Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) Author: Raoul Poupon, MD Section Editor: Keith D Lindor, MD Deputy Editor: Kristen M Robson, MD, MBA, FACG All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: Mar 04, 2019.

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 eventually leads to cirrhosis and liver failure. The terminology was changed from primary biliary cirrhosis to primary biliary cholangitis to more accurately describe the disorder and its natural history [1]. The prognosis of patients with PBC has improved greatly during the past two decades because of its diagnosis at earlier stages and the widespread use of ursodeoxycholic acid as treatment. As a result, far fewer patients require liver transplantation, and patients with stages I and II PBC appear to have a normal life expectancy. (See "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)" and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)" and "Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis)".) The management of PBC has two goals: ●

Treatment of the symptoms and complications that result from chronic cholestasis

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Suppression of the underlying pathogenic process: the destruction of small intralobular hepatic bile ducts

The treatment of PBC will be reviewed here. The pathogenesis and diagnosis of PBC, as well as the general management of patients with cirrhosis, are discussed elsewhere. (See "Pathogenesis of primary biliary cholangitis (primary biliary cirrhosis)" and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)" and "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

These issues are also discussed in a guidance statement from the American Association for the Study of Liver Diseases and in guidelines from the European Association for the Study of the Liver [2,3].

GENERAL MANAGEMENT As with patients with other forms of liver disease, attempts should be made to prevent superimposed insults to the liver in patients with primary biliary cholangitis by avoiding hepatotoxins and vaccinating patients who are not already immune against hepatitis A and B. Patients with cirrhosis may also require adjustments in medication dosing and treatment for complications related to cirrhosis. These issues are discussed in detail elsewhere. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis".)

TREATMENT OF COMPLICATIONS OF PBC There are a number of complications that occur in primary biliary cholangitis (PBC) that require therapy. These include: ●

Pruritus (see "Pruritus associated with cholestasis")

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Metabolic bone disease (see "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)")

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Hypercholesterolemia and xanthomas (see "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)")

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Malabsorption

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Vitamin deficiencies

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Hypothyroidism

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Anemia

Malabsorption — Patients with PBC who are clinically jaundiced may develop diarrhea and weight loss due to the malabsorption of dietary fat (steatorrhea) [4]. Steatorrhea in PBC is due primarily to the decreased biliary secretion of bile acids so that their concentration within the small intestinal lumen is below the critical micellar concentration [4,5]. Patients with concomitant sicca syndrome may also have pancreatic insufficiency, although this is a less common cause of malabsorption in PBC [4,5]. There are no reliable clinical findings that distinguish between these two causes of malabsorption. Symptomatic steatorrhea due to bile acid insufficiency can be partially corrected by restricting dietary fat. Medium-chain triglycerides (MCTs) can be added 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. https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEP… 2/26

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

Each milliliter of MCT oil contains 7.5 calories. Most patients can tolerate 60 mL per day without difficulty. MCT oil can be taken directly by the teaspoon or can be used as salad oil or as a substitute for shortening in cooking. (See "Overview of the treatment of malabsorption".) If pancreatic insufficiency is suspected, it is easier to empirically treat with pancreatic enzyme replacement than it is to diagnose. Preparations, such as pancrelipase, taken with meals are usually effective. A guidance statement issued by the American Association for the Study of Liver Diseases suggests providing 1000 to 1500 mg of calcium and 1000 international units of vitamin D daily through the diet and, if needed, supplements [3]. Deficiencies of fat-soluble vitamins — Patients with PBC may have malabsorption of the fatsoluble vitamins A, D, E, and K. Deficiencies of vitamin E are uncommon except in patients with advanced disease awaiting liver transplantation. In comparison, vitamin A deficiency occurs in approximately 30 percent of patients but is rarely symptomatic [6,7]. It correlates directly with serum retinol binding protein and albumin levels and inversely with serum bilirubin levels [6,7]. Vitamin A deficiency usually responds to dietary supplements of vitamin A, 15,000 units per day (three times the recommended daily allowance). In exceptional cases, as in the patient with night blindness, parenteral vitamin A may be required. (See "Overview of the treatment of malabsorption".) Vitamin D deficiency is best detected by measuring the serum concentration of calcidiol (25hydroxyvitamin D), the metabolite of vitamin D produced in the liver. Serum levels of calcidiol and calcitriol (the most active form of vitamin D) are usually normal in PBC except for patients who are deeply jaundiced and who are candidates for liver transplantation [8] (see "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)"). An annual measurement of serum vitamin A and calcidiol levels is sufficient in patients whose serum bilirubin concentration is elevated. Less frequent measurements (eg, every two to three years) are sufficient in patients with normal serum bilirubin levels. Measurements should be obtained more frequently in patients whose values are just above the lower limit of normal. Clinically important vitamin K deficiency rarely occurs in PBC unless the patient regularly takes cholestyramine and is deeply jaundiced. The prothrombin time is normal in most patients until late in the course of the disease when there are signs of liver failure. Only these patients require vitamin K supplementation. Hypothyroidism — Approximately 20 percent of patients with PBC have or will develop hypothyroidism [9]. It may predate the onset of primary biliary cholangitis or occur during its course. The thyroid injury is also due to autoimmune disease. In one study of patients with PBC, for example, the prevalence of antithyroglobulin and antimicrosomal antibodies was 20 and 34

