INTRODUCTION — Neonatal cholestasis is generally defined as conjugated hyperbilirubinemia that occurs in the newborn period or shortly thereafter (ie, within the first three months of life). Cholestasis results from diminished bile formation and/or excretion, which can be caused by a number of disorders, most commonly biliary atresia.
The most common causes of neonatal cholestasis will be reviewed here. Details about biliary atresia and the approach to infants with neonatal cholestasis, including differentiation between extrahepatic obstruction and intrahepatic disease, are discussed separately. (See "Approach to evaluation of cholestasis in neonates and young infants".)
DEFINITION AND CLASSIFICATION
●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.
●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).
Causes of neonatal cholestasis can be divided into the following categories (table 1A-B):
●Obstructive (eg, biliary atresia)
●Infectious (eg, congenital cytomegalovirus)
●Genetic/metabolic (eg, Alagille syndrome, progressive familial intrahepatic cholestasis [PFIC], and several inborn errors of metabolism)
●Alloimmune (eg, gestational alloimmune liver disease [GALD])
●Toxic (eg, intestinal failure-associated liver disease [IFALD], related to parenteral nutrition)
●Idiopathic (idiopathic neonatal hepatitis)
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, the most common cause of cholestasis in this age group. Biliary atresia must be differentiated from other causes of cholestasis promptly because early surgical intervention (ie, before two months of age) results in a better patient outcome. Furthermore, other treatable disorders require prompt diagnosis to initiate effective therapy (eg, tyrosinemia, galactosemia, hypothyroidism, and infectious causes).
OBSTRUCTIVE CAUSES
Biliary atresia — Biliary atresia is a progressive idiopathic disease of the extrahepatic biliary tree that presents with clinical signs of biliary obstruction in young infants. Biliary atresia is the most common cause of conjugated hyperbilirubinemia in young infants in resource-rich countries, accounting for approximately 20 to 30 percent of cases [1]. Infants with biliary atresia tend to be healthy at birth and develop progressive jaundice within the first eight weeks of life, often with acholic (pale-colored) stools. Studies have shown that infants later diagnosed with biliary atresia have mildly abnormal direct or conjugated bilirubin in the first days of life, presenting an opportunity for newborn screening [2].
Biliary atresia must be recognized promptly because early surgical intervention (eg, before 60 days of age) substantially improves outcome [3]. It is distinguished from other causes of neonatal cholestasis by a variety of tests, and the diagnosis is confirmed by intraoperative cholangiogram. Even when optimally managed, a majority of individuals with biliary atresia ultimately require liver transplantation.
The pathogenesis, clinical features, diagnosis, and treatment of biliary atresia are discussed in detail in a separate topic review. (See "Biliary atresia".)
Biliary cysts — Biliary cysts are a rare but treatable cause of conjugated hyperbilirubinemia. They were originally termed choledochal cysts because they usually involve the extrahepatic bile duct. Five anatomic variants have been described (figure 1), but most affected infants have diffuse enlargement of the common bile duct (type 1, representing 50 to 80 percent of biliary cysts [4]) [5,6]. In addition to jaundice, affected infants may have abdominal pain, an abdominal mass, and vomiting. Some infants in whom biliary cysts are diagnosed by prenatal ultrasound are asymptomatic during the neonatal period.
The cyst usually can be detected by ultrasonography and should be further evaluated by magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and/or intraoperative cholangiopancreatography [7]. Biliary cysts must be differentiated from cystic biliary atresia. In infants with biliary cysts, the intrahepatic bile ducts are normal or dilated rather than sclerosed. Ultrasonographic findings suggestive of biliary cysts rather than biliary atresia include larger cyst size, dilated intrahepatic bile ducts, and normal-appearing gallbladder [8].
Management depends on the type of cyst and presence of biliary obstruction, but most cases presenting during the neonatal period will require surgical resection rather than the Kasai procedure used for patients with biliary atresia. Removal of the cyst can prevent the development of ascending cholangitis or biliary adenocarcinoma [5]. A randomized trial showed that fibrotic liver disease is likely to develop even in asymptomatic infants and that early surgical intervention (≤1 month of age) is beneficial compared with late (≥1 month of age) intervention [9].
Prognosis is better for patients with biliary cysts than those with biliary atresia [10]. However, patients with biliary cysts may be at risk for later development of cholangiocarcinoma even after resection and should be monitored periodically with imaging and blood work. (See "Endoscopic retrograde cholangiopancreatography (ERCP) for biliary disease in children", section on 'Biliary cysts' and "Biliary cysts".)
Other obstructive causes — Other extrahepatic causes of biliary obstruction in young infants include:
●Inspissated bile/plug syndrome (eg, patients with cystic fibrosis [CF])
●Gallstones or biliary sludge
●Tumors
●Neonatal sclerosing cholangitis
INFECTIOUS CAUSES — Bacterial, protozoal, and viral infections can result in cholestasis. The proportion of cholestasis attributed to infection varies markedly across studies, likely depending on the population [1]. Common congenitally acquired pathogens include cytomegalovirus, toxoplasmosis, rubella, herpes, and syphilis. Less frequent causes are echovirus, adenovirus, and parvovirus B19. (See "Overview of TORCH infections".)
