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Gastrointestinal (GI) System ORGAN SYSTEMS

Primary biliary cholangitis (PBC)

Introduction

Autoimmune, slowly progressive, cholestatic, liver disease characterized by a triad of chronic cholestasis, circulating anti-mitochondrial antibodies (AMA), and characteristic liver biopsy findings.

History:

The first report of the disease dates back 1851 by Addison and Gull who described a clinical picture of progressive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al. in 1950 published the first detailed description of 17 patients with this condition and coined the term “primary biliary cirrhosis”. In 1959, Dame Sheila Sherlock reported a further series of PBC patients and recognised that the disease could be diagnosed in a pre-cirrhotic stage and proposed the term “chronic intrahepatic cholestasis” as more appropriate description of this disease. However, this nomenclature failed to gain acceptance and the term “primary biliary cirrhosis” lasted for decades. In 2014, to correct the inaccuracy and remove the social stigmata of cirrhosis as well as all the misunderstanding, disadvantages and discrimination emanating from this misnomer in daily life for patients, International liver associations agreed to rename the disease “primary biliary cholangitis”, as it is known nowadays.

Aetiology

Being one of the first conditions in which specific autoantibodies were recognized, PBC is regarded as a “model autoimmune disease. Both environmental factors and inherited genetic predisposition appear to contribute to its pathogenesis

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Primary biliary cirrhosis | Zabron, A., Edwards, R. J. and Khan, S. A. (2013) ‘The challenge of cholangiocarcinoma: dissecting the molecular mechanisms of an insidious cancer’, Disease Models & Mechanisms, 6(2), p. 281 LP-292. Available at: http://dmm.biologists.org/content/6/2/281.abstract.

Associated autoimmune disorders:

These disorders generally precede the onset of PBC by about 4 years
  • Autoimmune thyroid disorders
  • Raynaud syndrome
  • Sjogren syndrome

Pathophysiology

It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver causing cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.

Natural history:

intercept_-_pbc_liver_progression
PBC Progression | © Intercept Pharma.
primary-biliary-cirrhosis-pbc

Clinical features

More than half of patients diagnosed today with PBC are asymptomatic at presentation.

  • Fatigue (85%): Excessive manganese deposits in globus pallidum, elevated inflammatory cytokines
  • Pruritis (70%): Cholestasis, increased opioidergic tone
  • Xanthelasma: Hypercholesterolemia and hyperlipidemia
  • Osteoporosis: Disturbances in bone remodeling due to metabolic changes in PBC
  • Dyslipidemia: Reduction in biliary secretion of cholesterol. Toxic effects of unconjugated bilirubin
  • Jaundice (late sign): Cholestasis
img-therapeutic-areas-pbc
Natural history of PBC | Interceptpharma.com. (2017). Primary Biliary Cholangitis | Intercept Pharmaceuticals, Inc. [online] Available at: https://interceptpharma.com/research-development/therapeutic-areas/primary-biliary-cirrhosis/ [Accessed 7 Jul. 2017].

Complications

  • Oesophageal varices
  • Ascites
  • Spontaneous bacterial peritonitis
  • Hepatorenal syndrome
  • Hepatoma formation

Diagnosis

Biochemical tests:

Biochemical markers of cholestasis, particularly alkaline phosphatase, are elevated persistently for more than 6 months in the presence of serum AMA and in the absence of an alternative explanation
  • ↑ Serum ALP & γGT (> 6 months)
  • ↑ AMA (Anti-mitochondrial antibodies) (M/specific serological marker)

Mayo Risk score:

M/C used and best prognostic system

Mayo Risk score = 0.04 (Age) + 10.87 Loge (Bilirubin) – 22.53 Loge (Albumin) + 12.38 Loge (Prothrombin time) + 10.86 (Edema score)

Liver biopsy:

Histologic hallmark of the disease is a loss of biliary epithelial cells and small intrahepatic bile ducts with portal infiltration of T cells, B cells, macrophages, eosinophils, and natural killer cells
  • Nonsuppurative destructive cholangitis
  • Interlobular bile duct destruction
Lower (A) and higher (B) magnification photomicrographs of a liver biopsy sample in a patient with early primary biliary cirrhosis shows a moderately severe, mixed inflammatory infiltrate consisting mostly of lymphocytes and plasma cells concentrated around small bile ducts in the portal area. Note the absence of inflammation around hepatocytes (H and E stains) | GNU Free Documentation License, Version 1.2) from: http://commons.wikimedia.org/wiki/File:Primary_biliary_cirrhosis_intermed_mag_2.jpg. Accessed March 10, 2015.

Differential Diagnosis

  • Primary Sclerosing Cholangitis (PSC)
    • AMA (-)

Management

The aim of PBC therapy is to reverse injury from bile duct inflammation to relieve symptoms, prevent disease progression, relieve laboratory abnormalities, and prevent the consequences of chronic cholestasis, including pruritus, fatigue, osteoporosis, and fat-soluble vitamin deficiencies

  • Ursodeoxycholic acid (first-line): Protection of cholangiocytes, stimulation of biliary secretions of bile acids
  • Corticosteroids (budesonide): Anti-inflammatory, especially useful for interface hepatitis
  • Obeticholic acid: Reduces bile acid synthesis, downregulates bile acid uptake proteins
  • Fibrates: Activates peroxisome proliferator-activated receptors
Summary of standard therapy and promising future therapeutic options in PBC with respect to their action in the pathophysiologic chain of PBC. UDCA in a dose of 13–15 mg per kg body weight per day, administered in either one dose or divided into two administrations per day, is the only FDA-approved drug and the cornerstone in PBC therapy. Liver transplantation (LTx) is performed for liver failure in end-stage disease. The most advanced database for future therapeutic consideration is available for budesonide. Though speculative, current preliminary data suggest a future role for agonists to certain nuclear receptors: peroxisome proliferator activated receptor alpha (PPARα), farnesoid x receptor (FXR), vitamin D receptor (VDR), pregnane x receptor (PXR), and constitutive androstane receptor (CAR) | Hohenester, S., Oude-Elferink, R. P., & Beuers, U. (2009). Primary biliary cirrhosis. Seminars in immunopathology, 31(3), 283–307. https://doi.org/10.1007/s00281-009-0164-5

Liver transplantation:

Definitive therapy for advanced disease, with about 70% 10-year survival after transplantation.

Management of complications:

  • Pruritis: Local skin care, dermatologist referral, avoiding potential pruritogens, cholestyramine, and possibly opioid antagonists, sertraline, or rifaximin
  • Osteoporosis: Life-style modifications, calcium and vitamin D, alendronate, statins
  • Sjogren’s syndrome: Artificial tears, cyclosporine ophthalmic emulsion (stimulate tear production), saliva substitutes, cholinergic agents, and scrupulous oral and dental care

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