1. Introduction
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic autoimmune liver disease that primarily targets the small bile ducts within the liver. This immune-mediated destruction leads to cholestasis, a reduction in bile flow, and if left untreated, can progress to cirrhosis and liver failure. A hallmark of PBC is the presence of anti-mitochondrial antibodies (AMA) in the serum, a key diagnostic marker in the vast majority of cases. Autoreactive T cells also play a significant role in the pathogenesis of PBC. While considered a rare disease, the reported incidence of PBC has been on the rise, potentially due to increased awareness, improved diagnostic tools, and more widespread routine liver function testing, rather than a genuine increase in disease occurrence. Many individuals with PBC are asymptomatic at diagnosis, often identified incidentally through routine liver blood tests. Symptomatic patients commonly present with fatigue and pruritus (itching). The cornerstone of Primary Biliary Cirrhosis Diagnosis relies on a combination of factors: persistently elevated serum alkaline phosphatase (ALP), the presence of AMA, and histological findings from a liver biopsy consistent with PBC. In cases where AMA is absent, anti-nuclear antibodies (ANA) specific to PBC can be informative and might suggest a more aggressive disease progression. Ursodeoxycholic acid (UDCA) remains the primary and most effective treatment for PBC, capable of slowing or halting disease progression in many patients. However, a subset of individuals do not respond adequately to UDCA, highlighting the ongoing need for novel therapeutic strategies.
Alt text: Microscopic view of liver tissue exhibiting bile duct damage characteristic of primary biliary cirrhosis, a key histological feature in primary biliary cirrhosis diagnosis.
2. Epidemiology of PBC
2.1 Global Prevalence and Incidence
Epidemiological studies have reported considerable variability in PBC prevalence rates, ranging from 19 to as high as 402 cases per million individuals across different geographical regions. However, serological surveys conducted on large, seemingly healthy populations have revealed AMA prevalence as high as 0.5%. This discrepancy in reported incidence and prevalence may stem from genuine population-based differences, variations in diagnostic criteria applied, case-finding methodologies, and the level of physician awareness regarding PBC. A latitudinal pattern in PBC occurrence has been suggested, indicating a higher prevalence in Northern European and North American regions. This is supported by the highest reported incidence and prevalence rates in Scandinavia, Great Britain, and the northern Midwest of the United States. However, this geographical trend is not universally consistent, as evidenced by the high prevalence observed in certain Southern European areas like Sabadell, Spain. Some researchers suggest that PBC incidence is indeed increasing. For instance, studies in Sheffield and Newcastle-upon-Tyne, UK, documented increases in incidence rates between the 1970s and 1990s. This rise was mirrored by prevalence rates exceeding 200 cases per million by the mid-to-late 1990s. The question remains whether this increase reflects a true rise in disease incidence or is a consequence of enhanced detection of milder, asymptomatic cases, or slowly progressive PBC. Notably, the age at diagnosis, typically in the mid-to-late 50s, has remained relatively consistent over different study periods.
2.2 PBC Risk Factors
A striking female predominance is a hallmark of PBC, even among autoimmune diseases known for affecting women more frequently. The female to male ratio in PBC is reported to be as high as 10:1. Interestingly, the presence of serum AMA in the general population shows a less skewed sex ratio, suggesting that the progression from initial autoantigen loss of tolerance to clinically evident liver disease is more likely in females.
Beyond female sex, several environmental factors have been implicated as potential risk factors for PBC. These include a family history of PBC, a history of urinary tract or vaginal infections, co-existing autoimmune diseases, smoking (current or past), previous pregnancies, and exposure to certain chemicals like those found in nail polish and hair dyes. The role of chemical and infectious exposures has been further explored, with geographical clustering of cases observed near toxic waste sites in New York City and space-time clustering in North East England, lending support to these hypotheses.
Alt text: Visual representation of risk factors linked to primary biliary cirrhosis diagnosis, including genetics, environmental exposures, and autoimmune conditions, highlighting key elements in understanding primary biliary cirrhosis diagnosis.
3. Diagnosis of PBC
Primary biliary cirrhosis diagnosis should be considered when clinical findings suggest cholestasis, such as elevated serum alkaline phosphatase (ALP), jaundice, pruritus, or in cases of unexplained cirrhosis. A definitive primary biliary cirrhosis diagnosis can be established if at least two out of the following three criteria are met:
- Presence of serum AMA: Detected at titers ≥ 1:40.
- Elevated ALP: Unexplained persistent elevation of serum ALP ≥ 1.5 times the upper limit of normal (ULN) for at least 24 weeks.
- Compatible liver histology: Liver biopsy findings consistent with PBC, specifically non-suppurative cholangitis and interlobular bile duct injury (refer to Table 1 for diagnostic criteria).
In addition to these core criteria, patients with PBC often exhibit elevated aminotransferases and increased serum immunoglobulins, particularly IgM.
