PRIMARY BILIARY CIRRHOSIS

1. PRIMARY BILIARY CIRRHOSIS

2. PBC is seen in about 100–200 individuals per million, with a strong female preponderance and a median age of around 50 years at the time of diagnosis. • The cause of PBC is unknown; it is characterized by portal inflammation and necrosis of cholangiocytes in small- and medium-sized bile ducts.

3. primary biliary cirrhosis • Primary biliary cirrhosis (PBC) is characterized by a T-lymphocyte-mediated attack on small intralobular ducts • The pathogenesis of PBC is incompletely understood but appears to involve environmental and genetic factors. • It is likely that an environmental trigger (possibly and infection, chemical or toxin) causes bile duct epithelial injury, which in susceptible individuals leads to a T-cellmediated autoimmune response directed against bile duct epithelial cells.

4. Once immune mediated bile duct injury has been established, the disease progresses due to chronic cholestasis and resulting inflammation and scarring.

5. Pathology

6. Medium and small bile ducts are infiltrated with lymphocytes and undergo duct destruction.

7. Histopathologic analyses of liver biopsies of patients with PBC have resulted in identifying four distinct stages of the disease as it progresses. • The earliest lesion is termed chronic nonsuppurative destructive cholangitis and is a necrotizing inflammatory process of the portal tracts.

8. Laboratory findings

9. Laboratory findings in PBC show cholestatic liver enzyme abnormalities with an elevation in γ-glutamyl transpeptidase and alkalinephosphatase (ALP) along with mild elevations in aminotransferases (ALT and AST). • Immunoglobulins, particularly IgM, are typically increased.

10. What are the “liver tests”? Liver diagnostic tests ….…HbsAg, Anti-HCV, PCR, ANA, Ceruloplasmin …….

11. Hyperbilirubinemia usually is seen once cirrhosis has developed. Thrombocytopenia, leukopenia, and anemia may be seen in patients with portal hypertension and hypersplenism.

12. ANTIMITOCHONDRIAL ANTIBODIES  Antimitochondrial antibodies are the serologic hallmark of PBC. Antimitochondrial antibodies are found in 95 percent of patients with primary biliary cirrhosis when using the most sensitive detection techniques, and have a specificity of 98 percent for the disease. However, their role in pathogenesis is unclear. antibody titers do not correlate with diseaseseverity or rate of progression.

13. There is no apparent difference in the clinical spectrum or course of patients with PBC who are AMA-positive or AMA-negative . • Patients with either AMA-negative or AMA-positive PBC have a similar response to treatment with ursodeoxycholic acid or liver transplantation.

14. Cholestasis features prevail, and biliary cirrhosis is characterized by an elevated bilirubin level and progressive liver failure

15. Clinical features

16. Liver transplantation is the treatment of choice for patients with decompensated cirrhosis due to PBC. • A variety of therapies have been proposed, but ursodeoxycholic acid (UDCA) is the only approved treatment that has some degree of efficacy by slowing the rate of progression of the disease.

17. Increased fibrosis ensues with the expansion of periportal fibrosis to bridging fibrosis. • Finally, cirrhosis, which may be micronodular or macronodular, develops.

18. Currently, most patients with PBC are diagnosed well before the end-stage manifestations of the disease are present, and, as such,most patients are actually asymptomatic. • When symptoms are present, they most prominently include a significant degree of fatigue out of proportion to what would be expected for either the severity of the liver disease or the age of the patient.

19. Pruritus is seen in approximately 50% of patients at the time of diagnosis, and it can be debilitating. • It might be intermittent and usually is most bothersome in the evening. • In some patients, pruritus can develop toward the end of pregnancy, and there are examples of patients having been diagnosed with cholestasis of pregnancy rather than PBC.

20. Pruritus that presents prior to the development of jaundice indicates severe disease and a poor prognosis. • Physical examination can show jaundice and other complications of chronic liver disease, including hepatomegaly, splenomegaly,ascites, and edema.

21. Other features that are unique to PBC include hyperpigmentation, xanthelasma, and xanthomata,which are related to the altered cholesterol metabolism seen in this disease.

22. Hyperpigmentation is evident on the trunk and the arms and is seen in areas of exfoliation and lichenification associated with progressive scratching related to the pruritus. • Bone pain resulting from osteopenia or osteoporosis is occasionally seen at the time of diagnosis.

23. Liver biopsy shows characteristic features as described above and should be evident to any experienced hepatopathologist.

24. Up to 10% of patients with characteristic PBC will have features of AIH as well and are defined as having “overlap” syndrome. These patients are treated as PBC patients and may progress to cirrhosis with the same frequency as typical PBC patients.

25. Diagnosis

26. Diagnosis of Primary Biliary Cirrhosis • Recommendations: Diagnosis • 1. The diagnosis of PBC can be established when • two of the following three criteria are met: • ● Biochemical evidence of cholestasis based mainly • on alkaline phosphatase elevation. • ● Presence of AMA. • ● Histologic evidence of nonsuppurative destructive • cholangitis and destruction of interlobular • bile ducts.

27. PBC should be considered in patients with chronic cholestatic liver enzyme abnormalities. • It is most often seen in middle-aged women. • AMA testing may be negative, and it should be remembered that as many as 10% of patients with PBC may be AMA-negative.