Bacterial infections with gram-positive and gram-negative organisms also have been associated with cholestasis. As an example, jaundice may be the only presenting sign in patients with a urinary tract infection caused by Escherichia coli [11,12]. Bacterial infection also contributes to cholestasis in infants who receive parenteral nutrition [13,14]. (See "Urinary tract infections in neonates".)
GENETIC/METABOLIC DISORDERS
Alagille syndrome
●Genetics and pathogenesis – Alagille syndrome (MIM #118450) is inherited in an autosomal dominant fashion, with mutations in the JAG1 gene responsible for Alagille syndrome in more than 90 percent of patients; a small percentage have mutations in the NOTCH2 gene.
These mutations are associated with paucity of interlobular bile ducts, leading to chronic cholestasis and marked elevations of serum bile acids, which are thought to mediate the hepatocellular injury and key symptoms including intractable pruritus, jaundice, and xanthomas [15].
●Clinical features – Alagille syndrome is characterized by the paucity of interlobular bile ducts and the following associated features [16-18]:
•Hepatic:
-Chronic cholestasis (87 to 100 percent)
-Jaundice (66 to 85 percent)
-Cirrhosis (44 to 95 percent)
-Pruritus (59 to 88 percent)
-Xanthomas (30 to 42 percent)
•Cardiac – Murmur or cardiac anomalies (63 to 98 percent). The most common finding is peripheral pulmonic stenosis; other anomalies include tetralogy of Fallot, ductus arteriosus, septal defects, or coarctation of the aorta.
•Vertebral – Butterfly vertebrae (24 to 87 percent).
•Eyes – Most commonly posterior embryotoxon (prominent Schwalbe line 56 to 95 percent). Other findings may include optic disc abnormalities, hypopigmentation of the peripheral retina, pseudopapilledema, and true papilledema (associated with intracranial hypertension) [19].
•Ears – Hearing loss (40 to 60 percent).
•Facies – Dysmorphic facies (78 to 95 percent), consisting of broad nasal bridge, triangular facies (broad forehead and pointed chin), and deep-set eyes (picture 1).
•Renal – Renal involvement (19 to 74 percent). The most common finding is renal dysplasia; other disorders include glomerular mesangiolipidosis or renal tubular acidosis.
Short stature and/or failure to thrive are common in Alagille syndrome. Developmental delay is seen in approximately 10 percent of patients and may be due in part to malnutrition [18]. A multicenter study showed that children with Alagille syndrome had slightly lower full-scale intelligence quotient scores compared with those with progressive familial intrahepatic cholestasis (PFIC) or alpha-1 antitrypsin deficiency [20]. Supernumerary digital flexion creases have been reported in 35 percent of individuals with Alagille syndrome, compared with <1 percent of the general population [21,22]. Cerebral and systemic vascular malformations also may be present, including intracranial abnormalities that predispose to stroke [23]. One case series describes an association with chronic arthritis, with some features similar to juvenile idiopathic arthritis, typically beginning during childhood [24].
In addition to conjugated hyperbilirubinemia, other laboratory findings include elevations of serum aminotransferases, and gamma-glutamyl transpeptidase (GGTP), which is often disproportionally increased.
●Diagnosis – The clinical diagnosis of Alagille syndrome in the infant with cholestasis includes the characteristic clinical features and a liver biopsy demonstrating reduced number of the interlobular bile ducts. Marked paucity of the bile ducts may not be apparent in infants younger than six months of age. In fact, these infants may have bile duct proliferation, mimicking obstructive cholestasis [22].
In patients with clinical characteristics suggestive of Alagille syndrome, the diagnosis can also be made or confirmed by the finding of a JAG1 or NOTCH2 gene mutation. Individuals identified by genetic testing (eg, relatives of patients with Alagille syndrome) may have milder features and are less likely to meet criteria for clinical diagnosis [25]. Information about genetic testing and a clinical review are available at the Genetic Testing Registry website. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Alagille syndrome'.)
The histologic finding of paucity of interlobular bile ducts found in Alagille syndrome also may be observed in other disorders, including alpha-1 antitrypsin (AAT) deficiency, cystic fibrosis (CF), infection (eg, cytomegalovirus, syphilis), mitochondrial disorders, PFIC types 1 and 2 (PFIC1 and PFIC2), or arthrogryposis-renal dysfunction-cholestasis syndrome [26]. In some cases, no etiology is apparent, in which case, the disorder is termed “nonsyndromic” paucity of the interlobular bile ducts [27]. (See 'Infectious causes' above and 'Genetic/metabolic disorders' above.)
