Primary Biliary Cirrhosis View Online At

Primary Biliary Cirrhosis View online at http://pier.acponline.org/physicians/diseases/d472/d472.html

Module Updated: 2013-02-12 CME Expiration: 2016-02-12

Author Richard H. Moseley, MD

Table of Contents 1. Screening ...... 2 2. Diagnosis ...... 3 3. Consultation ...... 7 4. Hospitalization ...... 8 5. Therapy ...... 9 6. Patient Education ...... 14 7. Follow-up ...... 15 References ...... 16 Glossary...... 20 Tables ...... 21

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Primary Biliary Cirrhosis

Top 1. Screening Although general population screening for primary biliary cirrhosis is not indicated, consider screening certain family members of known patients. 1.1 Consider screening first-degree relatives of patients with PBC. Recommendations • Obtain blood levels of antimitochondrial antibody, alkaline phosphatase, ALT, and AST. Evidence • In a retrospective study, the prevalence of PBC in family members of patients with this disease was markedly increased when compared with estimates in the general population (1). • In one British study of 160 patients with PCB, improved methodology suggested that the overall prevalence of PBC in first-degree relatives of patients with PBC was less than 1%, similar to values seen in other autoimmune diseases. The highest prevalence was seen in daughters of patients (2). • An interview-based study of 1032 patients showed that having a first-degree relative with PBC is significantly associated with increased risk for PBC (3). • A concordance rate of 63% has been reported in monozygotic twins with PBC (4). • In a study from the U.S., 13.1% of first-degree relatives of patients with PBC tested positive for antimitochondrial antibodies (5). • Familial clustering of PBC has also been reported outside of the U.S and the United Kingdom (6). Rationale • Screening should be considered because the risk for PBC is increased in first-degree relatives of patients with PBC.

Primary Biliary Cirrhosis

Top 2. Diagnosis Consider the diagnosis of PBC in patients with chronic cholestasis manifested by unexplained elevations of serum alkaline phosphatase or unexplained pruritus without a rash. 2.1 Recognize that the symptoms of PBC may be absent or nonspecific. Recommendations • Although patients with PBC may be asymptomatic, ask about:

Factors associated with other autoimmune diseases, such as: o Sicca syndrome o CREST syndrome o Raynaud's phenomenon o Thyroid dysfunction o Rheumatoid arthritis o Celiac sprue Family history of cirrhosis Unexplained itching (pruritus) Unexplained fatigue Unexplained weight loss Urinary tract infections Medication history, including use of hormone replacement therapy Smoking history Evidence • Although fatigue and pruritus used to be the most common presenting symptoms of PBC, review articles indicate that the disease is now more widely recognized and many patients are diagnosed at earlier stages when they are asymptomatic (7; 8; 9). Fatigue may be a manifestation of untreated hypothyroidism, which occurs in approximately 20% of patients with PBC (8). • Approximately 50% to 60% of patients are asymptomatic at diagnosis (7; 8; 9; 10). • The cause of pruritus in PBC is unknown, but several hypotheses have been proposed, including bile acid accumulation and endogenous opioids (11). • A case-control study showed that smoking is strongly associated with PBC (OR, 2.04 [CI, 1.10 to 3.78]) (12). Rationale • Although PBC is uncommon, it can be diagnosed while asymptomatic and should be considered in patients with chronic cholestasis, especially patients who have other autoimmune diseases. • It is important to question patients about the use of medications, because some drugs may cause cholestasis similar to that associated with PBC. 2.2 Recognize that the clinical signs attributable to PBC may be absent or nonspecific. Recommendations • Although patients with PBC may have no clinical signs of the disease, look for:

Fatigue Weight loss Hyperpigmentation

Primary Biliary Cirrhosis

Xanthomas Hepatosplenomegaly, suggesting chronic liver disease Signs of advanced stage of liver disease, such as: o Spider nevi o Temporal and proximal limb muscle wasting o Ascites o Edema Jaundice, usually a later manifestation of the disease Evidence • Comprehensive review articles and guidelines emphasize that patients with certain elements in their history and physical exam may be more likely to have PBC. For example, pruritus, hyperpigmentation of the skin, and hepatomegaly in women with a cholestatic pattern of liver function tests are common in PBC but unusual in other liver disorders, such as acute and chronic hepatitis and alcoholic liver disease (7; 8; 9). • A case-control study showed that a significant proportion of patients with PBC suffer from severe fatigue, which correlates with the degree of daytime somnolence (13). Rationale • Although the signs of PBC are likely to be nonspecific if present, physical findings (e.g., hyperpigmentation, xanthomas, jaundice) may provide clues to the diagnosis, as well as an indication of the severity of liver disease. 2.3 Recognize laboratory abnormalities suggesting PBC. Recommendations • Look for the following laboratory abnormalities:

