PBC and PSC

1
PBC and PSC

• Michael Nunez, MD
• September 20, 2004

2
Cholestatic Liver Disease

• medication induced
• TPN
• infections
• sepsis
• choledocholithiasis
• pancreatic malignancy
• pregnancy related
• infiltrative liver diseases
• primary biliary cirrhosis (PBC)
• primary sclerosing cholangitis (PSC)
• secondary sclerosing cholangitis
• graft vs. host disease

3
Autoimmune Liver/Biliary Diseases

• PBC
• PSC
• autoimmune hepatitis
• autoimmune cholangitis (AMA-negative PBC)

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Primary Biliary Cirrhosis

• misnomer actually a nonsuppurative autoimmune
  cholangitis
• autoimmune disease of the liver
• predominantly affects middle-aged women
• results in destruction of interlobular bile ducts
• causes cholestasis and, eventually, cirrhosis
• no cure

5
PBC Epidemiology

• worldwide distribution
• 90 of patients are female (91 ratio)
• median age at presentation is 50 years (range
  21-91)
• prevalence of 20-400 patients per million
  population
• up to 650 per million in US women
• possible genetic association based on familial
  studies

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PBC Pathogenesis

• cause or trigger remains unknown (alloantigen?)
• immune (T-cell) mediated attack that targets the
  epithelial cells of interlobular bile ducts
• see B-cell elaboration of autoantibodies that may
  not be pathogenic
• AMA is not pathogenic
• intrahepatic bile duct destruction leads to
  cholestasis and fibrosis

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Normal Liver Biopsy
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PBC Pathology
damaged septal bile duct
damaged interlobular bile duct
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PBC Pathology
bridging fibosis
missing interlobular bile duct (ductopenia)
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PBC Clinical Presentation
findings frequency ()
fatigue 70
pruritus 55
asymptomatic 25
hyperpigmentation 25
hepatomegaly 25
splenomegaly 15
xanthelasma 10
jaundice 15
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PBC Associated Diseases
disease frequency ()
Sjögren's / sicca 70-100
arthropathy 5-40
CREST / scleroderma 15-20
thyroiditis 15-20
autoimmune skin disease 10
RTA (proximal or distal) 50-60
gallstones 30
celiac sprue rare
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PBC Diagnosis

• abnormal liver function tests
• alkaline phosphatase usually 3-4 times elevated
• normal or minimally elevated transaminases (lt3x)
• elevated serum cholesterol and IgM often seen
• jaundice, hypoalbuminemia, and coagulopathy seen
  in later stages of the disease
• serologic testing
• AMA present in 90-95 (the best have sens98,
  spec96)
• RF found in 70
• ASMA in 66
• anti-thyroid in 40
• ANA in 35

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PBC Diagnosis

• liver biopsy
• gold standard to make diagnosis and exclude other
  diagnoses
• stage 1 - portal triad inflammation
• stage 2 - parenchymal (interface) hepatitis
• stage 3 - fibrosis
• stage 4 cirrhosis
• imaging studies
• main utility in excluding biliary obstruction
• can see increased hepatic echogenicity
• can see lymphadenopathy in 25

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PBC Natural History and Prognosis

• AMA positive with normal LFTs and asymptomatic
• 29 patients followed (18 years average)
• 24 with PBC on biopsy (83)
• 2 with normal biopsies
• 24 developed abnormal LFTs at average of 5.6
  years
• 22 developed symptomatic disease
• no progression to cirrhosis or death from liver
  disease
• asymptomatic PBC (AMA and biopsy) with abnormal
  LFTs
• 40 develop symptoms in 5-7 years
• once symptomatic, life expectancy falls (median
  survival 10 years but a large range)

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PBC Natural History and Prognosis

• symptomatic PBC patients
• independent predictors of poor prognosis
• advanced age
• bilirubin level (gt10 portends 2 year avg.
  survival)
• poor synthetic function
• hepatomegaly
• ascites or edema
• variceal bleed
• advanced biopsy stage
• prognostic models have been developed and
  validatedhttp//www.mayoclinic.org/gi-rst/mayomo
  del2.html

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PBC Treatment

• traditional glucocorticoids
• one controlled trial with benefits on
  biochemistry and histology
• no change in mortality
• colchicine
• in 3 controlled trials, no prognostic or survival
  benefit
• azathioprine
• 248 patients without biochemical, histologic or
  survival benefit
• cyclosporine
• 349 patients without histologic or survival
  benefit
• methotrexate
• only one controlled trial with worse outcomes at
  6 years

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PBC Treatment

• ursodeoxycholic acid (UDCA)
• improves biochemistry, histology, and survival
• 13-15 mg/kg/day divided TID
• FDA approved for PBC
• budesonide and UDCA
• well studied only in UDCA non-responders no
  benefit in prognosis models
• in naïve patients, improved biochemistry and
  histology (vs. UDCA alone), but no information on
  prognosis
• AMA-negative PBC seems to behave and respond the
  same as PBC, but may overlap with autoimmune
  hepatitis.