Table 1. Diagnostic Criteria and Clinical Features of Primary Biliary Cholangitis
| 2 of 3 Required Criteria |
|---|
| Serum alkaline phosphatase > 1.5 times ULN1 |
| Presence of AMA2 |
| Liver histology with non-suppurative destructive cholangitis and destruction of interlobular bile ducts |
| Other Characteristic Clinical Features |
| PBC-specific ANA3 (Sp100 and gp210) |
| Elevated serum IgM |
| Hypercholesterolemia/Xanthomas |
| Sicca syndrome |
| Pruritus |
| Fatigue |
1ULN, upper limit of normal; 2AMA, anti-mitochondrial antibodies; 3ANA, anti-nuclear antibodies
3.1 AMA Tests in Primary Biliary Cirrhosis Diagnosis
The detection of AMA in the serum of PBC patients was first reported in 1965. Subsequently, in 1987, the antigens targeted by AMA were identified and cloned. These antigens, historically referred to as M2 antigens, include the lipoylated domains of the E2 and E3 binding protein (E3BP) components of the pyruvate dehydrogenase complex (PDC-E2), as well as the E2 components of the 2-oxo glutarate dehydrogenase (OADC-E2) and branched-chain 2-oxo acid dehydrogenase (BCOADC-E2) complexes.
Several methodologies are available for AMA testing. Historically, indirect immunofluorescence (IIF) microscopy was commonly used in clinical laboratories. However, IIF is limited by its specificity and sensitivity. Enzyme-linked immunoassays (EIA) utilizing recombinant proteins of the three known autoantigens are now widely available and are the most frequently used method in commercial laboratories due to their improved accuracy. The titer of AMA does not correlate with disease severity. The clinical significance of AMA-positive individuals without concurrent biochemical abnormalities remains a subject of debate. However, it is generally recommended to monitor these individuals with annual liver biochemistry tests to detect early signs of PBC development.
In cases where AMA is negative, primary biliary cirrhosis diagnosis relies on elevated serum ALP levels and compatible liver histology. Imaging techniques such as magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) may be helpful in excluding primary sclerosing cholangitis or other conditions that can cause chronic cholestasis. The presence of PBC-specific anti-nuclear antibodies (ANA) with rim-like and multiple nuclear dot patterns can provide further supportive evidence. Commercially available EIA tests for gp210 and Sp100 can detect most of these PBC-specific ANAs. Although AMA-negative PBC patients appear to have a similar disease course compared to AMA-positive cases, some studies suggest a potential association between PBC-specific ANA positivity and more severe disease progression.
3.2 Liver Histology in Primary Biliary Cirrhosis Diagnosis
The necessity of liver biopsy in AMA-positive PBC cases remains a point of discussion. While not mandatory for primary biliary cirrhosis diagnosis in AMA-positive patients when biochemical and serological criteria are met, liver biopsy can provide valuable clinical information, particularly for disease staging and in the context of clinical trials. Histological staging in PBC typically utilizes Ludwig’s and Scheuer’s classifications, ranging from stage I (portal-tract inflammation with lymphoplasmacytoid infiltrates and bile duct loss) to stage IV (cirrhosis). However, clinical management decisions are generally not significantly altered by biopsy findings, except perhaps for initiating hepatocellular carcinoma surveillance if cirrhosis is confirmed. Liver biopsy becomes essential for primary biliary cirrhosis diagnosis when AMA is absent to differentiate AMA-negative PBC from other conditions presenting with cholestasis, such as small-duct primary sclerosing cholangitis, sarcoidosis, or drug-induced cholestasis.
3.3 PBC-Autoimmune Hepatitis Overlap Syndrome
At presentation, many PBC cases exhibit mild elevations in serum aminotransferases, and a significant proportion (up to 50%) may show mild interface hepatitis on liver biopsy and test positive for ANA. These overlapping features can lead to a misdiagnosis of PBC-autoimmune hepatitis (AIH) overlap syndrome. However, true PBC/AIH overlap, characterized by more severe hepatocellular injury and features of AIH, such as responsiveness to corticosteroids and other immunosuppressants, is estimated to occur in less than 10% of PBC patients. While several diagnostic criteria for PBC/AIH overlap have been proposed, none are universally validated or accepted. PBC/AIH overlap should be considered when the ALP to aminotransferase ratio is less than 1.5, serum IgG is elevated, and anti-smooth muscle antibodies are present at titers greater than 1:80. In these suspected overlap cases, the use of immunosuppressive agents may be warranted.
Alt text: Diagnostic algorithm for primary biliary cirrhosis diagnosis, illustrating the roles of AMA testing, alkaline phosphatase levels, and liver biopsy in confirming primary biliary cirrhosis diagnosis.
