Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver...

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Cholestatic Liver Cholestatic Liver Disease Disease - PBC and PSC - PBC and PSC

Transcript of Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver...

Page 1: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Cholestatic Liver DiseaseCholestatic Liver Disease- PBC and PSC- PBC and PSC

Page 2: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 3: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Cholestasis: DefinitionCholestasis: Definition

Cholestasis implies that the liver is not producing or Cholestasis implies that the liver is not producing or secreting bile normallysecreting bile normallyBiochemically:Biochemically:– Elevated alkaline phosphatase, conjugated bilirubin or bothElevated alkaline phosphatase, conjugated bilirubin or both

Signs/symptoms:Signs/symptoms:– PruritusPruritus– JaundiceJaundice

Histologically Histologically – Bile lakesBile lakes– Cholate stasisCholate stasis– Ductular proliferationDuctular proliferation

Page 4: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 5: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 6: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 7: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Cholestasis: DefinitionCholestasis: Definition

Cholestasis can be divided into 2 basic Cholestasis can be divided into 2 basic categories:categories:

- Extrahepatic Obstructive JaundiceExtrahepatic Obstructive Jaundice

- Intrahepatic CholestasisIntrahepatic Cholestasis

Page 8: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Extrahepatic Obstructive Extrahepatic Obstructive CholestasisCholestasis

Extrahepatic obstruction of the bile ducts Extrahepatic obstruction of the bile ducts results in upstream ductal dilationresults in upstream ductal dilation– Seen on imaging Seen on imaging

The primary considerations are: The primary considerations are: – pancreatic cancer pancreatic cancer – cholangiocarcinomacholangiocarcinoma– choledocholithiasischoledocholithiasis– benign papillary stenosisbenign papillary stenosis

Page 9: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Intrahepatic CholestasisIntrahepatic Cholestasis

Direct effect on cannalicular membrane of Direct effect on cannalicular membrane of the hepatocyte by:the hepatocyte by:– Toxins, metabolitesToxins, metabolites– Drugs, alcoholDrugs, alcohol– Interleukins, tumor necrosis factorInterleukins, tumor necrosis factor

ALP (a hepatocellular enzyme) ALP (a hepatocellular enzyme) translocates to the basolateral membrane translocates to the basolateral membrane and is lost to serumand is lost to serum

Page 10: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Intrahepatic Cholestasis: Intrahepatic Cholestasis: EtiologiesEtiologies

– DrugsDrugsOCPs, anabolic steroids, NSAIDs, antibiotics (e-mycin), OCPs, anabolic steroids, NSAIDs, antibiotics (e-mycin), antipsychoticsantipsychotics

– Infiltrative disordersInfiltrative disordersLymphoma, amyloidosis, tuberculosis, sarcoidosis, Lymphoma, amyloidosis, tuberculosis, sarcoidosis, metastasesmetastases

– TPNTPN– SepsisSepsis– Pregnancy Pregnancy – Autoimmune (PBC/PSC, AIH overlap syndrome)Autoimmune (PBC/PSC, AIH overlap syndrome)– Inherited (benign recurrent intrahepatic cholestasis)Inherited (benign recurrent intrahepatic cholestasis)– Post-operativePost-operative– Paraneoplastic (Stauffer’s syndrome)Paraneoplastic (Stauffer’s syndrome)

Page 11: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 12: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 13: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Alkaline PhosphataseAlkaline Phosphatase

ALP is a protein located on the ALP is a protein located on the cannalicular membrane of the hepatocyte cannalicular membrane of the hepatocyte – NOT the bile duct cell– NOT the bile duct cellWidespread tissue distribution: Widespread tissue distribution: – LiverLiver– BoneBone– IntestineIntestine– KidneyKidney– placentaplacenta

Page 14: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Alkaline PhosphataseAlkaline Phosphatase