Elevated serum alkaline phosphatase and/or gamma glutamyl transpeptidase levels Normal or elevated conjugated bilirubin levels Slightly elevated ALT and AST levels A positive antimitochondrial antibody test Elevated serum levels of total immunoglobulin M Elevated serum cholesterol level Elevated serum ceruloplasmin level Negative tests for hepatitis A, B, and C viruses Normal serum iron, total iron binding capacity, and iron saturation levels • See table Laboratory and Other Studies for Primary Biliary Cirrhosis. Evidence • A major advance in our understanding of PBC occurred with identification and cloning of the antigens against which antimitochondrial antibodies are detected (14). • A review article indicates that antimitochondrial antibodies are the serologic hallmark of PBC (9). • Antimitochondrial antibodies are found in 95% of patients with PBC, and they have a specificity of 98% (15). Rationale • Laboratory tests are useful for excluding other causes of liver disease. 2.4 Obtain appropriate imaging studies in patients with chronic cholestasis and suspected PBC. Recommendations

Primary Biliary Cirrhosis

• Obtain a right upper quadrant ultrasound scan in patients with chronic cholestasis to exclude extrahepatic bile duct obstruction. • Consider cholangiography to exclude primary sclerosing cholangitis in patients with a negative antimitochondrial antibody test result and a history of colitis. • See table Laboratory and Other Studies for Primary Biliary Cirrhosis. Evidence • MRI and MR cholangiopancreatography provide support for the clinical and laboratory findings of PBC (16); a periportal halo sign on MRI may be highly specific for the diagnosis of PBC (17). • In one retrospective study of men with cholestatic liver biochemistry findings, routine endoscopic retrograde cholangiography did not add to the diagnostic evaluation, especially in the absence of colitis (18). Rationale • Imaging tests should be obtained in patients with chronic cholestasis to exclude extrahepatic bile duct obstruction or other biliary tree abnormalities in patients with a history of colitis. • Cholangiography provides excellent images of the biliary tree. • In many medical centers, MR cholangiography is an alternative to endoscopic retrograde cholangiopancreatography, which may be replaced as MRI technology improves. Comments • MR cholangiography is now widely available but is not as sensitive as endoscopic retrograde cholangiography. 2.5 Consider a liver biopsy to confirm the diagnosis and to assess the severity of PBC. Recommendations • Consult a hepatologist or gastroenterologist regarding liver biopsy to provide information about severity of the disease. • Consider transjugular liver biopsy if the patient has a coagulopathy, thrombocytopenia (<70,000 platelets), or ascites. • Consider a repeat liver biopsy if the initial biopsy is of inadequate size. • See table Laboratory and Other Studies for Primary Biliary Cirrhosis. Evidence • Liver biopsy is usually confirmatory rather than diagnostic, but also will provide information about the disease stage and a baseline against which subsequent liver biopsies can be judged in order to determine disease progression or response to medical treatment (9). Rationale • Liver biopsy should be done because some drugs or liver disorders may cause cholestasis similar to that associated with PBC. • Liver biopsy will also determine the histologic stage of the disease. Comments • The liver may not be affected uniformly, and advanced lesions may be missed if the liver biopsy specimen is small. Thin needle specimens obtained with ultrasound guidance from the left lobe of the liver are often too small to be helpful. 2.6 Recognize that the differential diagnosis of PBC includes all causes of chronic cholestasis in adults. Recommendations • Use clinical and laboratory evaluation to exclude other causes of chronic cholestasis. • See table Differential Diagnosis of Primary Biliary Cirrhosis.

Primary Biliary Cirrhosis

Evidence • A review article emphasizes that the differential diagnosis of PBC includes other causes of chronic cholestasis (20). Rationale • The clinical exam is frequently nonspecific in PBC, and other causes of cholestasis can be confused with PBC.

Primary Biliary Cirrhosis

Top 3. Consultation Consider specialty consultation for diagnosis in patients with unexplained cholestasis or suspected PBC. Refer patients to a gastroenterologist or hepatologist to discuss management options.

