Chole Stasis Gr 1
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Transcript of Chole Stasis Gr 1
7/27/2019 Chole Stasis Gr 1
Danilo A. Encarnacion, M.D., FPSG
October 8, 2013
Group 1-N1nja St0nes
- Cholestasis is the failure of normal bile to
reach the duodenum.*Bile secretion is a secretory function of the liver
Syndrome of Cholestasis:
Functionally - decrease in canalicular bile flow:
Decreased hepatic secretion of water and organic
anions (bilirubin and bile acids).
Morphologically - accumulation of bile in liver cells
and biliary passages.
Clinically - retention in the blood of all substances
normally excreted in the bile:
Two basic types:
Obstructive (EXTRAHEPATIC CHOLESTASIS)
-mechanical blockage in the duct system such as
can occur from a gallstone or malignancy
Metabolic (INTRAHEPATIC CHOLESTASIS)
-disturbances in bile formation that can occur
because of genetic defects or acquired as a side
effect of many medications.
Bile Salt Physiology
Bile salts are the main organic solutes in bile
A number of genes are involved in bile salt
synthesis and transport
Disturbances of bile salt transport are important
causes of acquired and genetic forms of
cholestatic liver disease in humans.
Human hepatobiliary transport proteins are involved in bile
formation, secretion and reabsorption. Transporter proteins
located in the basolateral membrane are responsible for
hepatic uptake of bile salts (NTCP, OATPs), bulky organic
anions, uncharged compounds (OATPs) and cations (OATPs,
OCT1). Transporter proteins located in the canalicular
membrane are responsible for the biliary secretion of bile
salts, phosphatidylcholine, cholesterol and glutathione and
the excretion of drugs and toxins. These are the bile salt
export pump BSEP (ABCB11), the phosphatidylcholinetranslocator MDR3 (ABCB4), the multispecific organic anion
transporter MRP2 (ABCC2) and the multidrug transporter
MDR1 (ABCB1). The organic anion transporters MRP3
(ABCC3), MRP4 (ABCC4) and MRP1 (ABCC1) are present a
very low levels in normal human liver but their expression is
strongly increased during cholestasis. Both MRP3 and MRP4
are able to transport bile acid conjugates out of the
hepatocyte. FIC1 (ATP8B1) has been characterized as an
aminophospholipid translocase. In the terminal ileum, the
apical sodium-dependent bile acid transporter (ASBT) is
responsible for bile acid reabsorption. Genetic defects have
been described for FIC1 (PFIC type 1, BRIC), BSEP (PFIC type 2),
MDR3 (PFIC type 3, ICP), MRP2 (DubinJohnson syndrome
and ASBT (bile acid malabsorption).
(refer table at the back)
I. Progressive Familial Intra-hepatic Cholestasis (PFIC)
Autosomal recessive diseases Cholestasis in infancy
PFIC type 1 (Bylers disease) PFIC type 2 PFIC type 3
7/27/2019 Chole Stasis Gr 1
For a first differentiation of various PFICsubtypes, measurement of the serum gamma-
glutamyltransferase (gamma-GT) activity is
Diseases associated with a low bile saltconcentration in bile have a low serum
These diseases have anintrahepatocellular blockade of bile saltsecretion in common.
Gamma-GT in human liver is mainly located inthe membranes lining the biliary tree.
Elevation of serum gamma-GT results from adetergent, membranolytic effect of bile salts on
Thus an intra- or extrahepatic obstruction ofbile flow, or bile devoid of phosphatidylcholine
(as in PFIC type 3), causes gamma-GT to be
released in the circulation.
1. PFIC type 1 (Byler disease) Often begins with cholestatic episodes
progressing to permanent cholestasis
with fibrosis, cirrhosis and liver failure
in the first two decades of life.
Children affected : small for their age often have diarrhea occasionally pancreatitis. The larger bile ducts are anatomically
normal and liver histology shows bland
canalicular cholestasis without muchbile duct proliferation, inflammation,
fibrosis or cirrhosis.
The coarse granular bile in the canaliculi iscalled Byler bile.
Serum gamma-GT activity is not elevated Primary bile salt levels, in particular
chenodeoxycholic acid, are increased.
Serum cholesterol is usually normal. Liver transplantation maybe necessary in the
Defect in chromosome 18q21-q22
Patients belonging to the Byler kindred aredescendants of Jacob and Nancy Byler, who
emigrated in the late 18th century from
Germany to the United States. The PFIC
syndrome has also been described in families in
the Netherlands, Sweden, Greenland and an
Arab population .
