Primary Biliary Cirrhosis

7/24/2012
Primary Biliary Cirrhosis and
Primary Sclerosing Cholangitis
Claudia O. Zein, MD, MSc
Digestive Disease Institute
Cleveland Clinic
Chronic Cholestatic Liver Disease in Adults
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Primary bile duct disorders (PBC, PSC)
Drug‐induced cholestasis
Cholestatic alcoholic liver disease
Sarcoidosis
Idiopathic adulthood ductopenia
Progressive familial intrahepatic cholestasis
Cystic fibrosis
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Chronic cholestatic disorder primarily affecting women over 40
and characterized by progressive nonsuppurative inflammation of
small bile ducts and presence of antimitochondrial antibodies
(AMA) in serum
• PBC begins with damage to the biliary epithelial cells of small intrahepatic bile ducts
• Subsequent progression ‐duct destruction, proliferation, granuloma formation, septal fibrosis and cirrhosis
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Pathogenesis of PBC
• PBC is considered an autoimmune disease
▫ Antimitochondrial antibodies (AMA)
 Present in ~95% of PBC patients, and in < 1% of healthy controls
 The dominant response is directed against the pyruvate dehydrogenase complex (PDC) on the inner mitochondrial membrane
▫ Highly specific bile duct injury of immune nature
PBC Pathogenesis: Genetic and environmental factors
• The initial BEC injury appears to result from a combination of genetic
susceptibility and environmental “triggering” factors
• Twin studies (concordance 0.63); increased prevalence in 1st degree
relatives (0.72%) and female offspring (2.3%); high prevalence of
autoimmune disorders (53%); candidate genes
• Potential “chemical” triggers: 2-nonynoic acid, nail polish, smoking
• Potential infectious triggers: E. coli (urinary tract infections), others
Selmi Gastroenterology 2004; Jones Hepatology 1999; Watt QJMed 2004; Prince Hepatology 2001;Ala
Hepatology 2006; Gershwin Hepatology 2005; Zein Hepatology 2006; Gershwin Hepatology 2007; Selmi
Hepatology 2003
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Epidemiology of PBC
• Incidence and prevalence –contemporary studies
▫ Incidence rates: 0.7 ‐ 49 cases / year per million population
▫ Prevalence rates: 6.7 ‐ 402 per million population
• Primarily affects women over 40 years old
▫ Female:Male ratio is 9:1
• Affects all races and occurs worldwide
▫ Geographical variation
• Increased diagnostic awareness has led to:
▫ Increased detection and earlier diagnosis has lead to earlier therapy and a recent fall on the number of LTs for PBC
1. Sood et al. Gastroenterology 2004; 2. Kim et al. Gastroenterology 2000; 3. Myszor et al. Qjmed 1989; 4.
Metcalf et al. Intl J Epi 1997; 5. James OF et al. Hepatology 1999; 6. Ray-Chadhuri et al. Hepatology 2001
A; 7. Mori et al. Ministry of Health and Welfare, Japan, 1997; 8. Myers et al. Hepatology 2009; 9. Lee J.
Clinical Gastroenterol and Hepatology 2007
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Clinical presentation
and Natural history of PBC
PBC – CLINICAL COURSE
• Silent
abnormal
biochemistries
• Asymptomatic
phase
AMA +, normal
biochemistries
death
• Symptomatic
phase
• Liver failure
fatigue/pruritus/
portal
hypertension
Up to 22 years, without treatment
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Clinical manifestations in PBC patients
• Most common symptoms at presentation:
▫ Fatigue (21%) and Pruritus (19%)
• Cummulative risk within 10 years:
▫ Fatigue and pruritus >55%
▫ Complications of portal hypertension 20%
• Other symptoms or findings often associated with PBC:
▫ Sicca syndrome (dry eyes/mouth)
▫ Xanthelasma, xanthomas
▫ Cutaneous calcinosis, Raynaud’s phenomenon, and Prince
et al. Gastroenterology 2002; Prince et al. Gut 2004
dysphagia
Predictors of clinical course and survival in PBC
• Presence of symptoms at diagnosis
▫ Asymptomatic patients  Longer survival from diagnosis compared to symptomatic
 Lower survival than matched general population
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Histological stage of disease
Sex
Age
Specific antibodies
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Survival free of LT
From: Nakamura M et al. Hepatology 2007, n=276
Predictors of Prognosis
Mathematical Models
• Mayo, European, Oslo, Barcelona, Newcastle
Biochemical markers
• Serum total bilirubin, albumin, PT
• Markers of fibrosis
Histological features
• Degree of piecemeal necrosis
• Features of overlap syndrome
Auto-antibodies
• Anti gp210, anti-PML, anti-sp100, anticentromere
Certain genetic
polymorphisms
• Apolipoprotein a
• TNF alpha
Clinical Scenario
• Esophageal Varices
• Ascites
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Is liver biopsy needed for PBC diagnosis?
