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Overview of the management of primary biliary cholangitis

Overview of the management of primary biliary cholangitis
Author:
Raoul Poupon, MD
Section Editor:
Keith D Lindor, MD
Deputy Editor:
Kristen M Robson, MD, MBA, FACG
Literature review current through: Feb 2022. | This topic last updated: Oct 27, 2021.

INTRODUCTION — Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is characterized by an ongoing immunologic attack on the intralobular bile ducts that leads to chronic cholestasis and cirrhosis. The terminology was changed from primary biliary cirrhosis to primary biliary cholangitis to more accurately describe the disorder and its natural history. The prognosis of patients with PBC has improved greatly because of its diagnosis at earlier stages and the widespread use of ursodeoxycholic acid as treatment.

The goals of management are:

Suppression of the underlying pathogenic process (ie, destruction of small intralobular hepatic bile ducts)

Treatment of symptoms that result from chronic cholestasis

Management of complications that result from chronic cholestasis

The focus of this topic is managing the underlying disease process, symptoms, and complications of PBC. The pathogenesis, clinical manifestations, diagnosis, and prognosis of PBC are discussed separately. (See "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)" and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)".)

Indications for and outcomes of liver transplantation for patients with PBC are discussed separately. (See "Liver transplantation in primary biliary cholangitis".)

The overlap syndrome of autoimmune hepatitis with PBC is discussed separately. (See "Autoimmune hepatitis variants: Definitions and treatment".)

Management of patients with cirrhosis is discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

MANAGING UNDERLYING DISEASE

General measures — The following measures apply to patients with PBC:

Immunizations Vaccinations for hepatitis A virus and hepatitis B virus are given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and immunizations that are given to the general population (eg, influenza) (figure 1 and figure 2). Immunization schedules are described separately. (See "Immunizations for patients with chronic liver disease", section on 'Vaccines in chronic liver disease'.)

Abstain from alcohol We advise patients to abstain from alcohol and, in particular, to avoid heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for men and >7 drinks per week or >3 drinks on a given day for women) [1].

Hepatology consultation We suggest that patients with PBC are referred to a hepatologist for long-term management.

Pretreatment testing — Prior to initiating pharmacologic therapy, the following laboratory tests are performed (see 'Assessing response' below):

Serum aminotransferases – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Alkaline phosphatase

Total bilirubin

Gamma-glutamyl transpeptidase

Platelet count

Baseline laboratory studies are used for assessing disease activity and monitoring response to therapy. (See 'Long-term monitoring' below.)

Therapy to slow disease progression — Approved treatments for PBC include ursodeoxycholic acid (UDCA) and obeticholic acid. However, obeticholic acid is not widely available outside North America. In the absence of obeticholic acid, it is the author's practice to use fibrates in conjunction with UDCA in patients with an inadequate response to UDCA alone. However, evidence to support this approach is limited. (See 'Investigational therapies' below.)

Initial therapy — Initial therapy for all patients with PBC is UDCA at a total daily dose of 13 to 15 mg/kg, given orally and usually administered twice daily (algorithm 1). UDCA is given as long-term therapy because PBC is a chronic disease. Improvement in liver biochemical tests (ie, alkaline phosphatase) is typically observed within three months of starting UDCA, although symptoms such as fatigue often do not improve with treatment. (See 'Managing symptoms' below.)

Liver biochemical testing is performed in three to six months after initiating therapy, while we determine biochemical response (ie, normalization of alkaline phosphatase) after one year of UDCA treatment [2]. (See 'Assessing response' below.)

Approximately 35 percent of patients have an inadequate biochemical response after one year of UDCA, and such patients are evaluated for subsequent treatment options [3,4]. (See 'Subsequent therapy' below and 'Investigational therapies' below.)

For most patients, UDCA is well-tolerated with few adverse effects (eg, modest weight gain [approximately 3 kg]) [5].

