Injury and Biliary Cirrhosis
As the intrahepatic level of bile salt and bile contents increases, there is activation of Kupffer cells and other cells to produce fibrosis.14, 15 Over time with chronic cholestasis, the typical periportal fibrosis accompanied by bile stasis and loss of bile ducts is characteristic of biliary cirrhosis. The fibrosis gradually increases within and between portal tracts.
Malabsorption and Malnutrition
Bile acids act as a detergent within the bowel lumen, solubilizing lipids and allowing their absorption by enterocytes. Because of the decreased concentration of bile acids in the bowel, some degree of steatorrhea is normal in neonates and is more pronounced in infants fed cow’s milk–based formula because it lacks the lipase activity found in human milk.16 Pathologic cholestasis exacerbates this fat malabsorption and predisposes the infant to fat-calorie malnutrition as well as deficiency in the fat-soluble vitamins (A, D, E, and K).17 One patient series found a high prevalence of fat-soluble vitamin deficiency among children waiting for a liver transplant, with a majority of patients having a deficiency in at least 1 of the vitamins A, D, E, and K.18
In addition to malabsorption and secondary deficiencies in specific micronutrients, children with chronic liver disease are likely to have higher resting energy expenditure than their healthy age cohort.19, 20 Thus, supplemental enteral feeding is sometimes required in chronic liver disease to maintain normal growth.
Pruritus in chronic cholestasis presumably results from the activity of an unknown “pruritogen,” which is normally excreted in bile and that at elevated levels can stimulate either peripheral or central itch pathways.21 Although there do not appear to be any published data regarding pruritus in neonates, it is a widespread and sometimes-debilitating problem among older patients with cholestatic liver disease.22
Because of the unique susceptibility of the neonatal liver, cholestasis is often a nonspecific response to systemic stress, resulting in a self-limited “idiopathic neonatal hepatitis.” However, it may also be the presenting sign of serious infectious or metabolic disease or of biliary tract anomalies that require surgical attention. To make matters more complicated, the neonatologist and gastroenterologist are often faced with an infant whose history includes prematurity, septic or ischemic insults, and recent or ongoing reliance on parenteral nutrition, all of which may contribute to cholestasis. In such cases, the decision regarding how extensively, and when, to search for other possible causes of cholestasis is a difficult one. Although it is almost impossible to enumerate all disorders that can result in neonatal cholestasis, a neonatologist is likely to find it helpful to know those entities that are common, require urgent diagnosis and treatment, or respond to specific therapy (Table 39-1).
Table 39-1A Somewhat Comprehensive List of Diagnoses That May Lead to Cholestasis in the Neonate ||Download (.pdf) Table 39-1 A Somewhat Comprehensive List of Diagnoses That May Lead to Cholestasis in the Neonate
Obstructive disorders of bile flow
Intrahepatic or extrahepatic duct obstruction from compression
Benign or malignant masses
Paucity of intrahepatic ducts
Cannilicular transport defects
Progressive familial intrahepatic cholestasis (PFIC 1–3)
Benign recurrent intrahepatic cholestasis (BRIC)
Dubin-Johnson and Rotor syndromes
Ductal malformations or ectasies
Congenital hepatic fibrosis (autosomal polystic kidney disease)
Inspissation of bile
Sclerosis of bile ducts
Neonatal sclerosing cholangitis
Herpes simplex Uipus
Human immunodeficiency virus
Hepatitis A, B, C, E
Urinary tract infection (endotoxemia)
Bile acid synthesis defect
Peroxisomal defects (eg, Zellweger sydrome, adrenoleukodystropy, D-bifunctional protein deficiency)
α1 alpantitrypsin (AAT) deficiency
Hereditary fructose intolerance
Glycogen storage disease type IV
Amino acid metabolism
Tyrosinemia type I
Arginosuccinate lyase deficiency
Lipids: Niemann-Pick type C, mucopolysaccharidosis, Gaucher disease
Niemann-Pick type C
Maternal drugs and alcohol
Intestinal failure associated with liver disease (sepsis, parenteral nutrition)
Neonatal hemochromatosis (neonatal iron storage disease)
Neonatal lupus erythematosus
Hemophagocytic lymphohistiocytosis (HLH)
Chromosomal or dysmorphic syndromes
Arthrogryposis-renal tubular dysfunction-cholestasis (ARC) syndrome
Hypoxic or ishemic injury
Cardio respiratory compromise events, shock
Congenital cardiac lesions
Aagenaes syndrome (lymphedema-cholestasis)
North American Indian childhood cirrhosis
As Figure 39-2 illustrates, the diagnostic categories of neonatal cholestasis have been refined over the past 4 decades. Research into the biochemistry and genetics of bile formation, often enabled by individual patients or families with inherited cholestatic disorders, has broken the previous majority diagnosis of “idiopathic neonatal hepatitis” into multiple specific genetic and metabolic entities.23
Major diagnoses resulting in neonatal cholestasis as of 1970 and 2004. Observe that the proportions of biliary atresia and viral hepatitis have remained constant. The previously large group of infants who were labeled with having “idiopathic neonatal cholestasis” has been broken down into multiple genetic disorders. The majority of these infants with chronic cholestasis can now be successfully diagnosed given sufficient time and resources. AAT, α1-antitrypsin. (Adapted with permission from Balistreri WF, Bezerra JA. Whatever happened to “neonatal hepatitis”? Clin Liver Dis. 2006;10(1):27–53.)
