sign in sign up
<<
Home , Chronic liver disease, Liver failure, Steatorrhea

DISORdERS, SERIES #4

Rad Agrawal, MD, FACP, FACG, AGAF, FASGE Primary Biliary Cholangitis

Duminda Suraweera Courtney Reynolds Shehan Thangaratnam Gaurav Singhvi

Primary biliary cholangitis, previously known as primary biliary , is a chronic, cholestatic, inflammatory characterized by destruction of intrahepatic ducts resulting in progressive liver damage. The etiology of primary biliary cholangitis is still not fully understood but likely involves both environmental and genetic factors. If symptomatic, patients often present with and pruritus. About 95% of individuals with primary biliary cholangitis will have a positive anti- mitochondrial antibody. Current treatment options are limited primarily to ursodeoxycholic acid, while those with decompensated liver disease will require . We provide a review of the etiology, pathogenesis, natural history, diagnosis and management of primary biliary cholangitis.

Epidemiology, Etiology and Pathogenesis rimary biliary cholangitis (PBC) has an incidence The etiology of PBC is not fully understood, but rate of 0.9 to 5.8 per 100,000 people with an both genetic predisposition and environmental triggers Pestimated female to male ratio of 10 to 1.1-3 PBC likely play an important role. The prevalence of PBC is is more common in patients in Northern Europe, the higher in families with an affected member, indicating United Kingdom and the northern United States. The a possible genetic component. Approximately 1.2% of prevalence seems to have increased over time, currently children of PBC patients develop PBC, with the highest ranging from 1.91 to 40.2 per 100,000 people.3 The risk in daughters of women with PBC.4 Monozygotic increase in prevalence is likely multifactorial with twins have a high concordance rate of 0.63 for PBC.5 increased disease diagnosis and increased survival with Additionally, several studies have shown a link between improved treatment. HLA alleles and PBC.6-9 Several studies have shown increased incidence in areas of heavy pollution in both the US and UK, Duminda Suraweera1 Courtney Reynolds1 Shehan suggesting that environmental toxins may play a role in Thangaratnam2 Gaurav Singhvi3 1Department the development of PBC.10,11 Furthermore PBC has also of Medicine, Olive View-UCLA Medical Center, been associated with infections, reproductive hormone Sylmar, CA 2Department of Chemistry, University replacement, hair dyes, nail polish, xenobiotics and of California Berkeley, CA 3David Geffen tobacco use.4,12,13 School of Medicine at UCLA, Los Angeles, CA (continued on page 50)

48 Practical • January 2016

Agrawal Jan 16.indd 48 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

(continued from page 48) The hallmark of PBC is the destruction of small epithelial cells leading to ductopenia and persistent . This is believed to be largely mediated by T-cell destruction.14 Hepatic damage and eventual results from ongoing retention of toxic substances.15 It is still unclear as to why biliary epithelial cells in particular are affected. Biliary epithelial cells express T-cell ligands that play a key role in induction of autolysis and may even act as antigen presenting cells, thereby amplifying the immune response.9 While it is unknown what initially triggers PBC, potential candidates include viral or bacterial infection, xenobiotics and human immunoregulatory 16 defects. Figure 1.

