Overall Bottom Line

PBC is a slowly progressive autoimmune liver disease that causes destruction to the small- and medium-sized intrahepatic bile ducts.
Most patients with PBC are diagnosed after abnormal liver chemistries are noted on routine testing. However, some patients come to medical attention because of complaints of fatigue and pruritus.
The cholestatic liver chemistries (AP and GGT) are elevated and more than 95% of patients have a positive AMA.
Ursodeoxycholic acid (13–15 mg/kg/day) is considered the treatment standard of care.
Though PBC can cause significant portal hypertension and other complications of ESLD including the rare development of HCC, the majority of patients do not die of liver disease.

Section 1: Background

Definition of disease

PBC is a chronic disease of unknown cause in which the small- and medium-sized intrahepatic bile ducts are progressively destroyed.
The first description of PBC may date back to the 1800s when cases of “xanthomatous cirrhosis” and “biliary cirrhosis without biliary obstruction” were described. The term “primary biliary cirrhosis” was first coined in 1950 and the first full description of the disease appeared in the New England Journal of Medicine in 1973.

The incidence and prevalence of this disease varies worldwide; PBC is most common in Northeast Europe and Scandinavia. The prevalence decreases with decreasing latitude.
In the USA the disease prevalence is estimated at about 40 cases per 100 000 and the incidence is around three cases per 100 000.
The prevalence of AMA in the general population may be as high as one in 200 (0.5%).
The incidence and prevalence of the disease appear to be rising.
Relatives of patients with PBC have a 1–5% risk of developing/having the disease.
The prevalence is ninefold higher in women compared to men.

The exact etiology of PBC remains unknown but both genetic predisposition and environmental exposure are important.
Significant associations between PBC and common genetic variants of the HLA Class II, IL12A and IL12RB2 loci suggest that the interleukin 12 immunoregulatory signaling axis is relevant to the pathophysiology of the disease. Thus, most individuals have a genetic predisposition to the disease.
Several groups have shown an increased familial prevalence of the disease ranging from 1% to 5%.
Exposure to various microbes and xenobiotics including tobacco smoke, have been associated with the disease.

PBC is an autoimmune disease characterized by the presence of highly specific AMA and bile duct destruction mediated by autoreactive T cells. Loss of self-tolerance appears to be due to exposure either to a cross-reactive microbial or xenobiotic antigen and/or modification of self-antigens. Poor macrophage clearance of apoptotic biliary epithelial cells and autophagy may contribute to inappropriate cell surface presentation of mitochondrial self-antigens by healthy biliary epithelial cells. These cells are then targeted for destruction by autoreactive T cells.
Eventually bile duct loss is significant enough to lead to cholestasis and possibly cirrhosis. For unknown reasons, portal hypertension and esophageal variceal bleeding may occur earlier than expected.

Clinical Pearls

No intervention has been demonstrated to prevent the development of the disease.

The diagnosis of PBC is based on finding two out of following three:
- Elevated cholestatic liver biochemistries (AP and GGT).
- AMA greater than 1:20.
- Histologic findings consistent with primary biliary cirrhosis including florid duct lesions and non-caseating granulomas.
The AMA is considered the hallmark of the disease and is highly sensitive and specific for the disease (present in >95% of patients).
Serum IgM is typically increased.

Differential diagnosis	Features
AIH	ANA, interface hepatitis on histology, and ALT/AST much greater than AP
Autoimmune cholangitis	Serum AMA negative, ANA positive in high titer, high IgG, liver biopsy consistent with PBC
Overlap AIH/PBC	Features of PBC and AIH. Higher ALT and IgG levels than in typical PBC. Bile duct damage and interface hepatitis on liver biopsy
PSC	Cholangiogram with biliary strictures and peribiliary fibrosis on histology
Extrahepatic biliary obstruction	Presence of secondary bile duct obstruction on imaging studies
Sarcoidosis	Absence of AMA; may be difficult to differentiate histologically from PBC
Drug-induced cholestasis	History reveals diagnosis
Idiopathic adulthood ductopenia	Bile duct loss without autoantibodies; no inflammation and fibrosis on histology

The typical PBC patient is a middle-aged woman; however, patients have presented as young as their teens and as late as the ninth decade of life.
Most commonly the patient is asymptomatic but noted to have abnormal liver chemistries during routine blood tests. Other patients are symptomatic and come to medical attention with complaints of fatigue and pruritus.
Less frequently a patient is diagnosed after presenting with evidence of portal hypertension or complications of cirrhosis.
Abnormal cholestatic liver chemistries, a positive AMA and a confirmatory liver biopsy most commonly clinch the diagnosis.

Sjögren’s syndrome.
CREST syndrome (calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia).
Other collagen vascular diseases.
Autoimmune thyroiditis (20% of PBC patients).
Celiac disease (6% of PBC patients).
Autoimmune thrombocytopenia.
Autoimmune hemolytic anemia.
Interstitial lymphocytic pneumonitis.