Biliary obstructive disorders, either intrahepatic or extrahepatic, make up the largest proportion (50%) of cases of conjugated hyperbilirubinemia in infants for which a single cause can be identified.24 Biliary atresia is the most common diagnosis in this group, which includes other “anatomic” problems of the bile ducts, such as choledochal cysts, choledochoceles, inspissated bile syndrome, strictures, and cholelithiasis. Both intrahepatic and extrahepatic biliary obstruction may occur as a result of compression of bile ducts by an extrinsic mass, for example, in hepatoblastoma.
There are a number of possible intrahepatic causes. Alagille syndrome due to jagged 1 protein or NOTCH receptor mutations may have significant cholestasis with high cholesterol and γ-glutamyl transferase (GGT) and with paucity of intralobular ducts on liver biopsy.25 There are also some infants with a so-called nonsyndromic paucity of bile ducts. There are a number of cholestatic genetic syndromes that result in abnormal bile flow due to canalicular bile transport mechanisms. One group is the progressive familial intrahepatic cholestasis (PFIC) disorders (Figure 39-1). They are autosomal recessive disorders affecting various transporters. PFIC1 or Byler disease is due to an adenosine triphosphate (ATP)–dependent amino phospholipid transporter or FIC1 (familial intrahepatic cholestasis 1). PFIC2 involves bile salt excretory protein (BSEP), which is an ATP-dependent bile acid transport protein.26 MDR3 defects involving an ATP-dependent phospholipid transport protein are found in PFIC3 patients, who are distinguished by having an elevated GGT and elevated triglycerides.27 Benign recurrent intrahepatic cholestasis (BRIC) is a category of cholestasis also caused by defective BSEP or FIC1 protein function but due to different mutations than in PFIC1/2 and having a milder clinical course.28 Other disorders of intrahepatic cholestasis include Dubin-Johnson syndrome and Rotor syndrome.29 Caroli disease and congenital hepatic fibrosis with portal hypertension occur in patients with autosomal recessive polycystic kidney disease (ARPKD)30 as a result of malformation of the ductal plate and embryologic stage in the formation of the liver.31, 32 Mutations in CFTR affect chloride and bicarbonate transport and may lead to inspissated bile and the cholangiopathy associated with cystic fibrosis.33, 34 Neonatal sclerosing cholangitis is another rare cause of intrahepatic obstruction.35
The other major category of cholestasis is related to hepatocellular injury and dysfunction. Although it is reasonable to categorize some disease as either hepatocellular or obstructive (eg, the PFICs), we have chosen to label them obstructive because they are due to a specific defect in bile transport rather than generalized hepatocellular dysfunction.
Viral hepatitis represents only 5% of neonatal cholestasis but is important to consider, as are other infectious hepatitides, since specific pharmacologic therapy may be necessary. A large list of viruses may cause neonatal cholestasis or hepatitis: cytomegalovirus (CMV), herpes simplex virus (HSV), human herpesvirus 6 (HHV-6), parvovirus B19, coxsackie virus, echovirus, and the classic hepatitis viruses A, B, C, and E.24, 36, 37 Nearly any bacterial, protozoal, or fungal infection severe enough to provoke a systemic inflammatory response can cause cholestasis, but several in particular should be considered: occult urinary tract infection, gram-negative sepsis, tuberculosis, syphilis, and listeria; fungemia due to central line contamination; and toxoplasmosis.
Metabolic diseases as a group cause some 20% of neonatal cholestasis, but a large number of specific diagnoses fall into this category, each of which is rare. Thus, if a preliminary biochemical screening produces signs of an inborn error of metabolism, it is essential to involve a medical geneticist early in the workup. Some of the more common disorders are discussed here.
α1-Antitrypsin (AAT) deficiency of the ZZ and SZ phenotypes predisposes to progressive liver injury and cholestasis, which can begin in infancy. AAT deficiency by itself is among the more common causes of neonatal cholestasis (20%).38 Other common inborn errors of metabolism that can cause cholestasis include galactosemia, hereditary fructose intolerance, and tyrosinemia.39 Galactosemia can present in the first days of life with lethargy, hepatic dysfunction, and lactic acidosis. Galactosuria can be identified by a positive test for urinary reducing substances. Hereditary fructose intolerance produces hypoglycemia, gastrointestinal symptoms, and liver and renal tubular dysfunction but should not present until the introduction of fructose-containing foods, typically after weaning. Untreated tyrosinemia results in severe liver injury that can cause acute liver failure or rapidly progressive cirrhosis with cholestasis and portal hypertension within the first year. Older children may have recurrent bouts of severe pain, cirrhosis, and hepatocellular carcinoma. Because outcomes are significantly improved with medical treatment in all of these disorders, it is important to make the diagnosis promptly.
The remaining metabolic disorders that can lead to cholestasis are extremely numerous but can be divided into several broad categories: mitochondrial respiratory chain disorders; fatty acid oxidation disorders; peroxisomal disorders; disorders of amino acid metabolism, including urea cycle defects; bile acid synthetic defects; congenital disorders of glycosylation; and glycogen storage diseases (see Table 39-1).
Panhypopituitarism, isolated cortisol deficiency, and perhaps hypothyroidism can all cause neonatal cholestasis.40, 41 Since rapid medical treatment is beneficial, an endocrine screening is recommended early in the evaluation.