For patients with PBC, UDCA as first-line therapy is supported by society guidelines and is associated with a long-term survival benefit, while the risks associated with UDCA are minimal [6,7]. Some meta-analyses and observational studies have demonstrated efficacy of UDCA [8-15]; however, other data have been inconsistent [16,17]. For example, a meta-analysis of 16 randomized trials including 1447 patients found that UDCA had no significant effect on overall or transplant-free mortality [17]. However, the median trial duration in this meta-analysis was two years, which may have been too short to demonstrate a survival benefit. Additionally, various dosing regimens were used, ranging from 7.7 to 15.0 mg/kg per day (median 10 mg/kg per day); thus, dosing in some trials was likely subtherapeutic. Despite these limitations, patients given UDCA had improved liver biochemistries (ie, alkaline phosphatase and total bilirubin) and a lower risk of histologic disease progression (risk ratio [RR] 0.62, 95% 0.44-0.88) compared with placebo [17].

Long-term cohort studies have suggested a survival benefit with UDCA therapy. In a systematic review of studies conducted by the Global PBC Study Group that included 4845 patients, UDCA was associated with higher rates of transplant-free survival at 5, 10, and 15 years compared with no treatment (90, 78, and 66 percent versus 79, 59, and 32 percent, respectively) [8].

Additional studies have suggested that UDCA was associated with lower rates of disease progression [18-20]. In a study of 162 paired liver biopsies in patients with PBC, UDCA was associated with lower annual rates of progression to advanced fibrosis or cirrhosis compared with placebo (7 versus 34 percent) [18].

For patients with PBC and cirrhosis, response to UDCA therapy has been associated with lower risk of cirrhosis-related complications. In a Veterans Administration database study, 501 patients with PBC and compensated cirrhosis who were treated with UDCA were identified (ie, 287 responders [defined as alkaline phosphatase <1.67 times the upper limit of normal after 24 months of therapy] with 1693 patient-years of follow up and 214 partial responders with 834 patient-years of follow-up) [21]. Response to UDCA was associated with lower risk of hepatic decompensation (adjusted hazard ratio [aHR] 0.54, 95% CI 0.31-0.95), all-cause mortality or transplantation (aHR 0.49, 95% CI 0.33-0.72), and liver-related mortality or transplantation (aHR 0.40, 95% CI 0.24-0.67) compared with partial or no response, after adjusting for patient characteristics such as age, sex, tobacco use, and body mass index. In a trial including 180 patients with PBC who had endoscopic surveillance every two years, UDCA resulted in lower rates of developing esophageal varices compared with placebo after four years' follow-up (16 versus 58 percent) [22].

UDCA, a hydrophilic bile acid, is thought to exert its beneficial effects in cholestatic liver disorders through several mechanisms of action [23,24]:

Increased hydrophilic index of the circulating bile acid pool

Stimulation of hepatocellular and ductular secretions

Cytoprotection against hydrophobic bile acid- and cytokine-induced injury

Immunomodulation and antiinflammatory effects

Subsequent therapy — For patients with an inadequate response to UDCA (ie, alkaline phosphatase above the upper limit of normal after one year of UDCA) but without cirrhosis, obeticholic acid can be used in combination with UDCA (algorithm 1) [6,25,26]. Obeticholic acid can also be used as monotherapy for patients without cirrhosis who are unable to tolerate UDCA [26]. However, obeticholic acid is contraindicated in patients with decompensated cirrhosis (Child-Pugh class B or C), a prior decompensation event (gastroesophageal varices, encephalopathy), or compensated cirrhosis with portal hypertension because hepatic decompensation and liver failure have been reported with obeticholic acid use in such patients [6,27-29]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Child-Pugh classification'.)

Improvement in liver tests typically occurs within six months of therapy with obeticholic acid in combination with UCDA, and biochemical response is defined as alkaline phosphatase ≤1.67 times upper limit of normal [25,26]. (See 'Assessing response' below.)

Obeticholic acid therapy improved liver biochemical tests in patients with PBC, while observational studies examining long-term outcomes have been ongoing [25,30]. In a 12-month trial including 217 patients with PBC who had inadequate response or intolerance to UDCA, patients were randomly assigned to three groups: obeticholic acid 5 mg daily (with an option to titrate to 10 mg daily), 10 mg daily, or placebo [25]. Patients in the active treatment groups had higher rates of biochemical response (defined as alkaline phosphatase <1.67 times the upper limit of normal and ≤15 percent from baseline value, and a normal bilirubin) compared with placebo (46 and 47 percent, respectively, versus 10 percent) [25]. Pruritus was more common in the obeticholic acid groups compared with placebo (56 and 68 percent, respectively, versus 38 percent).

