Primary Biliary Cholangitis
Primary Biliary Cholangitis (PBC), formerly known as primary biliary cirrhosis, is a chronic, progressive, autoimmune cholestatic liver disease characterized by the immune-mediated destruction of small intrahepatic bile ducts. The pathogenesis involves a complex interplay of genetic predisposition and environmental triggers that result in the loss of immune tolerance, primarily targeting the biliary epithelial cells. This leads to chronic nonsuppurative cholangitis, progressive bile duct loss, cholestasis, and eventually fibrosis and cirrhosis of the liver. The disease is associated with elevated serum antimitochondrial antibodies (AMAs) and various other autoantibodies. Health impacts include progressive liver dysfunction, pruritus, fatigue, hyperlipidemia, fat-soluble vitamin deficiencies, and, in advanced stages, portal hypertension, hepatic decompensation, and increased risk of hepatocellular carcinoma. Without effective intervention, PBC can significantly impair quality of life and reduce life expectancy due to end-stage liver disease.
This type is characterized by mild or asymptomatic disease, often detected through routine laboratory testing revealing elevated cholestatic liver enzymes, particularly alkaline phosphatase. Histologically, there is portal inflammation with lymphocytic infiltration and mild bile duct damage, but preserved overall liver architecture. Patients may have minimal or nonspecific symptoms such as fatigue or pruritus.
In advanced-stage PBC, there is significant destruction of intrahepatic bile ducts, marked cholestasis, and progressive hepatic fibrosis leading to cirrhosis. Clinical manifestations include jaundice, severe pruritus, xanthomas, portal hypertension, and complications of hepatic insufficiency. Histology demonstrates loss of bile ducts, bridging fibrosis, and nodular regeneration.
This variant involves features of both primary biliary cholangitis and autoimmune hepatitis (AIH). Patients exhibit serological and histological characteristics of both diseases, such as elevated transaminases and interface hepatitis in addition to cholestatic features. Overlap syndrome carries a higher risk of rapid progression and may require distinct therapeutic approaches.
Primary Biliary Cholangitis predominantly affects middle-aged women, with a female-to-male ratio of approximately 9:1. The estimated prevalence varies geographically, ranging from 20 to 40 cases per 100,000 population in North America and Northern Europe, with lower rates reported in Asia and other regions. The incidence is estimated at 1.5 to 5 cases per 100,000 persons per year. The typical age of onset is between 40 and 60 years. Familial clustering and higher concordance in monozygotic twins suggest a genetic predisposition, and several HLA and non-HLA gene associations have been identified. Environmental factors, such as urinary tract infections, cigarette smoking, and exposure to certain chemicals, have been implicated as potential triggers. Despite improved outcomes with modern therapies, PBC remains a significant cause of liver-related morbidity and mortality, especially in untreated or advanced cases.
The diagnosis of Primary Biliary Cholangitis is established through a combination of clinical, biochemical, serological, and histopathological criteria. The hallmark biochemical finding is a persistent elevation of serum alkaline phosphatase and gamma-glutamyl transferase, typically with mild to moderate increases in aminotransferases. The presence of serum antimitochondrial antibodies (AMA), particularly the M2 subtype, is highly specific and found in approximately 90–95% of patients. In AMA-negative cases, diagnosis relies on the presence of other PBC-specific autoantibodies such as anti-gp210 or anti-sp100, along with compatible clinical and biochemical features. Liver biopsy is not routinely required but may be performed in atypical cases, overlap syndromes, or to assess the degree of fibrosis. Histological examination reveals chronic nonsuppurative destructive cholangitis and interlobular bile duct loss. Imaging studies, such as abdominal ultrasound or magnetic resonance cholangiopancreatography, are utilized to exclude extrahepatic biliary obstruction and other causes of cholestasis. Diagnostic criteria generally require two of the following three: (1) elevated alkaline phosphatase for at least six months, (2) positive AMA, and (3) compatible liver histology.
Ursodeoxycholate, also known as ursodeoxycholic acid or ursodiol, is a bile acid used as a first-line pharmacological therapy for Primary Biliary Cholangitis, functioning to improve bile flow, reduce cholestasis, and delay disease progression. Obeticholic acid is a farnesoid X receptor agonist indicated for the treatment of PBC in adults, either as monotherapy in those intolerant to ursodeoxycholic acid or as an adjunct in patients with an inadequate response to ursodeoxycholic acid, working to modulate bile acid synthesis and decrease hepatic inflammation. Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist that has been investigated for its potential role in improving cholestasis and reducing liver inflammation in patients with PBC. Seladelpar lysine is a selective PPAR delta agonist that has been evaluated for the management of PBC, aiming to normalize cholestatic markers and provide symptomatic relief.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | elafibranor (Rec INN; USAN) | 923978-27-2 | C22 H24 O4 S | 384.489 |
 | seladelpar lysine (Rec INNM) | 851528-79-5 (free base); 928821-40-3 | C21 H23 F3 O5 S . C6 H14 N2 O2 . 2 H2 O | 626.683 |
 | obeticholic acid (Prop INN; USAN) | 459789-99-2 | C26 H44 O4 | 420.625 |
 | ursodeoxycholate; ursodeoxycholic acid (Prop INN; JAN); ursodiol (USAN; BAN) | 128-13-2 | C24 H40 O4 | 392.572 |
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