Chapter 21: Primary Biliary Cholangitis: A Review

INTRODUCTION

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a rare chronic inflammatory autoimmune cholestatic liver disease that generally affects middle-aged women. It is the most common chronic cholestatic liver disease in adults in the United States. The disease is a T-lymphocyte–mediated chronic destructive cholangitis with elevated serum levels of anti–mitochondrial autoantibodies (AMAs). The name change reflects the fact that cirrhosis occurs only in the late stage and therefore does not accurately characterize patients with early-stage disease. In this chapter, we will review the epidemiology, pathophysiology, clinical features, and diagnostic approach, as well as treatment modalities.

PATHOPHYSIOLOGY

Although the etiology of PBC remains unknown, several features suggest an autoimmune origin:

1. Deregulation of the humoral- and cell-mediated immune system

2. Presence of AMAs

3. T-lymphocyte–mediated bile duct destruction

4. PBC’s association with other autoimmune diseases

In general, the pathogenesis of PBC is dependent upon the interaction between the immune system and the biliary epithelial, resulting in chronic inflammation, cholestasis, and eventual fibrosis. Following is a brief overview of this delicate interplay.

• B- and T-cell interactions result in the production of AMAs that are specific to the E2 component of pyruvate dehydrogenase complex (PDC-E2), located on the inner mitochondrial membrane.

• B-cell activation is enhanced by costimulatory molecules CD40/CD40L, while macrophage activation occurs through JAK-STAT and NFkB signaling.

• Increased production of the inflammatory cytokines IFNy, TNFa, and IL-4 promote cytotoxic T-cell–induced apoptosis, B-cell–mediated antibody production, and biliary epithelial cell apoptosis.

• CYP7A1 and 2 convert cholesterol to bile acids (BA), which are then exported by bile salt exporter pumps.

• In healthy patients, BA are chaperoned by phosphatidylcholine and exported by multidrug resistance protein 3 (MDR3).

• In PBC, impaired activity of the anion exchanger (AE) leads to the accumulation of unchaperoned BA in the biliary epithelial membrane. Unchaperoned BA promote biliary epithelial senescence and apoptosis, resulting in hepatic stellate cell activation, inflammation, biliary stasis, and fibrosis.

ETIOLOGY/EPIDEMIOLOGY

Although the etiology of PBC remains unknown, it is likely an immune-mediated interaction between environmental stimuli in a genetically susceptible individual. The diagnosis is usually made between the ages of 30 and 60 years. The disease is predominately in females, with a female-to-male ratio of 9:1. Internationally, an estimated 1:1000 women over the age of 40 live with PBC. In European populations, the estimated incidence is between 1 and 2 per 100,000 population per year. In the United States, the age-adjusted reported incidence of PBC per 1 million person-years is 45 for women.¹

Infectious agents identified in the immune response in PBC include various bacteria, including Escherichia coli, and viruses. Of note, patients with PBC are more likely to have had a urinary tract infection within the 5 years preceding the diagnosis of PBC compared with match controls.

Several reports have described an increased risk of developing ...