1 / 81

Cholestatic Liver Disease - PBC and PSC

Cholestatic Liver Disease - PBC and PSC. Cholestasis: Definition. Cholestasis implies that the liver is not producing or secreting bile normally Biochemically: Elevated alkaline phosphatase, conjugated bilirubin or both Signs/symptoms: Pruritus Jaundice Histologically Bile lakes

neylan
Download Presentation

Cholestatic Liver Disease - PBC and PSC

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cholestatic Liver Disease- PBC and PSC

  2. Cholestasis: Definition • Cholestasis implies that the liver is not producing or secreting bile normally • Biochemically: • Elevated alkaline phosphatase, conjugated bilirubin or both • Signs/symptoms: • Pruritus • Jaundice • Histologically • Bile lakes • Cholate stasis • Ductular proliferation

  3. Cholestasis: Definition • Cholestasis can be divided into 2 basic categories: • Extrahepatic Obstructive Jaundice • Intrahepatic Cholestasis

  4. Extrahepatic Obstructive Cholestasis • Extrahepatic obstruction of the bile ducts results in upstream ductal dilation • Seen on imaging • The primary considerations are: • pancreatic cancer • cholangiocarcinoma • choledocholithiasis • benign papillary stenosis

  5. Intrahepatic Cholestasis • Direct effect on cannalicular membrane of the hepatocyte by: • Toxins, metabolites • Drugs, alcohol • Interleukins, tumor necrosis factor • ALP (a hepatocellular enzyme) translocates to the basolateral membrane and is lost to serum

  6. Intrahepatic Cholestasis: Etiologies • Drugs • OCPs, anabolic steroids, NSAIDs, antibiotics (e-mycin), antipsychotics • Infiltrative disorders • Lymphoma, amyloidosis, tuberculosis, sarcoidosis, metastases • TPN • Sepsis • Pregnancy • Autoimmune (PBC/PSC, AIH overlap syndrome) • Inherited (benign recurrent intrahepatic cholestasis) • Post-operative • Paraneoplastic (Stauffer’s syndrome)

  7. Alkaline Phosphatase • ALP is a protein located on the cannalicular membrane of the hepatocyte – NOT the bile duct cell • Widespread tissue distribution: • Liver • Bone • Intestine • Kidney • placenta

  8. Alkaline Phosphatase • In biliary obstruction, increased synthesis and release of the enzyme into the serum rather than impaired biliary secretion accounts for the elevation of ALP • In cholestasis, bile acids accumulate in the hepatocytes and solubilize the plasma membrane resulting in release of ALP into serum • The level not a reliable indicator of the severity of underlying liver disease

  9. Alkaline Phosphatase:Confirming Liver Source • Gamma-glutamyl transferase (GGT) • Can be isolated from hepatocytes and various extrahepatic tissues but NOT bone • 5’ Nucleotidase • Elevated 5NT is rarely associated with associated with an extrahepatic source • Fractionate the alkaline phosphatase • Any elevation in a transaminase is very specific for liver origin of ALP

  10. Primary Biliary Cirrhosis:Overview • Definition • Epidemiology • Pathogenesis • Natural history • Clinical features • Diagnosis • Pathology • Management • Complications • Transplantation

  11. Primary Biliary Cirrhosis:Definition • Chronic cholestatic liver disease • Hallmark serologic signature – the antimitochondrial antibody (AMA) • Chronic, non-suppurative destructive cholangitis on histology

  12. Primary Biliary Cirrhosis:Epidemiology • Worldwide • Predominantly women (9:1) • Diagnosed typically between ages 30-60 • In the United States: • Age adjusted incidence rate is 27/million person-years • Age adjusted prevalence is 402/million

  13. Primary Biliary Cirrhosis:Pathogenesis • Cause is unknown • Considered an autoimmune disorder • Intense humoral and cellular response to an intracytoplasmic antigen • Presence of highly specific autoantibodies • Involvement of T lymphocytes in the destruction of bile ducts • Often coexists with other autoimmune disorders

  14. Proposed Mechanisms for the development of PBC • Molecular mimicry (Microorganism infection) • Xenobiotics • Genetic

  15. Primary Biliary Cirrhosis:Natural History Springer et al. Am J Gastro 1999

  16. Primary Biliary Cirrhosis:Natural History Springer et al. Am J Gastro 1999

  17. Primary Biliary Cirrhosis:Natural History • In general, slowly progressive disorder • Consists of two phases: • Asymptomatic: • Lasting mean of 17 years • No liver related mortality during this time • Symptomatic: • Characterized by the onset of symptoms • Average time from symptom onset to death is 7 years

  18. Primary Biliary Cirrhosis:Natural History Predicting Survival – The Mayo Risk Score • In general, if bilirubin is > 10 there is a 50% survival at 2 years