Toxic hepatic injury can be the result of maternal use of medications or illicit drugs, as well as an iatrogenic illness caused by medications given to the infant after birth. Perhaps the most important of the toxic etiologies is intestinal failure-associated liver disease (IFALD; total parenteral nutrition [TPN] cholestasis).42 Infants with intestinal failure develop cholestasis and cirrhosis, probably due the combined effects of toxic elements in TPN (eg, lipid emulsion) and recurrent bacterial infection or translocation. IFALD is a major cause of end-stage liver disease requiring transplant, but new therapeutic approaches discussed in the management section can help to normalize liver function and may reduce the need for transplantation in the future. Cholestatic liver injury due to medications is often idiosyncratic and difficult to predict, but there has been a suggestion that fluconazole may predispose neonates to cholestasis.43, 44 Other agents more commonly associated with cholestatic liver injury in older patients should also be considered, such as amoxicillin-clavulanate, macrolides, and nonsteroidal anti-inflammatory drugs (NSAIDs).45
Prenatal exposure to certain agents, such as carbemazepine46, 47, and 48 and methamphetamine,49 has also been associated with neonatal cholestasis.
Immune-mediated injury to the hepatocytes is responsible for some causes of neonatal cholestasis. Examples include neonatal lupus erythematosus50, 51, and 52 and neonatal hemochromatosis (neonatal iron storage disorder),53 caused by maternal antibodies, and hemophagocytic lymphohistiocytosis (HLH).54
There are a number of genetic disorders that may present with cholestasis. Trisomy 18 and 21 are examples with dysmorphic features. Other examples are the ARC syndrome (arthrogryposis-renal dysfunction-cholestasis syndrome) and the Kabuki syndrome (associated with cleft palate).
Hypoxia or Hypoperfusion Injury
Infants who suffer hypoxic or hypoperfusion injury due to congenital or acquired cardiopulmonary disease,55, 56 shock, or hepatovenous obstruction (Budd-Chiari syndrome) will often present with jaundice. Frequently, these infants will have other evidence of end-organ injury, such as renal disease.
There are a few other disorders found in specific ethnic groups, such as Aagenaes syndrome (lymphedema with cholestasis syndrome)57, 58 and North American Indian childhood cirrhosis.59
Figure 39-3 presents some of the more important diagnoses leading to neonatal cholestasis according to anatomic location to illustrate the scheme used for organizing these disorders.
Common disorders, arranged according to anatomic site, leading to neonatal cholestasis. AAT, α1-antitrypsin; BRIC, benign recurrent intrahepatic cholestasis; PFIC, progressive familial intrahepatic cholestasis; UTI, urinary tract infection.
Initial Evaluation of the Cholestatic Infant
In the general pediatric setting, cholestasis is usually first identified by the presence of visible jaundice. Although most otherwise-healthy term infants with jaundice have self-limited unconjugated hyperbilirubinemia of benign origin, it is important to identify those few with conjugated hyperbilirubinemia. A consensus guideline from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) recommends obtaining fractionated bilirubin levels in infants who remain visibly jaundiced past 2 weeks of age.1 This is partly in response to the typical schedule of well-baby visits in the United States, according to which an infant who is healthy at 2 weeks of age may not normally be seen again by the pediatrician until 2 months of age. Two months is an unacceptably long delay for an infant who is subsequently found to have cholestatic jaundice, particularly given that the prevailing wisdom is that outcomes for surgical management of biliary atresia become significantly worse between 2 and 3 months of age.60, 61 Newly published evidence suggests that early elevation of direct bilirubin (within 48 hours of birth) may identify infants with biliary atresia.62 However, it remains to be seen whether biliary atresia can reliably be excluded on the basis of a normal fractionated bilirubin level at such a young age. In the NICU, cholestasis is frequently identified by laboratory screening in the absence of visible jaundice. Occasionally, evidence of cholestasis is specifically sought because there is suspicion of a disease that may entail cholestasis, for example, if there are morphologic signs of Alagille syndrome or a positive screening test for cystic fibrosis.
After confirming the presence of cholestasis by conjugated and unconjugated (or direct and indirect) bilirubin levels, the clinician is faced with 2 immediate questions. The first relates to the degree of illness. Since cholestasis may be a sign of severe infection, shock, or metabolic disease, it is important to determine if the cholestatic infant is in need of immediate specific treatment. Usually, this triage can be made on the basis of information already in hand, such as the clinical history, vital signs, and overall clinical assessment. Second, an initial assessment of liver function is important at this stage as well since an infant with impaired function is in need of more urgent diagnostic evaluation and possible listing for liver transplantation. Thus, it is important to obtain or review measures of blood glucose, ammonia, albumin, and coagulation times.
In an infant who is generally well, with preserved hepatic function, the clinician can then evaluate in a stepwise fashion. Table 39-2 presents a reference list of tests that the physician will need to consider ordering, arranged somewhat arbitrarily into stages according to when they might typically be appropriate. Of course, the severity of illness, the age of the infant, and the presence of diagnostic clues in the history and physical will influence the choice of tests in particular patients.
