Diagnosis and treatment of primary biliary cholangitis

Abstract

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

Case report

A 53-year old woman presents with severe fatigue and progressive pruritus for 5 months. Physical examination reveals jaundiced sclera, blood test results show elevated parameters of total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma-glutamyltranspeptidase (GGT). Serologies for viral hepatitis are negative. There is selective elevation of immunoglobulin M (IgM) and serology reveals antimitochondrial antibodies (AMA) at high titer. An abdominal ultrasound remains without signs of advanced liver disease and transient elastography (TE) is consistent with slight to moderate fibrosis (9.1 kPa).

Diagnosis of PBC

Timely diagnosis of primary biliary cholangitis (PBC) can be challenging because it is a rare disease and many patients present with asymptomatic elevation of liver enzymes. Indeed, at the time of diagnosis only a minority of the patients have symptoms such as pruritus, upper right quadrant abdominal pain, and fatigue, which are non-specific. PBC should be suspected in patients with an otherwise unexplained persistent elevation of serum ALP, particularly in middle-aged women as 90% of patients are female and the majority diagnosed between their 4^th and 6^th decade. In this setting, the presence of AMA or other PBC-specific anti-nuclear antibodies is sufficient to confirm the diagnosis and liver histology is not required.^1,2

Biochemical abnormalities and immunological markers

Elevation of ALP (and GGT) is the predominant biochemical feature of PBC, but other liver tests may be abnormal as well. ALT and AST levels are usually mildly elevated, as higher levels may be suggestive of co-existing autoimmune hepatitis (AIH). Increased serum immunoglobulin concentrations, particularly IgM, are also common in PBC. Hyperbilirubinemia is frequently observed in advanced disease but may present earlier than hypoalbuminemia and thrombocytopenia due to the cholestatic nature of the disease.^1,2

Up to 95% of patients with PBC have positive AMA titers (>1:40).³ However, positive serum AMA alone, without cholestasis, is not sufficient to diagnose PBC. Only one out of six AMA positive subjects with normal ALP developed PBC within 5 years.⁴ Other autoantibodies associated with PBC are antinuclear antibodies (ANA), which are present in approximately 50% of the patients. Within the wide spectrum of ANA target antigens, anti-gp210 (nuclear rim pattern on immunofluorescence) and anti-sp100 (multiple nuclear dots pattern) have been identified to be highly specific for PBC⁴ and are sufficient to establish the diagnosis.^1,2 Enzyme-Linked Immuno Sorbent Essay (ELISA) or immunoblot should be used to verify the presence of PBC-specific autoantibodies.²

Role of imaging

Although abdominal ultrasound does not contribute to the diagnosis of PBC, it is highly recommended for ruling out other causes of cholestasis (e.g. extra-hepatic biliary obstruction) and assessment of liver disease severity.¹

Liver stiffness measurement

Currently, TE (e.g. Fibroscan) is considered one of the most accurate surrogate markers (≥90% sensitivity and specificity) for the detection of severe liver fibrosis or cirrhosis in patients with PBC. This has a prognostic implication, because liver elasticity >9.6 kPa was associated with a 5-fold increased risk of decompensated cirrhosis, liver transplantation (LT) and death. In addition, an increase in liver stiffness over time seems to be an important prognostic factor of poor outcome.⁵ Although the use of TE in patients with PBC can thus be considered, further research is needed to validate these findings and to assess its utility in routine clinical care.

Liver biopsy

Histologically, PBC is characterized by non-suppurative cholangitis and the destruction of the small intrahepatic bile ducts. Destruction of the bile ducts may lead to progressive bile duct loss (ductopenia), fibrosis and eventually cirrhosis.^6,7 Although liver histology can be used for prognostication, non-invasive risk assessment is usually preferred. Still, as for the few patients without PBC-specific autoantibodies, liver biopsy remains essential for those in whom co-existence of AIH or non-alcoholic steatohepatitis is suspected.^1,2

Natural history

The disease progression rate varies greatly between individual patients but is largely characterized by the development of cirrhosis and its sequelae. Data on the untreated natural history are scarce, but one of the first clinical trials in PBC showed a rather fast histological progression in the absence of effective treatment. Within 4 years, progression towards cirrhosis was observed in 40% of patients with an early histological disease stage (stage I or II) and in 68% of patients with advanced disease (stage III).⁸ In the case of cirrhosis, patients are at risk of liver failure and develop hepatocellular carcinoma at an annual rate of 3–5%. In one of the largest community-based cohort studies, among 770 PBC patients in Northeast England, the median survival after PBC diagnosis was 9.3 years. This translated into a standardized mortality risk index of 2.9. During a follow-up of 5 years, 15% of the patients developed liver failure (i.e. ascites, variceal bleeding, hepatic encephalopathy or hyperbilirubinemia).⁹ After occurrence of decompensation, the subsequent survival was reported to be poor with a median survival of approximately 2 years.^10,11