3.1 Consult a gastroenterologist or hepatologist to confirm the diagnosis. Recommendations • Consult a gastroenterologist or hepatologist to do a liver biopsy and to interpret liver histologic findings. Evidence • In one study of 73 asymptomatic patients with PBC, the disease was progressive, and survival was decreased (21). • In a cohort of 250 patients followed up to 24 years, asymptomatic patients had a longer life expectancy than those with symptoms (22). Rationale • Liver biopsy is usually done with the guidance of a gastroenterologist or hepatologist and is useful in confirming both diagnosis and prognosis. • A trained gastroenterologist or hepatologist understands the limitations of various diagnostic tests. • Accurate diagnosis is essential to ensure appropriate management. 3.2 Consult a gastroenterologist or hepatologist to manage the complex care of patients with PBC. Recommendations • Consult a gastroenterologist or hepatologist for help in:

Monitoring drug therapy Assessment of liver function tests on therapy Considering colchicine or methotrexate therapy in patients who have had a partial response or no response to UCDA Management of hepatic decompensation Referral for evaluation for liver transplantation Evidence • Consensus. Rationale • Regular assessment by an experienced specialist will lead to appropriate selection of patients for liver transplantation.

Primary Biliary Cirrhosis

Top 4. Hospitalization Hospitalize patients when they develop complications of hepatic decompensation. 4.1 Hospitalize patients with PBC and clinical evidence of hepatic decompensation. Recommendations • Hospitalize patients with:

Variceal hemorrhage Hepatic encephalopathy Renal failure Spontaneous bacterial peritonitis Intractable ascites Evidence • The management of gastroesophageal varices and variceal hemorrhage in cirrhosis in patients with PBC is discussed in guidelines published by the American Association for the Study of Liver Diseases (23). • The management of ascites in cirrhosis in patients with PBC is discussed in guidelines published by the American Association for the Study of Liver Diseases (24). • A review article discusses the management of hepatic encephalopathy in cirrhosis in patients with PBC (25). • A review article discusses the management of renal failure in cirrhosis in patients with PBC (26). Rationale • Without immediate therapy, these complications may be fatal. • Patients with variceal hemorrhage or bacterial peritonitis are at high risk for dying.

Primary Biliary Cirrhosis

Top 5. Therapy Recommend lifestyle changes and treatment of comorbid disease. Consider drug treatment for PBC and its associated symptoms. [C]

5.1 Recommend lifestyle changes. Recommendations • In patients with PBC, recommend:

Avoiding alcohol Smoking cessation Regular weight-bearing exercise Hepatitis A and B vaccines Salt restriction, if ascites is present Maintaining adequate caloric intake to avoid muscle wasting Calcium and vitamin D in patients with osteoporosis Restriction of dietary fat if symptomatic steatorrhea is present Evidence • Total body sodium is increased in cirrhotic patients with ascites and hyponatremia, indicating that the decrease in serum concentration is a consequence of excess water due to impairment of free water excretion (27). • A sodium intake of 2000 mg/d is a practical and successful amount of sodium restriction in an outpatient setting (24). • Symptomatic steatorrhea due to bile acid insufficiency can be partially corrected by restricting dietary fat and by adding medium-chain triglycerides (28). • American Association for the Study of Liver Diseases guidelines recommend that patients with PBC be provided 1000 to 1500 mg of calcium and 1000 IU of vitamin D in the diet and as supplements if needed (8). Rationale • These restrictions are required to control the complications of hepatic decompensation. 5.2 Consider ursodeoxycholic acid as the initial treatment of PBC. Recommendations • In patients with PBC, initiate UDCA, 13 to 15 mg/kg·d in two divided doses. • See table Drug Treatment for Primary Biliary Cirrhosis. Evidence • In a randomized, controlled trial of 180 patients at one medical center, UDCA was associated with improvement of liver function tests; however, there was no improvement in symptoms of fatigue, pruritus, liver histology, or referral for liver transplantation (29). • In a randomized, multicenter study of 222 patients in Canada, UDCA was associated with improvement of liver function tests and liver histology, but no improvement in symptoms or referral for liver transplantation (30). • In a multicenter trial of 151 patients in the United States, UDCA was associated with improvement of liver function tests, but no improvement in symptoms or the need for liver transplantation (31). • In a trial done primarily in Europe, 145 patients were randomly assigned to receive UDCA or placebo for 2 years, and then all patients received UDCA for 2 additional years in open trial. The probability of liver transplantation or death was decreased in patients receiving UDCA (32).