Diagnosis is not necessary in establishing the diagnosis. A liver biopsy should be obtained when AMA is absent or if Laboratory Markers there is a mixed biochemical or clinical picture. When PBC should be considered in patients with an elevated pursuing a biopsy, it is important to obtain an adequate alkaline phosphatase level when other intrahepatic and sample, as the distribution of bile duct destruction can extrahepatic causes of cholestasis have been excluded be patchy. Generally, it is recommended that at least (Figure 1). Often abnormal laboratory markers are 10-15 portal tracts should be examined to rule out found incidentally prior to any symptom development.1 pathology.1 The characteristic histologic finding in PBC While serum aminotransferases are often elevated, is an inflammatory infiltrate centered around the bile this is not always the case. Total bilirubin may also ducts.2 Infiltrating cells form granulomas consisting be normal in early stages of the disease. Serum anti- of lymphocytes, neutrophils, macrophages and plasma mitochondrial antibody (AMA) is highly sensitive for cells. This inflammatory process mainly affects the PBC, with a positive result in 95% of patients with interlobular and septal bile ducts, sparing the large PBC and less than 1% in non-PBC patients.17-19 The extrahepatic ducts. The degree of duct deformity can targets of the anti-mitochondrial antibody all belong to be staged using Ludwig’s staging criteria (Table 1).24 the 2-oxo-acid dehydrogenase complex enzymes. They Stage 1 is described as portal inflammation, with stage function to catalyze oxidative decarboxylation of keto 2 described as an extension of this inflammation to the acid substrates in the inner mitochondrial membrane.20,21 periportal areas. Stage 3 consists of septal fibrosis or Approximately 5-10% of patients will have a negative or inflammatory bridging, and stage 4 is cirrhosis. low titer AMA. In these patients, antibodies to the major M2 components, such as PDC-E2 or 2-oxo-glutaric acid Imaging dehydrogenase complex, may be present. Antinuclear Abdominal imaging should be part of the workup for antibodies have also been shown to be present in PBC, PBC and should be pursued at the onset of laboratory though the sensitivity is typically around 40-50%.22 abnormalities or symptoms. Ultrasound is a cost- Anti-Sp100 and anti-gp210 have high specificity to effective, non-invasive test for the initial evaluation PBC and their presence is generally associated with of liver cirrhosis and has a sensitivity and specificity of more aggressive disease.22,23 Often these are specialized about 80%.25 The use of Doppler can further enhance tests that are not readily available, thus AMA should ultrasound leading to an increased sensitivity of 97% be used as a primary method for screening for PBC. and specificity of 93%.26 Ultrasound is typically the modality of choice to screen for Histology in patients with cirrhosis, typically every 6-12 months.1 While liver biopsy can be helpful, in patients with a Computer tomography can aid in the exclusion of other cholestatic liver profile and positive AMA, a biopsy etiologies such as mechanical biliary duct obstruction

50 Practical Gastroenterology • January 2016

Agrawal Jan 16.indd 50 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

Table 1. Ludwig’s Histological Staging of Primary Biliary Cholangitis Stage 1 Portal inflammation

Stage 2 Inflammation of portal and periportal areas

Stage 3 Septal fibrosis or inflammatory bridging

Stage 4 Cirrhosis

Table 2. Clinical Stages of Primary Biliary Cholangitis Pre-clinical Positive anti-mitochondrial antibody

