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BRIEF ARTICLE
REVIEW
INTRODUCTION
Abstract
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary
cirrhosis are the most commonly recognized cholestatic
liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized
in the pediatric population. In infants, the causes are
usually congenital or inherited. Even though jaundice is
a hallmark of cholestasis, it is not always seen in adult
patients with chronic liver disease. Patients can have
silent progressive cholestatic liver disease for years
prior to development of symptoms such as jaundice
and pruritus. In this review, we will discuss some of the
atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary
atresia, total parenteral nutrition induced cholestasis
and cholestasis secondary to drug induced liver injury.
2014 Baishideng Publishing Group Inc. All rights reserved.
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ALAGILLE SYNDROME
Alagille syndrome (ALGS), also known as Alagille-Watson syndrome or arteriohepatic dysplasia, is an autosomal-dominant disorder with variable penetrance. ALGS
may involve five body areas (liver, heart, skeleton, face,
and eye). The involvement of these areas is the basis for
the Classic Criteria described by Alagille to establish
the diagnosis[13] (Table 1). Other findings include vascular
malformations, vascular accidents, and renal structural
problems. The severity of the disease is determined primarily by the degree of the liver and cardiac involvement.
The etiology in approximately 97% of cases is due
to mutations in the JAG1 gene[14,15] while the remainder
is due to mutations in the NOTCH2 gene[16]. Both genes
are involved in the highly conserved Notch signally pathway. A diagnosis is made if the Classic Criteria is met (bile
duct paucity with at least three of five clinical features) or
by genetic testing of JAG1 and NOTCH2 if only some
features of ALGS are present[17]. Accurate diagnosis continues to be challenging because some clinical features
are not specific to ALGS and overlap with other genetic
disorders and syndromes.
Patients usually present at birth or within the first
three months of life with jaundice, alkaline phosphatase
elevation, and conjugated hyperbilirubinemia, due to bile
duct paucity as seen on liver biopsy. Bile duct obliteration
is progressive and increases with age. It eventually results
in cirrhosis and liver failure. The most common congenital heart disease seen in ALGS is peripheral pulmonary
stenosis[18,19]. Other abnormalities include atrial septal
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Disorder
Description
Cholestasis
Congenital heart disease
Vertebral abnormalities
Dysmorphic facies
BILIARY ATRESIA
SEPSIS
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TPN-INDUCED CHOLESTASIS
Total parenteral nutrition (TPN) is commonly administered in patients with intestinal failure, intolerance to enteral nutrition, or inadequate enteral intake. Mild elevation
in liver transaminases and ALP commonly occurs after
initiation of TPN, but is of little clinical consequence if
it remains stable. TPN-induced cholestasis occurs when
serum conjugated bilirubin rises to greater than 2 mg/dL.
It may be associated with rises in serum ALP, GGT, and
transaminases[43]. If unrecognized and untreated, it can
progress towards cirrhosis and liver failure. The pathophysiology of TPN-induced cholestasis is multifactorial
and complex. It can be divided into three categories: (1)
due to lack of enteral nutrition; (2) due to direct toxicity
of TPN components and from overfeeding; and (3) due
to the underlying disorders requiring the use of TPN[43].
Lack of enteral nutrition contributes to cholestasis
by multiple processes. There is a decrease of cholecystokinin release which slows gallbladder emptying and
subsequently results in gallbladder stasis, sludging, stone
formation, and promotes cholestasis. Lack of enteral
nutrition also decreases gastrointestinal motility, dampens
gut immunity, and increases intestinal permeability due
impaired mucosal healing. All of these changes contribute to bacterial overgrowth and translocation, resulting
in increased endotoxin within the portal circulation. The
increase in portal endotoxin eventually leads to a decrease
in bile flow and cholestasis[35,44].