Primary Biliary Cirrhosis

• In a randomized, double-blind, controlled trial of 192 patients in Spain, UDCA therapy was associated with improvement of liver function tests and liver histology, but the drug did not affect time to death or liver transplantation (19). • When data from three randomized, controlled studies were combined, UDCA prolonged time before liver transplantation for 4 years (33). • A meta-analysis of 16 randomized clinical trials showed that neither mortality nor liver transplantation, pruritus, fatigue, autoimmune conditions, quality of life, liver histology, nor portal pressure were significantly affected by UDCA (given in doses of 8 to 15 mg/kg·d for 3 months to 5 years). However, UDCA reduced ascites, jaundice, and biochemical variables such as serum bilirubin and liver enzymes (34). • In a study evaluating 254 pairs of liver biopsy specimens, the incidence of cirrhosis after 5 years of UDCA treatment was 4%, 12%, and 59% among patients with stages I, II, and III, respectively. At 10 years, the incidence was 17%, 27%, and 76%, respectively. The independent predictive factors of cirrhosis development in ursodiol patients were serum bilirubin >17 µmol/L, serum albumin <38 g/L, and moderate to severe lymphocytic piecemeal necrosis (35). • Analysis of individual histologic data from four large placebo-controlled trials demonstrated that UDCA, when initiated in the early stages of PBC, delays the histologic progression of the disease (36). • Using a modeling approach, long-term survival of UDCA-treated patients with early histologic stages of PBC was shown to be similar to that of an age- and sex-matched control population (37). • Survival in 192 patients with PBC treated with UDCA was similar to a matched control population in those showing a response to treatment defined by an alkaline phosphatase decrease greater than 40% of baseline values or normal values after 1 year of treatment (38). • Lower doses (10 to 12 mg/kg·d) and less bioavailable preparations may eliminate the therapeutic benefit of UDCA (39). • A prospective, multicenter study of 375 patients showed that the prognosis for patients with early PBC treated with UDCA is comparable to that of the general population. The prognosis for patients with advanced PBC treated with UDCA was significantly better in those with a biochemical response to UDCA, defined as a normalization of abnormal bilirubin and/or albumin levels (40). • Silymarin (milk thistle) was studied in combination with UDCA and offered little additional benefit (41). The safety or clinical efficacy of other herbal products has not been studied. Rationale • Studies have shown that UDCA is safe and well tolerated, and one study showed that it prolonged time before liver transplantation for at least 4 years. • UDCA is the only therapy for PBC approved by the U.S. Food and Drug Administration. 5.3 Recognize that the use of colchicine and methotrexate is controversial in the treatment of PBC. Recommendations • If the serum alkaline phosphatase level is ≥1.5 times normal after 1 year of UDCA, and a repeat liver biopsy shows no histologic improvement or worsening histologic findings, consider referring the patient to a hepatologist for consideration of colchicine, 0.6 mg twice per day. • If results of liver biopsy repeated after 1 year of UDCA and colchicine show no improvement, consider referring the patient to a hepatologist for consideration of methotrexate, 0.25 mg/kg per week. • See table Drug Treatment for Primary Biliary Cirrhosis. Evidence • In a randomized, controlled trial of 60 patients, the administration of colchicine, compared to placebo, was associated with significant improvements in liver function tests at 2 years. There was no improvement in symptoms or liver histology in the study. The likelihood of death due to liver- related causes after 4 years was significantly less in the patients receiving colchicine (42).

Primary Biliary Cirrhosis

• A randomized, controlled trial to determine if colchicine or methotrexate improves blood test results, symptoms, and liver histology in patients with PBC found that both colchicine and methotrexate improved biochemical test results and symptoms, but that the response to methotrexate was greater (43). • In one report of 10 patients, the addition of methotrexate to a regimen of UDCA and colchicine was associated with a significant decline in serum alkaline phosphatase and liver histology than observed after UDCA alone or in combination with colchicine (44). • In a randomized, controlled trial of 22 patients, additional administration of colchicine to UDCA was associated with improvement of liver function tests (45). • In a randomized trial of 74 patients comparing the combination therapy of colchicine and UDCA to UDCA alone, the combination of colchicine and UDCA did not significantly improve symptoms, liver function tests, or histologic features, except lobular inflammation (46). • In two studies of eight patients each with PBC responding insufficiently to UDCA, the addition of methotrexate to UDCA was associated with improvement in liver function tests and symptoms (47; 48). • In a prospective case study of 19 patients with biopsy-proven precirrhotic PBC, treatment with methotrexate was associated with improvement in liver function tests, symptoms, and liver histology (49). • In other trials, the combination of UDCA and methotrexate or low-dose methotrexate was not beneficial (50; 51; 52; 53). • The combination of colchicine and UDCA or methotrexate and UDCA may offer the most benefit to selected patients with early-stage disease (54). • A systematic review of randomized, controlled studies of colchicine in patients with PBC found insufficient evidence to support its use (55). • A systematic review of randomized clinical trials of methotrexate in patients with PBC found insufficient evidence to support its use (56). Rationale • Colchicine and methotrexate may be effective when UDCA has initially failed; some hepatologists have found these drugs useful, while others have not. • Moreover, there are studies showing that these drugs are effective and others showing that they are not. Comments • Given the controversy surrounding the use of colchicine and methotrexate in PBC, consultation with a hepatologist is always strongly recommended when considering their use. 5.4 Choose from among available options for treatment of pruritus. Recommendations • Use bile acid sequestrants as initial treatment for pruritus in patients with PBC. • Consider rifampin, naloxone, or sertraline as second-line treatment. • See table Drug Treatment for Pruritus. Evidence • The bile acid resins, such as cholestyramine and colestipol, are effective first-line agents in the management of cholestatic pruritus (57). • In a double-blind, controlled, crossover clinical trial of nine patients with PBC, patients were treated with rifampin and placebo sequentially, in random order. Patients treated with rifampin had a highly significant reduction in pruritus (58). • In a double-blind, placebo-controlled, crossover trial of 29 patients with pruritus, naloxone was associated with amelioration of pruritus (59). • In a study of 14 patients with unrelieved chronic pruritus of cholestasis, 13 patients reported amelioration of pruritus with oral nalmefene (60).