●Supportive care – Medical management of patients with Alagille syndrome depends on diagnosing and treating disease in each affected organ system [22]. The key considerations are as follows:
•Liver disease – Cholestatic liver disease is of variable severity and may stabilize by school age. It is managed conservatively, with treatment for pruritus and malabsorption as needed. Portoenterostomy (Kasai procedure) is not beneficial and is not recommended [28].
•Pruritus – Pruritus is a common complication of cholestasis, occurring in 80 percent of patients in one series, and can adversely affect quality of life [18,29]. Pruritus is often treated with drugs that lower serum bile acids, as discussed below. In historical series, pruritus was refractory to medical treatment in approximately 40 percent of affected patients. In these cases, biliary diversion or liver transplantation may be indicated [18,29,30].
•Nutrition – Malnutrition, with associated growth failure, and pubertal delay are common and likely multifactorial and should be treated proactively with high-energy supplements (often requiring nasogastric or gastrostomy feeding) and fat-soluble vitamin supplementation. Pancreatic insufficiency appears to be uncommon in Alagille syndrome, so supplementation with pancreatic enzymes is unlikely to be an effective therapy for malnutrition [31].
•Associated anomalies – The extent of cardiac or renal disease is highly variable, and management is tailored to the involvement in the individual patient.
Patients with cerebral vascular anomalies are at risk for intracranial bleeding. There should be a low threshold for brain imaging in the setting of head injury or symptoms.
●Pharmacotherapy – Medications used to treat pruritus include ursodeoxycholic acid (ursodiol), rifampin, or bile acid sequestrants (eg, cholestyramine, colesevelam), with variable success, and maralixibat. Colesevelam (Welchol) is available in pill form that may be more palatable than cholestyramine or other bile acid resins [32]. In addition, treatment with naltrexone may improve pruritus in children with cholestatic liver disease, as suggested by several case series and one small randomized trial [33-36].
Maralixibat is an inhibitor of intestinal bile acid transport, acting on the apical sodium-dependent bile acid transporter. In a randomized trial in 29 patients with Alagille syndrome (mean age 5.4 years), maralixibat reduced mean serum bile acids, pruritus, and xanthomas; improved linear growth and quality of life; and was generally well tolerated (NCT02160782) [37,38]. Treatment effects were generally maintained in the open-label extension (mean duration 2.6 years). Whether maralixibat attenuates the progression of liver disease has not been established.
Maralixibat has been approved by the US Food and Drug Administration for treatment of cholestatic pruritus in Alagille syndrome [39]. The starting dose is 190 micrograms/kg daily for seven days, and the dose is then increased to 380 micrograms/kg daily (maximum dose 28.5 mg daily).
Because maralixibat inhibits bile acid absorption, it may cause diarrhea due to the effect of the unabsorbed bile salts on colonic epithelium. Additionally, bile salt depletion can cause malabsorption of fat and fat-soluble vitamins (vitamins A, D, E, and K), which may need supplementation. Although maralixibat is poorly absorbed, in some cases, it may exacerbate abnormalities of liver function tests. Therefore, serum bilirubin, alanine and aspartate transaminases, alkaline phosphatase, GGTP, and prothrombin time (international normalized ratio [INR]) should be monitored at baseline and during the course of therapy.
Maralixibat may be used in combination with ursodeoxycholic acid for patients with severe pruritus. It generally should not be used in combination with cholestyramine (which binds maralixibat in the intestinal lumen, thereby inhibiting its activity). If cholestyramine is used, there should be a six-hour gap between its administration and that of maralixibat.
●Prognosis – The prognosis of patients with Alagille syndrome depends in large part on the severity of the liver disease and associated anomalies (cardiac, renal, and vascular malformations). As an example, a multicenter study reported longitudinal follow-up of a cohort of pediatric patients with Alagille syndrome and clinically significant liver disease followed at tertiary care centers. By young adulthood, 4 percent had died, 76 percent had undergone liver transplantation, and 40 percent of those surviving with their native liver had portal hypertension [40]. Patients who did not undergo early liver transplantation tended to have spontaneous improvement in cholestasis, reflected by moderate improvement in serum bilirubin, GGTP, xanthomas, and pruritus during childhood. However, many of these patients experienced a "second wave" of liver disease during adolescence, with signs and complications of portal hypertension, often leading to liver transplantation. In a large multicenter international retrospective study of 1433 patients with Alagille syndrome, overall native liver survival was 54 percent at 10 years of age and 40 percent at 18 years. Median total bilirubin levels between 6 and 12 months of age were found to be predictive of later outcomes. Patients who had a median total bilirubin <5 mg/dL in infancy had a 79 percent chance of reaching adulthood with their native liver [41].
Earlier studies with long-term follow-up reported high rates of jaundice and poorly controlled pruritus (70 to 85 percent) and death (33 percent) as well as lower rates of liver transplantation (33 percent), likely representing lower access to liver transplantation [42,43]. Outcomes were somewhat better for those who presented after the neonatal period.