In In biliary obstructionbiliary obstruction, increased synthesis and , increased synthesis and release of the enzyme into the serum rather than release of the enzyme into the serum rather than impaired biliary secretion accounts for the impaired biliary secretion accounts for the elevation of ALPelevation of ALPIn In cholestasischolestasis, bile acids accumulate in the , bile acids accumulate in the hepatocytes and solubilize the plasma hepatocytes and solubilize the plasma membrane resulting in release of ALP into membrane resulting in release of ALP into serumserumThe level not a reliable indicator of the severity The level not a reliable indicator of the severity of underlying liver diseaseof underlying liver disease

Page 15: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Alkaline Phosphatase:Alkaline Phosphatase:Confirming Liver SourceConfirming Liver Source

Gamma-glutamyl transferase (GGT)Gamma-glutamyl transferase (GGT)– Can be isolated from hepatocytes and various Can be isolated from hepatocytes and various

extrahepatic tissues but NOT boneextrahepatic tissues but NOT bone

5’ Nucleotidase5’ Nucleotidase– Elevated 5NT is rarely associated with Elevated 5NT is rarely associated with

associated with an extrahepatic sourceassociated with an extrahepatic source

FractionateFractionate the alkaline phosphatase the alkaline phosphataseAny elevation in a transaminase is very Any elevation in a transaminase is very specific for liver origin of ALPspecific for liver origin of ALP

Page 16: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 17: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Obstructive Obstructive JaundiceJaundice

Intrahepatic Intrahepatic CholestasisCholestasis

Alkaline PhosAlkaline Phos ElevatedElevated ElevatedElevated

BilirubinBilirubin ElevatedElevated +/-+/-

Large bile ductsLarge bile ducts DilatedDilated NormalNormal

Small bile ductsSmall bile ducts ProliferationProliferation Normal-Normal-abnormalabnormal

HistologyHistology Bile lakesBile lakes Cholate stasisCholate stasis

Page 18: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:OverviewOverview

DefinitionDefinitionEpidemiologyEpidemiologyPathogenesisPathogenesisNatural historyNatural historyClinical featuresClinical featuresDiagnosisDiagnosisPathologyPathologyManagementManagementComplicationsComplicationsTransplantationTransplantation

Page 19: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:DefinitionDefinition

Chronic cholestatic liver diseaseChronic cholestatic liver disease

Hallmark serologic signature – the Hallmark serologic signature – the antimitochondrial antibody (AMA)antimitochondrial antibody (AMA)

Chronic, non-suppurative destructive Chronic, non-suppurative destructive cholangitis on histologycholangitis on histology

Page 20: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis: EpidemiologyEpidemiology

WorldwideWorldwide

Predominantly women (9:1)Predominantly women (9:1)

Diagnosed typically between ages 30-60Diagnosed typically between ages 30-60

In the United States:In the United States:– Age adjusted incidence rate is 27/million Age adjusted incidence rate is 27/million

person-yearsperson-years– Age adjusted prevalence is 402/millionAge adjusted prevalence is 402/million

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Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:PathogenesisPathogenesis

Cause is unknownCause is unknown

Considered an autoimmune disorderConsidered an autoimmune disorder– Intense humoral and cellular response to an Intense humoral and cellular response to an

intracytoplasmic antigenintracytoplasmic antigen– Presence of highly specific autoantibodiesPresence of highly specific autoantibodies– Involvement of T lymphocytes in the Involvement of T lymphocytes in the

destruction of bile ductsdestruction of bile ducts– Often coexists with other autoimmune Often coexists with other autoimmune

disordersdisorders

Page 22: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Proposed Mechanisms for the Proposed Mechanisms for the development of PBCdevelopment of PBC

Molecular mimicryMolecular mimicry(Microorganism infection)(Microorganism infection)

XenobioticsXenobiotics

GeneticGenetic

Page 23: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History

Springer et al. Am J Gastro 1999

Page 24: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History

Springer et al. Am J Gastro 1999

Page 25: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History

In general, slowly progressive disorderIn general, slowly progressive disorder

Consists of two phases:Consists of two phases:– Asymptomatic: Asymptomatic:

Lasting mean of 17 yearsLasting mean of 17 years

No liver related mortality during this timeNo liver related mortality during this time

