Review

Pediatric Cholestasis:
Epidemiology, Genetics, Diagnosis,
and Current Management
Saul J. Karpen, M.D., Ph.D.

In the setting of jaundice, a common condition of new-
borns, those with true liver disease rather than physio-
logical and transient jaundice often elude early diagnosis.
Estimates in North America of the incidence of cholestatic
disease are ~1:2500 newborns, although recent epidemi-
ological exploration into the current incidence is needed.
Detailed causes of neonatal cholestasis have recently
been reviewed1 within the broad categories of genetic/
metabolic, infectious, immune-mediated, and unknown
etiologies.2 Across North America and Europe, ~40% of
cholestasis cases in newborns are caused by a fibroin-
flammatory cholangiopathy, biliary atresia. Biliary atresia
is of unknown cause, although recent evidence strongly
suggests it is a cholangiopathy that has its origins during
embryological development rather than from an acquired
postnatal cause.3-7 This short review will highlight the
principal causes, broad diagnostic approaches, and cur-
rent management of pediatric cholestatic disorders, with a
focus on decisions that can include using modern genetic
techniques for precise and timely diagnosis. Excluded from
this report will be cholestasis from gallstone-based biliary
obstructions and acute liver failure.
The definition of cholestasis, or slow bile flow, is gen-
erally made from clinical and laboratory-based data.2,8
The principal serum laboratory test that correlates with
cholestasis is an elevated direct (or conjugated) bilirubin
level. Recent joint North American/European guidelines
for neonatal cholestasis provide a direct bilirubin concen-
tration >1.0 mg/dL (17 μM) as laboratory justification to
explore potential cholestatic diagnoses. However, there
are cholestatic conditions that do not alter direct biliru-
bin excretion into bile as profound as interfering with the
main driver of bile flow, the canalicular secretion of con-
jugated bile acids.9,10 Conjugated bile acids are the prin-
cipal solute in bile, acting as amphipathic nutritional and
signaling molecules in hepatocytes, cholangiocytes, and
enterocytes, modified by bacterial microbes before being
reabsorbed in the terminal ileum via the ASBT (SLC10A2)
apical bile acid transporter.9 After entry into the portal

Abbreviations: ALGS, Alagille syndrome; BASD, bile acid synthesis defect; BESP, bile salt export pump; FXR, farnesoid X receptor;
GGT, gamma-glutamyltransferase; KPE, Kasai portoenterostomy; NTCP, sodium taurocholate cotransporting polypeptide; PFIC,
progressive familial intrahepatic cholestasis.
From the Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Emory University School of
Medicine/Children’s Healthcare of Atlanta, Atlanta, GA.
Potential conflict of interest: Dr. Karpen consults for Albiero, Intercept, Retrophin, LogicBio and Spruce Biosciences.
Received July 16, 2019; accepted October 23, 2019.

View this article online at wileyonlinelibrary.com

© 2020 by the American Association for the Study of Liver Diseases

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Review Pediatric Cholestasis Karpen

circulation, bile acids return to the liver via specific trans- TABLE 1. SELECT GENETIC CONTRIBUTIONS TO
porters on the sinusoidal surface of hepatocytes (mainly CHOLESTASIS
NTCP [sodium taurocholate cotransporting polypeptide],
Common Disease
SLC10A1), destined for canalicular excretion via BSEP [bile Gene Name Function References
salt export pump], (ABCB11) to participate in the formation 19
ATP8B1 PFIC1 Canalicular P type
of bile. Taken together, this is the process of enterohe- ATPase
20
patic circulation of bile acids (recently reviewed by Dawson ABCB11 PFIC2 Canalicular conjugated
bile acid transporter
and Karpen,9 Trauner et al.,10 and Dawson11). Clinically, JAG1 ALGS Involved in bile duct 18

cholestasis in the newborn period can be silent but often development

40
NOTCH2 ALGS Involved in bile duct
presents with reduced stool pigment, which has served
development
as a basis for screening for biliary atresia in several coun- TJP2 Cholangiolar bile duct 41,42

tries.12-14 Taken together, the combination of prolonged tight junctions

43
DCDC2 Neonatal sclerosing Ciliary function
jaundice, direct hyperbilirubinemia, and acholic stools cholangitis
44
strongly suggests cholestasis, of which timely diagnosis of NR1H4 FXR deficiency Nuclear receptor for
bile acids
the underlying cause, including biliary atresia, leads to an 21
ABCB4 PFIC3 Canalicular phospho-
increased opportunity to improve outcomes (see later). lipid transport
45
HSB3B7 (and BASDs Bile acid synthesis
others) from cholesterol
PEDIATRIC CHOLESTASIS AFTER THE For graphical representation of these and other pediatric cholestatic
NEWBORN PERIOD disorders, see recent review by Feldman and Sokol.1