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

percent, respectively [9]. (See "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis'.) The most accurate test to diagnose primary hypothyroidism is an elevation in the serum thyroid stimulating hormone (TSH) concentration. Serum thyroid hormone-binding proteins are increased in PBC; as a result, total but not free serum T4 levels may be normal [10]. Hypothyroidism is treated with thyroid hormone replacement in a dose that keeps TSH levels in the normal range. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Treatment of primary hypothyroidism in adults".) Xanthomas — Fewer than 5 percent of patients with PBC develop xanthomas, which are deposits of cholesterol in the skin. Xanthelasmas (cholesterol-filled, soft, yellow plaques that usually appear on the medial aspects of the eyelids bilaterally) are more common and may occasionally be striking in appearance (picture 1). ●

Tuberous xanthomas typically occur over extensor surfaces such as the knee and elbow, do not cause symptoms, and do not require treatment (picture 2).

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Planar xanthomas may occur on the palms of the hands and soles of the feet and are often painful. These xanthomas can limit manual dexterity, and those on the soles make it painful to walk (picture 3).

These lesions develop in patients whose serum cholesterol has been greater than 600 mg/mL (15.6 mmol/L) for more than three months [11]. This degree of hypercholesterolemia is uncommon in PBC, and in our experience, symptomatic xanthomas occur only in deeply jaundiced patients who are candidates for liver transplantation. Because planar xanthomas greatly diminish quality of life, they are usually treated. Treatment consists of large-volume plasmaphereses performed at one- to two-week intervals [12]. Each plasmapheresis decreases the serum cholesterol concentration by approximately 50 percent. Once the serum cholesterol level approaches normal, xanthomas will gradually resolve. This treatment is inconvenient, expensive, and indicated in only a small minority of patients with PBC. Most such patients undergo liver transplantation because of severe liver disease. Anemia — Iron deficiency anemia is a problem in some patients who appear to have early stage PBC. A thorough search for a site of gastrointestinal (GI) bleeding is indicated even in the absence of overt bleeding. Some of these patients have unexpectedly severe portal hypertension, despite normal or nearly normal serum bilirubin and albumin concentrations and no evidence of cirrhosis on liver biopsy [13,14]. The reason for this is uncertain but has been ascribed to nodular regenerative hyperplasia of the liver [15]. These patients may have intermittent occult bleeding from congestive gastropathy or esophageal varices, rather than the massive upper gastrointestinal hemorrhage usually associated with portal hypertension.

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

Therapy begins with establishing the diagnosis of iron deficiency and beginning oral iron replacement (see "Treatment of iron deficiency anemia in adults"). If this is ineffective, the usual modalities to prevent bleeding from portal hypertension should be considered. We use the following sequence of therapies: ●

Patients with varices or portal hypertensive gastropathy documented by endoscopy are started on a nonselective beta blocker (such as propranolol) in a dose that lowers the resting pulse by 25 percent.

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If this is unsuccessful and chronic GI bleeding can be documented, esophageal variceal band ligation should be considered.

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If these measures fail, distal splenorenal shunt surgery is indicated in the patient whose nutritional status, serum bilirubin, and albumin are all normal or near normal [16].

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Transjugular intrahepatic portosystemic stent shunt (TIPS) and evaluation for liver transplantation are indicated in patients with more advanced PBC whose bleeding is not controlled by the preceding measures.

Liver failure — Patients with advanced PBC, similar to patients with other types of end-stage cirrhosis, develop signs and symptoms of liver failure such as ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, muscle wasting, and massive bleeding from esophageal varices. Management is similar to that in other causes of liver failure. (See 'Liver transplantation' below.) Fatigue — Fatigue is common in patients with PBC and can be severely debilitating. However, there is no recommended therapy for treating fatigue, although various agents have been studied [17-20]. Liver transplantation does not appear to improve systemic symptoms, particularly fatigue [21]. Dry eyes or mouth — The following measures can be used for patients with PBC with dryness of the eyes or mouth (xerostomia) [3]: ●

For dry eyes, use artificial tears initially and pilocarpine or cevimeline in patients refractory to artificial tears. Cyclosporine ophthalmic emulsion can be used in those refractory to other agents, preferably under the supervision of an ophthalmologist.

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For dry mouth and dysphagia, saliva substitutes can be tried. Pilocarpine or cevimeline can be used in patients who remain symptomatic despite saliva substitutes.