Table 39-2Tests Often Used in the Evaluation of Neonatal Cholestasis ||Download (.pdf) Table 39-2 Tests Often Used in the Evaluation of Neonatal Cholestasis
|Test or Procedure ||Diagnosis or Information Sought |
Review clinical history
|Evidence of infection, ischemia or shock, cardiac disease, neurologic or metabolic decompensation or other urgent condition; history of parenteral nutrition |
|Initial testing |
| total and direct bilirubin ||Confirm cholestatic jaundice |
AST. ALT Alk Phos, GGT albumin and total protein
Ongoing liver or biliary injury
Liver synthetic function
| INR (PT, PTT), fibrinogen ||Synthetic function, need for intensive support |
| glucose ||Metabolic function, need for intensive support |
| ammonia, lactic acid, pyruvate ||Liver metabolic function, mitochondrial hepatopathies |
| CBC with differential. ESR. CRP ||Infection, hematologic disease |
| review newborn screen ||Cystic fibrosis (IRT), galactosemia, fatty acid oxidation disorders |
| ultrasound with Doppler ||Gailstones, choledochal cyst, presence of gallbladder (argues against biliary atreia), portal hypertension/splenomegaly, hepatic echotexture (cirrhosis, masses) |
| Urinalysis and culture ||Occult urinary tract infection |
|Follow-up testing |
| α1-Antitrypsin phenotype (Pi type) ||α1-antitrypsin deficiency |
| fat-soluble vitamin levels ||Fat malabsorption, chronicity of cholestasis, need for supplemental vitamins |
1-25-Hydroxy vitamin D
INR and/or factors V, VII, and VIII plasma α-tocopherol/total lipid ratio paracenteis if ascites exists
Vitamin D status
Vitamin A status
Vitamin K status
Vitamin E status
Infections, biliary leakage, portal hypertension
| blood culture, CSF culture and examination ||Serious bacterial infections |
| infectious studies: CMV, HHV-6, HSV, adenovirus, enteroviruses. HIV, toxoplasma titers ||Intrauterine infections |
TSH. TA free and stimulated Cortisol
urine reducing substances and/or erythrocyte galactose1-phosphate uridyl transferase plasma amino acids; urine organic acids with succinyl acetone; α-fetoprotein serum iron and ferritin
|Further testing as indicated |
Cardiology consult and/or echocardiogram
skull x-ray for calcifications
Estaolish normal cardiac anatomy and function Alagille syndrome
Butterfly vertebrae (Alagille syndrome)
liver biopsy with electron microscopy
hepatobiliary scintigraphy (HIDA scan)
Proliferation vs paucity of bile ducts, hepatitis
Demonstrate excretion of bile (rule out biliary atresia)
|MRCP/ERCP ||Precise biliary anatomy: strictures, choledochal cysts, stones |
|operative cholangiogram ||Biliary atresia, choledochal cyst |
genetics consult and/or specific genetic testing
|Posterior embryotoxon (Alagille syndrome): infectious retinitis |
|CFTR mutation analysis and/or sweat chloride ||Cystic fibrosis |
comparative genomic hybridization (or karyotype and FISH analysis)
serum and urine bile acids (while not on ursodeoxycholic)
Broad range of chromosomal anomalies
Disorders of bile acid synthesis
plasma amino acids
very long chain fatty acids
Defects in fatty acid oxidation
urea cycle defects (eg, citrullinemia)
peroxisomal disorders (eg, adrenoleukodystrophy)
Congenital disorders of glycosylation
Alagille syndrome; PFIC 1, 2, and 3: A1AT deficiency
The initial step in the diagnostic workup usually will include a complete biochemical evaluation for liver injury (AST [aspartate aminotransferase], ALT [alanine aminotransferase], alkaline phosphatase, GGT), as well as selected specific diagnostic tests, such as ultrasound of the liver and gallbladder, and urinalysis and culture. Depending on the degree of suspicion, other serious bacterial infections will need to be ruled out in the initial phase.
The pertinent history will include questions of prematurity; sepsis; shock or asphyxia; cardiac disease or cyanosis; timing and content of feedings (lactose, fructose); parenteral nutrition; and surgeries. The stool color and pattern are important, as is the appearance of the urine. In severe cholestasis, the stools are typically beige, clay, or light colored (acholic stools) and the urine dark in color. Reports of the infant with bruising or poor coagulation ability and use of vitamin K as well as other fat-soluble vitamin supplementation should be obtained. The maternal and pregnancy history should include infections, chronic conditions such as lupus, medications, and episodes of jaundice during the pregnancy. A mother’s history of cholelithiasis, thrombophilia,63 and prior pregnancies is important. It can be helpful to search the infant’s medication history for drugs that have been associated with cholestasis. (Several were mentioned previously.) The family history may offer additional information that would be helpful, such as consanguinity and ethnic background. (PFIC1, for example, is more common among the Amish.) The presence of early-onset emphysema or chronic lung disease in the immediate family may suggest AAT deficiency.
The general appearance of the infant may provide immediate clues to a genetic or dysmorphic syndrome such as the trisomies, Alagille syndrome, or Zellweger syndrome. Gestational age, head circumference, and growth pattern may signal the presence of a genetic disorder or infectious process in the immediate neonatal period. The ophthalmologic examination may also be helpful. Findings of chorioretinitis and cataracts can suggest congenital infection, optic nerve appearance consistent with septo-optic dysplasia may lead to the diagnosis of hypopituitarism, and posterior embryotoxon is a feature (though not a pathognomonic one) of Alagille syndrome.
The presence of a murmur or other cardiac abnormalities may provide clues that the cholestasis is due to cardiac disease or part of a syndrome such as trisomy 21 or Alagille syndrome (which may include peripheral pulmonic stenosis). Dextrocardia and situs inversus is associated with biliary atresia along with splenic malformation (absent spleen or polysplenia).