The components of TPN itself, especially when
given in excess, may cause cholestasis. Infusion of lipids at greater than 1 g/kg per day may exceed the liver
s capacity to clear the lipid particles, resulting in steatosis
and cholestasis[45,46]. High rate of glucose infusion causes
elevation in insulin level, which activates fatty acid synthesis and inhibits fatty acid breakdown. Once the livers
capacity to transport the fatty acids through lipoproteins
production is overwhelmed, fatty acids will accumulate
within the hepatocytes, resulting in steatosis and cholestasis[47]. This is particularly true when TPN is administered
continuously without periods of fasting and in states of
insulin resistance. Trace elements such as copper and
manganese have also been implicated in causing cholestasis[48].
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INTRAHEPATIC CHOLESTASIS OF
PREGNANCY
Intrahepatic cholestasis of pregnancy (ICP) is a reversible
form of cholestasis, which occurs in the second or third
trimester of pregnancy and is characterized by symptoms
of pruritus, elevation in fasting serum bile acid levels, and
spontaneous relief of signs and symptoms within 4-6 wk
after delivery[53,54]. The incidence of ICP ranges from 0.1%
to 15.6%[55]. Geographic variations in incidence rates have
been noted, reflecting greater susceptibility in certain
regions of the world such as Bolivia, Chile and the Scandinavian countries[56,57].
The pathogenesis of ICP is multifactorial and includes genetic, hormonal and environmental factors.
Studies have demonstrated mutations in the ABCB4
gene leading to abnormalities in the MDR3 protein in
approximately 16% of patients with ICP[58-62]. Such mutations lead to dysfunction of bile transport across the
canaliculus. Hormonal factors also play a role. There is a
greater incidence of ICP in twin pregnancies where peak
estrogen levels are higher than in singleton pregnancies.
ICP also occurs most commonly in the third trimester
when serum concentrations of estrogen are highest. In
addition, high-dose of oral contraceptives and progesterone can trigger ICP[53]. We recommend that progesterone
treatment be avoided in pregnant women with a prior history of ICP and discontinued in patients with cholestasis
occurring during pregnancy. For reasons that are unclear,
ICP occurs more commonly in the colder months in
Chile and Scandinavia, indicating that undefined environmental factors may also contribute to the occurrence of
ICP[57].
The primary presenting symptom of ICP is intense
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Antimicrobials
CNS Agents
Anti-inflammatory/
Immunologics
Endocrine
Statins
Anesthetics
Cardiovascular
Others
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cholestasis with hepatitis (with parenchymal inflammation), and cholestasis with bile duct injury and inflammation. Chronic drug-induced cholestasis may vary from
asymptomatic with mild ductopenia noted on liver biopsy
to progressive inflammation, fibrosis, loss of interlobular
bile ducts, and eventually permanent cholestasis, resulting in a disorder known as the vanishing bile duct syndrome. Cholestasis may also involve the large extrahepatic biliary tract producing a pattern similar to PSC in
rare occasions.
The pathophysiology of DILI is poorly understood.
Few medications, such as acetaminophen or valproic acid,
produce hepatoxicity through a predictable dose-dependent mechanism. The mechanism in the majority of cases
is rather due to idiosyncratic drug reactions unrelated to
the dose or the mechanism of action of the drug[76]. In
some cases there may be a component of immunoallergic
drug reactions contributing to DILI as illustrated by the
presence of fever, rash, and eosinophilia[85]. There is evidence of genetic predisposition given that certain HLA
haptotypes are more susceptible to DILI associated with
flucloxacillin and amoxicillin-clavulanate[86,87].
In the majority of cases of DILI, complete recovery
should occur upon discontinuation of the suspected
medication or herbal product. Jaundice is one of the
strongest prognostic factors and is associated with a
higher rate of mortality/liver transplantation, also known
as Hys Law[88]. The rate of mortality/liver transplantation is about 9%-12% based on three large series from
the United States, Spain, and Sweden[77,80,89]. Prognosis is
better for cholestatic compared to hepatocellular DILI,
based on the data from Spain and Sweden but the opposite was found in results from the United States.
A list of medications commonly associated with intrahepatic cholestasis is listed in Table 2. A searchable
database of hepatotoxic drugs and herbal products is
available online from the National Institute of Health:
http://www.livertox.nih.gov.
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