– Symptomatic:Symptomatic:Characterized by the onset of symptomsCharacterized by the onset of symptoms

Average time from symptom onset to death is 7 Average time from symptom onset to death is 7 yearsyears

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Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History

Predicting Survival – Predicting Survival – The Mayo Risk ScoreThe Mayo Risk Score

In general, if bilirubin In general, if bilirubin is > 10 there is a 50% is > 10 there is a 50% survival at 2 yearssurvival at 2 years

Page 27: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Clinical Features at PresentationClinical Features at PresentationAsymptomaticAsymptomatic 40-60%40-60%

FatigueFatigue 21-85%21-85%

PruritusPruritus 19-55%19-55%

Sicca symptomsSicca symptoms up to 70%up to 70%

HepatomegalyHepatomegaly 25%25%

SplenomegalySplenomegaly 15%15%

JaundiceJaundice uncommonuncommon

XanthelasmaXanthelasma uncommonuncommon

Page 28: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Other Associated ConditionsOther Associated Conditions

Metabolic bone diseaseMetabolic bone disease

Fat soluble vitamin deficienciesFat soluble vitamin deficiencies

HypercholesterolemiaHypercholesterolemia

Autoimmune thyroiditisAutoimmune thyroiditis

CREST/Raynaud’sCREST/Raynaud’s

Renal tubular acidosisRenal tubular acidosis

Celiac sprueCeliac sprue

Page 29: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:DiagnosisDiagnosis

Elevated alkaline phosphataseElevated alkaline phosphatase– Typically 3-4 X ULNTypically 3-4 X ULN– ALT/AST usually < 200ALT/AST usually < 200

Unremarkable biliary imagingUnremarkable biliary imaging

Elevated immunoglobulinsElevated immunoglobulins– Typically IgMTypically IgM

Characteristic autoantibody (AMA)Characteristic autoantibody (AMA)

Characteristic histologyCharacteristic histology

Page 30: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:DiagnosisDiagnosis

Autoantibodies:Autoantibodies:Antimitochondrial Antibodies (AMA)Antimitochondrial Antibodies (AMA)– Present in 95% of patient with PBCPresent in 95% of patient with PBC– Sensitivity and specificity are > 95%Sensitivity and specificity are > 95%– Usually present in high titerUsually present in high titer

Antinuclear/Smooth Muscle Antibodies Antinuclear/Smooth Muscle Antibodies (ANA/ASMA)(ANA/ASMA)– Not specificNot specific– Seen in 1/3 to ½ of individuals with PBCSeen in 1/3 to ½ of individuals with PBC

Page 31: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Liver BiopsyLiver Biopsy

Staging: Ludwig’s or Scheuer’s ClassificationStaging: Ludwig’s or Scheuer’s ClassificationStage 1Stage 1 portal inflammation/florid duct portal inflammation/florid duct

lesionlesionStage 2Stage 2 periportal inflammaton periportal inflammaton

(interface hepatitis), ductular (interface hepatitis), ductular proliferationproliferation

Stage 3Stage 3 bridging fibrosis, ductopeniabridging fibrosis, ductopeniaStage 4Stage 4 cirrhosiscirrhosis

Page 32: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis – Primary Biliary Cirrhosis – Histological FeaturesHistological FeaturesPrimary Biliary Cirrhosis – Primary Biliary Cirrhosis – Histological FeaturesHistological Features

Stage Stage 11Stage Stage 11

Stage Stage 22Stage Stage 22

Stage Stage 33Stage Stage 33

Stage Stage 44Stage Stage 44

Histological Staging – PBCHistological Staging – PBC

Page 33: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary Cirrhosis

Portal hepatitisPortal hepatitisPortal hepatitisPortal hepatitis

Stage 1: Florid Duct Lesion Stage 1: Florid Duct Lesion Stage 1: Florid Duct Lesion Stage 1: Florid Duct Lesion