A careful abdominal examination to determine any masses or hepatosplenomegaly and the presence of ascites or caput medusa will assist in assessing possible causes (tumors, cysts) and degree of cirrhosis or portal hypertension. Disorders of the mitochondrial respiratory chain and some other genetic diseases, such as Niemann-Pick disease, may be suspected based on a careful neurological examination.
Ataxia and hypotonia with decreased deep tendon reflexes may also be features of vitamin E deficiency as a result of fat malabsorption and inadequate vitamin E supplementation. Bone fractures and radiologic abnormalities of bone are features of significant rickets due to vitamin D deficiency. The presence of rashes may signal a concern for congenital infections, and bruising may be a sign of coagulopathy due to vitamin K deficiency, disseminated intravascular coagulation (DIC), or hematologic abnormalities.
Icthyosis of the skin and abnormal joint mobility may suggest ARC syndrome. Lymphedema may be a feature of Aagenaes syndrome in an infant with Norwegian ethnicity. The infant with typical biliary atresia will often have normal weight gain and may present as an apparently healthy baby except for jaundice, acholic stools, and hepatomegaly. In fact, the parents have often either not noticed the child’s jaundice or have assumed it to be physiologic and are therefore surprised at the diagnosis.
Table 39-2 provides a list of possible diagnostic tests for cholestasis. The initial laboratory tests are used to confirm conjugated hyperbilirubinemia with both direct and total bilirubin. The AST and ALT are enzymes that appear in the blood if there is hepatocellular injury from metabolic dysfunction, inflammation, or apoptosis. They are not tests of liver synthetic function and may even be normal in some forms of end-stage liver disease when there are few remaining hepatocytes. Among NICU patients, this can, for example, be observed in neonatal hemochromatosis. These infants may have severely impaired liver synthetic function and yet only mildly elevated AST and ALT. Alkaline phosphatase and GGT are enzymes that not only reflect cholangiocyte and bile duct injury but also can be normal when the source of cholestasis is at a canalicular transport level, as in PFIC1 and PFIC2 (so-called low-GGT cholestasis).
There are a number of general laboratory tests that reflect liver synthetic function, such as those for glucose, ammonia, and cholesterol, since the liver participates in their metabolism and storage. Elevated ammonia may be due to urea cycle defects or portosystemic shunting, as well as to hepatocellular dysfunction. Proteins synthesized by the liver include albumin and most of the coagulation factors (except for factor VIII), which have a short half-life in serum. Low levels of coagulation factors and coagulopathy may also be due to deficiency in vitamin K, especially in cholestatic patients, or to consumption by DIC. Therefore, some care is required in interpreting coagulation times. Due to its widespread availability, speed of measurement, and convention, the initial test is usually the international normalized ratio (INR). INR testing can be repeated several hours after an intravenous dose of vitamin K to assess the contribution of vitamin K deficiency to the coagulopathy. Since factor V is not dependent on vitamin K for synthesis, the next step may be to obtain quantitative coagulation factors levels (eg, of factors V, VII, and VIII). One must not forget to measure the other fat-soluble vitamins E, A, and D, which are not well absorbed in cholestatic conditions.
Infectious causes of cholestasis are most important to detect and treat as early as possible in infants. A complete blood cell count (CBC) with differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) assessment followed by appropriate TORCH (toxoplasmosis, rubella, cytomegalovirus, HSV) titers and viral serology or polymerase chain reaction (PCR) as recommended in Table 39-2 should be obtained. Depending on the clinical status of the patient, blood and urine cultures are also necessary as endotoxemia and gram-negative sepsis, or even occult urinary tract infection,64 are significant causes of conjugated hyperbilirubinemia.
Endocrine causes should be evaluated, as panhypopituitarism is a well-documented cause of cholestasis.40, 65, 66 Screening with thyroid-stimulating hormone (TSH), free levorotatory thyroxine (T4), and cortisol is usual.
Genetic and metabolic assessment begins with an AAT phenotype (Pi type in some laboratories) and level. Phenotype testing is performed by electrophoresis and is important since the blood level of AAT may vary in the perinatal period67 or in response to inflammation.68 Plasma amino acids and urine succinylacetone with urine organic acids and α-fetoprotein offer a means to screen for tyrosinemia. Urine reducing substances (while the infant is on lactose-containing formula) and erythrocyte galactose-1-phosphate uridyl transferase (GALT) will screen for galactosemia. The newborn screen or other testing (CFTR mutation analysis or sweat chloride) should be checked as well for cystic fibrosis. Serum or plasma lactate, pyruvate, and acylcarnitine panel screen for mitochondrial disorders. Quantitative serum bile salts may detect the possibility of a bile salt synthetic defect, in which case a urine bile salt analysis (while off ursodeoxycholate therapy) is warranted. Peroxisomal disorders may be screened with very long chain fatty acids, and disorders of glycosylation may be detected by a glycosylated transferrin level. Specific genetic testing for the more common inherited causes of neonatal cholestasis is available from several laboratories (see GeneReviews.org or http://www.ncbi.nlm.nih.gov/gtr/), and several genes (JAG1, Alagille syndrome; ATP8B1, PFIC1; ABCB11, PFIC2; ABCB4, PFIC3; and SERPINA1, AAT deficiency) may be tested using a single sample with the Jaundice Chip assay69 from Cincinnati Children’s Hospital.