TREATMENT OF THE UNDERLYING DISEASE PROCESS

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There has been less success in treating the primary immunologic attack on the bile ducts in patients with primary biliary cholangitis (PBC). The only approved treatments are ursodeoxycholic acid (ursodiol, UDCA) and obeticholic acid. However, obeticholic acid is available only through specialty pharmacies in the United States and Canada. 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 'Fibrates' below.) Ursodeoxycholic acid — The use of UDCA in the treatment of PBC and its mechanism of action are discussed in detail elsewhere. Summarized briefly, UDCA (13 to 15 mg/kg per day) delays the progression to end-stage liver disease, enhances survival, and is well tolerated (figure 1A-B). UDCA is thus advocated as first-line therapy in PBC. The extent of the biochemical response to UDCA during the first year of therapy is a simple and useful marker of long-term prognosis. About 35 percent of patients have a suboptimal response to UDCA [22]. These patients need adjuvant therapy. (See "Trials of ursodeoxycholic acid for the treatment of primary biliary cholangitis (primary biliary cirrhosis)".) UDCA has also been evaluated in combination with other drugs including colchicine [23-25], methotrexate [26], and mycophenolate mofetil [27,28]. None of these combinations has consistently proven to be effective. (See 'Investigational approaches' below.) Obeticholic acid — For patients with compensated liver disease (Child-Pugh A) and with an inadequate response to UDCA (alkaline phosphatase levels >1.67 times the upper limit of normal after one year of UDCA), obeticholic acid can be used in combination with UDCA [3,29,30]. Obeticholic acid can also be used as monotherapy for patients with compensated liver disease who are unable to tolerate UDCA [31]. However, for patients with decompensated liver disease (Child-Pugh B or C), we do not use OCA because the benefit is uncertain [3,32]. The use of obeticholic acid was an addition to the 2018 practice guidance statement from the American Association for the Study of Liver Diseases [3]. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Child-Pugh classification'.) Obeticholic acid is a derivative of the primary human bile acid chenodeoxycholic acid (CDCA). It 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. Obeticholic acid appears to be effective in reducing alkaline phosphatase, gamma-glutamyl transpeptidase, and aminotransferase levels. Obeticholic acid has not been demonstrated to improve survival or disease-related symptoms [30,33,34]. The primary side effect is pruritus. Monitoring — Patients taking UDCA or obeticholic acid are monitored with liver biochemical tests [3]. Improvement typically occurs within six months. Approximately 40 percent of patients treated with UDCA will have normalization of their liver biochemical tests after one year. In patients with a suboptimal response (transaminases persistently above five times the upper limit of normal after at least six months of UDCA plus obeticholic acid), we obtain a liver biopsy to assess disease https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEP… 6/26

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activity. (See 'Follow-up' below and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Liver biopsy'.) Monitoring the antimitochondrial antibody titer is not useful in assessing the response to therapy in PBC. Antibody titers tend to be stable over time in an individual patient, and do not correlate with disease severity or rate of progression [35,36]. Furthermore, the response to therapies such as UDCA and liver transplantation is not affected by the presence or absence of antimitochondrial antibodies [37]. Controversial approaches — Two drugs, methotrexate and colchicine, have a long history in the care of patients with PBC, but their role remains uncertain. Data supporting the benefit have been derived mostly from case series and small controlled trials, not all of which have suggested a benefit. While they continue to be used in some centers, their role is generally considered to be unproven. Colchicine — The potential mechanisms of action of colchicine in PBC are uncertain, but may include the modulation of local cytokine and autacoid production by chronically stimulated macrophages, monocytes, and lymphocytes [38,39]. Colchicine also inhibits endothelial adhesiveness for neutrophils, diminishes the expression of L-selectins on neutrophil cell surfaces, and affects the activity of cytokines such as interleukin-2 and tumor necrosis factor in patients with PBC [40]. Several small controlled trials have compared colchicine to placebo in the treatment of PBC [4144]. None has demonstrated unequivocally that colchicine improves survival free of liver transplantation. A systematic review of 10 trials involving a total of 631 patients found no significant benefit on mortality, the need for liver transplantation, or improvement in liver biochemical tests or histology [45]. However, colchicine improved pruritus in several controlled trials. However, some studies have observed improvement in liver biochemical tests, although the clinical significance is unclear. ●

In a study of 60 patients, the administration of colchicine, compared with placebo, was associated with significant improvements in serum alkaline phosphatase, alanine and aspartate aminotransferase, albumin, bilirubin, and cholesterol at two years [41]. The likelihood of death due to liver-related causes after four years was significantly less in the patients started on colchicine.

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The results of two other studies were similar but not statistically significant [42,43]. When data were analyzed after eight years in one of these studies, biochemical tests were still improved in the colchicine-treated patients, but the survival benefit was lost [44].