• Typical clinical presentation in: ▫
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Middle age female patient
AMA positive
AP >=1.5 x ULN
AST < 5x ULN
• Then:
▫ Positive predictive value for PBC >98%
• Value of liver biopsy:
▫ Staging
▫ Diagnosis in non‐typical cases
Zein CO. Clin Gastro and Hepatol 2003
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Histology
Histology
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Histologic Stages of PBC
Stage
Features
I
Inflammation confined to the portal triads
II
Extension of periportal lesions
Portal fibrosis
III
Fibrous septae
IV
Cirrhosis
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Management of Patients with PBC
Primary Therapy
•UDCA (13-15 mg/kg/d)
-indefinitely-
Symptoms and Specific
Complications
•Pruritus
•Fatigue
•Bone loss
•Fat-soluble vitamin def.
Complications of
advanced liver disease
•Coagulopathy
•Portal hypertension
•Ascites
•Encephalopathy
UDCA in PBC
• Ursodeoxycholic acid (13‐15 mg/kg/day) is endorsed by the AASLD and EASL for use in PBC
• UDCA benefits: ▫ Liver tests
▫ Histological progression
▫ Survival
▫ Development of esophageal varices
• Safe and well tolerated
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UDCA in PBC: Survival Benefit
Probability of Survival according to Histological Stage
5
10
Years
Poupon et al. Hepatology 1999
UDCA in PBC: Survival Benefit
“Good” biochemical response
Nobiochemical response
Pares et al. Gastroenterology 2006
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PBC: Management of Pruritus
• Common in PBC
▫ Usually worse at night
▫ Unknown cause
• Management
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Cholestyramine (4 g tid 2 to 4 hours before or after UDCA)
Rifampicin (150 mg bid –monitor liver tests and blood count)
Naltrexone (start 12.5 mg/d and up to 50 mg PO qd)
Uncontrolled data: Sertraline (75‐100 mg/d)
Plasmapheresis – For very severe cases
PBC Related Fatigue
• Most common symptom in PBC (up to 78% of patients) • There is evidence of CNS mediation of this symptom:
▫ Excessive daytime somnolence(1)
▫ Autonomic dysfunction(2)
Management:
• Exclude other causes: hypothyroidism, anemia, depression, sleep deprivation, adrenal insufficiency
• There is no proven beneficial medical therapy
• Not helpful: Odansetron, antioxidants, fluvoxamine, fluoxetine, UDCA, Modafinil
(1. Newton et al. Hepatology 2006; 2. Newton et al. Hepatology 2007;
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PBC: Management of hypercholesterolemia
• Elevation of LDL and HDL • It has not been demonstrated that this is associated with increased cardiovascular risk
• Statins appear to be safe
• Recommendation: Treat according to individual patients CV risk factor profile
Bone Loss in PBC
• PBC is often associated with decreased bone mass • Non-pharmacological Interventions
▫ Calcium and Vitamin D
▫ Weight‐bearing Exercises
▫ BMD every 2 ‐ 4 years
• In the setting of osteopenia or osteoporosis, biphosphonates should be considered
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Other clinical manifestations in PBC
• Lipid soluble vitamin deficiencies
▫ May occur in PBC patients with advanced disease
▫ Measure vitamins A, D, E annually if bilirubin >2
• Portal hypertension
▫ Most often develops when patient has established
cirrhosis
▫ However, clinically significant portal hypertension may
occur in patients with pre-cirrhotic PBC
▫ EGD recommended every 1 to 3 years if cirrhotic or if
MRS>4.1
Liver transplantation in PBC
• Excellent graft and patient survival after liver transplantation for PBC (>90% at 5 years)
• Recurrent disease may recur in the transplanted liver 15
7/24/2012
Conclusions
• PBC typically affects females over 40 years of age
• Characteristic association with AMAs –highly disease specific
• Genetic and environmental factors play a pathogenetic role
• The diagnosis of PBC may not require liver biopsy, however biopsy is essential for staging
• UDCA (13‐15 mg/kg/d) is recommended indefinitely in all patients with PBC. UDCA impacts natural history and survival
Chronic cholestatic liver disease that occurs more commonly in
males, characterized by diffuse inflammation and fibrosis
of both intra- and extra-hepatic bile ducts, and may lead
to liver cirrhosis, portal hypertension, and liver failure.