Alpha-1 antitrypsin deficiency — The presentation of some forms of AAT deficiency (MIM #613490) can include neonatal cholestasis. The frequency of AAT deficiency in infants with neonatal cholestasis ranges from 1 to 10 percent in different series [44-46]. AAT is an antiprotease and the natural inhibitor of the serine proteases released by activated neutrophils [47]. In patients with AAT liver disease, the abnormal protein accumulates within the endoplasmic reticulum, resulting in liver injury in a subset of patients by unclear mechanism [48].
The diagnosis of AAT deficiency is established by the protease inhibitor (PI) phenotyping system defined by isoelectric focusing of plasma [48]. The primary alleles associated with liver disease are PI*Z homozygosity or PI*SZ heterozygosity [48]. Of note, "null" genotypes, which result in no protein production, are not associated with liver disease, although they do cause severe lung disease that presents in adulthood (see "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'AAT phenotypes'). Affected individuals typically have decreased plasma AAT concentration because of impaired hepatic production. However, a normal AAT level does not exclude the diagnosis, because inflammation and tissue injury can markedly increase plasma AAT concentrations. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
PI*Z homozygotes most commonly present as neonatal hepatitis with cholestasis beginning in the first few months of life, and approximately 65 percent of these have severe liver disease [49,50]. Other clinical presentations among newborns include hepatomegaly with elevated aminotransferase levels (but without hyperbilirubinemia) and early evidence of moderate to severe liver disease with ascites and bleeding diathesis. Interestingly, AAT-associated liver disease that presents in the neonatal period often resolves spontaneously, and this presentation is not necessarily associated with a worse prognosis compared with later presentation during childhood [49,51,52]. The diagnosis and natural history of AAT deficiency are discussed in more detail in a separate topic review (see "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency", section on 'Hepatic disease'). Liver transplantation has improved the prognosis of infants with severe liver disease [53].
Arthrogryposis-renal dysfunction-cholestasis syndrome — The cardinal features of arthrogryposis-renal dysfunction-cholestasis syndrome (MIM #208085) are arthrogryposis (multiple joint contractures), renal dysfunction, and cholestasis. The syndrome was previously thought to be rare but was found in 7 percent of infants presenting with cholestasis to a center in Korea [54]. The disorder is caused by mutations in the VPS33B or VIPAR genes and is an autosomal recessive trait; many patients are from consanguineous families [55,56].
In addition to the three cardinal features, affected infants generally have severe growth failure, ichthyosis, and central nervous system anomalies and may have cardiac defects, recurrent infections, and diarrhea. Unlike in many other cholestatic conditions, serum GGTP is usually normal. The infants also have a bleeding tendency, and patients undergoing liver biopsy often experience severe hemorrhage [54,55]. Thus, the diagnosis should be made by mutation analysis, and organ biopsy should be avoided. Although the severity of the phenotype varies, virtually all affected infants die during infancy [54,57].
Cystic fibrosis — Neonatal cholestasis is an uncommon presentation of CF, occurring in fewer than 5 percent of patients with CF [58]. In affected infants, jaundice and hepatomegaly slowly resolve. Infants with CF are more likely to present with meconium ileus or steatorrhea with failure to thrive. The CF transmembrane conductance regulator (CFTR) is located on the apical surface of the biliary epithelium, explaining some of the biliary tract disease seen in patients with CF [59]. (See "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Hepatobiliary disease".)
Inborn errors of metabolism — A variety of inborn errors of metabolism can present with neonatal cholestasis. These include disorders of carbohydrate (eg, galactosemia), amino acid (eg, tyrosinemia) and lipid metabolism, and bile acid synthetic and mitochondrial disorders. These disorders are outlined in the table (table 1A), and selected disorders are highlighted below.
Galactosemia — Galactosemia (MIM #230400) is usually the result of galactose-1-phosphate uridyl transferase (GALT) deficiency. Affected infants present with mixed (conjugated and unconjugated) hyperbilirubinemia after the onset of galactose-containing feedings (eg, human or cow's milk); sepsis is also common at presentation. Associated features include vomiting, diarrhea, failure to thrive, renal tubular acidosis, cataracts, and coagulopathy.
The diagnosis is suggested by the presence of reducing substances in the urine and is confirmed by an assay of GALT activity in erythrocytes, leukocytes, or liver. Newborn screening for galactosemia is available in all states in the United States. Treatment requires elimination of dietary galactose and milk products, with substitution of soy formula (which does not contain any lactose). (See "Galactosemia: Clinical features and diagnosis".)
Tyrosinemia — Hereditary tyrosinemia type 1 (also known as hepatorenal tyrosinemia; MIM #276700) is caused by deficiency of fumarylacetoacetate hydrolase and presents in infancy. It is characterized by progressive liver disease, renal tubular acidosis, and neurologic impairment. Young infants present with cholestasis and coagulopathy, which is often disproportionate to the apparent degree of liver disease. Older infants and children may present with chronic liver disease (with or without cholestasis) and painful crises, mimicking porphyria.