Obeticholic acid is a derivative of the primary human bile acid chenodeoxycholic acid (CDCA) and is a ligand for the farnesoid X receptor, which plays a role in bile acid homeostasis. Obeticholic acid is a more potent agonist of the receptor (approximately 100-fold higher potency) than CDCA [31,32].

Assessing response — Patients on pharmacologic therapy to slow disease progression (eg, UDCA, obeticholic acid) are monitored with liver biochemical tests (alkaline phosphatase, AST, ALT, and total bilirubin) and platelet count every three to six months to monitor response to therapy and assess disease activity [6]. (See 'Initial therapy' above and 'Subsequent therapy' above.)

Investigational therapies

Fibrates — Fibrates (fenofibrate, a specific peroxisome proliferator-activated receptor [PPAR] alpha agonist, and bezafibrate, a pan-PPAR agonist) have been shown to improve liver biochemistries in treatment-naïve patients, as well as in patients with incomplete biochemical responses to UDCA [33-38]. In the United States, bezafibrate is not available, while use of other fibrates (eg, fenofibrate) is off-label.

Bezafibrate – For patients who do not respond to UDCA alone, the author uses bezafibrate in combination with UDCA, as bezafibrate is available in France but is not available in the United States. Patients who respond have alkaline phosphatase ≤1.5 times the upper limit of normal after three to six months of bezafibrate therapy. (See 'Assessing response' above.)

Bezafibrate was effective for achieving biochemical response in patients with PBC. In a 24-month trial including 100 patients with incomplete biochemical response to UDCA, patients receiving bezafibrate (400 mg daily) plus UDCA were more likely to achieve complete biochemical response compared with patients given placebo plus UDCA (31 versus 0 percent; difference, 31 percentage points, 95% CI 10-50) [37]. Biochemical response was defined as normal levels of alkaline phosphatase, AST, ALT, total bilirubin, and albumin as well as a normal prothrombin index (a derived measure of prothrombin time). Serious adverse events occurred in 14 of 50 patients (28 percent) in the bezafibrate group and in 12 of 50 patients (24 percent) in the placebo group.

Fenofibrate – In a retrospective study of 120 patients with an incomplete response to UDCA, the addition of fenofibrate was associated with a decreased risk of achieving a composite endpoint of mortality, hepatic decompensation, or liver transplantation (adjusted hazard ratio [HR] 0.40, 95% CI 0.17-0.93) [38].

Adding a fibrate to UDCA therapy has other potential benefits including improvements in symptoms such as itching and fatigue [36,37]. For example, in a study of 48 patients with PBC treated with UDCA, adjuvant therapy with bezafibrate (400 mg daily) resulted in partial or complete relief from itching in 23 of 24 patients (96 percent) in whom itching was assessed [36].

Other drugs — Budesonide is a glucocorticoid with high first-pass metabolism within the liver, resulting in fewer systemic side effects compared with prednisolone. Use of budesonide is reserved for patients without cirrhosis but with marked inflammatory changes on liver biopsy who have not responded to first- and second-line therapies. (See "Overview of budesonide therapy for adults with inflammatory bowel disease", section on 'Pharmacology' and 'Initial therapy' above and 'Subsequent therapy' above.)

Whether budesonide is beneficial for patients with PBC is uncertain. Two randomized trials showed budesonide combined with UDCA to be more effective in improving liver biochemistries and histology than UDCA alone in patients with PBC [39,40]. However, a small study including nonresponders to UDCA found minimal benefit for adding budesonide to UDCA therapy, while budesonide was associated with decreased bone mineral density [41].

Drugs of uncertain or no benefit — For patients with PBC, we do not use colchicine [42,43] or methotrexate [44] because data have not established drug efficacy. Thus, their role remains uncertain.

Other drugs have been studied for treating PBC, but none of them have been beneficial. These include penicillamine [45,46], cyclosporine [47], prednisolone [48], mycophenolate mofetil [49], and silymarin [50].