Patients with PBC are at risk of developing extrahepatic complications. In comparison to the normal population, there is a 32-fold increased risk of osteoporosis.¹² Furthermore, hyperlipidemia is observed in up to 76% of PBC patients.¹³ Although it is a well-established risk factor for cardiovascular disease in the general population, reports within the population with PBC vary. Irrespective of the lipid spectrum, recent meta-analyses indicated a 57% excess risk of coronary artery disease in the population with PBC.¹⁴

Therapies

First-line treatment

Ursodeoxycholic acid (UDCA) is a choleretic and hydrophilic endogenous bile acid that was initially developed for treating bile stones. In patients who received UDCA, a decline of liver enzymes was observed, which led to various clinical trials to evaluate the effect of UDCA in PBC. These studies showed an improvement of liver enzymes and bilirubin. Although bilirubin is an early well-established independent predictor of prognosis of PBC, Lammers et al. recently substantiated the prognostic value of ALP as surrogate marker of clinical outcome in addition to bilirubin.¹⁵ In their clinical trial, Corpechot and colleagues showed that 7% of the patients treated with UDCA progress to cirrhosis annually, opposed to 34% in the placebo group.¹⁶ Still, it was recently estimated that even with UDCA, approximately 40% of PBC patients developed cirrhosis within 10 years of follow-up.¹⁷ With respect to clinical outcome, recent meta-analyses of randomized controlled trials (RCT) by the Cochrane hepatobiliary group again failed to show a difference in LT-survival between placebo and UDCA-treated patients.¹⁸ However, the available RCTs included small numbers of patients, assessed insufficient dosages of UDCA, and had only short follow-up, and are thus inadequate to reliably evaluate treatment effect on survival. As UDCA is safe in the optimal dose of 13–15 mg/kg/day and has only limited side effects (mainly gastrointestinal), current guidelines have not refrained from recommending UDCA as the standard first-line therapy in PBC. Recently, this general recommendation was supported by the results of a large multicenter long-term follow-up cohort among 3902 patients.¹⁹ In this study, Harms et al. substantiated the therapeutic benefit of UDCA as the 10 year LT-free survival of the UDCA-treated patients was markedly higher compared to that of the untreated population (79.7% versus 60.7%, p<0.001). This positive association between UDCA and improved LT-free survival was present in all patients, irrespective of the baseline stage or grade of disease.

About 40% of patients, however, remain with an incomplete response to UDCA according to either the traditional biochemical response criteria (i.e. Paris I/II, Rotterdam, Barcelona, Toronto) or the recently proposed (continuous) GLOBE and UK-PBC scores, which are considered the most accurate prognostic models in PBC. On a positive note, the hazard of LT or death among these patients is still 1.8-fold lower compared to untreated patients, which highlights that UDCA should be initiated and continued for life. However, those with an incomplete response remain at elevated risk of cirrhosis. In a large international cohort 15% of the UDCA-treated patients developed cirrhosis-associated complications within 15 years, after which the median survival of 2 years is comparable to the untreated natural history.²⁰ The response criteria are thus highly relevant to select patients in need of additional second-line therapy, although more recent studies suggest complete normalization of ALP and a reduction of bilirubin to <0.6 times the upper limit of normal may be most desirable.²¹ Treatment algorithm is displayed in Figure 1.

Figure 1.

Treatment algorithm for primary biliary cholangitis (PBC). UDCA: ursodeoxycholic acid; OCA: obeticholic acid; AIH: autoimmune hepatitis; NASH: non-alcoholic steatohepatitis.