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

A randomized trial assigned 90 patients to colchicine, UDCA, or placebo [46,47]. Pruritus was significantly decreased with colchicine and UDCA. Colchicine improved biochemical tests modestly, whereas UDCA decreased serum alkaline phosphatase and aminotransferase activities more than placebo or colchicine. Serum bilirubin levels fell only in those receiving UDCA. UDCA but not colchicine reduced ductular proliferation. The authors concluded that UDCA was superior to colchicine for the therapy of PBC [46].

Methotrexate — Methotrexate was first used to treat PBC because of encouraging experience with this drug in several patients with primary sclerosing cholangitis [48], another cholestatic liver disease with some similarities to PBC [49]. In the low doses used to treat PBC (0.25 mg/kg body weight per week orally), methotrexate may act as an immunomodulatory and/or antiinflammatory agent rather than as an antimetabolite [50-54]. (See "Use of methotrexate in the treatment of rheumatoid arthritis".) Although some reports have described encouraging results with methotrexate (given alone or in combination with UDCA and/or colchicine) in some patients (picture 4) [55-60], not all studies have demonstrated a favorable response to methotrexate [61-65]. In one series, methotrexate and colchicine significantly improved serum levels of alkaline phosphatase, aminotransferases, liver histology, and pruritus in 73 of 91 patients (80 percent) whose PBC responded suboptimally to UDCA (which had been given for a mean of 3.4 years) [66]. No benefit on mortality or need for liver transplantation was found in a meta-analysis of five trials [64]. The largest controlled trial (the "Primary biliary cirrhosis ursodiol plus methotrexate or its placebo, the 'PUMPs' trial"), found no benefit from the addition of methotrexate to UDCA on survival free of liver transplantation, although the drug appeared to be safe [26]. Similarly, 10-year results of a randomized trial comparing UDCA plus methotrexate or colchicine found no benefit on transplant-free survival, although a potential benefit was suggested in a subset of patients with early-stage disease [65]. Twenty-nine patients from this trial continued their medications and were followed for an additional 10 years [67]. The 56 patients who did not continue their medications did so because of treatment failure, drug toxicity, unrelated illness, or patient preference. Of the 11 patients taking methotrexate plus UDCA, nine were still alive, whereas two had died from causes unrelated to their liver disease. Of the 18 patients taking colchicine plus UDCA, 12 were alive and well. Three had progressive liver disease (two underwent liver transplantation and one died from pneumonia), whereas three died from unrelated causes. Thus, the role of methotrexate in the management of PBC is unclear. Some will use it in patients who appear to have progressive disease despite treatment with UDCA after careful discussion of the uncertain clinical benefit. Drugs that are ineffective and/or toxic — Several drugs are ineffective or toxic in PBC. These include prednisolone [68], azathioprine [69,70], penicillamine [71], cyclosporine [72-75], and https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEP… 8/26

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silymarin [76]. Investigational approaches 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 [77-82]. In the United States, fenofibrate is approved for treatment of hyperlipidemia and bezafibrate is not available. ●

Bezafibrate – For patients who do not respond to UDCA alone, the author uses bezafibrate in combination with UDCA, as bezafibrate is available in France. In a 24-month, phase 3 trial including 100 patients with incomplete biochemical response to UDCA, patients receiving bezafibrate (400 mg daily) plus UDCA were more likely to achieve a complete biochemical response compared with patients given placebo plus UDCA (31 versus 0 percent; difference, 31 percentage points, 95% CI 10-50) [81]. Biochemical response was defined as normal levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 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.

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Fenofibrate – In a retrospective study of 120 patients with an incomplete response to UDCA, the addition of fenofibrate (145 mg daily) was associated with a decreased risk of achieving a composite endpoint of mortality, hepatic decompensation, or liver transplantation (adjusted hazard ratio 0.40, 95% CI 0.17-0.93) [82].

Adding a fibrate to UDCA therapy has other potential benefits including improvements in symptoms such as itching and fatigue [80,81]. 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 [80]. Budesonide — Budesonide is a glucocorticoid absorbed in the small intestine. As an oral dose, 90 percent is metabolized during first-pass hepatic metabolism in healthy individuals. Compared with prednisolone, glucocorticoid receptor binding activity of budesonide is 15 to 20 times higher, so its effect on liver inflammation and biliary alkaline secretion may be greater. In patients with inflammatory bowel disease and autoimmune hepatitis, oral budesonide has been shown to exert fewer systemic side effects than conventional glucocorticoids. Two randomized trials showed budesonide (6 to 9 mg per day) combined with UDCA to be more effective in improving liver biochemistries and histology than UDCA alone in patients with stage I to III PBC [83,84]. Triple therapy with UDCA, budesonide and mycophenolate mofetil — Combination therapy with UDCA, budesonide and mycophenolate mofetil improved liver biochemical tests and histology https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HEP… 9/26