Cholestasis can appear in older infants and children

forms of PFIC and ALGS.18-21 Since that time, many more
with etiological contributions that include infectious,
single gene contributions to genetic forms of cholestasis
drug-related, along with immune-mediated, oncological,
have been discovered; the key genes are listed in Table 1.
and genetic/metabolic causes. After the newborn period,
In addition to defining causation of disease, these genes’
cholestatic disorders often present with pruritus as a com-
functions in driving bile flow has led to novel targets
panion to new-onset jaundice, sometimes instigated by an
for cholestatic therapies, often specific for the gene-
intercurrent illness or new drug therapy. The differential
and patient-specific mutation. Other than ALGS and
diagnosis in the older child with cholestasis overlaps with
select mutations in ABCB4, which can cause disease as
the genetic diagnoses of the cholestatic newborn, but
a heterozygous mutation, the other genetic cholestatic
with considerations for various hepatotropic viruses (ade-
diseases are autosomal recessive in nature and thus re-
novirus, Epstein-Barr virus, enteroviruses, hepatitis B virus,
quire biallelic functional impairments from select gene
and hepatitis C virus). Intriguingly, genetic forms of chol-
variants. Current modern hepatology analysis and man-
estasis can present after the newborn period, especially if
agement incorporates knowing the gene defects, which
there are missense gene variants that have partial activ-
can directly impact on outcomes. Perhaps the most rel-
ity. The genes that underlie the imprecise and pregenomic
evant example where knowledge of the gene defect
era diagnosis of progressive familial intrahepatic choles-
directs care are protein-truncating defects in ABCB11
tasis (PFIC) are best understood when the gene product’s
that can lead to substantial accumulation of intracel-
functional contributors to bile flow are known.15,16 Finally,
lular bile acids and hepatocellular carcinoma before 18
several inherited cholangiopathies can present after the
months of age.22
newborn period (Caroli disease, cystic fibrosis liver disease,
Alagille syndrome [ALGS], to name a few), as well as in-
flammatory cholangiopathies such as primary sclerosing DIAGNOSIS OF PEDIATRIC CHOLESTASIS
cholangitis in the setting of inflammatory colitis.17
Several recent reviews and guidelines have addressed
the approaches to the cholestatic child1,2 with the general
GENETICS OF PEDIATRIC CHOLESTASIS
issues of degree of impairment and age as principal indi-
In 1997 and 1998, four crucial genes were identified cators of the best first steps. Infants and children should
that led to a clearer understanding of the causes of three undergo standard blood tests (glucose, liver indices with

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Review
direct bilirubin, gamma-glutamyltransferase [GGT], and
prothrombin time/international normalized ratio at any
age), along with a hepatic ultrasound to evaluate for
vascular or abdominal situs anomalies and obstructive
disease (e.g., gallstones or choledochal cysts). A major still-
unresolved concern for pediatricians and subspecialists is
timely referral of the infant with prolonged jaundice who
ultimately has a high likelihood of an underlying choles-
tatic disorder. The crucial issues often relate to the general
normal appearance of most children with biliary atresia,
apart from jaundice (difficult to quantify), direct hyperbili-
rubinemia, and acholic stools,3 yet the effectiveness of the
surgical intervention (Kasai portoenterostomy [KPE], see
later) diminishes after 45 to 60 days of age.23 In children
with cholestasis, GGT levels are extremely helpful to the
clinician, because nonelevated levels are seen in those dis-
orders where bile acid secretion across the canaliculus into
bile is markedly impaired (e.g., ATP8B1, ABCB11, and FXR
[farnesoid X receptor] deficiencies and bile acid synthesis
defects [BASDs]). In distinction, cholangiopathies such as
biliary atresia, ABCB4 and DCDC2 deficiencies, as well as
ALGS often present with elevated GGT levels. With the
increasing worldwide use of modern next generation se-
quencing, the roles for liver biopsy in the evaluation are
becoming less essential.1,2,24-26
CURRENT MANAGEMENT OF PEDIATRIC
CHOLESTASIS
Biliary atresia is a diagnosis made in the operating room
by a surgeon. Performance of a cholangiogram that does
not demonstrate a patent biliary tree will lead to resection
of the obstructed extrahepatic tree and replacement with
a Roux-en-Y loop of intestine, the KPE.27 General manage-
ment principles of neonatal cholestasis include attention to
choice of an medium-chain triglyceride-enriched formula,
increased kilocalories, along with fat-soluble vitamin supple-
mentation, because cholestatic infants can have profound
deficiencies of vitamins A, D, E, and K.28 There is a paucity of
effective anticholestatic therapeutics, but bile acid binding
resins and ursodeoxycholic acid are empirically employed
by many clinicians. More recently, attention to interfer-
ence with the enterohepatic circulation of bile acids or FXR
agonism29-31 may be direct anticholestatic approaches.10,32
Inhibition of ASBT has been recently used to address pru-
ritus.33 Precision gene variant-specific approaches with
chaperones and potentiators are exciting and potentially
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Pediatric Cholestasis Karpen
applicable for select ATP8B1, ABCB11, and ABCB4 missense
mutations.34-38 Finally, BASDs respond to administration of
the end product of bile acid synthesis: cholic acid.39
Taken together, there is hope and excitement to treat
cholestasis via current therapeutic approaches to reduce
bile acid–mediated toxicities (FXR agonism or ASBT in-
hibition) or direct posttranslational enhancements of
variant membrane transporter functions (chaperones or
potentiators).
CORRESPONDENCE
Saul J. Karpen, M.D., Ph.D., Raymond F. Schinazi Distinguished
Biomedical Chair, Professor of Pediatrics, Division Chief, Pediatric
Gastroenterology, Hepatology and Nutrition, Emory University School
of Medicine/Children’s Healthcare of Atlanta, 1760 Haygood Dr.,
HSRB E204, Atlanta, GA 30322. E-mail: skarpen@emory.edu
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