Second-line treatment options

Obeticholic acid

Obeticholic acid (OCA), a Farnesoid-X-Receptor-agonist with anti-cholestatic, anti-inflammatory and anti-fibrotic effects, serves as second-line therapy in PBC. In the randomized stage III clinical trial, POISE, patients with an suboptimal response to UDCA (i.e. ALP level ≥ 1.67x ULN or total bilirubin >ULN but < 2x ULN, after 1 year treatment with UDCA) or UDCA intolerance were treated additionally with OCA.²² Primary endpoint was defined as ALP below 1.67 times the upper limit of normal and normal bilirubin levels after 12 months of treatment. The primary endpoint was achieved in 45% of patients treated with a dose-escalating 5–10 mg regime and a fixed dose of 10 mg OCA opposed to 10% in the placebo group. Dose-dependent pruritus was the most common side effect (56% of patients with 5–10 mg OCA and 68% of patients with 10 mg OCA versus 38% of patients in the placebo arm). Pruritus led to treatment discontinuation in 10% in 10 mg group and in 1% in the 5–10 mg group. The Food and Drug Administration reported fatal outcomes in patients with advanced liver cirrhosis (Child-Pugh B and C) probably due to overdose of OCA. Therefore, patients with established liver cirrhosis should start with an initial dose of 5 mg/week and gradually increased up to a maximum of 2 × 10 mg per week. Meanwhile, long-term treatment results have been published confirming efficacy, by sustained reduction in markers of cholestasis (ALP, AST, GGT), and tolerability over a period of up to 6 years.²³ Pruritus remains a relevant side effect as it led to treatment discontinuation in 4% during the open-label extension phase.²⁴ Nevertheless, reliable data on inhibition of fibrosis progression in PBC and pharmacokinetic data in cirrhosis are still lacking.²⁵ OCA monotherapy has been licensed for patients with UDCA-intolerance. A 12-week trial showed an ALP reduction in 54% of patients with 10 mg OCA per day opposed to 0.8% of patients treated with placebo.²⁶ Multiple non-steroidal FXR agonists are being developed.

Bezafibrate

Bezafibrate is a pan-peroxisome-proliferator-activated receptor (PPAR) agonist that has beneficial effects on major biochemical markers in PBC, which have been shown in a meta-analysis of phase II trials.²⁷ In the BEZURSO phase III clinical trial, patients with insufficient response to UDCA monotherapy (but with different inclusion criteria than the POISE trial) were additionally treated with 400 mg/day bezafibrate versus placebo over 24 months.²⁸ The primary endpoints, normalization of ALT, ALP, albumin, total bilirubin and prothrombin index, were achieved by 31% of patients treated with UDCA and bezafibrate (vs. 0% of patients under placebo). Two-thirds of patients showed complete normalization of ALP levels. Liver stiffness, assessed via TE, decreased in 15% of patients treated with bezafibrate, whereas it increased in 22% of placebo-treated patients. Additionally, and of great importance to the population with symptomatic PBC, bezafibrate led to a significant improvement of pruritus. Still, bezafibrate is currently not registered for the treatment of PBC and thus used off-label when prescribed to PBC patients.

Side effects such as increases in serum creatinine and hepatotoxicity, occasionally myalgia, and rarely rhabdomyolysis have been reported. Increases in creatinine usually are not associated with significant nephropathy and may not require cessation of treatment. Bezafibrate is not available in the United States, where fenofibrate with a narrower PPAR-spectrum could be used. Newer and more selective PPAR agonists are being evaluated in phase II and III studies. Advantages and disadvantages of OCA and bezafibrate are displayed in Figure 2.

Figure 2.

Advantages and disadvantages of obeticholic acid (OCA) and bezafibrate.

Triple therapy (UDCA, OCA, bezafibrate)

Combination therapy of UDCA, OCA, and bezafibrate was initially evaluated in patients that showed no biochemical response in the POISE trial. After 6 months of triple therapy, the primary endpoint defined as ALP and bilirubin levels within the normal range was achieved in 44% of patients.²⁹ Recent data by Corpechot et al. confirmed the positive effect of triple therapy with UDCA, OCA, and bezafibrate in a proof-of-concept study.³⁰ Patients with an incomplete response to combination of UDCA with either OCA or fibrates showed improvement of biochemical liver tests and increased rates of ALP normalization after at least 12 weeks of triple therapy. Nevertheless, further studies for assessing the long-term efficacy and safety are required.

New drugs under investigation

Several new drugs are under clinical investigation, targeting different pathogenic processes in PBC. Farnesoid X receptors (FXR) and PPAR regulate bile acid homeostasis. Besides OCA, colifexor and tropifexor are non-steroidal FXR agonists in clinical development. In a Canadian retrospective study, Fenofibrate, a more selective PPAR-alpha agonist, in combination with UDCA showed improvement in surrogate endpoints in addition to fewer hard endpoints but with tendency of bilirubin increase in advanced liver fibrosis.³¹ Seladelpar, a PPAR-delta agonist, showed promising first results.³² However, the development of this drug was recently halted due to safety signals in follow-up biopsies within the fatty liver disease program. Elafibranor, a PPAR-alpha/delta dual agonist, was evaluated in a 12-week trial. This drug was well tolerated and induced reduction of ALP and inflammatory markers. Nevertheless, long-term benefits need to be proven.³³ Plasma membrane-bound G protein-coupled receptor and sphingosine-1-phosphate receptor 2 are other receptors regulating bile acid homeostasis but so far, agonists of these have not advanced into clinical trials. Budesonide, a drug with immunosuppressive effects and stimulation of biliary bicarbonate secretion, was reported to significantly reduce ALP without improvement in liver histology in a controlled trial, but the full paper has not been published yet.³⁴

