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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 ( xanthomatous biliary
cirrhosis)
Etiology
Immunological disturbance Cytotoxic T-cells attack the biliary
epithelium
Mitochondrial antigens and antibodies
100 % of PBC M2 serum antigen specific for PBC
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ANA (antinuclear antibody) in 1/3 of cases Anti-M9 in early PBC; healthy relativesAssociation with infection
Mycobacterium gordonae Retroviral infection
Inconclusive observationsClinical Features
Presentation 99% are female 40-60 years old Insidious: pruritus without jaundice Jaundice: 6 months to 2 years within the
onset of pruritus
Clinical Features
Presentation RUQ discomfort is frequent as well as
fatigue
Well-nourished, sometimes pigmentedwoman
Liver is usually enlarged and firm and spleenis palpable
Symptomatic
Serum bilirubin is twice the normal Serum Alk. Phos. : 4x the normal SGPT: 2x the normal Serum albumin is normal Serum AMA 1:40 ERCP: normal hepatic ducts
Asymptomatic
Routine laboratory screen serum alk. Phos. (+) AMA Investigation of other disease,
especially collagen or thyroid
HepatomegalyCourse
Asymptomatic patients: 10 yearssurvival
Symptomatic : 7 years survival Weight loss is slow Diarrhea: steatorrhea The course is afebrile and abdominal
pain is unusual DU and hemorrhage is common Bleeding esophageal varices Hepatocellular carcinoma is rare.
Associated diseases:
Collagenoses (almost any autoimmunedisease)
Rheumatoid arthritis Dermatomyositis Mixed connective tissue disease SLE
Biochemical tests
Serum bilirubin : < 35ummol/l (2mg/100ml)
Alk. Phos. is raised Increased total cholesterol; serum
albumin is normal
Prognosis
Determinants Serum bilirubin
o >100ummol/l (6mg/dl) unlikely tosurvive > 2 years
Serum albumin
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Immunologic Infections
o Cryptosporidiosiso Immunodeficiency diseases
Clinical features
Males 2x than females Weight loss, fatigue, RUQ pain and
pruritus.
Pediatric diseaseo 2-13 yearso 50% with inflammatory bowel
disease
o Alk. Phos can be normal in 50%o Intra-hepatic disease
predominates.
Laboratory
Cholestasis with alk. Phos. 3x normal. SMA may be present.
ERCP
Diagnostic Areas of stricture and dilatation
(beading)
Cholangiocarcinoma
A complication in 10% Mean survival is only 6 months after
diagnosis
ERCP for diagnosisColorectal cancer
Seems to be low riskPrognosis
Mean survival is about 10-12 yearsTreatment
Endoscopic (stent application ) Transplantation No satisfactory treatment
*Overview of VIRAL HEPATITIS(refer to table at the
back)
I. Hepatitis A
Clinical Features
Incubation periodAverage 30 days
Range 15-50 days
Jaundice by age group:6-14 yrs : 40%-50%
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pruritus, fatigue, loose stools and weightloss
SGPT is less than 500 U/L Spontaneous recoveryRelapsing hepatitis
6% to 12% of cases Acute infection then remission (4-15weeks)
with subsequent relapse.
SGPT is normal during remission butincrease to more than 1000 U/L duringrelapse.
Pathogenesis is unknownExtrahepatic Manifestations
evanescent rash (14%)
arthralgias (11%)
Leucocytoclastic vasculitis, glomerulonephritis,
and arthritis, in which immune complex disease
is believed to play an etiologic role.
ComplicationsPost-hepatitis syndrome
prolonged malaise elevated serum SGPT persistence of IgM anti-HAV acute liver failure is rare
Prevention
General measures
Hygienic practices
Passive Immunoprophylaxis
1. Human immune globulin (IG)
85% to 95% for pre-exposure 1-2 weeks of exposure will prevent
or attenuate infection
beyond 2 weeks will be ineffective. 0.02mL/kg provides for 3
months and 0.05 mL/kg for 4 to
6 months.
Active Immunoprophylaxis
1. Live attenuated Vaccines
2. Inactivated Vaccine ( Havrix)
Highly immunogenic 90% to 98% seroconversion
after a single 25U dose and 100% seroconversion rate
after three doses.
3. Recombinant Polypetide Vaccines
II. Hepatitis B Virus (HBV)
Late 1960s : Australia antigen was discovered
by Blumberg and associates.
Envelope of the hepatitis B virus. Serves as the marker of the
virus differentiating it from
hepatitis A
Giving it a name hepatitis B(formerly known as serum
hepatitis)1970: Dane visualized the virus as a 42nm
particle ( Dane particle)
How Do You Acquire the Infection in the
Western region?
Transfusion and transplant recipients Individuals with multiple sexual
partners
Healthcareworkers Intravenous drug users Prisoners and other institutionalised
peopleHow Do You Acquire the Infection in the
Western region?