2. PFIC type 2 As in PFIC type 1, the serum gamma-GT activity
in these patients is not elevated and bile duct
proliferation is absent.
Different from PFICType 1 as:The disease often starts as nonspecific
giant cell hepatitis, which is
indistinguishable from idiopathic
neonatal giant cell hepatitis;Patients are frequently or permanently
Rapidly progresses to persistent and
progressive cholestasis requiring liver
transplantation within the first decade.
The liver histology shows more
inflammation than in PFIC type 1, with
giant cell transformation, lobular and
Amorphous or filamentous bile in
contrasts with the coarsely granular bileof PFIC type 1 patients.
Extrahepatic manifestations are uncommon. Mutations in the BSEP3. PFIC type 3 Symptoms present somewhat later in life than
in PFIC types 1 and 2, and liver failure also
occurs at a later age.
Jaundice may be less apparent during the earlystages of disease.
The serum gamma-GT activity is usuallymarkedly elevated in these patients and the
liver histology shows extensive bile duct
proliferation, portal and periportal fibrosis.
Mutations in MDR3 gene (phospholipase) Bile salt enters the canaliculus and bile ducts
without protective phospholipid making them
toxic to the hepatocytes and cholangiocytes.
4. Benign Recurrent Intrahepatic Cholestasis(BRIC)
Also as Summerskil syndrome. Autosomal recessive No progression to chronic liver disease in a
majority of patients.
During the attacks: (self limiting) severely jaundiced Pruritus Steatorrhoea weight loss.
As in PFIC 1 the serum gamma-GT is notelevated.
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Some patients also have renal stones,pancreatitis and diabetes.
The gene involved in recurrent familialintrahepatic cholestasis has been mapped to
the FIC1 locus .
Ursodeoxycholic acid is of no benefit in BRIC . Case reports indicate that rifampicine may
reduce the number of cholestatic episodes.
II. DrugInduced Cholestasis
Drug-induced cholestatic liver injury can resultfrom direct damage to the hepatic parenchyma
immunoallergic or toxic mechanisms impaired transmembrane transport of
cholephilic compounds destined for
*Prototypic Cholestatic Hepatotoxins and Mechanisms
Of Injury (refer to table at the back)
III. Intrahepatic Cholestasis of Pregnancy
Liver Diseases in Pregnancy
High estrogen state:
Intrahepatic cholestasis of pregnancy Gallstones and sludge occur more
Altered fatty acid metabolism:
Acute fatty liver of pregnancyVascular diseases affect the liver:
Pre-eclampsia HELLP Syndrome
Vertical transmission of hepatitis B & CPathophysiology
Liver is an estrogen sensitive organ
Estrogen affects organic anion transport(bilirubin, bile acids)
Bilirubin excretion very mildly impaired during
Biliary phospholipids secretion may be impaired
(gene mutation, estrogen effect)
Pregnancy is associated w/ decreases in GI
motility, including gall bladder motility
The Liver in Pregnancy
Pregnant women more likely to become
jaundiced if cholestatic or hepatocellular injury
Spider angiomata and palmar erythema develop
in up to 2/3 pregnancies due to effects of
estrogen and progesterone
Cholecystectomy generally safe3rd Trimester see increased alk phos 2/2
developing placenta (not liver)
Intrahepatic Cholestasis of Pregnancy (IHCP)
Incidence 0.1% - 1% of pregnancies
Recurrence in subsequent pregnancies
Pruritis develops in late 2nd and 3rd trimester
High transaminases - 40% > 10 x (Hay)
Bilirubin < 5mg/dL
Total bile acids increase 100 fold
ICHP Clinical Features:
Pruritis is the defining characteristic
About 50% develop jaundice
Disappears rapidly after delivery
Severity is variable
Rarely see a familial, progressive course to
Ursodeoxycholic acid 10mg- 10mg/Kg/day
CholestyramineVitamin K p.r.n.
Reassurance and support
Consider early delivery in severe cases
Unbearable maternal pruritis or risk offetal distress/death
Deliver at 38 weeks if mild, at 36 weeksfor severe cases if jaundice
IV. Primary Biliary Cirrhosis
A disease of unknown cause
Progressive destruction of intra-hepatic ducts Associated elevation of cholesterol and
skin xanthomas ( xan