Primary Biliary Cholangitis: The Latest Data on an Evolving Disorder

Rowen K. Zetterman, MD


January 04, 2019

What we once called "primary biliary cirrhosis" is now termed "primary biliary cholangitis" (PBC).[1] The original name never quite fit, given that patients with PBC usually do not have cirrhosis at the time of clinical presentation.[2] "Chronic nonsuppurative destructive cholangitis" was an early attempt at renaming the disorder,[3] but "primary biliary cirrhosis" was too ingrained in the language of physicians at that time, so it never caught on.

PBC is a cholestatic, autoimmune disorder characterized by intrahepatic bile duct destruction, mononuclear portal inflammation, cholestasis, periportal fibrosis, and eventual cirrhosis.[4] The disorder predominantly affects women (nine women for every man) and usually manifests in midlife between 30 and 65 years of age, though it can develop earlier or later in age as well.[4] The majority of patients (95%) will have circulating antimitochondrial antibodies (AMAs) that develop before the onset of clinical disease.[5] AMAs are also observed in approximately 1% of otherwise normal adults.

Once a diagnosis of PBC is established, progression to cirrhosis within 4 years can occur in untreated patients.[2] Today, patients are often diagnosed at earlier stages, so the time of progression to advanced disease may take longer. Progression of disease is also delayed by currently available effective therapies.[6] Elevation of serum alkaline phosphatase and bilirubin levels at the time of diagnosis are predictive of outcome in untreated patients.[7] Patients with an alkaline phosphatase level less than twice the upper limit of normal (ULN) and a serum bilirubin level less than onefold elevated at 1 year after diagnosis have better survival than those with higher levels.

The natural history of PBC may also be changing.[8] Now, patients tend to be older at initial diagnosis; have milder clinical disease at presentation; and have improved response to ursodeoxycholic acid (UDCA), lower decompensation rates, and longer transplant-free survival. Whether this is related to earlier diagnosis of disease due to routine liver enzyme testing of adults or to changes in response to triggering agents for the disease is unclear.

The pathogenesis of PBC remains unknown. It seems evident that it is an autoimmune disorder, given its association with other autoimmune conditions, such as sicca complex and Hashimoto thyroiditis, and the presence of circulating AMAs.[6] Genetic susceptibility[9] may play a role, as observed by the familial tendency[10]; the greater co-occurrence of PBC in identical twins[11]; and the increased risk for concurrent disease in first-, second-, and third-degree relatives of affected patients.[12]

Clinical Presentation and Diagnosis

The clinical features of PBC are variable at presentation. Patients may be asymptomatic or present with slowly progressive or rapidly progressive clinical disease.[4] For those asymptomatic at presentation, symptoms usually develop within 5 years of diagnosis. Symptoms and signs[4,6] include fatigue; pruritus that typically precedes jaundice; bone disease related to osteopenia; hypercholesterolemia; and associated autoimmune disorders,[13] including sicca complex or Sjögren syndrome, hypothyroidism, sprue, pancreatic insufficiency, and scleroderma. Eventual cirrhosis is likely for patients with untreated PBC with subsequent portal hypertension and its complications. Patients can also present with esophageal varices from presinusoidal portal hypertension resulting from periportal fibrosis in the absence of cirrhosis.

AMA-negative PBC[6] occurs in 5% of cases. These patients may require a liver biopsy to establish the diagnosis, though other presenting symptoms and signs may indicate the likelihood of PBC. Antinuclear antibody patterns at immunofluorescence, such as multiple nuclear dot and rim-like patterns[14] corresponding to gp210 and sp100 antigens on enzyme-linked immunosorbent assay,[9] may be helpful for diagnosis in AMA-negative patients, given their specificity for PBC.

Patients with PBC need continuing follow-up, treatment, screening for complications of disease, and referral to liver transplant centers with development of cirrhosis or hepatocellular carcinoma.[15]

Patients with PBC[4,6] are typically female and in middle age, have an AMA titer > 1:40; and have pruritus and an elevated alkaline phosphatase level, immunoglobulin M level, cholesterol level, and erythrocyte sedimentation rate. An elevated alkaline phosphatase level in an AMA-positive woman is highly suggestive of the diagnosis of PBC.[15]

An overlap syndrome between PBC and autoimmune hepatitis[16] can develop in some patients, be more clinically aggressive than PBC alone, and may require treatment of both conditions. Progression of PBC to predominate autoimmune hepatitis also occurs.

Fat-soluble vitamin deficiencies related to fat malabsorption from cholestasis occur. Nontropical sprue or celiac disease,[17,18] autoimmune pancreatitis,[19] and pancreatic insufficiency[18] may also be associated.

Radiographic imaging at initial presentation (eg, hepatic ultrasound) should be considered to exclude other causes of biliary tract disease. Portal hypertension related to presinusoidal fibrosis or cirrhosis should also be excluded, especially if evidence of hepatic encephalopathy, ascites, or esophageal varices is identified.

Hepatocellular carcinoma occurs in patients with PBC with a risk similar to other causes of cirrhosis (1%-6% per year).[6] For patients who develop cirrhosis from PBC, 6-month surveillance for hepatocellular carcinoma should be done using ultrasound or other imaging modalities.