Ultrasound is the most useful imaging modality for evaluating cholestasis, and every infant with newly identified or worsening cholestasis deserves an evaluation by ultrasound. Liver echotexture and size, ascites, or the presence of splenomegaly can help suggest cirrhosis and portal hypertension. Ultrasound may also document stones in the gallbladder or common bile duct, dilated bile ducts, intrahepatic mass lesions, presence of the gallbladder, choledochal cysts, and abnormal vascular anatomy or situs anomalies. Doppler measurement of blood flow can also demonstrate vascular occlusion or hepatofugal portal flow, which may be indicative of portal hypertension. Lack of a pancreas with fibrosis or calcifications may suggest cystic fibrosis. Extrahepatic masses that may impinge or compress the biliary tract and result in cholestasis may be found. Abnormal visceral anatomy suggestive of congenital syndromes or cystic kidney lesions may also contribute clues to the diagnosis.
Several ultrasonographic findings are useful in supporting the diagnosis of biliary atresia. The “triangular cord sign” refers to the finding of an echogenic tubular or triangular structure near the bifurcation of the portal vein. Observational studies suggest that the triangular cord is specific but not sensitive enough to use for making surgical decisions.70, 71, 72, 73, and 74 The presence and size of the gallbladder are also relevant, as an abnormally small or absent gallbladder is consistent with biliary atresia.74 The absence of the triangular cord sign and the presence of a normal gallbladder are reassuring, but neither sign is sensitive enough to use in place of liver biopsy or cholangiogram when a diagnosis of biliary atresia is considered.
The hepatobiliary iminodiacetic acid (HIDA) scan (generically hepatobiliary scintigraphy) is a quantitative nuclear medicine technique used to assess liver function and biliary excretion. A radiolabeled analog of iminodiacetic acid (eg, technetium TC 99m mebrofenin) is injected intravenously, and a series of 2-dimensional images is obtained by γ-camera over minutes to hours following the injection. The tracer is actively taken up by hepatocytes and secreted into bile. A HIDA scan can quantify the uptake of tracer by the liver, giving an indirect assessment of hepatocellular function, and in a normally functioning biliary system, subsequent images can demonstrate the gallbladder and bowel filling with tracer (Figure 39-4). In cholestatic infants, who may have slow excretion regardless of the diagnosis, images may be obtained as late as 24 hours after injection, though in a healthy patient the gallbladder can usually be visualized within minutes.76 Hepatobiliary scintigraphy is highly sensitive for complete extrahepatic obstruction, in that it is (almost77) unheard-of for an infant with biliary atresia to show excretion by HIDA scan. However, it is nonspecific.78, 79 In our experience, many infants with nonsurgical causes for cholestasis fail to show excretion, especially when the conjugated bilirubin is high. Most institutions use a protocol in which the infant receives phenobarbital or ursodeoxycholate for 3–5 days prior to the scan. These agents increase the rate of bile excretion from hepatocytes and therefore may allow excretion to be visualized in infants with intrahepatic causes of cholestasis (improving the specificity of the study).80,81
Hepatobiliary scintigraphy (hepatobiliary iminodiacetic acid, HIDA) images. A, Characteristic of an infant with a nonobstructive cause of cholestasis. Although it may take hours for the radiotracer to be excreted, ultimately the gallbladder and bowel are easily visualized. B, Typical image in biliary atresia. The liver has taken up the tracer, but the gallbladder and bowel are not visualized even after 24 hours. The density (right) on the image is the left kidney, and the lower density is the bladder. (Reproduced with permission from Nadel HR. Hepatobiliary scintigraphy in children. Semin Nucl Med. 1996;26(1):25–42.)
Computed Tomography or Magnetic Resonance Imaging
Imaging with computed tomographic (CT) or magnetic resonance imaging (MRI) scans may allow better detection of detail than ultrasound, with the disadvantages of radiation or sedation and increased cost. In particular, magnetic resonance cholangiopancreatography (MRCP) is capable of detecting cholelithiasis and define pancreaticobiliary anatomy, including choledochal cysts. A few series have reported on the accuracy of MRCP in distinguishing biliary atresia from other causes of cholestasis.82, 83 Although the method currently does not appear to offer an alternative to biopsy or cholangiogram, it is an area of research, and new contrast agents may increase its utility.84
Cholangiography (Transhepatic or Operative) or Endoscopic Retrograde Cholangiopancreatography
Other means of determining biliary anatomy include percutaneous transhepatic cholangiogram or endoscopic retrograde cholangiopancreatography (ERCP). ERCP in infants requires proper equipment and expertise, but in experienced hands appears to be safe. Several large series showed ERCP had excellent sensitivity for biliary atresia with specificity better than noninvasive techniques such as MRCP and HIDA.85, 86, and 87 Therefore, it offers a viable alternative to operative cholangiogram in selected patients at certain centers. Ultimately, operative cholangiogram may be required to accurately diagnose biliary atresia or abnormalities of the biliary tract and guide appropriate therapy, such as hepatoportojejeunostomy or Kasai procedure.
Plain radiographic films can provide valuable indirect information to guide the diagnosis of the cholestatic infant. Often, films of the chest and abdomen have already been obtained in the normal course of care of an infant by the time cholestasis is identified, and these films should be reviewed. Chest radiographs may confirm lung or cardiac disease and may show dextrocardia, which is associated with biliary atresia. A finding of butterfly vertebrae suggests Alagille syndrome. Abdominal radiographs may show calcifications from cholelithiasis or nephrocalcinosis. Other specific radiographic studies may be useful in selected cases. For example, skull films may detect calcifications due to congenital infections or have patterns suggestive of underlying neurologic disorder or hypopituitarism. Long-bone changes may signal rickets and vitamin D deficiency. Other genetic syndromes, such as Hurler syndrome, may be suggested by radiographic findings.