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in 13 of 15 patients who had responded suboptimally to UDCA [85]. Such an approach could be considered in patients with progressive disease after a discussion of the uncertain safety and efficacy, but additional studies are needed. Antiretroviral treatment — Biochemical improvement was observed in an open-label study involving lamivudine and zidovudine [86]. The rationale was based upon the hypothesis of a possible retroviral cause of PBC [87,88]. Liver transplantation — PBC is a common, albeit decreasing, indication for liver transplantation. Liver transplantation should be strongly considered in patients with advanced disease as reflected by: ●

Serum bilirubin exceeding 6 mg/dL (103 micromol/L)

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Decompensated cirrhosis with an unacceptable quality of life

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Anticipated death within a year due to treatment-resistant ascites and spontaneous bacterial peritonitis, recurrent variceal bleeding, encephalopathy, or hepatocellular carcinoma

The prevalence of recurrent PBC post transplantation is reported to be as high as 30 percent after 10 years. Among factors proposed to affect the rate of recurrence is the use of tacrolimus as the mainstay for immunosuppression. Despite the possibility of recurrence, liver transplantation has greatly improved survival in patients with PBC, with reported survival rates of greater than 90 percent at one year and 80 to 85 percent at five years [89]. (See "Liver transplantation in primary biliary cholangitis (primary biliary cirrhosis)".)

FOLLOW-UP Long-term monitoring for patients with PBC includes the following [3]: ●

Liver tests every three to six months

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Thyroid stimulating hormone annually

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Bone mineral densitometry every two years

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Monitor vitamin A, D, and prothrombin time annually if bilirubin is >2.0 mg/dL

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Upper endoscopy every two to three years if known cirrhosis, a Mayo risk score of >4.1, or transient elastography score >17 kPa

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Ultrasound every six months in patients with known or suspected cirrhosis (see "Surveillance for hepatocellular carcinoma in adults")

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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-toread 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 ●

There are a number of complications that occur in patients with primary biliary cholangitis (PBC) that require therapy. (See 'Treatment of complications of PBC' above.) These include:

• Pruritus (see "Pruritus associated with cholestasis") • Metabolic bone disease (see "Evaluation and treatment of low bone mass in primary biliary cholangitis (primary biliary cirrhosis)")

• Hypercholesterolemia and xanthomas (see "Hypercholesterolemia in primary biliary cholangitis (primary biliary cirrhosis)")

• Malabsorption • Vitamin deficiencies • Hypothyroidism • Anemia

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PBC is a progressive disease in most patients. It eventually becomes irreversible, and therefore untreatable. The only widely accepted treatment is ursodeoxycholic acid (UDCA). It is the only treatment aimed at modifying the natural history of the disease recommended in guidelines issued by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. We recommend that all patients with PBC receive treatment with UDCA (13 to 15 mg/kg per day in divided doses given with meals and at bedtime), which should be continued indefinitely (Grade 1A). For patients with an inadequate response to UDCA, treatment options include obeticholic acid (for patients with compensated liver disease) or fibrates in combination with UDCA. (See 'Treatment of the underlying disease process' above.)

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Optimal management of patients who have progressive disease despite UDCA and obeticholic acid or UDCA and bezafibrate (the author’s practice) is unclear. They can be identified by having persistent liver biochemical abnormalities and/or worsening liver histology. Such patients ideally should be treated within the context of a clinical study. (See 'Investigational approaches' above.)

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Randomized trials have not demonstrated a benefit of methotrexate or colchicine in altering the natural history of PBC. Thus, we suggest against routine use of methotrexate or colchicine given alone or in combination with UDCA (Grade 2B). (See 'Controversial approaches' above.)

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Liver transplantation should be strongly considered in patients with advanced disease as reflected by (see 'Liver transplantation' above):

• Serum bilirubin exceeding 6 mg/dL (103 micromol/L) • Decompensated cirrhosis with an unacceptable quality of life • Anticipated death within a year due to treatment-resistant ascites and spontaneous bacterial peritonitis, recurrent variceal bleeding, encephalopathy, or hepatocellular carcinoma

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REFERENCES 1. Beuers U, Gershwin ME, Gish RG, et al. Changing nomenclature for PBC: From 'cirrhosis' to 'cholangitis'. Hepatology 2015; 62:1620.