Primary Biliary Cirrhosis

• In a randomized, placebo-controlled trial of 16 patients with pruritus of chronic cholestasis, oral naltrexone was associated with substantial relief of cholestatic pruritus (61). • In a crossover, double-blind, placebo-controlled study, naltrexone, an oral opioid antagonist, improved pruritus in 9 out of 20 patients, including 5 in whom pruritus disappeared completely (62). • Sertraline (50 to 100 mg/d) improved pruritus in 40 patients followed prospectively as part of a double-blind, randomized clinical trial of UDCA and either methotrexate or placebo (63). • In a randomized, double-blind, placebo-controlled trial, sertraline (75 to 100 mg/d) was an effective, well-tolerated treatment for patients with pruritus due to chronic liver disease, including patients with PBC (64). • A small double-blind, placebo-controlled study showed that gabapentin offered no benefit and may actually aggravate pruritus in patients with cholestasis (65). Rationale • The management of pruritus in patients with PBC may improve quality of life. 5.5 Use antiresorptive therapy in patients with evidence of osteoporosis. Recommendations • When the diagnosis of PBC is made, assess bone mineral density with dual-energy x-ray absorptiometry and every 2 years thereafter. • Consider antiresorptive therapy with a bisphosphonate. • Consider raloxifene for patients who cannot tolerate a bisphosphonate. Evidence • Age and severity of disease, but not menopausal status, are the major risk factors for osteoporosis in PBC (66). • There is an approximately two-fold relative increase in the risk for any fracture, hip fracture, and ulna/radius fracture in patients with PBC compared to age-matched controls in the general population (67). • In one prospective, controlled pilot study, therapy with a bisphosphonate, etidronate, was shown to prevent corticosteroid-induced osteoporosis (68). • A randomized, controlled trial comparing the effects of etidronate to placebo in the treatment of osteoporosis in 67 patients with PBC and osteopenia (defined by a bone mineral density T-score <- 2.0) found that cyclical etidronate administered with supplemental calcium did not significantly improve bone density (69). • In a randomized, controlled trial of normal, postmenopausal women, a dietary intake of calcium, 1500 mg/d, and vitamin D, 1000 IU/d, was beneficial (70). • In one small study, etidronate was more effective and better tolerated than sodium fluoride in preventing bone loss in PBC (71). • In a randomized, controlled trial of 994 women with postmenopausal osteoporosis, daily treatment with oral alendronate was associated with increased bone mass at all skeletal sites (72). • In a randomized trial of 32 women with PBC, oral alendronate (10 mg/d) effectively increased bone mass and had greater antiresorptive effects than etidronate (400 mg/d) (73). • In a double-blind, randomized, placebo-controlled trial, alendronate (70 mg/wk) significantly improved bone mineral density in patients with PBC-associated bone loss with a bone mineral density T-score <-1.5 (74). Rationale • Osteoporosis is a manifestation of PBC. • Severe osteoporosis may cause bone fractures. 5.6 Consider liver transplantation in patients with hepatic decompensation. Recommendations

Primary Biliary Cirrhosis

• Consider liver transplantation in patients with liver failure manifested by variceal hemorrhage, ascites, and hepatic encephalopathy. • When appropriate, consider liver transplantation before patients become severely debilitated. Evidence • Orthotopic liver transplantation is an effective treatment for patients with advanced PBC (75). • A review article reports 1-, 5-, and 10-year patient survival of 83%, 77%, and 69%, and graft survival of 79%, 71%, and 64%, respectively, in patients undergoing liver transplantation for advanced PBC. PBC may recur after liver transplantation, although the impact of recurrent disease on survival is unclear (76). Rationale • Liver transplantation improves the survival of patients with liver failure due to PBC.

