Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis (PBC), is a chronic cholestatic disease caused by progressive, non-suppurative inflammation of the intrahepatic small bile ducts.
Etiology and Pathogenesis
The interaction of genetic and environmental factors leads to immune dysregulation. The mechanisms of autoimmune biliary epithelial cell damage involve:
- Humoral immunity: Antimitochondrial antibodies (AMA) play a key role in humoral immunity, with a positivity rate of 90–95%. The antigens recognized by AMA are primarily located on the inner mitochondrial membrane, with the main autoantigen being the pyruvate dehydrogenase complex within the multienzyme complex.
- Cellular immunity: Biliary epithelial cells abnormally express HLA-DR and HLA-DQ antigen molecules, triggering cytotoxic effects mediated by T lymphocytes specific to autoantigens, resulting in persistent damage to the bile ducts.
Clinical Manifestations
PBC is more common in middle-aged females, with a male-to-female ratio of approximately 1:9. The disease has an insidious and slow onset, with a natural course that can be divided into four stages:
- Preclinical stage: AMA-positive, asymptomatic, with normal liver function. This stage can last for over a decade and is often detected during screening.
- Asymptomatic stage with abnormal liver function: Approximately 20–60% of patients at initial diagnosis are asymptomatic. Diagnosis is made based on elevated serum alkaline phosphatase (ALP) levels and positive AMA. Symptoms typically appear within 2–4 years.
- Symptomatic stage with abnormal liver function.
- Cirrhotic stage.
The clinical manifestations of the latter two stages are as follows:
- Fatigue and pruritus are the most common initial symptoms. Fatigue is present in approximately 78% of patients, while pruritus, occurring in 20–70%, is more specific and may develop months to years before jaundice. It often worsens at night.
Chronic intrahepatic cholestasis reduces bile secretion and excretion into the intestinal lumen, impairing fat digestion and absorption. This can result in steatorrhea and fat-soluble vitamin deficiencies, leading to rough skin, hyperpigmentation, night blindness (vitamin A deficiency), osteomalacia and osteoporosis (vitamin D deficiency), and bleeding tendencies (vitamin K deficiency).
Prolonged bile duct obstruction leads to elevated serum lipids and cholesterol, causing xanthelasmas due to cholesterol-laden histiocytes.
Hepatomegaly is common, with progressive enlargement as jaundice worsens. Tenderness is usually absent. Over time, the disease progresses to cirrhosis.
PBC often coexists with other autoimmune diseases, such as Sjögren's syndrome, thyroiditis, and rheumatoid arthritis.
Laboratory and Auxiliary Examinations
Urine and stool tests
Urine bilirubin is positive, urinary urobilinogen is normal or reduced, and stool color may be pale.
Liver function tests
Serum bilirubin levels are moderately elevated, primarily conjugated bilirubin, reflecting the severity of bile duct loss and piecemeal necrosis. Serum cholesterol is often elevated but decreases in liver failure. ALP and γ-GT are typically elevated before jaundice and other symptoms appear, with ALP elevation being the most prominent biochemical abnormality in PBC.
Immunological tests
Over 95% of patients are AMA-positive, with a titer >1:40 being diagnostic. AMA is a specific marker for PBC, particularly the M2 subtype, which has a positivity rate of 90–95%. Serum AMA may be positive 6–10 years before clinical symptoms appear in many patients. Approximately 50% of PBC patients are ANA-positive. Other PBC-specific antibodies include anti-liver lipid protein antibody (SP100) and anti-nuclear pore complex protein antibody (GP210), which are useful markers in AMA-negative cases. Serum immunoglobulin levels, particularly IgM, are elevated.
Imaging studies
Ultrasound, CT, MRI, MRCP, or ERCP are often used to assess disease progression and exclude other biliary conditions such as tumors and gallstones. Portal hypertension may be observed when PBC progresses to cirrhosis.
Histological examination
Histological features and staging include:
- Stage I (cholangitis stage): Dense lymphocytic infiltration around damaged bile ducts. Non-caseating granulomas, known as florid duct lesions, are characteristic and most commonly seen in stages I and II.
- Stage II (periportal inflammation stage): More extensive damage with a reduction in the number of interlobular bile ducts within the portal tracts.
- Stage III (progressive fibrosis stage): Inflammation and fibrosis extend beyond the portal tracts, with portal tract expansion and bridging fibrosis between portal areas.
- Stage IV (cirrhotic stage): Evident cirrhosis with regenerative nodules, bile duct obstruction, and bile plugs within hepatocytes and bile canaliculi.
Diagnosis and Differential Diagnosis
In asymptomatic patients, testing for AMA, ALP, and IgM can help detect early cases. PBC should be considered in middle-aged females who present with pruritus, fatigue, jaundice, and hepatomegaly, along with biochemical changes indicative of cholestatic jaundice, and no evidence of extrahepatic bile duct obstruction.
A diagnosis of PBC can be made if two of the following three criteria are met:
- Biochemical evidence of cholestasis, primarily characterized by significant elevations in ALP and γ-GT.
- Positivity for AMA, AMA-M2, GP210, or SP100.
- Histological findings consistent with PBC.
Differential diagnosis should focus on excluding secondary biliary cirrhosis caused by intrahepatic or extrahepatic bile duct obstruction. Additionally, differentiation from autoimmune hepatitis and cholestatic drug-induced liver injury is necessary.
Treatment
Ursodeoxycholic acid (UDCA)
UDCA is the first-line treatment recommended for PBC. The dose is 13–15 mg/(kg·d). It enhances bile acid secretion, counteracts the cytotoxic effects of hydrophobic bile acids, and protects biliary epithelial cells and hepatocytes. Among patients who respond to UDCA, 90% show improvement within 6–9 months.
Other treatments
In cases where UDCA is ineffective, medications such as budesonide, fibrates (fenofibrate, bezafibrate), and obeticholic acid (OCA) may be considered depending on the disease severity. For steatorrhea, supplementation with medium-chain triglycerides and a low-fat diet is recommended. Fat-soluble vitamin deficiencies should be addressed with supplementation of vitamins A, D3, and K, along with calcium. Severe pruritus may be managed with ion-exchange resins like cholestyramine.
Prognosis
The prognosis of PBC varies widely. Symptomatic patients have an average survival time of 10–15 years. In patients with esophageal or gastric varices, the 3-year survival rate is only 60%. Poor prognostic factors include lack of response to UDCA, advanced age, progressive elevation of serum total bilirubin, GP210 positivity, declining liver synthetic function, and continued histological progression of the disease.