Affected individuals have increased urinary excretion of succinylacetone and markedly elevated blood tyrosine concentration. Newborn screening for tyrosinemia type 1 is available in most states in the United States. The diagnosis and management of this disorder are discussed separately. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1' and "Newborn screening".)
Citrin deficiency — Citrin deficiency (neonatal-onset type II citrullinemia; MIM #605814) is caused by a mutation of the SLC25A13 gene. Infants with citrin deficiency have transient intrahepatic cholestasis, diffuse fatty liver and parenchymal cellular infiltration associated with hepatic fibrosis, low birth weight, and growth retardation [60]. Citrin deficiency as a cause of neonatal intrahepatic cholestasis is more common in infants of Japanese or Chinese ancestry but has also been reported in other populations and is recognized to be pan-ethnic [61,62]. Liver function may be abnormal (eg, hypoproteinemia, decreased concentrations of coagulation factors, and/or hypoglycemia). Symptoms remit with fat-soluble vitamin supplementation and the use of lactose-free formula or formulas containing medium-chain triglycerides. Later in life, some of these patients may develop adult-onset citrullinemia type II (MIM #603471), which is characterized by fatty liver, hyperammonemia, and neurologic symptoms [63,64]. (See "Urea cycle disorders: Clinical features and diagnosis", section on 'Differential diagnosis'.)
Disorders of lipid metabolism — Disorders of lipid metabolism, including Wolman, Niemann-Pick type C, and Gaucher disease type 2, occasionally can present with cholestasis.
Wolman disease (also known as lysosomal acid lipase deficiency and cholesterol ester hydrolase deficiency; MIM #278000) is an autosomal recessive disorder characterized by hepatosplenomegaly, hepatic fibrosis, adrenal calcification, adrenal insufficiency, malabsorption, and poor weight gain and is usually fatal in infancy [65,66]. (See "Causes of primary adrenal insufficiency in children", section on 'Defects in cholesterol biochemistry'.)
Niemann-Pick type C (MIM #257220) and Gaucher disease type 2 (MIM #230900) are discussed in detail separately. (See "Overview of Niemann-Pick disease" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)
Disorders of bile acid metabolism — Primary disorders of bile acid synthesis are caused by inherited defects in the enzymes that are necessary for synthesis of the two main bile acids (cholic acid and chenodeoxycholic acid). Cholestasis results from an inadequate production of these bile acids, which are essential for bile flow, and increased production of aberrant bile acids, which are hepatotoxic.
Affected infants typically develop severe cholestatic jaundice from birth and progressive liver failure, sometimes with stools that are loose, fatty (steatorrhea), or pale-colored (acholic), and occasionally with pruritus [67,68]. Laboratory testing typically reveals conjugated hyperbilirubinemia and elevated aminotransferase activity (alanine transaminase [ALT] and aspartate transaminase [AST]), with paradoxically normal GGTP [69]. The clinical presentation of these disorders is variable. Milder forms may present in anicteric school-aged children as fat-soluble vitamin deficiency, pruritus, and/or neurologic disease with less prominent liver disease [70]. Types of single enzyme defects include [71]:
●Bile acid synthesis defect type 1 (MIM #607765) – 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase deficiency, due to a mutation in the HSD3B7 gene [68,72,73].
●Bile acid synthesis defect type 2 (MIM #235555) – Delta[4]-3-oxosteroid 5-beta reductase deficiency, due to a mutation in the AKR1D1 gene [74,75].
●Bile acid synthesis defect type 3 (MIM #613812) – Oxysterol 7-alpha-hydroxylase deficiency, due to a mutation in the CYP7B1 gene [76]. Mutations in this gene are also associated with a type of hereditary spastic paraplegia (SPG5). (See "Hereditary spastic paraplegia", section on 'Autosomal recessive HSP'.)
●Bile acid synthesis defect type 4 (MIM #214950) – Alpha-methylacyl-CoA racemase deficiency, due to a mutation the AMACR gene [77,78].
●Bile acid synthesis defect type 5 (MIM #616278) – Due to a mutation in the ABCD3 gene [79].
●Bile acid synthesis defect type 6 (MIM #617308) – Due to a mutation in the ACOX2 gene [80].
●Sterol 27-hydroxylase defect (MIM #213700) – Also known as cerebrotendinous xanthomatosis. (See "Cerebrotendinous xanthomatosis".)