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2. European Association for the Study of the Liver. Electronic address: [email protected], European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67:145. 3. Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019; 69:394. 4. Lanspa SJ, Chan AT, Bell JS 3rd, et al. Pathogenesis of steatorrhea in primary biliary cirrhosis. Hepatology 1985; 5:837. 5. Levy C, Lindor KD. Management of osteoporosis, fat-soluble vitamin deficiencies, and hyperlipidemia in primary biliary cirrhosis. Clin Liver Dis 2003; 7:901. 6. Phillips JR, Angulo P, Petterson T, Lindor KD. Fat-soluble vitamin levels in patients with primary biliary cirrhosis. Am J Gastroenterol 2001; 96:2745. 7. Kaplan MM, Elta GH, Furie B, et al. Fat-soluble vitamin nutriture in primary biliary cirrhosis. Gastroenterology 1988; 95:787. 8. Kaplan MM, Goldberg MJ, Matloff DS, et al. Effect of 25-hydroxyvitamin D3 on vitamin D metabolites in primary biliary cirrhosis. Gastroenterology 1981; 81:681. 9. Elta GH, Sepersky RA, Goldberg MJ, et al. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983; 28:971. 10. Schussler GC, Schaffner F, Korn F. Increased serum thyroid hormone binding and decreased free hormone in chronic active liver disease. N Engl J Med 1978; 299:510. 11. AHRENS EH Jr, PAYNE MA, KUNKEL HG, et al. Primary biliary cirrhosis. Medicine (Baltimore) 1950; 29:299. 12. Cohen LB, Ambinder EP, Wolke AM, et al. Role of plasmapheresis in primary biliary cirrhosis. Gut 1985; 26:291. 13. Thornton JR, Triger DR, Losowsky MS. Variceal bleeding is associated with reduced risk of severe cholestasis in primary biliary cirrhosis. Q J Med 1989; 71:467. 14. Navasa M, Parés A, Bruguera M, et al. Portal hypertension in primary biliary cirrhosis. Relationship with histological features. J Hepatol 1987; 5:292. 15. Nakanuma Y, Ohta G. Nodular hyperplasia of the liver in primary biliary cirrhosis of early histological stages. Am J Gastroenterol 1987; 82:8.

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16. Boyer TD, Kokenes DD, Hertzler G, et al. Effect of distal splenorenal shunt on survival of patients with primary biliary cirrhosis. Hepatology 1994; 20:1482. 17. Khanna A, Leighton J, Lee Wong L, Jones DE. Symptoms of PBC - Pathophysiology and management. Best Pract Res Clin Gastroenterol 2018; 34-35:41. 18. Kaplan MM, Bonis PA. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med 2005; 143:546. 19. 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. 20. 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. 21. 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. 22. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 48:871. 23. Shibata J, Fujiyama S, Honda Y, Sato T. Combination therapy with ursodeoxycholic acid and colchicine for primary biliary cirrhosis. J Gastroenterol Hepatol 1992; 7:277. 24. Almasio PL, Floreani A, Chiaramonte M, et al. Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis. Aliment Pharmacol Ther 2000; 14:1645. 25. Battezzati PM, Zuin M, Crosignani A, et al. Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients. Aliment Pharmacol Ther 2001; 15:1427. 26. Combes B, Emerson SS, Flye NL, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 2005; 42:1184. 27. Jones EA, ten Kate FJ, ter Borg F, et al. Combination therapy with mycophenolate mofetil and ursodeoxycholic acid for primary biliary cirrhosis. Eur J Gastroenterol Hepatol 1999; 11:1165. 28. Jones EA. Rationale for trials of long-term mycophenolate mofetil therapy for primary biliary cirrhosis. Hepatology 2002; 35:258. 29. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm503964.htm (Accesse d on June 01, 2016). https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HE… 14/26

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30. Nevens F, Andreone P, Mazzella G, et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med 2016; 375:631. 31. Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology 2018; 67:1890. 32. https://www.fda.gov/Drugs/DrugSafety/ucm576656.htm (Accessed on February 22, 2019). 33. Kowdley KV, Luketic VA, Jones DE, et al. Teh first new monotherapy therapeutic PBC study in a decade? An international study evaluating the farnesoid X receptor agonist obeticholic acid in PBC. Hepatology 2011; 54:416A. 34. Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148:751. 35. Kaplan MM. Primary biliary cirrhosis. N Engl J Med 1996; 335:1570. 36. Van Norstrand MD, Malinchoc M, Lindor KD, et al. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 1997; 25:6. 37. Kim WR, Poterucha JJ, Jorgensen RA, et al. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 1997; 26:22. 38. Wangoo A, Haynes AR, Sutcliffe SP, et al. Modulation of platelet-derived growth factor B mRNA abundance in macrophages by colchicine and dibutyryl-cAMP. Mol Pharmacol 1992; 42:584. 39. Kershenobich D, Rojkind M, Quiroga A, Alcocer-Varela J. Effect of colchicine on lymphocyte and monocyte function and its relation to fibroblast proliferation in primary biliary cirrhosis. Hepatology 1990; 11:205. 40. Miller LC, Kaplan MM. Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis: decrease by colchicine and relationship to HLA-DR4. Am J Gastroenterol 1992; 87:465. 41. Kaplan MM, Alling DW, Zimmerman HJ, et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986; 315:1448. 42. Warnes TW, Smith A, Lee FI, et al. A controlled trial of colchicine in primary biliary cirrhosis. Trial design and preliminary report. J Hepatol 1987; 5:1. https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HE… 15/26