Management Considerations

New guidelines for the treatment and management of patients with PBC are available from the British Society of Gastroenterology/UK PBC Group[15] and the European Association for the Study of the Liver.[20]

Pruritus is a common component of PBC[15,21,22] that interferes with quality of life but not prognosis. Pruritus appears to be related to cholestasis and perhaps to the distribution of bile acids within the skin. Symptoms are often worse in the evening and at night[21] and can develop at any time in the progression of PBC. As a rule of thumb, intrahepatic cholestasis from such conditions as PBC are often associated with itching first and later jaundice, whereas patients with extrahepatic cholestasis (eg, extrahepatic bile duct obstruction) may develop jaundice before itching occurs.

First-line therapy for pruritus in PBC should include nonabsorbable bile acid-binding resins, such as cholestyramine.[22,23] If response to cholestyramine is inadequate, you can consider using rifampin.[22] For rifampin-treated patients, liver tests and circulating blood counts should be obtained periodically. Opioid antagonists (eg, naltrexone) can also be useful in selected patients.[15,23] UDCA is not effective in reducing pruritus.[22]

Sicca complex symptoms are common, occurring in approximately 50% of patients with PBC.[15,17] This autoimmune disorder is associated with destruction of lacrimal and salivary glandular epithelium, resulting in dry eyes and dry mouth.[24] Women with PBC are more likely to develop symptoms of sicca complex than are men. Associations with sicca complex include vaginal dryness, oral candidiasis, dysphagia, and dental caries.[15] Therapy should include topical agents, such as artificial tears, oral lubrication agents, and vaginal moisturizers.[15,20]Pilocarpine may reduce symptoms in those with poor response to topical agents.[24,25]

Bone disease is a concern in patients with PBC. Osteopenia or hepatic osteodystrophy can develop.[26,27] Metabolic bone disease associated with PBC includes both osteomalacia and osteoporosis.[27] Fractures, especially of vertebrae, may result from minimal trauma. Bone mineral density testing at the time of PBC diagnosis should be completed, with periodic retesting during disease follow-up. Calcium supplementation for all patients, with PBC and vitamin D supplementation for those with suspected osteomalacia[27] or use of antiresorptive agents, such as bisphosphonates, should be considered for those with osteoporosis and reduced bone mineral density.[28]

Hypercholesterolemia is common in PBC.[20] Whether a significant increase in cardiovascular mortality occurs as a consequence of hypercholesterolemia in PBC is unclear.[29,30] For those patients with associated metabolic syndrome or other cardiovascular risk factors, treatment of hypercholesterolemia can include oral statins,[30] which appear to be safe and will reduce circulating cholesterol levels.[31,32]

Chronic fatigue is a common debilitating symptom in patients with PBC[33] that does not respond to treatment and may persist beyond liver transplantation. No specific treatment is available. In a recent study, rituximab did not improve fatigue in patients with PBC.[34]

Treating PBC

UDCA treatment of patients with PBC slows progression of clinical disease,[35,36] especially in those with early disease.[36,37] UDCA results in enrichment of biliary bile acids,[38] produces changes to the bile acid pool, increases ductular secretion, and may provide anti-inflammatory and cytoprotective effects.[39]

UDCA is recommended as first-line therapy for patients with PBC at a dose of 13-15 mg/kg/day.[20] UDCA can reduce biochemical parameters of cholestasis in treated patients.[15]

Analysis of multicenter trials of patients with moderate disease[40] and long-term follow up of treated patients[41] indicate that patients receiving UDCA have improved survival and reduced need for liver transplantation. Those with early-stage disease have slower progression of hepatic fibrosis[42] during UDCA therapy. Patients with early disease who respond to UDCA treatment have survival rates similar to those of the general population[43] and to age- and gender-matched controls.[44]

Not all patients with PBC will respond to UDCA,[45] and patients treated with UDCA may still have progression of PBC.[46] Inadequate response to UDCA is defined as an alkaline phosphatase level > 1.67 times ULN or an elevated bilirubin < 2 times ULN[15] despite treatment.

Obeticholic acid (OCA) is a farnesoid X receptor agonist and a semisynthetic analogue of chenodeoxycholic acid.[47] Prior studies of patients with PBC receiving OCA plus UDCA or OCA monotherapy have demonstrated a biochemical response to OCA treatment.[48] OCA is considered a second-line therapy for patients with PBC[15,20] and is approved in the United States for those who do not respond or have an inadequate response to UDCA. It is also available as monotherapy for patients intolerant of UDCA.[15]

Patients are initiated on 5 mg/day of OCA and increased to 10 mg/day at 3 months if there is inadequate improvement in serum alkaline phosphatase and bilirubin levels.[20] For those with advanced liver disease from PBC, reduced OCA dosage should be used as defined in the current product insert with the drug. The addition of OCA to the treatment of patients with PBC will substantially increase the overall cost of lifetime treatment.[49]

Fibrates (bezafibrate and fenofibrate) have also been evaluated in the treatment of patients with PBC who have an inadequate response to UDCA.[50,51,52] Fibrates coupled with UDCA improve biochemical response, especially in those with early disease.[42,51] Long-term effectiveness of fibrates on the clinical outcome of PBC remains to be determined,[49] and fibrates are not currently approved for PBC treatment.

Liver transplantation remains an important treatment for those with complications of advanced liver disease from PBC. Recurrent PBC may develop in the new graft after liver transplantation.[53]

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