●Amidation defects:
•Amino acid n-acyltransferase deficiency (MIM 602938) – Due to a mutation in the BAAT gene
•Bile acid CoA ligase deficiency (MIM 603314) – Due to a mutation in the SLC27A5 gene [81]
The diagnosis of a bile acid synthesis disorder is made using fast atom bombardment mass spectrometry and gas chromatography/mass spectrometry to demonstrate abnormal bile acids in the urine. Administration of bile acids (such as ursodiol) will obscure bile acid analysis by this method and must be discontinued one week prior to urine collection for this assay. Genetic testing is also becoming more widely available [82].
Treatment with primary bile acids (cholic acid, not ursodeoxycholic acid [ursodiol]) given orally normalizes liver function in some patients, depending on the specific defect and degree of illness at time of diagnosis [71,83,84]. Cholic acid (Cholbam) was approved for this purpose by the US Food and Drug Administration in 2015 [85]. Efficacy has been demonstrated for bile acid synthesis defects types 1, 2, and 4 [71,86]. Amidation defects (amino acid n-acyltransferase deficiency or bile acid CoA ligase deficiency) respond to treatment with oral glycocholic acid, rather than cholic acid [71,87]. A detailed review of bile acid synthesis disorders is available through the National Organization for Rare Disorders website [71].
Other disorders are classified as secondary bile acid defects because they involve defects in the transport of bile acids. These include:
●Zellweger spectrum disorders (see "Peroxisomal disorders", section on 'Zellweger syndrome')
●Smith-Lemli-Opitz syndrome (see "Causes of primary adrenal insufficiency in children", section on 'Defects in cholesterol biochemistry')
Mitochondrial disorders — A variety of mitochondrial disorders can present in the newborn period or early infancy with conjugated hyperbilirubinemia and hepatic dysfunction, with associated elevated serum aminotransferases, hypoglycemia, coagulopathy, and lactic acidosis [88,89]. Affected infants typically have lethargy and vomiting and often have neurologic signs such as weak cry, poor suck, hypotonia, apnea, and seizures. However, the type and degree of organ involvement varies among these disorders. There is also considerable variability in clinical phenotype within a single disorder because of differential content of mutant mitochondrial DNA (known as heteroplasmy). The main mitochondrial disorders that present with liver disease in infancy are outlined in the table (table 2).
Laboratory findings include hypoglycemia, acidosis, increased plasma lactate, elevated molar ratio of plasma lactate to pyruvate (greater than 20), elevation of the arterial ketone body ratio of beta-hydroxybutyrate to acetoacetate (greater than 2), and elevated creatinine kinase.
The diagnosis is confirmed by genotyping for the suspected gene (eg, DGUOK, POLG1, MPV17, TWINKLE, or TRMU); laboratories that perform these tests can be found at the Genetic Testing Registry website. A number of panels are also available for parallel sequencing of multiple genes involved in mitochondrial disorders. Alternatively, direct measurement of respiratory chain enzyme activities can be performed in freshly frozen samples of affected tissues (liver, muscle, and, sometimes, skin fibroblasts or lymphocytes). Fatty acid oxidation defects should be considered in the differential diagnosis as they may present with a similar picture. (See "Overview of fatty acid oxidation disorders".)
Liver transplantation is successful in some patients but may be contraindicated in those with neurologic or cardiac involvement [88,90,91]. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Acute liver failure in children: Management, complications, and outcomes", section on 'Liver transplant'.)
Progressive familial intrahepatic cholestasis — PFIC accounts for 10 to 15 percent of cases of neonatal cholestasis and 10 to 15 percent of liver transplants in children [44,92]. PFIC is classified into a number of different subtypes based on genetic etiology. Initially, the PFIC types were classified by numbers (PFIC types 1 through 5), but with the increased use of exome sequencing and other advanced genomic testing, the number of distinct genetic disorders has outpaced the classification system.
●PFIC2 – The most common type presenting in infancy is PFIC2 (MIM #601847), which is caused by mutations in the ABCB11 gene, encoding the bile salt export pump [93]. Affected infants tend to have a rapid and severe course, with marked elevations in serum bile acids and intractable pruritus, and sometimes coagulopathy due to vitamin K malabsorption. Despite the severe cholestasis, concentrations of GGTP are paradoxically normal.
●PFIC1 and PFIC4 – Somewhat less common are PFIC1 (MIM #211600; due to mutations in the ATP8B1 gene, also known as Byler disease) and PFIC4 (MIM #615878; due to mutations in the TJP2 gene) [94]. These types may present any time in infancy and also tend to have severe cholestasis. As in PFIC2, the GGTP is normal.
●PFIC3 – The least common type to present as neonatal cholestasis is PFIC3, also known as MDR3 deficiency (MIM #602347), caused by mutations in the ABCB4 gene [95]. It is distinguished from the other types of PFIC by marked elevations of GGTP.
In addition to these traditionally recognized PFIC gene associations, several new genes have been identified as causing a PFIC phenotype. These include PFIC5 (MIM #617049), caused by mutations in the NR1H4 gene, which encodes the nuclear bile acid receptor FXR, identified in two families with neonatal cholestasis and a severe phenotype with rapid progression of liver disease [96]. Mutations in the MYO5B gene, the causative gene for microvillus inclusion disease, have also been reported in children with cholestasis and persistently low GGTP levels [97,98].