Primary Biliary Cirrhosis

Top 6. Patient Education Inform patients about the course of the disease and the management of symptoms. 6.1 Discuss with patients the treatment of PBC, possible complications, and the option of liver transplantation. Recommendations • Inform patients that early treatment is more likely to be successful. • Inform patients with clinically advanced disease of the possible complications of PBC. • Advise patients with cirrhosis and signs of liver failure (jaundice, esophageal varices) about the importance of regular follow-up and the option of liver transplantation. • Inform patients that there are no contraindications to pregnancy with UDCA therapy. Evidence • In a combined analysis of three randomized, controlled trials of PBC, long-term UDCA therapy improved survival free of liver transplantation in patients with moderate or severe disease (33). • In a prospective case study of 19 patients with biopsy-proven, precirrhotic PBC, treatment with methotrexate was associated with improvement in liver function tests, symptoms, and liver histology (49). Rationale • Information about PBC helps patients to understand their disease and prognosis. • Many patients with precirrhotic PBC may respond to medical treatment

Primary Biliary Cirrhosis

Top 7. Follow-up Ensure regular follow-up to monitor disease progression and response to therapy. 7.1 Monitor patients at appropriate intervals and use clinical status to guide management. Recommendations • Do a history and physical exam every 4 to 6 months, looking for signs of hepatic decompensation. • Monitor liver function tests every 4 to 6 months. • Monitor for weight loss, jaundice, and pruritus. • Check for esophageal varices by upper endoscopy every 2 to 3 years in compensated patients without varices, and every 1 to 2 years in compensated patients with small varices. • Consider the addition of a nonspecific β-blocker (nadolol, propranolol, or carvedilol) to decrease the likelihood of an initial bleed from esophageal varices. • Consider periodic ultrasound scans because of the increased risk for liver cancer in patients with PBC. • Consider band ligation in patients with history of variceal bleeding. • Consider liver biopsy every 2 to 3 years to assess for disease progression and response to therapy, although this is not mandatory. • At the onset of hepatic decompensation, refer patient for liver transplantation. Evidence • These recommendations are based on guidelines published by the American Association for the Study of Liver Diseases (8). Rationale • Close follow-up is essential for optimal care of patients with PBC.

Primary Biliary Cirrhosis

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Primary Biliary Cirrhosis

26. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med. 2009;361:1279-90. (PMID: 19776409) 27. Arroyo V, Clària J, Saló J, Jiménez W. Antidiuretic hormone and the pathogenesis of water retention in cirrhosis with ascites. Semin Liver Dis. 1994;14:44-58. (PMID: 8016662) 28. Ros E, García-Pugés A, Reixach M, Cusó E, Rodés J. Fat digestion and exocrine pancreatic function in primary biliary cirrhosis. Gastroenterology. 1984;87:180-7. (PMID: 6724261) 29. Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology. 1994;106:1284-90. (PMID: 8174890) 30. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1994;19:1149-56. (PMID: 8175136) 31. Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, et al. 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Ikeda T, Tozuka S, Noguchi O, Kobayashi F, Sakamoto S, Marumo F, et al. Effects of additional administration of colchicine in ursodeoxycholic acid-treated patients with primary biliary cirrhosis: a prospective randomized study. J Hepatol. 1996;24:88- 94. (PMID: 8834030) 46. Poupon RE, Huet PM, Poupon R, Bonnand AM, Nhieu JT, Zafrani ES. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA-PBC Study Group. Hepatology. 1996;24:1098-103. (PMID: 8903382) 47. 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;18:9-14. (PMID: 8101853) 48. 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. 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50. González-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol. 1997;27:143-9. (PMID: 9252088) 51. Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology. 1995;22:1158-62. (PMID: 7557866) 52. Hendrickse MT, Rigney E, Giaffer MH, Soomro I, Triger DR, Underwood JC, et al. Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial. Gastroenterology. 1999;117:400-7. (PMID: 10419922) 53. Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology. 2005;42:1184-93. (PMID: 16250039) 54. 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;39:915-23. (PMID: 15057894) 55. Gong Y, Gluud C. Colchicine for primary biliary cirrhosis: a Cochrane Hepato-Biliary Group systematic review of randomized clinical trials. Am J Gastroenterol. 2005;100:1876-85. (PMID: 16086725) 56. Giljaca V, Poropat G, Stimac D, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2010;(5):CD004385. (PMID: 20464729) 57. Datta DV, Sherlock S. Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology. 1966;50:323-32. (PMID: 5905351) 58. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology. 1988;94:488-93. (PMID: 3275568) 59. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, et al. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med. 1995;123:161-7. (PMID: 7598296) [Full Text] 60. Bergasa NV, Schmitt JM, Talbot TL, Alling DW, Swain MG, Turner ML, et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology. 1998;27:679-84. (PMID: 9500694) 61. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology. 1997;113:1264-9. (PMID: 9322521) 62. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol. 2002;37:717-22. (PMID: 12445410) 63. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol. 2003;98:2736-41. (PMID: 14687826) 64. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666-74. (PMID: 17326161) 65. Bergasa NV, McGee M, Ginsburg IH, Engler D. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2006;44:1317-23. (PMID: 17058231) 66. Guanabens N, Pares A, Ros I, Caballeria L, Pons F, Vidal S, et al. Severity of cholestasis and advanced histological stage but not menopausal status are the major risk factors for osteoporosis in primary biliary cirrhosis. J Hepatol. 2005;42:573-7. (PMID: 15763344) 67. Solaymani-Dodaran M, Card TR, Aithal GP, West J. Fracture risk in people with primary biliary cirrhosis: a population-based cohort study. Gastroenterology. 2006;131:1752-7. 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Top Glossary ALT alanine aminotransferase AST aspartate aminotransferase bid twice daily CI confidence interval CREST limited cutaneous systemic sclerosis INR international normalized ratio iv intravenous MR magnetic resonance MRI magnetic resonance imaging OR odds ratio PBC primary biliary cirrhosis tid three times daily UDCA ursodeoxycholic acid