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Epidemiology of PSC
• Prevalence in the US: 10‐60 cases per million population • Incidence of 9 per million population(1)
• Males are predominantly affected (2:1)
• Most cases are diagnosed after the age of 40
• Frequently (60‐80% of PSC cases) associated with inflammatory bowel disease
Bambha K et al. Gastroenterology 2003
Etiology and pathogenesis of PSC
• Exact etiopathogenesis of PSC –unknown, however believed to be multifactorial
▫ Data supporting genetic predisposition
 Familial occurrence of PSC
 Association of certain haplotypes with the disease
▫ Data supporting Immune‐mediation
 Presence of autoantibodies (ANCA, ANA, ASMA, and others)
 Association with other autoimmune disorders
 Hyper‐γ‐globulinemmia
▫ Bacterial/toxin damage
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Clinical presentation
• Most patients are asymptomatic at diagnosis
▫ Cholestatic biochemical profile found incidentally in a
patient with known IBD
▫ Hypergammaglobulinemia
▫ Positive ANA, ASMA, pANCA may be found
• Symptomatic patients
▫ Most common initial symptoms are fatigue and pruritus
▫ Jaundice, abdominal pain, weight loss
▫ Symptoms of bacterial cholangitis
Natural history of PSC
• Mean OLT free survival
~10 years
• Asymptomatic patients
appear to have better
survival compared to
those with symptoms
Bambha et al. Gastroenterology 2003
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Diagnosis of PSC
• Cholangiographic evidence of diffuse biliary strictures and dilatation, with classic beading appearance, involving intra and extrahepatic biliary ducts
▫ ERCP –gold standard for diagnosis ▫ MRCP –non‐invasive, cost‐effective option • Differential diagnosis
▫ Choledocholithiasis, previous biliary surgical trauma, HIV, ischemic stricture post OLT, histiocytosis X, ischemic
• Role of liver biopsy:
▫ Not routinely necessary for the diagnosis of PSC
▫ Often nonspecific, false negatives may occur
▫ Helpful in cholestasis in IBD with normal cholangiogram
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Management of Patients with PSC
No proven beneficial
Medical therapy
Role of Endoscopic
therapy
Symptoms and Specific
Complications
•Pruritus
•Fatigue
•Bone loss
•Fat-soluble vitamin def.
•Pre-cirrhotic portal
hypertension possible
•Peristomal varices
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UDCA in PSC: Effects on Survival
Survival Free of Liver Transplantation: 105 PSC patients
(13-15 mg/kg/d UDCA)
Lindor KD, N Engl J Med 1997
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High dose UDCA in PSC: 28-30 mg/kg/d
Lindor et al. Hepatology 2009
Endoscopic therapy
• Most patients will develop dominant strictures
▫ Stenosis with diameter <1.5mm in the CBD or <1mm in HD
• Repeated endoscopic interventions are often needed
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Antibiotic therapy mandatory
Stents tend to occlude earlier –exchange in 2 – 3 months
Balloon dilatation alone may be preferred
Brush cytology and biopsy before endoscopic therapy to exclude malignancy
• Limitations
▫ High grade stenosis >2cm above the bifurcation –consider percutaneous cholangiography
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Liver transplantation
• Only effective therapy ▫ Excellent survival rates (>90% at 1 year)
▫ However, PSC recurs in 15‐20% of cases and recurrence may be often associated with loss of the graft ▫ These patients also have a higher frequency of other post OLT complications including hepatic artery thrombosis (HAT)
Special considerations
• Cholangiocarcinoma
▫ Lifetime risk ~7‐15%
▫ Rate of development 0.5 to 1.5% per year ▫ Guidelines suggested for surveillance based on expert opinion:
▫ Imaging and Ca19‐9 annually
▫ High index of suspicion required
 Suspect in deteriorating clinical status, worsening liver tests, Ca 19‐9 >100 without cholangitis
 Imaging –MRI/MRCP
 ERCP w/ biopsy and brushings for conventional cytology and fluorescence in situ hybridization (FISH) and digital image analysis (DIA) if available
 Utility of PET scan and EUS with FNA still under study
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Special considerations
• Patients with PSC are also at higher risk for development of other malignancies
▫ HCC
▫ Pancreatic cancer
▫ Gallbladder cancer • Annual US and early cholecystectomy if GB polyps is recommended
▫ Colon cancer
 Even higher risk than in UC alone
• Patients with PSC & IBD –colonoscopy at diagnosis and q 1‐2 yrs
Special considerations: “Variant forms”
• IgG‐4 associated autoimmune cholangitis
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Approximately 10% of cases of PSC
Increased sIgG4, bile duct infiltration of IgG4 plasma cells
More aggressive course
May be steroid‐responsive
• Small duct PSC
▫ Histology typical of PSC with normal cholangiogram
▫ Approximately 25% progress to large duct PSC
▫ Cholangiocarcinoma has not been described in small duct PSC
• PSC with AIH features
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Conclusions
• PSC is a relatively uncommon but progressive disease
• ERCP remains the gold standard for diagnosis, but MRCP is a promising non‐invasive method
• High dose UDCA is not recommended for PSC therapy
• No effect on survival
• Associated with adverse endpoints
• Associated with increased CR neoplasia in PSC/UC patients
• Endoscopic therapy for management of dominant strictures • Cholangiocarcinoma may occur; PSC patients should be followed with a high suspicion index
PBC
PBC compared to PSC
Mean age
Sex ratio
Prevalence
IBD association
50
PSC
40
9F:1M
1F:2M
6 to 400 per million
10 to 100 per million
Not characteristic
>70%
Sicca association
50%
Not characteristic (2%)
AMA positive
>95%
Not characteristic
Clinical picture, AMA,
cholestatic labs –biopsy
not essential but helpful
Clinical picture, ERCP
Diagnosis
Cholangiography
Histopathology
Normal
Multifocal strictures
Small bile duct
destruction, proliferation,
granulomas
Ductopenia, fibrous
obliterative cholangitis
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