Newborns of long-term carriers
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Interpretation of hepatitis B virus serologic
markers
HBsAg HBV infection acute or
chronic
HBeAg High levels of HBV
replication and
infectivity
Anti-HBe Low levels of HBV
replication andinfectivity
HBV DNA Genetic material of the
hepatitis B virus
Anti-HbC (IgM) Recent HBV infection
Anti-HBc (IgG) Recovered or chronic
HBV infection
Anti-HBs Immunity to HBV
infection
Anti-HBc (IgG) + anti-
HBs
Past HBV infection
Anti-HBc (IgG) +HBsAg
Chronic HBV infection
Clinical Features
Incubation period:Average 60-90 days
Range 45-180 days
Clinical illness (jaundice)
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Prevention of Hepatitis B
HBV infection can be prevented in non-infected
individuals by vaccination with HBV vaccine.
However the millions of infected people will not
benefit
By 1998, 80 countries had introduced
vaccination programmes
Hepatitis B VaccinesEngerix-B Recombivax
Children 10g 2.5g
Adults 20g 10g
Each at 0, 1 and 6 monthsAASLD Practice Guideline Hepatitis B
Update in Recommendations for Treatment
o Series of 3 injections at 0, 1 and 6months
o Vaccination is effective in over 90% ofrecipients
III. Hepatitis C Virus
Clinical Features
Incubation period:
Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice):
30-40% (20-30%)
Chronic hepatitis:70%
Persistent infection: 85-100%
Immunity: No protective antibody response
identified
Hepatitis C Virus Infection
Typical Serologic Course
Prevention of Hepatitis C
Screening of blood, organ, tissue donors
High-risk behavior modification
Blood and body fluid precautions
Treatment of Viral Hepatitis
Hepatitis C
interferon 3 MU t.I.w. and Ribavirin 1 to1.2 gm/day for 12 months
No response (after 6 months) Sustained response:
40%
Interferon x 6 months
Side effects: hemolytic anemia ( 20% ) due toRibavirin
Miscellaneous causes of cholestasis
Bacterial infection
In childhood or post-operatively Hepato-cellular Endotoxin effect on Na+/K+-ATPase
Prolonged parenteral nutrition
Neonates especially Due to lithocholate formed by bacterial
7- -dehydroxylation of
chenodeoxycholic acid in the intestinal
tract.
Hodgkins disease
Biliary precipitation of insoluble solutes
Unconjugated bilirubin precipitateforming as intra-hepatic pigment stones
Protoporphyrins precipitates inerythrocytic protoporphyria
Intrahepatic atresia (infantile cholangiopathy)
Viral injury to intra-hepatic bile ducts
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Zellwegers syndrome Presents before 6 months of age with
progressive cholestasis and
hepatomegaly.
Mental retardation, characteristicfacies, hypotonia and renal cyst.
Defective hepatic peroxisomes Short survival
Primary biliary cirrhosisPrimary sclerosing cholangitis
Treatment
Medical
Surgical
o Medical management1. Pruritus
Routine : Cholestyramine
Variable effect: Anti-Histamine;UDCA;phenobarbitone
Careful use: Rifampicin Experimental: Naloxone; nalmefene;
ondansetron; S-adenosyl-L-methinine;
propofol
*Drugs for Pruritus
Cholestyramine Known to bind bile salts in the
intestines so eliminating them in the
feces
Unclear mechanism Nausea and vomiting; reluctance on the
part of the patient
Good for primary biliary cirrhosis,primary sclerosing cholangitis, biliary
atresia and bilary stricture.
UDCA Choleretic effect or by reducing toxic
bile salts
Only in primary biliary cirrhosis Anti-histamine
As sedatives Phenobarbitone
For resistant itching Naloxone
Opiate antagonist Not appropriate for long term use
Ondansetron (5HT3) Small placebo controlled trials
Propofol Hypnotic product Short-term benefit; give IV
S-adenosyl-L-methionine
Improves membrane fluidity Inconsistent effects
Rifampicin Inhibits bile acid uptake Potential side efects
Hepatotoxicity Emergence of resistant
organism
Formation of gallstone Steroids
Glucocorticoids will relieve itching butat the expense of severe bone thinning
particularly in postmenopausal women.
Bright light therapy 10,000 lux Based on circadian pattern of
cholestatic pruritus
Beneficial Ileal diversion
In children with intractable itching
Palsmapheresis Intractable pruritus with
hypercholesterolemia and
xanthomatous neuropathy
Effective but temporary and costly aswell as labour intensive
Hepatic transplantation Intractable itching
2. Nutrition
Acute cholestasis Vit K deficeincy
Vit K (10 mg) daily for 2-3days
Chronic cholestasis Vitamin A,D,K replaced as necessary
Potential bile salt deficiency Chronic cholestasis
Dietary fat (if steatorrhea)
reduce neutral fat(40 g daily) add medium chain triglycerides
(up to 40 g daily)
Fatsoluble vitamins
Oral K 10 mg/day
A 25000U/day
D 400-4000U/day
IV K 10 mg/month
IM A 100 000 U / 3-monthly
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Calcium
extra low fat milk
oral calcium
Bone changesPredominantly osteoporosis
Monitoring of serum 25-hydroxyvitaminD levels
Treatment with vitamin D 50 000 unitsorally 3x a week or 100 000 units IMmonthly.