GranulomGranulomaaGranulomGranulomaa

Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

Histological Staging – PBC – Stage 1Histological Staging – PBC – Stage 1

Page 34: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 35: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary CirrhosisStage 2: Ductular Stage 2: Ductular ReactionReaction

Stage 2: Ductular Stage 2: Ductular ReactionReaction

Periportal Periportal HepatitisHepatitisPeriportal Periportal HepatitisHepatitis

Histological Staging – PBC – Stage 2Histological Staging – PBC – Stage 2

Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

Page 36: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 37: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary Cirrhosis

Stage 3: ScarringStage 3: ScarringStage 3: ScarringStage 3: Scarring

Bridging Bridging Necrosis/ Necrosis/

Septal FibrosisSeptal Fibrosis

Bridging Bridging Necrosis/ Necrosis/

Septal FibrosisSeptal Fibrosis

Histological Staging – PBC – Stage 3Histological Staging – PBC – Stage 3

Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

Page 38: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 39: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary CirrhosisPrimary Biliary Cirrhosis

Stage 4: CirrhosisStage 4: CirrhosisStage 4: CirrhosisStage 4: Cirrhosis

CirrhosisCirrhosisCirrhosisCirrhosis

Histological Staging – PBC – Stage 4Histological Staging – PBC – Stage 4

Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103Scheuer P, Proc R Soc Med 1967; 60:1257Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

Page 40: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 41: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

Page 42: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

Page 43: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TreatmentTreatment

UDCA in a dose of 13-15 mg/kg/day is the UDCA in a dose of 13-15 mg/kg/day is the only FDA approved therapy for PBConly FDA approved therapy for PBC

Dose is importantDose is important

Number of studies have demonstrated a Number of studies have demonstrated a clear benefitclear benefit

Used in all stages of PBCUsed in all stages of PBC

Page 44: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Actions of UDCAActions of UDCA

Protects against cytotoxic effects of di-Protects against cytotoxic effects of di-hydroxy bile acidshydroxy bile acids

Modulates expression of HLAModulates expression of HLA

Stabilizes bile canalicular membraneStabilizes bile canalicular membrane

Choleretic effectCholeretic effect

Decreased apoptosisDecreased apoptosis

Decreased cytokine productionDecreased cytokine production

Page 45: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Poupon et al. NEJM 1994

Page 46: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Poupon et al. NEJM 1994

Page 47: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Pares et al. Gastro 2006

Responder Nonresponder

Page 48: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:ManagementManagement

Liver chemistries every 3-6 monthsLiver chemistries every 3-6 monthsThyroid study (TSH) annuallyThyroid study (TSH) annuallyBone mineral density scan (DEXA) every Bone mineral density scan (DEXA) every 2-4 years2-4 yearsFat soluble vitamin levels if bilirubin > 2Fat soluble vitamin levels if bilirubin > 2Upper endoscopy if cirrhotic or Mayo risk Upper endoscopy if cirrhotic or Mayo risk score > 4.1score > 4.1Ultrasound +/- AFP every 6-12 months if Ultrasound +/- AFP every 6-12 months if cirrhoticcirrhotic

Page 49: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:ManagementManagement

Fatigue:Fatigue:– Modafanil 100-200mg/dModafanil 100-200mg/d

Pruritus:Pruritus:– Cholestyramine up to 4g qidCholestyramine up to 4g qid– Rifampicin 150mg/dRifampicin 150mg/d– Naltrexone 12.5 mg/d (up to 50mg/d)Naltrexone 12.5 mg/d (up to 50mg/d)

Sicca:Sicca:– Artificial tears, saliva substitutesArtificial tears, saliva substitutes– Good dental hygieneGood dental hygiene– Pilocarpine or cevimelinePilocarpine or cevimeline

Osteopenia/Osteoporosis:Osteopenia/Osteoporosis:– 1000-1500mg/d calcium + 1000 IU Vit D1000-1500mg/d calcium + 1000 IU Vit D– BisphosphanatesBisphosphanates

Hyperlipidemia:Hyperlipidemia:– No treatment, no increased risk of cardiovascular diseaseNo treatment, no increased risk of cardiovascular disease