Asymptomatic Liver function test abnormalities

Symptomatic Symptoms of pruritus and fatigue

Advanced Cirrhosis

as well as help assess for advanced disease such as predictive value of the GLOBE score for transplantation fibrosis or . Cholangiography may or death, calculated via C-statistics, was 0.81 (CI be pursued to exclude other diseases such as 95%). Without treatment, the 10-year survival is 50- sclerosing cholangitis. Recently, transient elastography 70% for asymptomatic patients and estimated at 5-8 has been utilized to evaluate liver fibrosis and has been years if symptomatic; liver failure develops in 15- found to have over 90% sensitivity and specificity for 25% of patients within 5 years.1 Interestingly, portal detecting advanced fibrosis in patients with PBC.27-29 hypertension can develop prior to cirrhosis in PBC patients and most commonly manifests with esophageal Natural History varices that are present in up to a third of untreated PBC is a progressive cholestatic liver disease that in its advanced patients. The etiology is unclear but is thought end stage can progress to cirrhosis. By clinical stage, to be due to nodular regeneration.1 Thus, screening PBC can be divided into pre-clinical, asymptomatic, with endoscopy for should begin symptomatic and advanced, which correspond to prior to development of cirrhosis, with initiation of positive AMA only; positive AMA with liver function a non-selective beta-blocker if needed. Initiation test abnormalities; the former along with symptoms of of standardized treatment with urseodeoxycholic pruritus and fatigue; and cirrhosis, respectively (Table acid (UDCA) in the 1990s has been shown to delay 2).1 Progression is determined by whether patients progression: one trial in France showed 7% vs 34% undergo treatment and by response to treatment.30 progression from stage I or II to stage III or IV in the Recently a new scoring system has been developed to UDCA vs placebo groups.32 Nonetheless, improvement risk stratify patients with PBC using age and several in survival has been inconsistently demonstrated.33-35 laboratory markers.31 The GLOBE score is calculated Poor prognostic factors include continued elevated as follows: 0.044378 x age at start of UDCS therapy + alkaline phosphatase while on UDCA treatment, higher 0.93982 x bilirubin times the upper limit of normal at bilirubin levels, low albumin and high IgG levels.36 1-year follow-up + 0.335648 x alkaline phosphatase Lack of response to UDCA has also been linked to time the upper limit of normal at 1-year follow- higher risk of hepatocellular carcinoma once cirrhosis up – 0.002581 x platelet counts per 109/L at 1 year develops. follow-up + 1.21685. The authors found the overall Other common complications of PBC include

Practical Gastroenterology • January 2016 51

Agrawal Jan 16.indd 51 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4

hyperlipidemia, osteoporosis and vitamin deficiencies. Hyperlipidemia is characterized by a disproportionate increase in HDL, and overall levels can rise enough to cause xanthomas (Figure 2). Patients are not generally treated, as an increased risk of atherosclerotic events has not been demonstrated. Notably though, one meta- analysis did find a higher risk of coronary artery disease (CAD) in PBC patients (OR 1.27) while a similar study by the same author did not find any increased risk of stroke.37,38 and weight loss often occur in PBC patients due to of dietary .39 likely occurs due to a decrease in biliary secretion of bile acids. Osteoporosis is a frequent comorbidity, seen in 20-44% of patients with advanced disease; the proposed mechanism is inhibition of osteoblasts Figure 2. through retained bilirubin.40 Osteoporotic patients have normal vitamin D metabolism and are infrequently clinically symptomatic but may be monitored with Uncommon associated conditions include DEXA scans and treated in the standard method with rheumatoid arthritis, which has been estimated to coexist calcium/vitamin D and/or bisphosphonates. Fat-soluble with PBC in 1.8-5.6% of cases and is thought to result vitamin deficiencies should be tested once cirrhosis or from common non-HLA risk loci identified in genome advanced disease develops and can be managed with wide association studies.49-53 Notably, this should be supplementation. Late vitamin E deficiency may explain distinguished from the more common occurrence of associated with PBC.1 rheumatoid arthritis and liver fibrosis. Systemic lupus erythematous (SLE) has been identified in 34 patients Associated Disorders with PBC, 97% of which were female.54 Rarely, PBC is strongly associated Sjogren’s disease and coexisting PBC and primary sclerosing cholangitis autoimmune (AIH) and less commonly with occur.55 Finally autoimmune thyroid disease, most other autoimmune diseases. It has been estimated that frequently Hashimoto’s thyroiditis, has also been linked up to half of PBC patients have a coexistent autoimmune to PBC.56 disease.41-43 In particular, PBC-AIH overlap syndrome has been well documented although the exact criteria Management for diagnosing this disorder have been controversial. The most commonly used diagnostic criteria is the Ursodeoxycholic Acid Paris criteria, which specifies that two conditions must Currently UDCA is the only approved therapy for PBC. be met to support each separate diagnosis (Table 3).44 Several studies have shown that the use of UDCA is In prior studies, PBC-AIH has been associated with associated with improved liver biochemistries.57,58 worse prognosis compared to either individual entity Furthermore longitudinal studies have shown a survival however in the majority of cases patients who did benefit.33,34,36 While patients with histological evidence poorly were not treated with dual therapy (i.e., UDCA of early disease tend to respond better to UDCA, even and or other immunosuppression).45-47 patients with advanced disease benefit from UDCA.34 The association with Sjogren’s and less commonly UDCA has even been shown to reduce the requirements scleroderma and CREST have also been well of liver transplant in patients with PBC.59 Other studies, documented and most commonly result in symptoms however, have found no benefit with UDCA.60,61 It is of xerostomia and keratoconjunctivitis sicca but also thought that these reviews included data from trials have been associated with esophageal dysmotility. with shorter durations and lower doses of UDCA than Management is symptomatic with artificial tears, what is believed therapeutic. It has become clear that pilocarpine drops, saliva substitutes and adequate dental the efficacy of UDCA is dose dependent. 48 care. (continued on page 54)