Liver transplantation — Liver transplantation is an option for patients with progressive disease despite medical therapy (eg, decompensated cirrhosis with complications such as variceal bleeding and hepatocellular carcinoma). Patient selection for transplantation, timing of transplantation and outcomes in patients with PBC are discussed separately. (See "Liver transplantation in primary biliary cholangitis".)

MANAGING SYMPTOMS

Pruritus — Pruritus is a characteristic cholestatic symptom in patients with PBC, and the approach to management is discussed separately. (See "Pruritus associated with cholestasis".)

Fatigue — Fatigue is common in patients with PBC and can impact quality of life. Fatigue may have several contributing causes (eg, hypothyroidism, sleep disorder), and the evaluation of the patient with fatigue is discussed separately. (See "Approach to the adult patient with fatigue".)

There is no specific therapy for treating fatigue associated with PBC, although various agents have been studied [51-54]. In addition, liver transplantation did not consistently improve some systemic symptoms, particularly fatigue [55]. (See "Liver transplantation in primary biliary cholangitis", section on 'Outcome after liver transplantation'.)

Dry eyes or mouth — The following measures can be used for patients with PBC with dryness of the eyes or mouth (xerostomia) [6]:

For dry eyes, artificial tears can be used initially, while other agents (eg, cyclosporine ophthalmic emulsion) can be used in those refractory to initial measures, preferably under the supervision of an ophthalmologist. Management of dry eye disease is discussed in more detail separately. (See "Dry eye disease".)

For dry mouth and dysphagia, saliva substitutes can be tried. For example, pilocarpine can be used in patients who remain symptomatic despite saliva substitutes. (See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome", section on 'Treatment of dry mouth'.)

LONG-TERM MONITORING — Our approach to long-term monitoring for patients with PBC includes [6]:

Liver biochemical and function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and platelet count every three to six months.

Vitamin A level, vitamin D level, and prothrombin time annually. (See 'Fat-soluble vitamins' below.)

Thyroid-stimulating hormone annually to screen for hypothyroidism. Hypothyroidism is common in patients with PBC and may coexist at diagnosis or develop during the course of disease [56]. (See "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis'.)

Diagnosis and management of hypothyroidism is discussed separately. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Treatment of primary hypothyroidism in adults".)

Bone mineral densitometry every two years. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)".)

For patients with cirrhosis:

Upper endoscopy every two to three years to screen for gastroesophageal varices. (See "Primary and pre-primary prophylaxis against variceal hemorrhage in patients with cirrhosis", section on 'Screening for varices'.)

Liver ultrasound every six months to screen for hepatocellular carcinoma. (See "Surveillance for hepatocellular carcinoma in adults".)

COMPLICATIONS

Cholestasis-related issues

Metabolic bone disease — The evaluation and treatment of low bone mass in patients with PBC is discussed separately. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)".)

Fat malabsorption — For patients with PBC who are jaundiced, chronic cholestasis and subsequent reduced bile acid secretion may result in fat malabsorption [57,58]. (See "Overview of nutrient absorption and etiopathogenesis of malabsorption".)

Management of fat malabsorption includes restriction of dietary fat and supplementation with medium-chain triglycerides (MCTs) if caloric supplementation is required to maintain body weight. The digestion and absorption of MCTs are not nearly as dependent upon bile acids as are the long-chain fatty acids, which are the major constituent of dietary triglycerides. Treatment of malabsorption is discussed in more detail separately. (See "Overview of the treatment of malabsorption in adults", section on 'General management'.)

Clinical manifestations of fat malabsorption include diarrhea and weight loss, and these are discussed separately [59]. (See "Approach to the adult patient with suspected malabsorption".)

Fat-soluble vitamins — Patients with PBC (especially those with jaundice and/or on the transplantation waiting list) are at risk for deficiencies in the fat-soluble vitamins A, D, E, and K [60]. (See 'Long-term monitoring' above.).

For patients with fat-soluble vitamin deficiency, supplementation with water-soluble preparations is discussed separately. (See "Overview of the treatment of malabsorption in adults", section on 'Nutrient repletion and supplementation'.)