Page 50: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TransplantationTransplantation

PBC was the leading indication for OLT in PBC was the leading indication for OLT in the U.S. in the mid 1980sthe U.S. in the mid 1980s

Despite increased numbers of transplants, Despite increased numbers of transplants, patients with PBC requiring OLT have patients with PBC requiring OLT have decreased by 20%decreased by 20%

Outcome of OLT in PBC is more favorable Outcome of OLT in PBC is more favorable than almost all other liver diseasesthan almost all other liver diseases

Once listed, priority is based on MELDOnce listed, priority is based on MELD

Page 51: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:OverviewOverview

DefinitionDefinitionEpidemiologyEpidemiologyPathogenesisPathogenesisNatural historyNatural historyClinical featuresClinical featuresDiagnosisDiagnosisPathologyPathologyComplicationsComplicationsManagementManagementTransplantationTransplantation

Page 52: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:DefinitionDefinition

Chronic cholestatic liver diseaseChronic cholestatic liver disease

Frequently associated with Inflammatory Frequently associated with Inflammatory Bowel DiseaseBowel Disease

Unknown etiologyUnknown etiology

Diffuse inflammation and fibrosis of the Diffuse inflammation and fibrosis of the biliary treebiliary tree

Leads to biliary cirrhosis and portal Leads to biliary cirrhosis and portal hypertensionhypertension

Page 53: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:EpidemiologyEpidemiology

First described in 1927First described in 1927

By 1980, only 100 cases reported in the By 1980, only 100 cases reported in the English literatureEnglish literature

Estimated prevalence of PSC is 6 to 8 Estimated prevalence of PSC is 6 to 8 cases per 100,000 personscases per 100,000 persons

Diagnosis is made in the third and fourth Diagnosis is made in the third and fourth decades of lifedecades of life

Male predominance (3:1)Male predominance (3:1)

Page 54: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Inflammatory Bowel DiseaseInflammatory Bowel Disease

Strong association with IBDStrong association with IBD– Prevalence of IBD in PSC is 60-80%Prevalence of IBD in PSC is 60-80%

– Usually ulcerative colitis (up to 86%)Usually ulcerative colitis (up to 86%)Crohn’s disease (colitis) – 13%Crohn’s disease (colitis) – 13%

– Prevalance of PSC in IBD is 2.5-7.5%Prevalance of PSC in IBD is 2.5-7.5%

Page 55: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Inflammatory Bowel DiseaseInflammatory Bowel Disease

Unique featuresUnique features::

““pan” colitispan” colitis

More quiescent courseMore quiescent course

Rectal sparingRectal sparing

Backwash ileitisBackwash ileitis

Increased risk of colorectal cancerIncreased risk of colorectal cancer

Increased risk of pouchitis (undergoing IPAA)Increased risk of pouchitis (undergoing IPAA)

Inreased risk of peristomal varices (ileostomy)Inreased risk of peristomal varices (ileostomy)

Page 56: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:PathogenesisPathogenesis

Larusso et al. Hepatology 2006

Page 57: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Natural HistoryNatural History

Larusso et al. Hepatology 2006

Page 58: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Natural HistoryNatural History

Broome et al. Gut 1992

Page 59: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Clinical Features at PresentationClinical Features at Presentation

AsymptomaticAsymptomatic 15 - 44%15 - 44%SymptomaticSymptomatic

FatigueFatigue 7575PruritusPruritus 7070JaundiceJaundice 30-6930-69Hepatomegaly Hepatomegaly 34-6234-62Abdominal painAbdominal pain 16-3716-37Weight lossWeight loss 10-3410-34SplenomegalySplenomegaly 3030Ascending cholangitisAscending cholangitis 5-285-28HyperpigmentationHyperpigmentation 2525Variceal bleedingVariceal bleeding 2-142-14AscitesAscites 2-102-10

Page 60: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:DiagnosisDiagnosis

Cholestatic liver chemistriesCholestatic liver chemistries– Transaminases elevated (2-3XULN)Transaminases elevated (2-3XULN)