Parenteral is more appropriate thanoral route.
Daily oral intake of elemental Ca; extraskimmed milk; exposure to sunlight;
encourage mobility
Avoid corticosteroidsTwo roads diverged in a wood, and I
I took the one less traveled by,
And that has made all the difference.
-Robert Frost
Authors/Editors: Boni & Janine
*Tatak SaGaD!
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GENETIC CHOLESTASIS-gin labayan lang ni ni Doc
Disease Chromosome Gene Phenotype Therapy
PFIC type 1
(Bylers Disease)
18q21 FIC 1 (ATP8B1) P-type ATPase,
acts as an aminophospholipid
translocator
First recurrent,
later permanent
cholestasis, bile
duct proliferation
is a late
phenomenon.Diarrhea,
pancreatitis,
pruritus, short
stature. Coarse
granular bile on
EM. Normal
gamma-GT
Ursodeoxycholic acid,
bile diversion, liver
transplantation
Benign recurrent
intrahepatic
cholestasis
18q21 FIC1 (ATP8B1) Recurrent
episodes of
cholestasis with
severe pruritus,
steatorrhea and
weight loss.
Normal gamma-GT
Cholestyramine and/or
rifampicine as
symptomatic
antipruritus therapy
PFIC type 2 2q24 BSEP (ABCB11), bile salt export
pump
Neonatal hepatitis,
progressive
cholestasis,
pruritus, short
stature, bile duct
proliferation is a
late phenomenon,
lobular and portal
fibrosis. BSEPprotein absent.
Amorphous bile on
EM. Normal
gamma-GT
Ursodeoxycholic acid
bile diversion, liver
transplantation
PFIC type 3 7q21 PGY3 (ABCB4, MDR 3), P-
glycoprotein 3
Cholestasis, portal
hypertension,
extensive bile duct
proliferation and
periportal fibrosis.
MDR3 is not
expressed.Elevated gamma-
GT
Ursodeoxycholic acid,
liver transplantation
Intrahepatic
cholestasis of
pregnancy
e.g. 7q21 e.g. MDR3 Cholestasis in third
trimester of
pregnancy. High
gamma-GT in case
of MDR3 defect;
low gamma-GT
cases may be
caused by genetic
Ursodeoxycholic acid
causes symptomatic
relief in the mother
and decreases fetal
loss
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defects of other
transporter
proteins. High
incidence of fetal
loss
Aagenaes syndrome 15q LCS1, LCS2 Episodic
cholestasis,
lymphedema,
normal gamma-GT
Liver transplantation
but persistence of
lymphedema
Familial
Hypercholanemia
9q12q13
9q22q32
TJP2/ZO-2 BAAT Elevated bile acids,
severe pruritus, fat
malabsorption,
failure to thrive,
rickets, vitamin K
coagulopathy
Liver transplantation
Bile acid synthesis
defects
e.g. 8q2.3 3-5-C27-hydroxysteroid
oxidoreductase; 4-3-
oxosteroid-5 reductase; 3-
hydroxy C27 steroid
dehydrogenase/isomerase;
oxysterol 7-hydroxylase;
24,25-dihydroxy-cholanoic
cleavage enzyme.
Intrahepatic
cholestasis,
neonatal giant cell
hepatitis. Normal
or elevated
gamma-GT, low or
elevated serum
total bile acids
Ursodeoxycholic acid,
chenodeoxycholic acid
or cholic acid alone or
in combination,
depending on subtype
Prototypic Cholestatic Hepatotoxins and Mechanisms Of Injury
Clinical Manifestation Causative Agents Mechanism of Injury
Cholestatic hepatitis Chlorpromazine Idiosyncrasy/hypersensitivity
Phenothiazines
Tricyclic antidepressants
Erythromycins
Clavulanic acid
NSAIDs
Bland cholestasis Estrogens Selective interference with bile excretory
mechanisms
Oral contraceptive steroids
17-alkylated androgenic
steroids
Cyclosporine A
Tamoxifen
Griseofulvin
Glibenclamide
Cholangiodestructive cholestasis Aniline-contaminated
rapeseed oil
Injury to bile ducts
-Naphthyl isothiocyanate
Paraquat
Floxuridine
Sporidesmin
Unconjugated hyperbilirubinemia/
hypercholanemia
Rifamycin SV / rifampicin Selective interference with sinusoidal uptake
Cholecystographic dyes
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Viral Hepatitis - Overview
A B C D E
Source of Virus Feces Blood/blood-
derived body
fluids
Blood/blood-
derived body
fluids
Blood/blood-
derived body
fluids
Feces
Route of
transmission
Fecal-oral Percutaneous
permucosal
Percutaneous
permucosal
Percutaneous
permucosal
Fecal-oral
Chronic infection No Yes Yes Yes No
Prevention Pre/post-exposure
immunization
Pre/post-exposure
immunization
Blood donorscreening; risk
behaviour
modification
Pre/post-exposure
immunization
Ensure safedrinking water
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