Hypercholesterolemia — Hypercholesterolemia (ie, cholesterol values above 200 mg/dL [5.2 mmol/L]) is a common feature of PBC, and the clinical features and management of hypercholesterolemia are discussed separately. (See "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)".)

Xanthomas — Cutaneous xanthomas (ie, deposits of cholesterol in the skin) associated with hyperlipidemia are usually asymptomatic, although treatment may be desired for cosmetic reasons (picture 1). (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Clinical manifestations'.)

Pharmacologic treatment of dyslipidemia often leads to improvement in xanthomas caused by hyperlipidemia. The xanthoma types and treatment of cutaneous xanthomas are discussed separately. (See "Cutaneous xanthomas".)

Cirrhosis-related issues

Portal hypertension — Patients with PBC may develop portal hypertension as a result of biliary cholangitis, and complications of portal hypertension (eg, variceal bleeding, ascites) are discussed separately. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis" and "Portal hypertension in adults".)

Patients with PBC who have developed complications of cirrhosis and portal hypertension (eg, ascites, spontaneous bacterial peritonitis, variceal bleeding), are regarded as having decompensated cirrhosis and have a worse prognosis than those with cirrhosis but without complications. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Prognosis'.)

Hepatocellular carcinoma — Patients with PBC and cirrhosis are at risk for developing hepatocellular carcinoma, and this is discussed separately. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Hepatocellular carcinoma'.)

The approach to surveillance for HCC in high-risk patients is discussed separately. (See "Surveillance for hepatocellular carcinoma in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary biliary cholangitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Primary biliary cholangitis (primary biliary cirrhosis) (The Basics)")

SUMMARY AND RECOMMENDATIONS

Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is characterized by an ongoing immunologic attack on the intralobular bile ducts that leads to chronic cholestasis and cirrhosis. The goals of management are (see 'Introduction' above):

Suppression of the underlying pathogenic process (ie, destruction of small intralobular hepatic bile ducts)

Treatment of symptoms that result from chronic cholestasis

Management of complications that result from chronic cholestasis

The following measures apply to all patients with PBC (see 'General measures' above and "Hepatic ductopenia and vanishing bile duct syndrome in adults", section on 'Measures for all patients'):

Immunizations – Vaccinations for hepatitis A virus and hepatitis B virus are given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and immunizations that are given to the general population (eg, influenza). Immunization schedules are described separately. (See "Immunizations for patients with chronic liver disease", section on 'Vaccines in chronic liver disease'.)

Abstain from alcohol – We advise patients to refrain from alcohol and, in particular, to avoid heavy alcohol use (ie, >14 drinks per week or >4 drinks on a given day for men and >7 drinks per week or >3 drinks on a given day for women).

Hepatology consultation for long-term management.

Pharmacologic therapy for PBC includes (algorithm 1):

For all patients with PBC, we suggest ursodeoxycholic acid (UDCA) as first-line therapy because it improved liver biochemical tests and was associated with slower disease progression and improved long-term survival (Grade 2C). Hepatology experts routinely use UDCA 13 to 15 mg/kg per day, typically given in two divided doses and continued indefinitely because of the chronic nature of PBC. (See 'Initial therapy' above.)

For patients with an inadequate response or intolerance to UDCA but who do not have cirrhosis, we suggest subsequent therapy with obeticholic acid (where available), used in combination with UDCA or as monotherapy (Grade 2C). Obeticholic acid improved liver biochemical tests in patients with PBC, while long-term outcome data are awaited. (See 'Subsequent therapy' above.)

For patients with an inadequate response to UDCA and without access to obeticholic acid, the author uses bezafibrate in combination with UDCA. (See 'Investigational therapies' above.)

Patient selection for transplantation, timing of transplantation, and outcomes in patients with PBC are discussed separately. (See "Liver transplantation in primary biliary cholangitis".)

Pruritus is a characteristic cholestatic symptom in patients with PBC, and management of pruritus is discussed separately. (See "Pruritus associated with cholestasis".)