IgG may be modestly elevated IgG may be modestly elevated

Various autoantibodies positive in majorityVarious autoantibodies positive in majority

Radiography (cholangiography) is Radiography (cholangiography) is diagnosticdiagnostic

Histology not necessary and often not Histology not necessary and often not helpfulhelpful

Page 61: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:DiagnosisDiagnosis

Autoantibodies:Autoantibodies:

p-ANCAp-ANCA 50-80%50-80%

ANAANA 7-77%7-77%

ASMAASMA 13-20%13-20%

AMAAMA <2%<2%

– Not specific and have no role in the routine Not specific and have no role in the routine diagnosis of PSCdiagnosis of PSC

Page 62: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:DiagnosisDiagnosis

Cholangiography:Cholangiography:Diagnostic (both ERC and MRC)Diagnostic (both ERC and MRC)MR preferred MR preferred – sens >80% and spec >87%sens >80% and spec >87%

Multifocal stricturing, “beaded” pattern of Multifocal stricturing, “beaded” pattern of the biliary treethe biliary treeBoth intra- and extrahepatic ducts involvedBoth intra- and extrahepatic ducts involved– <25% intrahepatic only<25% intrahepatic only– <5% extrahepatic only<5% extrahepatic only

Page 63: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 64: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 65: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:
Page 66: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:DiagnosisDiagnosis

Liver Biopsy:Liver Biopsy:

Not necessaryNot necessary

Useful in “small duct” Useful in “small duct” PSCPSC

Characterized by Characterized by periductal concentric periductal concentric “onion-skin” fibrosis“onion-skin” fibrosis

Page 67: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

General:General:

Metabolic bone diseaseMetabolic bone disease

PruritisPruritis

Unique:Unique:

CholangitisCholangitis

Gallbladder diseaseGallbladder disease

CholangiocarcinomaCholangiocarcinoma

Page 68: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

Bacterial Cholangitis:Bacterial Cholangitis:

Recurrent cholangitis can be an indication for Recurrent cholangitis can be an indication for OLT with a MELD exceptionOLT with a MELD exception

Inreased complication rate with ERCP in PSC Inreased complication rate with ERCP in PSC (7-20%) (7-20%) – Try to avoid in most casesTry to avoid in most cases

ERC is indicated in symptomatic dominant ERC is indicated in symptomatic dominant stricturesstrictures– Worsening chemistries, jaundice, pruritis, cholangitisWorsening chemistries, jaundice, pruritis, cholangitis

Page 69: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

Cholangiocarcinoma:Cholangiocarcinoma:

Dreaded complicationDreaded complication

10 year cumulative incidence of 7-9%10 year cumulative incidence of 7-9%

Found in 42% of patients at autopsyFound in 42% of patients at autopsy

12-15% of patients who undergo OLT12-15% of patients who undergo OLT

50% of the time CCA is diagnosed 50% of the time CCA is diagnosed concomitantly with PSC or within 1 year of concomitantly with PSC or within 1 year of diagnosis of PSCdiagnosis of PSC

Page 70: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

Cholangiocarcinoma:Cholangiocarcinoma:Making the diagnosis is difficultMaking the diagnosis is difficult– Can’t distinguish early CCA from dominant strictureCan’t distinguish early CCA from dominant stricture

U/S, CT, MR have PPV of 38-48%U/S, CT, MR have PPV of 38-48%ERC has a PPV of 23%ERC has a PPV of 23%ERC w/brush cytology has a sensitivity of 18-ERC w/brush cytology has a sensitivity of 18-40%40%Tumor markers:Tumor markers:– CA 19-9 using a cut-off of 130 U/mL (sens 79% and CA 19-9 using a cut-off of 130 U/mL (sens 79% and

spec 98%)spec 98%)

Page 71: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

Cholangiocarcinoma:Cholangiocarcinoma:

Dismal prognosisDismal prognosis

Median survival of 5 to 11 monthsMedian survival of 5 to 11 months

No established medical therapyNo established medical therapy

? OLT? OLT

Page 72: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications

Gallbladder Disease:Gallbladder Disease:

