Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

Transcription

1 Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis Claudia O. Zein, MD, MSc Digestive Disease Institute Cleveland Clinic Chronic Cholestatic Liver Disease in Adults Primary bile duct disorders (PBC, PSC) Drug induced cholestasis Cholestatic alcoholic liver disease Sarcoidosis Idiopathic adulthood ductopenia Progressive familial intrahepatic cholestasis Cystic fibrosis 1

2 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 2

3 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

4 Epidemiology of PBC Incidence and prevalence contemporary studies Incidence rates: cases / year per million population Prevalence rates: 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

5 Clinical presentation and Natural history of PBC PBC CLINICAL COURSE Silent abnormal biochemistries Asymptomatic phase Symptomatic phase death Liver failure AMA +, normal biochemistries fatigue/pruritus/ portal hypertension Up to 22 years, without treatment 5

6 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 Prince Cutaneous et al. Gastroenterology calcinosis, 2002; Prince Raynaud s et al. Gut 2004phenomenon, and 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 Histological stage of disease Sex Age Specific antibodies 6

7 Survival free of LT From: Nakamura M et al. Hepatology 2007, n=276 Predictors of Prognosis Mathematical Models Biochemical markers Histological features Auto-antibodies Certain genetic polymorphisms Clinical Scenario Mayo, European, Oslo, Barcelona, Newcastle Serum total bilirubin, albumin, PT Markers of fibrosis Degree of piecemeal necrosis Features of overlap syndrome Anti gp210, anti-pml, anti-sp100, anticentromere Apolipoprotein a TNF alpha Esophageal Varices Ascites 7

8 Is liver biopsy needed for PBC diagnosis? Typical clinical presentation in: 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

9 Histology Histology 9

10 Histologic Stages of PBC Stage I II III IV Features Inflammation confined to the portal triads Extension of periportal lesions Portal fibrosis Fibrous septae Cirrhosis 10

11 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 11

12 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

13 PBC: Management of Pruritus Common in PBC Usually worse at night Unknown cause Management 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 ( 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; 13

14 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 14

15 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

16 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. 16

17 Epidemiology of PSC Prevalence in the US: 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 17

18 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

19 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 19

20 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 20

21 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

22 High dose UDCA in PSC: 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 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 22

23 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 23

24 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 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 24

25 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 PSC Mean age Sex ratio 9F:1M 1F:2M Prevalence 6 to 400 per million 10 to 100 per million IBD association Not characteristic >70% Sicca association 50% Not characteristic (2%) AMA positive >95% Not characteristic Diagnosis Clinical picture, AMA, cholestatic labs biopsy not essential but helpful Clinical picture, ERCP Cholangiography Normal Multifocal strictures Histopathology Small bile duct destruction, proliferation, granulomas Ductopenia, fibrous obliterative cholangitis 25