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    Cholestasis

    Danilo A. Encarnacion, M.D., FPSG

    October 8, 2013

    Group 1-N1nja St0nes

    Definition

    - Cholestasis is the failure of normal bile to

    reach the duodenum.*Bile secretion is a secretory function of the liver

    Syndrome of Cholestasis:

    Functional

    Morphological

    Clinical

    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:

    -bile acids

    -cysteinyl-leukotrienes.

    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).

    GENETIC CHOLESTASIS

    (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

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    For a first differentiation of various PFICsubtypes, measurement of the serum gamma-

    glutamyltransferase (gamma-GT) activity is

    useful.

    Diseases associated with a low bile saltconcentration in bile have a low serum

    gamma-GT activity.

    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

    these membranes.

    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

    first decade.

    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

    jaundiced

    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

    portal fibrosis.

    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

    by :

    immunoallergic or toxic mechanisms impaired transmembrane transport of

    cholephilic compounds destined for

    biliary secretion.

    *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

    frequently

    Altered fatty acid metabolism:

    Acute fatty liver of pregnancyVascular diseases affect the liver:

    Pre-eclampsia HELLP Syndrome

    Viral hepatitis:

    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

    normal pregnancy

    Biliary phospholipids secretion may be impaired

    (gene mutation, estrogen effect)

    Pregnancy is associated w/ decreases in GI

    motility, including gall bladder motility

    Physiological Consequences:

    The Liver in Pregnancy

    Pregnant women more likely to become

    jaundiced if cholestatic or hepatocellular injury

    occur

    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

    cirrhosis

    IHCP Therapy:

    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