Our approach to long-term monitoring for patients with PBC includes (see 'Long-term monitoring' above):

Liver biochemical and function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase and total bilirubin) and platelet count every three to six months

Vitamin A, vitamin D, and prothrombin time annually

Thyroid-stimulating hormone annually

Bone mineral densitometry every two years

For patients with PBC and cirrhosis:

-Upper endoscopy every two to three years to screen for gastroesophageal varices

-Liver ultrasound every six months to screen for HCC

The evaluation and treatment of low bone mass in patients with PBC is discussed separately. (See "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)".)

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  40. Rautiainen H, Kärkkäinen P, Karvonen AL, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005; 41:747.
  41. Angulo P, Jorgensen RA, Keach JC, et al. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31:318.
  42. Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology 2004; 39:915.
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  45. Dickson ER, Fleming TR, Wiesner RH, et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312:1011.
  46. Neuberger J, Christensen E, Portmann B, et al. Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis. Gut 1985; 26:114.
  47. Wiesner RH, Ludwig J, Lindor KD, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990; 322:1419.
  48. Mitchison HC, Palmer JM, Bassendine MF, et al. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 1992; 15:336.
  49. Talwalkar JA, Angulo P, Keach JC, et al. Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid. J Clin Gastroenterol 2005; 39:168.
  50. Angulo P, Patel T, Jorgensen RA, et al. Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 32:897.
  51. Khanna A, Leighton J, Lee Wong L, Jones DE. Symptoms of PBC - Pathophysiology and management. Best Pract Res Clin Gastroenterol 2018; 34-35:41.
  52. Kaplan MM, Bonis PA. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med 2005; 143:546.
  53. Theal JJ, Toosi MN, Girlan L, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology 2005; 41:1305.
  54. Silveira MG, Gossard AA, Stahler AC, et al. A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis. Am J Ther 2017; 24:e167.
  55. Pells G, Mells GF, Carbone M, et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol 2013; 59:67.
  56. Elta GH, Sepersky RA, Goldberg MJ, et al. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983; 28:971.
  57. Phillips JR, Angulo P, Petterson T, Lindor KD. Fat-soluble vitamin levels in patients with primary biliary cirrhosis. Am J Gastroenterol 2001; 96:2745.
  58. Maillette de Buy Wenniger L, Beuers U. Bile salts and cholestasis. Dig Liver Dis 2010; 42:409.
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  60. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51:237.
Topic 3623 Version 44.0

References

1 : https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics (Accessed on July 11, 2018).

2 : Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase.

3 : Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid.

4 : Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis.

5 : Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis.

6 : Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases.

7 : EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis.

8 : Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study.

9 : Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.

10 : Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials.

11 : Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.

12 : The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.

13 : A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.

14 : Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.

15 : Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group.

16 : Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses.

17 : Ursodeoxycholic acid for primary biliary cirrhosis.

18 : The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.

19 : Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis.

20 : Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression.

21 : Ursodeoxycholic Acid Response Is Associated With Reduced Mortality in Primary Biliary Cholangitis With Compensated Cirrhosis.

22 : Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis.

23 : Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action.

24 : Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited.

25 : A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis.

26 : A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

27 : A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

28 : A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.

29 : Primary biliary cholangitis: 2021 practice guidance update from the American Association for the Study of Liver Diseases.

30 : Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid.

31 : 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity.

32 : New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.

33 : Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid.

34 : Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid.

35 : The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study.

36 : Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response.

37 : A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

38 : Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes.

39 : Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial.

40 : Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial.

41 : Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

42 : A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results.

43 : Colchicine for primary biliary cirrhosis.

44 : Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial.

45 : Trial of penicillamine in advanced primary biliary cirrhosis.

46 : Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.

47 : A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis.

48 : A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results.

49 : Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.

50 : Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.

51 : Symptoms of PBC - Pathophysiology and management.

52 : Modafinil for the treatment of fatigue in primary biliary cirrhosis.

53 : A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue.

54 : A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis.

55 : The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort.

56 : Increased incidence of hypothyroidism in primary biliary cirrhosis.

57 : Fat-soluble vitamin levels in patients with primary biliary cirrhosis.

58 : Bile salts and cholestasis.

59 : Management of osteoporosis, fat-soluble vitamin deficiencies, and hyperlipidemia in primary biliary cirrhosis.

60 : EASL Clinical Practice Guidelines: management of cholestatic liver diseases.