Genetics and management of these disorders are described separately. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Progressive familial intrahepatic cholestasis'.)
ALLOIMMUNE
Gestational alloimmune liver disease (neonatal hemochromatosis) — Gestational alloimmune liver disease (GALD) is caused by transplacental passage of reactive maternal immunoglobulins [99]. It was previously known as neonatal hemochromatosis or neonatal iron storage disease, but those terms are misleading because the disorder is unrelated to hereditary hemochromatosis and iron deposition is a consequence, rather than a cause, of the liver injury.
●Clinical presentation – GALD is characterized by hepatic failure and hepatic and extrahepatic iron accumulation (hemosiderosis) during the neonatal period [100]. The onset is intrauterine, and newborns present with signs of severe liver failure, including coagulopathy, ascites, and hypoalbuminemia. Hyperbilirubinemia typically is both conjugated and unconjugated, although conjugated bilirubin levels may be only modestly elevated [100]. Hepatic cirrhosis in the neonate is common, underscoring the antenatal timing of the hepatic insult [101].
●Diagnosis – The diagnosis may be suspected on the basis of the iron studies. Traditionally, demonstration of extrahepatic (or extra reticuloendothelial) iron was required for the diagnosis [100,102,103]. However, now that the alloimmune mechanism has been recognized, cases may be identified by the characteristic immunohistologic features of alloimmune disease that are present (specifically, the anti-human C5b-9 complex). Cases with these immunohistochemical findings and with either mild or severe disease and no iron overload have been reported [104,105].
●Pathogenesis – GALD is a result of maternal alloimmune injury (analogous to erythroblastosis fetalis) caused by transplacental passage of specific reactive maternal immunoglobulin G (IgG) [106,107]. The maternal alloantibody activates fetal complement cascade to produce a membrane attack complex and fetal liver injury. The characteristic feature of GALD is high levels of immunostaining for the anti-human C5b-9 complex (the terminal complement cascade) [99]. The target protein of the maternal immune response has not been identified.
GALD can occur in the first pregnancy as well as subsequent pregnancies, suggesting that sensitization occurs during the pregnancy and not just at parturition (as is thought to be the case for most other gestational alloimmune diseases) [108]. The rate of recurrence of GALD in pregnancies subsequent to the index case is approximately 95 percent, including fetal loss as well as neonatal liver failure. The high recurrence rate is consistent with the mechanism of fetal alloimmune injury, rather than a genetic pattern of inheritance [108,109].
●Treatment – Treatment for GALD may include antenatal and/or postnatal therapy, depending on when the disorder is identified:
•Antenatal therapy – For pregnant women with a previous pregnancy that resulted in an infant with GALD, antenatal therapy with high-dose intravenous immunoglobulin (IVIG) dramatically reduces the risk for recurrence of disease and also reduces the risk for fetal loss [109-112]. In a series of 188 pregnancies treated with IVIG (1 g/kg body weight/week beginning in week 14 or 18 of the pregnancy), 94 percent had no evidence of liver disease, compared with 30 percent for infants born of untreated pregnancies [112]. Among the 11 pregnancies with poor outcomes despite antenatal therapy, two ended with fetal loss and the nine live-born infants had severe GALD-related liver disease.
•Postnatal management – The combination of exchange transfusion and IVIG is the current treatment of choice for neonates with GALD [107,113-116]. Liver transplantation remains an option for infants who do not respond to IVIG treatment.
Treatment with high-dose IVIG, usually given in combination with exchange transfusion, was described in a series of 16 infants with GALD [116]. The treated infants had a substantially increased rate of survival without liver transplantation (75 percent) as compared with historical controls (17 percent). A subsequent update suggests transplant-free survival up to 79 percent (35 of 44 infants treated with IVIG) [117]. Although this approach is based on limited clinical evidence, it is logical in view of the alloimmune mechanism of disease and the effectiveness of IVIG in gestational therapy [114].
Outcomes for infants who do not receive exchange transfusion or IVIG are poor, with approximately 10 percent survival without liver transplantation [109,113]. Liver transplantation can be curative, but transplantation is difficult in this age group due to lack of appropriate donors and the increased risk of vascular and infectious complications. Thus, early referral is important. The outcomes of liver transplantation for GALD are fair but similar to the outcomes for other causes of acute liver failure in this age group [113,118].
TOXIC
Intestinal failure (parenteral nutrition)-associated liver disease — Intestinal failure-associated liver disease (IFALD) is defined as liver disease that arises as a consequence of the medical and surgical management strategies for intestinal failure, including short bowel syndrome. It is sometimes known as parenteral nutrition-associated liver disease because parenteral nutrition plays an important role in the pathogenesis of the disease. IFALD is the preferred term, in recognition that several other factors contribute to the disorder, including immaturity, intercurrent infections, and lack of enteral feedings.