Primary Biliary Cirrhosis

Top Tables

Laboratory and Other Studies for Primary Biliary Cirrhosis

Test Sensitivity (%) Specificity (%) Notes

Alkaline phosphatase Usually elevated

Gamma glutamyl transpeptidase Usually elevated

ALT Usually mildly elevated

Bilirubin Normal or elevated

Albumin May be decreased if liver disease is advanced

Cholesterol May be increased

Immunoglobulin M May be increased

Ceruloplasmin May be increased

Antimitochondrial antibody 95 98 Usually present to diagnose PBC (8); found in 95% of patients with PBC, and has a specificity of 98% (15)

Antineutrophil antibody May be present in 30%-50% of patients with PBC (19)

Smooth muscle antibody May be present in 5%-10% of patients with PBC (19)

Prothrombin time/INR Insensitive and nonspecific level

Cholangiogram Consider cholangiography to exclude primary sclerosing cholangitis in patients with a negative antimitochondrial antibody test result

Liver biopsy Histologic findings in PBC are often staged on a scale of zero to four (8). Stage zero: normal liver Stage one: inflammation confined to the portal areas Stage two: inflammation and/or fibrosis confined to portal and periportal areas Stage three: bridging fibrosis (i.e., linkage of portal triads by scarring or inflammation) Stage four: cirrhosis

Dual-energy x-ray absorptiometry Osteoporosis is a manifestation of PBC

ALT = alanine aminotransferase; INR = international normalized ratio; PBC = primary biliary cirrhosis.

Primary Biliary Cirrhosis

Differential Diagnosis of Primary Biliary Cirrhosis

Disease Characteristics

Primary biliary cirrhosis Fatigue and pruritus are common symptoms. PBC can be diagnosed while asymptomatic and should be considered in patients with chronic cholestasis, especially in patients who have other autoimmune diseases Antimitochondrial antibodies are found in 95% of patients with PBC, and they have a specificity of 98% (15)

Gallstones History of pain or fever Excluded by ultrasound, CT, or MRI scan

Mechanical, extrahepatic bile duct obstruction (tumors, cysts, postsurgical strictures) History of surgery, weight loss, and abnormal bile ducts by imaging tests CT may be suggestive; cholangiography is usually diagnostic

Primary sclerosing cholangitis History of inflammatory bowel disease with characteristic cholangiogram More common in men

Alcoholic hepatitis History of alcohol abuse Cholestatic profile occurs rarely

Cholestatic viral hepatitis History of exposure, presence of viral markers Hepatitis viral markers are diagnostic

Granulomatous hepatitis History of sarcoidosis, or fever of unknown etiology Abnormal chest x-ray or granulomas in liver biopsy

Autoimmune hepatitis History of associated autoimmune diseases Elevated immunoglobulin G and/or autoantibodies

Adult bile ductopenia Blood test results indistinguishable from PBC Diagnosis is based on liver biopsy

Benign, recurrent intrahepatic cholestasis Cholangiogram is normal with recurrent attacks, with normal liver function tests between episodes Rare

Drug-induced cholestasis History of particular drug exposure (e.g., androgens, amoxicillin-clavulanic acid, chlorpromazine, erythromycin, nitrofurantoin, haloperidol, cimetidine, ampicillin, sulfamethoxazole-trimethoprim, oral hypoglycemic agents) Recognized by careful medication history

CT = computed tomography; MRI = magnetic resonance imaging; PBC = primary biliary cirrhosis.