One of the most helpful tests in the diagnosis of cholestasis is the liver biopsy. Biopsy can be performed percutaneously at the bedside, transvascularly in the interventional radiology suite, or operatively. When there is proliferation of bile ducts or bile plugging in ductules, biliary obstruction as in biliary atresia is most likely. A paucity of intralobular bile ducts suggests Alagille syndrome. Giant cell transformation or hepatitis refer to a nonspecific reaction in the neonatal liver and can be associated with multiple disorders. Deficiency of AAT may be suspected if there are multiple periodic acid–Schiff (PAS)–positive granules in hepatocytes. The liver biopsy may also be used for cultures, electron microscopic diagnosis, and other metabolic or genetic testing as appropriate, based on clinical evaluation. The most significant risk of liver biopsy is bleeding. Significant hemorrhage requiring transfusion is possible, though with ultrasound guidance percutaneous biopsy is relatively safe.88, 89, and 90 Often, the risk and pain involved in biopsy are weighed against the risk of delaying a diagnosis. In an infant older than about 2 months, in whom a delay in the diagnosis of biliary atresia can mean a higher likelihood of poor outcome, the decision to biopsy may be made sooner, saving the time required for less-invasive imaging studies such as HIDA.
The first priority in the management of infants with conjugated hyperbilirubinemia is to diagnose and treat those causes that are rapidly life threatening, such as gram-negative sepsis, adrenal insufficiency, metabolic disease, or shock. The specific management of biliary atresia, acute liver failure, and various infectious causes of cholestasis are discussed in chapters 40 and 41. With that in mind, we focus here on problems common to chronic cholestatic liver disease in general and their management in infants. Good supportive care of these cholestatic infants is important and can often prevent the nutritional and other complications of liver disease. Several of the common agents used in the management of neonates with cholestatic liver disease are summarized in Table 39-3.
Table 39-3Medical Treatments That Are Frequently Useful in the Treatment of Infants With Cholestatic Liver Disease ||Download (.pdf) Table 39-3 Medical Treatments That Are Frequently Useful in the Treatment of Infants With Cholestatic Liver Disease
|Agent ||Purpose ||Usual Dose |
|Phenobarbital ||Enhances bile excretion prior to biliary scintigraphy; antipruritic. ||5–6 mg/kg divided twice daily for at least 3 days prior to scan |
Solubilized ADEK Multivitamin (AquADEK™)
Single-agent prophylactic dosing for cholestatic infant
|1 mL/day |
|Vitamin Aa ||Treatment of vitamin A deficiency ||5000–25,000 IU/day |
|Vitamin Da ||Treatment of vitamin D deficiency ||400–4000 IU/day cholecalciferol |
|Vitamin Ka ||Acute correction of vitamin K-deficiency coagulopathy; treatment of chronic vitamin K deficiency || |
2.5 mg IV daily × 3 days
2.5 mg PO weekly to 5 mg PO daily
|Vitamin Ea ||Treatment of vitamin E deficiency ||25–50 IU/kg/d α-tocopherol |
| ||Water-soluble form (TPGS) enhances absorption of other fat-soluble vitamins ||15–25 IU/kg/day TPGD (Liqui-E™) |
|Medium-chain triglyceride (MCT) ||Enhances fat absorption in cholestasis and pancreatic insufficiency ||30%–70% of total lipid intake |
|Ursodiol (UDCA) || |
Alters bile acid & cholesterol balance
|10–15 mg/kg/dose 2–3 times daily |
|Rifampicin ||Antipruritic ||10 mg/kg/d divided once or twice daily |
|Cholestyramine || ||240 mg/kg/d divided 3 times daily |
|Furosemide ||Loop diuretic, control of ascites ||1 mg/kg/dose given 1–2 times daily |
|Spironolactone ||Potassium-sparing diuretic, control of ascites ||1–3 mg/kg/day divided 1–2 times daily |
|Lactulose || |
Enhances excretion of ammonia
|2–10 mL/day divided 4 times daily |
|Diphenhydramine ||Antihistamine, antipruritic ||5 mg/kg/d divided 4 times daily |
|naltrexone ||Opioid antagonist, antipruritic ||1–2 mg/kg/d |
Patients with cholestasis have impaired fat absorption as a consequence of inadequate bile salts in the intestinal lumen. Medium-chain triglycerides (MCTs) do not require bile salts for absorption. Changing the primary feedings to a formula high in MCTs or supplementing the feedings with MCTs to provide 30%–50% of the total fat calories in the form of MCTs can be helpful.
With malabsorption of fat comes malabsorption of the fat-soluble vitamins A, D, E, and K. All cholestatic infants should receive prophylactic doses of the fat-soluble vitamins and periodic screening for deficiency. The treatment table (Table 39-3) summarizes typical dosing. Keep in mind that infants with cholestasis sometimes require much higher doses of the fat-soluble vitamins than are usually recommended; however, these vitamins can be toxic, and levels must be monitored during supplementation.
Besides specific fat and vitamin deficiencies, infants with liver disease can have elevated energy requirements19, 20 and may need up to 130% or more of the usual daily caloric requirement to meet growth needs. To achieve this goal, supplemental nutrition may need to be given by nasogastric, orogastric, or gastrostomy feeds. In some cases, parenteral nutrition should be considered.
