Chole Stasis Gr 1

7/27/2019 Chole Stasis Gr 1

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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


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


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

Documents

Chole Stasis Gr 1