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Cholestatic Liver DiseaseCholestatic Liver Disease- PBC and PSC- PBC and PSC
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
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
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
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
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)
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
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
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
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
Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:OverviewOverview
DefinitionDefinitionEpidemiologyEpidemiologyPathogenesisPathogenesisNatural historyNatural historyClinical featuresClinical featuresDiagnosisDiagnosisPathologyPathologyManagementManagementComplicationsComplicationsTransplantationTransplantation
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
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
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
Proposed Mechanisms for the Proposed Mechanisms for the development of PBCdevelopment of PBC
Molecular mimicryMolecular mimicry(Microorganism infection)(Microorganism infection)
XenobioticsXenobiotics
GeneticGenetic
Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History
Springer et al. Am J Gastro 1999
Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:Natural HistoryNatural History
Springer et al. Am J Gastro 1999
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
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
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
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
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
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
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
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
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
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
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
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
Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
Primary Biliary Cirrhosis:Primary Biliary Cirrhosis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
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
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
Poupon et al. NEJM 1994
Poupon et al. NEJM 1994
Pares et al. Gastro 2006
Responder Nonresponder
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
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
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
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:OverviewOverview
DefinitionDefinitionEpidemiologyEpidemiologyPathogenesisPathogenesisNatural historyNatural historyClinical featuresClinical featuresDiagnosisDiagnosisPathologyPathologyComplicationsComplicationsManagementManagementTransplantationTransplantation
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
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)
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%
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)
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:PathogenesisPathogenesis
Larusso et al. Hepatology 2006
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Natural HistoryNatural History
Larusso et al. Hepatology 2006
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:Natural HistoryNatural History
Broome et al. Gut 1992
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
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
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
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
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
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:ComplicationsComplications
General:General:
Metabolic bone diseaseMetabolic bone disease
PruritisPruritis
Unique:Unique:
CholangitisCholangitis
Gallbladder diseaseGallbladder disease
CholangiocarcinomaCholangiocarcinoma
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
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
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%)
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
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
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
UDCAUDCA
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment
CorticosteroidsCorticosteroids
ColchicineColchicine
AzathioprineAzathioprine
CyclosporineCyclosporine
MethotrexateMethotrexate
UDCAUDCA
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)
Primary Sclerosing Cholangitis:Primary Sclerosing Cholangitis:TreatmentTreatment
Chapman et al. Hepatology 2009
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
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
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