4.0 Natural History of PBC
The natural history of PBC appears to have become less severe in recent years. This improvement may be attributed to earlier primary biliary cirrhosis diagnosis and the identification of milder disease forms. However, the observed decrease in liver transplantation rates for PBC in Europe and North America suggests a genuine shift in the disease’s natural course, coinciding with the introduction and widespread use of ursodeoxycholic acid (UDCA) for PBC treatment. Prior to the UDCA era, the median time from diagnosis to symptom onset was 2 to 4.2 years, and survival was significantly reduced compared to the general population. Several prognostic models have been developed to predict disease progression and survival in PBC. The Mayo risk score, incorporating factors such as age, total serum bilirubin, serum albumin, prothrombin time, and fluid retention, is the most widely validated and used prognostic tool.
5.0 Treatment of PBC
5.1 Ursodeoxycholic Acid (UDCA)
Ursodeoxycholic acid (UDCA) remains the only established and first-line treatment for PBC, recommended at a daily dose of 13–15 mg/kg, typically divided into two or three administrations. UDCA is generally well-tolerated, with minimal adverse effects, although moderate weight gain has been reported. Randomized, placebo-controlled trials of sufficient duration have demonstrated that UDCA can prevent portal hypertension and the development of esophageal varices, and significantly delay the need for liver transplantation. Furthermore, UDCA treatment has been shown to improve survival rates, particularly in patients with elevated baseline serum bilirubin levels (greater than 1.4 mg/dl). Importantly, survival rates for UDCA-treated patients with early-stage PBC (stage I or II) are comparable to those of age-matched healthy individuals.
Despite the proven efficacy of UDCA, a significant proportion of PBC patients, up to 40%, exhibit an incomplete biochemical response to UDCA therapy and are at increased risk of disease progression. Various response criteria have been developed and validated to define biochemical response to UDCA (Table 2). The Paris I criteria have been identified as the most robust predictor of prognosis in a large UK study involving over 2,300 PBC patients. According to the Paris I criteria, approximately 79% of PBC patients treated with adequate UDCA doses for at least 2 years achieved a biochemical response. A major challenge in the development of new PBC therapies lies in determining whether regulatory agencies will accept biochemical response criteria as clinically meaningful endpoints for drug approval.
Table 2. Definitions of Biochemical Response After 1 Year of UDCA Therapy
| Paris I | All of the following: – ALP level ≤ 3 × ULN – AST level ≤ 2 × ULN – Normal bilirubin level |
|---|---|
| Paris II | All of the following: – ALP and AST level ≤ 1.5 × ULN – Normal bilirubin level |
| Barcelona | Decrease in ALP level > 40% of baseline level or a normal level |
| Toronto | ALP level normalization |
| Rotterdam | Normalization of abnormal bilirubin and/or albumin levels |
5.2 Methotrexate
Several case series have reported encouraging results with methotrexate, used either alone or in combination with UDCA, in PBC patients. One of the more promising studies showed that methotrexate combined with colchicine improved serum alkaline phosphatase, aminotransferases, liver histology, and pruritus in a significant proportion of UDCA non-responders. However, a meta-analysis of five trials found no benefit of methotrexate on mortality or liver transplantation need, and a large controlled trial reported no survival benefit or reduction in liver transplantation risk with the addition of methotrexate to UDCA. Therefore, methotrexate is not currently a recommended standard therapy for PBC.
5.3 Obeticholic Acid (OCA)
Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist with pleiotropic effects, including the regulation of bile acid synthesis. OCA has shown promising results in Phase 2 clinical trials as an add-on therapy to UDCA in PBC patients with an incomplete response to UDCA. The most common side effect of OCA is pruritus. Phase 3 clinical trials are underway to further evaluate the efficacy and safety of OCA in this patient population. OCA has been approved for use in PBC in some countries for patients with an inadequate response to UDCA or who are intolerant to UDCA.
5.4 Rituximab
Rituximab, a humanized anti-CD20 monoclonal antibody, initially developed for B-cell lymphomas and later used in rheumatoid arthritis, has been investigated in PBC patients with incomplete responses to UDCA in two open-label studies. These studies demonstrated only modest effects. Given the potential for serious toxicities, including progressive multifocal leukoencephalopathy, and cautionary findings in animal models of PBC, further development of rituximab for PBC is unlikely.
5.5 Novel Therapeutic Approaches
The development of animal models of PBC has significantly advanced our understanding of the immunological mechanisms underlying PBC initiation and progression. These models have also been instrumental in pre-clinical testing of novel therapeutic strategies. For example, cytotoxic T lymphocyte antigen 4 immunoglobulin has shown promise in reducing liver inflammation in a murine model of PBC induced by the xenobiotic 2-octynoic acid. Ongoing research continues to explore new therapeutic targets and approaches for PBC, particularly for patients who do not respond adequately to UDCA.
Highlights
- Primary biliary cholangitis (PBC) is a chronic autoimmune disease targeting the biliary epithelial cells of the liver.
- Primary biliary cirrhosis diagnosis is based on at least 2 of 3 key criteria: persistent elevation of serum alkaline phosphatase, presence of anti-mitochondrial antibodies (AMA), and liver biopsy histology consistent with PBC.
- Ursodeoxycholic acid (UDCA) treatment delays disease progression in most PBC cases, but new therapies are needed for UDCA non-responders.
Footnotes
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