IFALD is particularly common among premature infants with short bowel syndrome. The pathogenesis and management of IFALD are discussed in detail in a separate topic review. (See "Intestinal failure-associated liver disease in infants".)
IDIOPATHIC NEONATAL HEPATITIS — Idiopathic neonatal hepatitis is defined as prolonged conjugated hyperbilirubinemia without an obvious etiology after a complete evaluation has excluded identifiable infectious and metabolic/genetic causes. Characteristic findings on liver biopsy are multinucleated giant cells; variable inflammation with infiltration of lymphocytes, neutrophils, and eosinophils; and little or no bile duct proliferation [119]. However, these findings also are seen in other conditions, including alpha-1 antitrypsin (AAT) deficiency and progressive familial intrahepatic cholestasis (PFIC), among others.
With identification of specific disorders that had been previously included in this category, the reported incidence of idiopathic neonatal hepatitis has declined [120]. In a study of infants presenting with idiopathic cholestasis, outcomes were favorable, with a high rate of spontaneous resolution [120]. With continued improved diagnostic advances and identification of other specific causes, this entity, which is a diagnosis of exclusion, will become increasingly rare.
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
●Definition – 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). The hallmark of cholestasis is accumulation of components of bile in the bloodstream, due to diminished bile flow and/or excretion, and most frequently manifested as conjugated hyperbilirubinemia. (See 'Definition and classification' above.)
●Causes – Neonatal cholestasis can be caused by obstruction, infection, genetic disorders (including metabolic defects), or alloimmune or toxic mechanisms (table 1A-B). Key considerations are:
•Biliary atresia – Biliary atresia is the most common cause of neonatal cholestasis. It must be differentiated from other causes promptly because early surgical intervention (ie, before two months of age) results in a better patient outcome. It is distinguished from other causes of neonatal cholestasis by a variety of tests, and the diagnosis is confirmed by intraoperative cholangiogram. (See 'Biliary atresia' above and "Biliary atresia".)
•Infections – A variety of congenital and neonatally acquired infections can cause cholestasis, including those in the TORCH group of infections, and neonatal urinary tract infection. (See 'Infectious causes' above.)
•Genetic/metabolic disorders – Genetic causes of neonatal cholestasis include the following, as well as others detailed in the table (table 1A):
-Alagille syndrome, which is characterized by chronic cholestasis with paucity of the interlobular bile ducts on liver biopsy. Associated features found in most patients include cardiac anomalies, butterfly vertebrae, posterior embryotoxon of the eye, and characteristic facial features (picture 1). (See 'Alagille syndrome' above.)
-Cystic fibrosis (CF), which should be considered in infants with neonatal cholestasis, although it is an uncommon presentation of the disease. (See 'Cystic fibrosis' above.)
-Several inborn errors of metabolism present with cholestasis during the neonatal period, including galactosemia, tyrosinemia, citrin deficiency (neonatal-onset type II citrullinemia), and disorders of lipid and bile acid metabolism or mitochondrial function. Early identification is important because specific treatment is available for many of these disorders. (See 'Inborn errors of metabolism' above.)
-Progressive familial intrahepatic cholestasis (PFIC) accounts for 10 to 15 percent of cases of neonatal cholestasis and 10 to 15 percent of liver transplants in children. (See 'Progressive familial intrahepatic cholestasis' above.)
-Gamma-glutamyl transpeptidase (GGTP) is elevated in the most common types of neonatal cholestasis, including biliary atresia. A few disorders are distinguished by relatively low or normal concentrations of GGTP, including the most common types of PFIC, bile acid synthetic disorders, and arthrogryposis-renal dysfunction-cholestasis syndrome. (See 'Progressive familial intrahepatic cholestasis' above and 'Disorders of bile acid metabolism' above and 'Arthrogryposis-renal dysfunction-cholestasis syndrome' above.)
•Alloimmune – Gestational alloimmune liver disease (GALD; previously known as neonatal hemochromatosis), mediated by transplacental passage of specific maternal antibodies, presents with neonatal liver failure. The combination of exchange transfusion and intravenous immunoglobulin (IVIG) is the treatment of choice for affected neonates. For pregnant women with a previous pregnancy that resulted in an infant with GALD, treatment with high-dose IVIG dramatically reduces the risk for recurrence of disease. (See 'Gestational alloimmune liver disease (neonatal hemochromatosis)' above.)
•Parenteral nutrition – Intestinal failure-associated liver disease (IFALD) is caused at least in part by prolonged exposure of a young infant to parenteral nutrition. The pathogenesis and management are discussed separately. (See 'Intestinal failure (parenteral nutrition)-associated liver disease' above and "Intestinal failure-associated liver disease in infants".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert J Shulman, MD, and Stephanie H Abrams, MD, MS, who contributed to earlier versions of this topic review.