Primary Biliary Cirrhosis

Drug Treatment for Primary Biliary Cirrhosis

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Ursodeoxycholic acid, Ursodiol 13-15 mg/kg total daily dose, dosed Asthenia, dyspepsia, peripheral edema, (Actigall, Urso) bid. Start at 250 mg qd and increase hypertension, nausea, pruritus, every 3-4 days diarrhea

Colchicine (Colcrys) 0.6 mg bid GI side effects, myelosuppression, Avoid if taking a moderate-strong If ursodiol is inadequate after 1 year myopathy, neuropathy, nephrotoxicity, CYP3A4 inhibitor or P-gp inhibitor. elevated hepatic enzymes Decrease dose with CKD. Avoid alcohol

Methotrexate, MTX (Rheumatrex, 15 mg weekly Renal toxicity, ocular side effects, Use by experienced physician. Avoid If ursodiol and colchicine are Trexall) arrhythmias, stomatitis, alopecia, with pregnancy. Risk of malignancy. inadequate after 1 year photosensitivity Significant toxicities: hematologic, GI, hepatic, pulmonary, dermatologic. Caution with CKD. Severe bone marrow suppression with NSAIDs

Drugs for Pruritus

Bile acid sequestrants GI side effects, increased triglycerides. Avoid with complete biliary obstruction. First line for pruritus Decreased absorption of vitamins A, D, Administer other drugs >1 hr before or E, K with chronic use 4-6 hr after. Binds exogenous thyroid hormones. Release chloride (caution with CKD)

Cholestyramine(Prevalite, Locholest) 4-16 g total daily dose, dosed bid before meals

Colestipol (Colestid) Granules: 5 g tid

Opioid antagonists Nausea, CNS side effects Avoid with opioid dependence or acute opioid withdrawal

Naltrexone (ReVia) 50 mg qd Increased CPK Hepatic injury with excessive dosing. May need to decrease dose with CKD

Naloxone 0.2 μg/kg·min IV for 24 hours Caution with cardiac disease

Other agents for pruritus

Rifampin (Rifadin, Rimactane) 300-450 mg qd GI side effects, adverse renal effects, If CrCl<10, decrease dose by half. hepatotoxicity, CNS side effects, Potent inducer of CYP3A4 and inducer thrombocytopenia, edema. Flu of other CYP isoenzymes (many drug syndrome when taken intermittently interactions)

Sertraline (Zoloft) 50-100 mg qd Platelet dysfunction, GI side effects, Suicidality, particularly in young xerostomia, CNS side effects, adults. Avoid: abrupt discontinuation, hyponatremia, rare serotonin other serotonergic drugs, MAO-I. Mild syndrome or NMS inhibitor of CYPs 2D6 and 3A4

= first-line agent; = black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CPK = creatine phosphokinase; CrCl = creatinine clearance; CYP = cytochrome P450 isoenzyme; GI = gastrointestinal; IM = intramuscular; IV = intravenous; MAO-I = monoamine oxidase inhibitor; NMS = neuroleptic malignant syndrome; NSAID = nonsteroidal anti-inflammatory drug; P-gp = P-glycoprotein; PO = oral; prn = as needed; q12hr = every 12 hours; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Primary Biliary Cirrhosis

Drug Treatment for Pruritus

Agent Mechanism of Action Dosage Benefits Side Effects Notes

Cholestyramine Bile acid resin 4-16 g/d 90% effective in relief of Unpalatable, constipation, can 57 pruritus interfere with absorption of medications

Colestipol Bile acid resin 5 g tid 90% effective in relief of Constipation, can interfere with 20 pruritus absorption of medications

Rifampin Competes with bile acids for 300-450 mg/d Relief of cholestatic pruritus Idiosyncratic hepatotoxicity 58 hepatic uptake

Naloxone Opioid antagonist 0.2 µg/kg iv per min for 24 Relief of cholestatic pruritus Self-limited, opioid withdrawal- 59 hours like syndrome

Nalmefene Opioid antagonist 60-120 mg/d Relief of cholestatic pruritus Self-limited, opioid withdrawal- 60 like syndrome

Naltrexone Opioid antagonist 50 mg/d Relief of cholestatic pruritus Self-limited, opioid withdrawal- 61 like syndrome

Sertraline Serotonin reuptake inhibitor 50-100 mg/d Improvement in cholestatic Well tolerated 63; 64 pruritus iv = intravenous; tid = three times daily