Liver transplantation

Despite adequate treatment, a proportion of the patients develop end-stage liver disease and liver failure. For these patients, LT is the only therapeutic option. Other, more rare indications for LT in PBC are hepatocellular carcinoma and refractory pruritus. LT in PBC is associated with a favorable outcome with 5-year survival rates more than 80–85%.¹ Still, recurrence of PBC was observed in 22% of the patients after 5 years and 36% after 10 years, and was associated with graft loss and death.³⁵ The risk of PBC recurrence after LT might be related to the type of immunosuppression, as a lower risk has been described among those using cyclosporine.^35,36 A more recent report also suggested a lower risk of PBC recurrence (hazard ratio (HR) 0.42), graft loss (HR 0.44) and overall mortality (HR 0.67) among those patients who started preventive use of UDCA within 2 weeks of LT.³⁶

Monitoring and treatment of associated symptoms and complications

Pruritus occurs in 20–70% of PBC patients at any stage of disease. Besides non-pharmacological interventions, cholestyramine can be administered as therapy according to recent guidelines.^1,2 Rifampicin is effective but harbors a risk of hepatotoxicity thus liver function monitoring is required.¹ Other drugs such as naltrexone, sertraline, or histamines are available but without strong evidence in improving pruritus in PBC.³⁷ The positive effects of bezafibrate on pruritus were observed in a previous trial³⁸ and have now been confirmed in the FITCH trial, a placebo-controlled trial in patients with PBC and primary sclerosing cholangitis.³⁹ The primary endpoint of the study, a 50% reduction of pruritus, was achieved in 38% of patients in the bezafibrate treatment arm opposed to 12% in the placebo arm. These findings strengthen the positive effects of bezafibrate and provide further arguments for considering bezafibrate as first-line itch-therapy in PBC. Treatment options for pruritus are displayed in Figure 3.

Figure 3.

Treatment options for pruritus in primary biliary cholangitis (PBC)

Fatigue can severely impair health-related quality of life in the early stages of disease, is associated with increased mortality in PBC, and often persists even after LT. Exclusion of other potential reasons for fatigue such as hypothyroidism, depression, sleeping disorders, anemia or other medications is required.¹ Besides physical activity, modafinil has shown some positive effects in PBC patients, the frequent side effects, however, restrict its use in clinical practice.⁴⁰

As osteoporosis is a common complication in PBC patients, measurement of bone mineral density should be performed at baseline and every 2 years depending on the individual risk profile (e.g. severity of osteoporosis).^1,2 Substitution of vitamin D and calcium and treatment of osteoporosis should be offered according to current guidelines.^1,2,41

Sicca syndrome of the eyes, mouth and genitourinary tract is a frequent side complication in PBC and should be investigated and treated accordingly (e.g. eye drops, lubricants). In severe cases, the use of pilocarpine, cevimeline or other agents can be discussed after consulting with ophthalmologists.²

In the case of indication for hyperlipidemia treatment for cardiovascular risk profile, therapy does not differ from non-PBC patients.

Vaccination against hepatitis A and B should be offered to all PBC patients.

HCC screening via ultrasound should be executed every 6 months in patients with PBC and cirrhosis. Furthermore, screening for esophageal varices should be performed according to the most recent Baveno recommendations.⁴²

Author contributions

AL and RdV contributed equally to conception and writing of the review; AvdM and CS helped with the conception and design, writing the paper, critical reading, and final approval.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CS has received lecture fees from Falk Pharma. AvdM reports speaker fees from MSD, Gilead Sciences, AbbVie Pharmaceuticals and Zambon Nederland BV, received an unrestricted grant from Gilead Sciences, and reports travel expenses covered by Dr. Falk Pharma. The other authors have nothing to disclose regarding the work under consideration for publication.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AL and CS are supported by the DFG, CRU306, CS is supported by the Helmut and Hannelore Greve Foundation and the YAEL Foundation.