Ascites, the accumulation of intraperitoneal fluid, is a result of end-stage cirrhosis and portal hypertension exacerbated by hypoproteinemia. It may complicate respiration and limit feeding volumes. It also creates a risk of spontaneous bacterial peritonitis and can make children uncomfortable. Medical management includes fluid and salt restriction, albumin supplementation, and careful use of diuretics.91 Oral spironolactone is often added to oral or intravenous furosemide to limit the potassium losses caused by furosemide.
In chronic liver disease with portal hypertension, varices form throughout the gastrointestinal tract, but the most dangerous are usually in the lower esophagus. The splenomegaly resulting from portal hypertension leads to thrombocytopenia, and hepatic dysfunction and vitamin K deficiency cause coagulopathy, both of which may worsen the bleeding from varices or portal hypertensive gastropathy.
Medical management with venous access, volume resuscitation, acid suppression, and octreotide is primary. The infant must be stabilized if at all possible prior to any attempt at endoscopic treatment. Banding, which is common in older patients, is difficult in infants due to the size of the equipment, so endoscopic therapy will often be sclerotherapy (endoscopic injection of a sclerosing agent into the variceal vessels). Occasionally, interventional radiology with TIPSS or vascular embolization may be helpful. Balloon tamponade or surgical intervention to perform a portosystemic shunt may be necessary in refractory bleeding until liver transplantation can be performed in appropriate cases. The role of nonselective β-blocker therapy for the prophylaxis of bleeding is controversial in infants.
Pharmacologic treatment of pruritus can include ursodeoxycholate; antihistamines (diphenhydramine, hydroxyzine); cholestyramine; rifampin; and naloxone. In severe cases, a combination of medications is often used.21, 22, 92 Surgical approaches have included biliary diversion93, 94 or ileal exclusion,95 which have had particular success reducing or eliminating pruritus (and xanthomas) in some patients with Alagille syndrome or PFIC. However, in the most refractory cases, pruritus can be an indication for liver transplantation.
Specific management of neonatal cholestasis depends on the diagnosis but is broadly divided into surgical and nonsurgical diseases. Biliary atresia, choledochal cyst, and the other extrahepatic obstructive disorders require surgical intervention, and once the diagnosis is reasonably certain, the patient will undergo operative cholangiogram proceeding to Kasai hepatoportoenterostomy. Various infections that can lead to cholestasis benefit from specific medical treatment, which is covered elsewhere in this volume.
The bile salt synthetic defects sometimes benefit from bile salt analogs such as ursodeoxycholate.96, 97, and 98 Galactosemia, fructose intolerance, glycogen storage diseases, and urea cycle disorders are treated with dietary management. Tyrosinemia is now treated with 2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexandione (NTBC).99
Intestinal failure-associated liver disease should be thought of as multifactorial, and treatment should begin with optimizing enteral feeding, attempting to prevent septic complications, treating bacterial overgrowth when suspected, adding oral ursodeoxycholate, and minimizing intravenous soy-based lipid emulsions. Other intravenous fat emulsions, which are higher in omega-3 fatty acids, lower in phytosterols, and higher in vitamin E such as fish oil-based100, 101 (Omegaven) or combination soy, MCTs, olive oil, fish oil (SMOF)102, 103, and 104 lipid emulsion have also proven effective in decreasing cholestatic liver disease and the need for combined liver and small intestinal transplantation.105
Management of neonatal hemochromatosis has changed over the decade since the mid-2000s as our understanding of the pathophysiology has changed. This disease is now regarded as an alloimmune disorder53 and is treated with exchange transfusion and intravenous immunoglobulin (IVIG).106 It may be prevented in at-risk pregnancies by maternal IVIG therapy during pregnancy.107 Some cases may still require liver transplantation.
As previously discussed, there has been remarkable progress in the diagnosis and management of neonatal cholestasis with fewer idiopathic “neonatal hepatitis” cases. It is difficult to generalize since outcomes depend on the specific etiology. The few published series point to the fact that severe cholestasis is often a sign of significant illness. In 1 report of 27 NICU patients with cholestasis, one-third died or underwent liver transplantation. Infants in this poor-outcome group had significantly higher conjugated bilirubin levels than those with good outcomes (6.32 ± 1.93 vs 2.64 ± 0.33).3 However, most neonatal cholestasis is not severe and is nonspecific and self-limited. In the recent large series mentioned in the epidemiology section, almost 70% of infants with a direct bilirubin in the range of 2–5 mg/dL had no specific diagnosis associated with cholestasis.2
It is safe to say that in infants with ongoing extrahepatic illness, such as cardiac disease, prolonged dependence on parenteral nutrition, or severe metabolic defects, cholestasis is likely to be a poor prognostic sign. That said, remarkable improvements in the care of IFALD make short-bowel syndrome an increasingly survivable long-term diagnosis. And, in infants who have recovered from their primary disease and are otherwise doing well, residual cholestasis is likely to resolve over time.
The newborn liver is uniquely susceptible to cholestasis in the setting of inflammation or other systemic insults.
Most neonatal cholestasis is of the mild, self-limiting, nonspecific variety.
Sometimes, neonatal cholestasis can herald a life-threatening disease.
The list of possible diagnoses is extremely long, and choosing a safe, cost-effective, efficient, and minimally invasive diagnostic algorithm is challenging.
Attempts should be made to rule out biliary atresia or to proceed to surgery by 2 months of age.
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