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43. Bodenheimer H Jr, Schaffner F, Pezzullo J. Evaluation of colchicine therapy in primary biliary cirrhosis. Gastroenterology 1988; 95:124. 44. Zifroni A, Schaffner F. Long-term follow-up of patients with primary biliary cirrhosis on colchicine therapy. Hepatology 1991; 14:990. 45. Gong Y, Gluud C. Colchicine for primary biliary cirrhosis: a Cochrane Hepato-Biliary Group systematic review of randomized clinical trials. Am J Gastroenterol 2005; 100:1876. 46. Vuoristo M, Färkkilä M, Karvonen AL, et al. A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology 1995; 108:1470. 47. Miettinen TA, Färkkilä M, Vuoristo M, et al. Serum cholestanol, cholesterol precursors, and plant sterols during placebo-controlled treatment of primary biliary cirrhosis with ursodeoxycholic acid or colchicine. Hepatology 1995; 21:1261. 48. Knox TA, Kaplan MM. Treatment of primary sclerosing cholangitis with oral methotrexate. Am J Gastroenterol 1991; 86:546. 49. Wiesner RH, LaRusso NF, Ludwig J, Dickson ER. Comparison of the clinicopathologic features of primary sclerosing cholangitis and primary biliary cirrhosis. Gastroenterology 1985; 88:108. 50. Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 1993; 92:2675. 51. Weigand K, Zaugg PY, Frei A, Zimmermann A. Long-term follow-up of serum N-terminal propeptide of collagen type III levels in patients with chronic liver disease. Hepatology 1984; 4:835. 52. Weinstein GD, Jeffes E, McCullough JL. Cytotoxic and immunologic effects of methotrexate in psoriasis. J Invest Dermatol 1990; 95:49S. 53. Segal R, Yaron M, Tartakovsky B. Methotrexate: mechanism of action in rheumatoid arthritis. Semin Arthritis Rheum 1990; 20:190. 54. Suarez CR, Pickett WC, Bell DH, et al. Effect of low dose methotrexate on neutrophil chemotaxis induced by leukotriene B4 and complement C5a. J Rheumatol 1987; 14:9. 55. Kaplan MM, Knox TA. Treatment of primary biliary cirrhosis with low-dose weekly methotrexate. Gastroenterology 1991; 101:1332.

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56. Kaplan MM, DeLellis RA, Wolfe HJ. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment. Ann Intern Med 1997; 126:682. 57. Kaplan MM, Schmid C, Provenzale D, et al. A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis. Gastroenterology 1999; 117:1173. 58. Bonis PA, Kaplan M. Methotrexate improves biochemical tests in patients with primary biliary cirrhosis who respond incompletely to ursodiol. Gastroenterology 1999; 117:395. 59. Buscher HP, Zietzschmann Y, Gerok W. Positive responses to methotrexate and ursodeoxycholic acid in patients with primary biliary cirrhosis responding insufficiently to ursodeoxycholic acid alone. J Hepatol 1993; 18:9. 60. Babatin MA, Sanai FM, Swain MG. Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy. Aliment Pharmacol Ther 2006; 24:813. 61. Hendrickse MT, Rigney E, Giaffer MH, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology 1999; 117:400. 62. Lindor KD, Dickson ER, Jorgensen RA, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 1995; 22:1158. 63. Bach N, Bodian C, Bodenheimer H, et al. Methotrexate therapy for primary biliary cirrhosis. Am J Gastroenterol 2003; 98:187. 64. Giljaca V, Poropat G, Stimac D, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev 2010; :CD004385. 65. 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. 66. Kaplan MM, Bonder A, Ruthazer R, Bonis PA. Methotrexate in patients with primary biliary cirrhosis who respond incompletely to treatment with ursodeoxycholic acid. Dig Dis Sci 2010; 55:3207. 67. Leung J, Bonis PA, Kaplan MM. Colchicine or methotrexate, with ursodiol, are effective after 20 years in a subset of patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol 2011; 9:776.