PSC patients are predisposed to gallstone PSC patients are predisposed to gallstone diseasedisease

Recent reports of high incidence low and Recent reports of high incidence low and high grade dysplasia as well as carcinomahigh grade dysplasia as well as carcinoma

Any PSC patient with GB mass lesion Any PSC patient with GB mass lesion detected on imaging (regardless of size) detected on imaging (regardless of size) should have cholecystectomyshould have cholecystectomy

Page 73: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

Page 74: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

Page 75: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

UDCAUDCA

Page 76: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

CorticosteroidsCorticosteroids

ColchicineColchicine

AzathioprineAzathioprine

CyclosporineCyclosporine

MethotrexateMethotrexate

UDCAUDCA

Page 77: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

UDCA:UDCA:Early small pilot trials demonstrated both Early small pilot trials demonstrated both histologic and biochemical improvement with histologic and biochemical improvement with doses of 10-15mg/kg/ddoses of 10-15mg/kg/dA DBPCT of 105 patients did not demonstrate A DBPCT of 105 patients did not demonstrate improvement in significant clinical endpoints improvement in significant clinical endpoints (death, OLT, histologic progression)(death, OLT, histologic progression)A trial of increased dose of UDCA A trial of increased dose of UDCA (17-23mg/kg/d) demonstrated a (17-23mg/kg/d) demonstrated a trendtrend toward toward increased survival (underpowered)increased survival (underpowered)

Page 78: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment

Chapman et al. Hepatology 2009

Page 79: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ManagementManagement

Upper endoscopy (if cirrhotic)Upper endoscopy (if cirrhotic)Fat soluble vitamin levels (periodically)Fat soluble vitamin levels (periodically)DEXA every 2-3 yearsDEXA every 2-3 yearsColonoscopy with surveillance biopsies Colonoscopy with surveillance biopsies every 1-2 years (if concomitant IBD)every 1-2 years (if concomitant IBD)Ultrasound annually (to evaluate for GB Ultrasound annually (to evaluate for GB mass lesion)mass lesion)Consider annual CA 19-9 +/- advanced Consider annual CA 19-9 +/- advanced imaging studyimaging study

Page 80: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TransplantTransplant

Indications for OLT do not differ from other liver Indications for OLT do not differ from other liver diseasesdiseases– Unique indications may include intractable pruritus, recurrent Unique indications may include intractable pruritus, recurrent

cholangitis, CCAcholangitis, CCA

Organs are allocated according to MELD scoreOrgans are allocated according to MELD scoreFive year survival rates of 85%Five year survival rates of 85%– 20-25% have disease recurrence after 10 years20-25% have disease recurrence after 10 years

Listing with CCA requires a regional review Listing with CCA requires a regional review board appeal to the Liver and Intestinal board appeal to the Liver and Intestinal Committee of UNOSCommittee of UNOS– Criteria: unicentric mass lesion < 3cm with no intra/extrahepatic Criteria: unicentric mass lesion < 3cm with no intra/extrahepatic

metastasis following neoadjuvant therapy with external beam metastasis following neoadjuvant therapy with external beam and bile duct luminal radiation plus capcitibeneand bile duct luminal radiation plus capcitibene

Page 81: Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition Cholestasis implies that the liver is not producing or secreting bile normally Biochemically:

PBCPBC PSCPSC

IncidenceIncidence Rare Rare RareRare

SexSex F>MF>M M>FM>F

PathologyPathology Small ductSmall duct Large ductLarge duct

Co-existent Co-existent diagnosisdiagnosis

AutoimmuneAutoimmune Inflammatory Inflammatory Bowel DiseaseBowel Disease

ERC/MRCERC/MRC NormalNormal DiagnosticDiagnostic

BiopsyBiopsy Diagnostic Diagnostic Often Often nonspecificnonspecific

AutoantibodyAutoantibody Diagnostic Diagnostic (AMA)(AMA)

Not specificNot specific