  19. Primary Biliary Cirrhosis:Clinical Features at Presentation • Asymptomatic 40-60% • Fatigue 21-85% • Pruritus 19-55% • Sicca symptoms up to 70% • Hepatomegaly 25% • Splenomegaly 15% • Jaundice uncommon • Xanthelasma uncommon

  20. Primary Biliary Cirrhosis:Other Associated Conditions • Metabolic bone disease • Fat soluble vitamin deficiencies • Hypercholesterolemia • Autoimmune thyroiditis • CREST/Raynaud’s • Renal tubular acidosis • Celiac sprue

  21. Primary Biliary Cirrhosis:Diagnosis • Elevated alkaline phosphatase • Typically 3-4 X ULN • ALT/AST usually < 200 • Unremarkable biliary imaging • Elevated immunoglobulins • Typically IgM • Characteristic autoantibody (AMA) • Characteristic histology

  22. Primary Biliary Cirrhosis:Diagnosis Autoantibodies: • Antimitochondrial Antibodies (AMA) • Present in 95% of patient with PBC • Sensitivity and specificity are > 95% • Usually present in high titer • Antinuclear/Smooth Muscle Antibodies (ANA/ASMA) • Not specific • Seen in 1/3 to ½ of individuals with PBC

  23. Primary Biliary Cirrhosis:Liver Biopsy Staging: Ludwig’s or Scheuer’s Classification Stage 1 portal inflammation/florid duct lesion Stage 2 periportal inflammaton (interface hepatitis), ductular proliferation Stage 3 bridging fibrosis, ductopenia Stage 4 cirrhosis

  24. Histological Staging – PBC Primary Biliary Cirrhosis – Histological Features Stage 1 Stage 2 Stage 3 Stage 4

  25. Histological Staging – PBC – Stage 1 Primary Biliary Cirrhosis Stage 1: Florid Duct Lesion Granuloma Portal hepatitis Scheuer P, Proc R Soc Med 1967; 60:1257 Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

  26. Histological Staging – PBC – Stage 2 Primary Biliary Cirrhosis Stage 2: Ductular Reaction Periportal Hepatitis Scheuer P, Proc R Soc Med 1967; 60:1257 Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

  27. Histological Staging – PBC – Stage 3 Primary Biliary Cirrhosis Stage 3: Scarring Bridging Necrosis/ Septal Fibrosis Scheuer P, Proc R Soc Med 1967; 60:1257 Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

  28. Histological Staging – PBC – Stage 4 Primary Biliary Cirrhosis Stage 4: Cirrhosis Cirrhosis Scheuer P, Proc R Soc Med 1967; 60:1257 Ludwig, et al., Virch Arch Pathol Anat 1978; 379:103

  29. Primary Biliary Cirrhosis:Treatment • Corticosteroids • Colchicine • Azathioprine • Cyclosporine • Methotrexate

  30. Primary Biliary Cirrhosis:Treatment • Corticosteroids • Colchicine • Azathioprine • Cyclosporine • Methotrexate

  31. Primary Biliary Cirrhosis:Treatment • UDCA in a dose of 13-15 mg/kg/day is the only FDA approved therapy for PBC • Dose is important • Number of studies have demonstrated a clear benefit • Used in all stages of PBC

  32. Primary Biliary Cirrhosis:Actions of UDCA • Protects against cytotoxic effects of di-hydroxy bile acids • Modulates expression of HLA • Stabilizes bile canalicular membrane • Choleretic effect • Decreased apoptosis • Decreased cytokine production

  33. Poupon et al. NEJM 1994

  34. Poupon et al. NEJM 1994

  35. Nonresponder Responder Pares et al. Gastro 2006

  36. Primary Biliary Cirrhosis:Management • Liver chemistries every 3-6 months • Thyroid study (TSH) annually • Bone mineral density scan (DEXA) every 2-4 years • Fat soluble vitamin levels if bilirubin > 2 • Upper endoscopy if cirrhotic or Mayo risk score > 4.1 • Ultrasound +/- AFP every 6-12 months if cirrhotic

  37. Primary Biliary Cirrhosis:Management Fatigue: • Modafanil 100-200mg/d Pruritus: • Cholestyramine up to 4g qid • Rifampicin 150mg/d • Naltrexone 12.5 mg/d (up to 50mg/d) Sicca: • Artificial tears, saliva substitutes • Good dental hygiene • Pilocarpine or cevimeline Osteopenia/Osteoporosis: • 1000-1500mg/d calcium + 1000 IU Vit D • Bisphosphanates Hyperlipidemia: • No treatment, no increased risk of cardiovascular disease

  38. Primary Biliary Cirrhosis:Transplantation • PBC was the leading indication for OLT in the U.S. in the mid 1980s • Despite increased numbers of transplants, patients with PBC requiring OLT have decreased by 20% • Outcome of OLT in PBC is more favorable than almost all other liver diseases • Once listed, priority is based on MELD

More Related