28. Liver biopsy is most important in this setting of AMA-negative PBC. • In patients who are AMA-negative with cholestatic liver enzymes, PSC should be ruled out by way of cholangiography

29. With the high disease specificity of a positive AMA test, the role of liver biopsy to diagnose PBC is questionable with ALP >1.5 times normal and AST < 5 times normal. Liver biopsy may be recommended in AMA-negative patients and to exclude other concomitant diseases such as AIH and NASH

30. TREATMENT

31. Primary Biliary Cirrhosis Treatment of the typical manifestations of cirrhosis are no different for PBC than for other forms of cirrhosis. UDCA has been shown to improve both biochemical and histologic features of the disease.

32. Improvement is greatest when therapy is initiated early; the likelihood of significant improvement with UDCA is low in patients with PBC who present with manifestations of cirrhosis. • UDCA is given in doses of 13–15 mg/kg per day;the medication is usually well-tolerated, although some patients have worsening pruritus with initiation of therapy.

33. A small proportion of patients may have diarrhea or headache as a side-effect of the drug. • UDCA has been shown to slow the rate of progression of PBC, but it does not reverse or cure the disease. • Patients with PBC require long-term follow-up by a physician experienced with the disease.

34. Certain patients may need to be considered for liver transplantation should their liver disease decompensate. • The main symptoms of PBC are fatigue and pruritus, and symptom management is important.

35. Several therapies have been tried for treatment of fatigue, but none of them have been successful; frequent naps should be encouraged. • Pruritus is treated with antihistamines, narcotic receptor antagonists (naltrexone), and rifampin. Cholestyramine, a bile salt sequestering agent, has been helpful in some patients but is somewhat tedious and difficult to take.

36. Plasmapheresis has been used rarely in patients with severe intractable pruritus. • There is an increased incidence of osteopenia and osteoporosis in patients with cholestatic liver disease, and bone density testing should be performed. • Treatment with a bisphosphonate should be instituted when bone disease is identified.

38. AASLD PRACTICE GUIDELINESDiagnosis and Management of PrimarySclerosing Cholangitis HEPATOLOGY, Vol. 51, No. 2, 2010 CHAPMAN ET AL.

39. The AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). • The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). • The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C).

40. Definition • Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts, leading to the formation of multifocal bile duct strictures. • PSC is likely an immune mediated, progressive disorder that eventually develops into • cirrhosis, • portal hypertension and • hepatic decompensation, in the majority of patients. • Small duct PSC is a disease variant which is characterized by typical cholestatic and histological features of PSC but normal bile ducts on cholangiography. • PSC overlap syndromes are conditions with diagnostic features of both PSC and other immune mediated liver diseases including autoimmune hepatitis and autoimmune pancreatitis.

41. Secondary sclerosingcholangitis (SSC) is characterized by a similar multifocal biliarystricturing process due to identifiable causes such as • long-term biliary obstruction, • infection, • inflammation which in turn leads to destruction of bile ducts and secondary biliary cirrhosis. • Immunoglobulin G4 (IgG4)-positive sclerosingcholangitis might represent a separate entity.

42. SCLEROSING CHOLANGITIS

43. LIVER LESIONS

44. Diagnosis of PSC. • A diagnosis of PSC is made in patients with a cholestatic biochemical profile, when cholangiography (MRC, ERC, PTC) shows characteristic bile duct changes with multifocal strictures and segmental dilatations, and secondary causes of sclerosing cholangitis have been excluded. • Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC.

46. Signs and Symptoms • The clinical presentation is variable; typical symptoms include RUQ abdominal discomfort, fatigue, pruritus, and weight loss. • Physical examination is abnormal in approximately half of symptomatic patients at the time of diagnosis; jaundice, hepatomegaly, and splenomegaly are the most frequent abnormal findings. • Many patients with PSC are asymptomatic with no physical abnormalities at presentation. • The diagnosis is made incidentally when persistently cholestatic liver function tests are investigated. • Approximately 60%-80% of patients with PSC have concomitant IBD, most often ulcerative colitis (UC).

47. Serum Biochemical Tests. • Serum biochemical tests usually indicate cholestasis; elevation of serum alkaline phosphatase is the most common biochemical abnormality in PSC. However, a normal alkaline phosphatase activity does not exclude the diagnosis. • Serum aminotransferase levels are elevated in the majority of patients (2-3 times upper limits of normal), but like the alkaline phosphatase can also be in the normal range. • Serum bilirubin levels are normal at diagnosis in the majority of patients. • IgG serum levels are modestly elevated in approximately 60% of patients (1.5 times the upper limit of normal).

48. Autoantibodies/Serology • A wide range of autoantibodies can be detected in the serum of patients with PSC indicating an altered state of immune responsiveness or immune regulation. • Most are present at low prevalence rates and at relatively low titers (Table 3). • They have no role in the routine diagnosis of PSC including the P-ANCA which is nonspecific, although it may draw attention to colon involvement in a cholestatic syndrome.

50. Imaging Studies • Transabdominal ultrasound (US) is usually nondiagnostic and may even be normal, although bile duct wall thickening and/or focal bile duct dilatations are often identified. • However, gallbladder abnormalities, including wall thickening, gallbladder enlargement, gallstones, cholecystitis, and mass lesions, are identified in up to 41% of patients with PSC who undergo US examinations. • The findings on computed tomography (CT) cross sectional or coronal imaging of the upper abdomen are also nonspecific. • It should be noted that lymphadenopathy in the abdomen is common in PSC and should not be over interpreted as metastases or a lymphoproliferative disorder. • No information exists on the emerging technology of CT cholangiography for the diagnosis or evaluation of PSC.