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68. 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. 69. Christensen E, Neuberger J, Crowe J, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology 1985; 89:1084. 70. Gong Y, Christensen E, Gluud C. Azathioprine for primary biliary cirrhosis. Cochrane Database Syst Rev 2007; :CD006000. 71. Gong Y, Klingenberg SL, Gluud C. Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis--Cochrane Hepato-Biliary Group. Aliment Pharmacol Ther 2006; 24:1535. 72. Minuk GY, Bohme CE, Burgess E, et al. Pilot study of cyclosporin A in patients with symptomatic primary biliary cirrhosis. Gastroenterology 1988; 95:1356. 73. 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. 74. Lombard M, Portmann B, Neuberger J, et al. Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology 1993; 104:519. 75. Gong Y, Christensen E, Gluud C. Cyclosporin A for primary biliary cirrhosis. Cochrane Database Syst Rev 2007; :CD005526. 76. 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. 77. Kurihara T, Niimi A, Maeda A, et al. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000; 95:2990. 78. Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33:235. 79. Iwasaki S, Ohira H, Nishiguchi S, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study. Hepatol Res 2008; 38:557. 80. Reig A, Sesé P, Parés A. Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response. Am J Gastroenterol 2018; 113:49. https://www.uptodate.com/contents/overview-of-the-treatment-of-primary-biliary-cholangitis-primary-biliary-cirrhosis/print?search=CIRROSE HE… 18/26

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81. Corpechot C, Chazouillères O, Rousseau A, et al. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J Med 2018; 378:2171. 82. Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther 2016; 43:283. 83. Leuschner M, Maier KP, Schlichting J, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117:918. 84. 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. 85. Rabahi N, Chrétien Y, Gaouar F, et al. Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone. Gastroenterol Clin Biol 2010; 34:283. 86. Mason AL, Farr GH, Xu L, et al. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99:2348. 87. Lytvyak E, Montano-Loza AJ, Mason AL. Combination antiretroviral studies for patients with primary biliary cirrhosis. World J Gastroenterol 2016; 22:349. 88. Mason AL, Lindor KD, Bacon BR, et al. Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther 2008; 28:886. 89. 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 37.0

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GRAPHICS Xanthelasma

Yellow plaques are present bilaterally. With permission from: Slomovits TL (Ed), Basic and clinical science courses section, American Academy of Ophthalmology, San Francisco 1996. Graphic 67919 Version 2.0

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Tuberous xanthomas

Tuberous xanthomas on the elbow of a woman with primary biliary cholangitis and a marked elevation in the serum cholesterol concentration (1400 mg/dL [36.4 mmol/L]). Courtesy of Marshall M Kaplan, MD. Graphic 75143 Version 2.0

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Planar xanthomas

Bilateral planar xanthomas in the palms of a 35-year-old woman with primary biliary cholangitis. Xanthomas started in the creases and expanded. At the time that the xanthomas began to form, the serum bilriubin level was 18.6 mg/dL and serum cholesterol concentration was 970 mg/dL (25.2 mmol/l). Courtesy of Marshall M Kaplan, MD. Graphic 57793 Version 2.0

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Response to ursodeoxycholic acid in primary biliary cholangitis

Probability of response (defined as the absence of treatment failure) to ursodeoxycholic acid (UDCA) in primary biliary cholangitis. Patients were randomized to UDCA (solid line) or placebo (dashed line) for the first 24 months and then all patients were treated with UDCA for the next 24 months. The probability of a beneficial response at four years was significantly higher in the patients treated with UDCA throughout the study. Data from: Poupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group, N Engl J Med 1994; 330:1342. Graphic 59511 Version 4.0

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Ursodeoxycholic acid slows disease progression in primary biliary cholangitis

Effect of ursodeoxycholic acid (UDCA) on progression to liver transplantation or death in primary biliary cholangitis. Patients were randomized to UDCA (dashed line) or placebo (solid line) for the first 24 months and then all patients were treated with UDCA for the next 24 months. The relative risk for liver transplantation or death was 0.32 in patients treated with UDCA throughout the study. Data from: Poupon RE, Poupon R, Balkau B, and the UDCA-PBC Study Group, N Engl J Med 1994; 330:1342. Graphic 82631 Version 4.0

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

Normalization of liver biopsy after methotrexate for primary biliary cholangitis

Sequential liver biopsies in patient with primary biliary cholangitis (PBC). Top panel: Liver biopsy performed five years after the diagnosis of PBC and one year after treatment with colchicine (0.6 mg BID). The portal triads are greatly enlarged, somewhat edematous and infiltrated with mononuclear inflammatory cells. There is bridging of adjacent triads, and early nodule formation is evident. The biopsy is that of stage III to IV PBC. Bottom panel: Repeat liver biopsy after six years on methotrexate. The biopsy is normal except for a few portal triads that are minimally enlarged and infiltrated with mononuclear cells. There are no longer any features of PBC. The patient is asymptomatic and liver enzymes are normal. Masson trichrome, x 94. Reprinted by permission from: Kaplan M, DeLellis R, Wolfe H. Ann Intern Med 1997; 126:682. Graphic 75170 Version 4.0

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Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate

Contributor Disclosures Raoul Poupon, MD Consultant/Advisory Boards: Intercept Pharma. Keith D Lindor, MD Grant/Research/Clinical Trial Support: National Institute of Health [Primary sclerosing cholangitis (Vancomycin and vidofludimus calcium)]. Kristen M Robson, MD, MBA, FACG Nothing to disclose Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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