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PBC Management

• osteopenia and osteoporosis
• lose bone mass at twice rate of controls
• risk of osteoporosis 8 times matched controls
• 50 of post transplant PBC patients suffer
  fractures
• treatment exercise, calcium and vitamin D
  (25,000-100,000 IU/week)
• bisphosphonates need further study
• fat soluble vitamins
• monitor vitamins D, A and E
• trial of vitamin K for prolonged prothrombin time
• pruritus
• cholestyramine 4-16 gm/day divided before and
  after breakfast
• rifampin or oral naltrexone can be useful in
  non-responders
• can require transplantation

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PBC Transplantation

• survival is better if transplanted before a
  life-threatening complication or patient is on
  life support
• common indications
• portal hypertensive bleeding
• refractory ascites
• encephalopathy
• hepatorenal syndrome
• disabling fatigue
• disabling pruritus
• severe muscle wasting
• one-year survival rates 90 5-year gt80
• post-transplant recurrence (by biopsy) in 30-50
  by 10 years but usually takes a benign course

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Primary Sclerosing Cholangitis

• most common type of sclerosing cholangitis in
  U.S.
• autoimmune disease of the biliary tree
• chronic inflammation and fibrosis of the bile
  ducts
• may occur in association with other diseases
  (IBD, scleroderma, SLE, sprue)
• but lacks a specific etiology (AIDS infections,
  parasites, operative injury, cystic fibrosis,
  RPC)
• no cure

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PSC Epidemiology

• prevalence of 6-8 per 100,000
• up to 44 are asymptomatic at diagnosis
• 80 of patients have concomitant IBD and 90 of
  those have ulcerative colitis (some years before
  symptoms)
• 3-6 of UC patients and 1 of Crohns patients
  have PSC
• PSC and IBD progress independently
• median age at diagnosis is 39 (neonates to
  octogenarians)
• malefemale 1.51

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PSC Pathogenesis

• theory unknown trigger (toxin, infection,
  ischemia) in a genetically susceptible host
• familial clustering reported
• class II and III HLA associations
• common autoantibodies (ANCA in 65-85)
• humoral and cellular immune dysfunction
• intra- and extra-hepatic bile duct inflammation
  and fibrosis
• stricture formation and obliteration
• intra- and extra-hepatic ducts usually involved
• 5 predominantly extra-hepatic
• 25 predominantly intra-hepatic
• leads to cholestasis and cirrhosis

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PSC Pathology
normal liver
onion skin fibrosis in PSC
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PSC Pathology
fibrous obliteration
bile duct distortion
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PSC Clinical Presentation
symptom frequency ()
jaundice 30-72
pruritus 28-69
abdominal pain 24-72
weight loss 29-79
fatigue 65-66
fever/cholangitis 13-45
asymptomatic 20-44
Course may be very variable with spontaneous
remission for prolonged periods.
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PSC Diagnosis

• symptoms
• high index of suspicion in IBD patients
• physical findings
• hepatomegaly
• splenomegaly
• laboratory
• alkaline phosphatase elevation (usually 3-fold or
  higher)
• 6 have normal alkaline phosphatase
• modest transaminase elevations (usually lt 3-fold)
• bilirubin may be normal
• small subset have marked eosinophilia
• 65-85 are ANCA positive

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PSC Diagnosis

• liver biopsy
• onion skin fibrosis is most common (50
  patients)
• obliterative fibrous cholangitis is
  pathognomonic (10)
• most findings can be confused with chronic
  hepatitis or auto-immune hepatitis
• imaging studies
• non-specific findings variably present
• dilated intra-hepatic ducts may be seen
• cholangiography
• ERCP considered the gold standard
• MRCP reported to have PPV of 90 and sens/spec of
  85 compared to ERCP
• 75 will have strictures at the bifurcation

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PSC Cholangiography
MRCP
ERCP
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PSC Cholangiography
MRCP
ERCP
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PSC Cholangiography
MRCP
ERCP
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PSC Natural History and Prognosis

• median survival or time to transplant is 12
  years, but very variable and less predictable
  than PBC
• some predictors of poor prognosis (Mayo model)
• advanced age
• degree of bilirubin elevation
• low albumin
• high AST level
• variceal bleeding
• Child-Pugh classification is used by UNOS
  (transplant listing)
• class A 90 7 year survival
• class B 68 7 year survival
• class C 25 7 year survival

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PSC Natural History and Prognosis

• malabsorption
• steatorrhea
• calcium malabsorption and osteoporosis
• fat-soluble vitamin deficiencies
• portal hypertension
• bleeding
• ascites
• cholangiocarcinoma
• median survival of 5 months
• diagnosed in 3-20 of patients
• found in 30-40 of PSC patients at autopsy
• found in 23-33 of PSC patients at transplant
• tumor markers unproven as screening tools

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PSC Management

• medical palliation
• pruritus
• cholestyramine
• cholestipol
• rifampin
• bacterial cholangitis
• antibiotics (gram neg bacilli,enterococci,
  bacteroides)
• steatorrhea
• fat-soluble vitamins
• medium-chain triglycerides
• interventional palliation
• ERCP
• dilation of dominant strictures
• short-term stenting (7-14 days)
• stone removal

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PSC Transplantation

• indications
• complications of portal hypertension
• hepatic dysfunction
• disabling refractory symptoms
• recurrent cholangitis
• usually done with a Roux-en-Y biliary anasamosis
• excellent patient and graft survival rates
• if cholangiocarcinoma is found in native liver,
  survival drops to 30 at one year
• PSC recurs in 15-20