Primary Biliary Cholangitis: advances in management and treatment of the disease

Abstract

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.

Rheumatic Manifestations in Autoimmune Liver Disease

“…(2) presence of serum AMA at significant titers; and (3) histological non-suppurative cholangitis and destruction of small or medium-sized bile ducts on biopsy specimen. The differential diagnosis includes a cholestatic drug reaction, biliary obstruction, sarcoidosis, AIH and PSC ( Table 4) 69 .…”

“…Ustekinumab, a monoclonal antibody against the p40 subunit, however, demonstrated only a very modest decrease in ALP after 28 weeks of therapy, and was otherwise deemed ineffective 19 . Other therapies targeting T cells 96 , including those that bind CTLA-4 (abatacept) or antagonize CD40 (FFP104) are under investigation 69,97,98 . Of note, the use CTLA-4 Ig in PBC murine model prevents cholangitis manifestations (AMA production, intrahepatic T-cell infiltrates, and bile duct damage) and reduces disease severity in established murine disease 99 .…”

Biliary epithelium: A neuroendocrine compartment in cholestatic liver disease

“…5 Diagnosis requires at least two positive diagnostic criteria, which include a persistent increase in alkaline phosphatase levels for greater than 6 months, a positive anti-mitochondrial antibody titer, or a positive liver biopsy. 74…”

Autoantibodies associated with primary biliary cholangitis are common among patients with systemic lupus erythematosus even in the absence of elevated liver enzymes

“…PBC is typically associated with the presence of antimitochondrial antibodies (AMA, type M2) which, in addition to persistently elevated serum alkaline phosphatase (ALP) and liver histology consistent with PBC, constitutes one of the three diagnostic criteria. However, several subtypes of ANA, such as anti-speckled 100-kDa (Sp100), anti-promyelocytic leukaemia protein (PML) and antiglycoprotein 210-kDa (gp210), are also specific markers [32]. PBC can initially be subclinical with elevated cholestatic liver enzymes and over decades progress to cholestatic disease with portal hypertension [29].…”