52 Practical Gastroenterology • January 2016

Agrawal Jan 16.indd 52 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4

(continued from page 52) Table 3. Paris Criteria For Diagnosis of Primary Biliary Angulo et al. conducted a randomized trial to Cholangitis- Overlap Syndrome compare the efficacy of different doses of UDCA: low dose (5-7mg/kg/day), standard dose (12-15mg/ Primary Biliary Cholangitis kg/day) and high dose (23-25mg/kg/day).62 At 1 year follow-up, improvements in aspartate aminotransferase, Serum alkaline phosphatase (ALP) level 2 folder ursodeoxycholic acid enrichment, alkaline phosphatase, greater than upper limit of normal or serum and Mayo risk score were significantly greater in gamma-glutamyltransferase level 5-fold greater the standard and high-dose groups compared to the than upper limit of normal low-dose group. There was no significant difference between the standard and high-dose groups. The authors Positive test for anti-mitochondrial antibody concluded that a dose of 12-15mg/kg/day is likely the preferred dose for the treatment of PBC. Yet another Liver biopsy specimen showing floridbile duct study found that high doses of UDCA did not provide lesions a clinically significant benefit.63 There is no required dose adjustment for liver or renal disease. However bile Autoimmune Hepatitis acid binding sequesterants, such as cholestyramine and certain antacids, may interfere with UDCA absorption. It Serum alanine aminotransferase level 5-fold is recommended that these medications be administered greater than upper limit of normal at separate times to limit potential interactions.1 Response to UDCA is monitored using liver IgG level 2-fold greater than upper limit of normal biochemistries. Normalization of liver biochemistries or a positive test for anti-smooth muscle antibody occur in about 20% of patients in a period of 2 years, with an additional 15% to 35% normalization in 5 Liver biopsy showing moderate or severe years.64 An estimated 90% of improvement occurs periportal or periseptal lymphocytic piecemeal within the first 6-9 months. In addition to improved necrosis liver biochemistries, the use of UDCA is associated with reduced histological progression, decreased development of varices, and lower serum low-density lipoprotein cholesterol levels.65-67 However it has been patients from 1995 to 2006. The authors found that while shown to be ineffective in treating fatigue, pruritus, the average number of total liver transplants increased at bone disease and the autoimmune features of PBC.68 a rate of 249 transplants a year, transplants due to PBC Currently there are no other agents that have been decreased at an average rate of 5.4 cases per year, an consistently shown to be effective in the management overall decrease of 20%.59 The same study also looked of PBC, either as monotherapy or in combination at transplant rates of patients with primary sclerosing therapy with UDCA. Penicillamine, corticosteroids, cholangitis and found no change over the same period. chlorambucil, mycophenolate, methotrexate, Overall transplantation yields excellent results with 90- azathioprine, , cyclosporine and malotilate 95% 1-year patient survival, 1-year graft survival of 88% have failed to show benefit as monotherapy.69-80 and 5-year graft survival of 78%.83 It is recommended Combination therapy with UDCA in addition to that liver transplant referral be initiated at the onset of colchicine, methotrexate or silymarin have not been decompensated liver disease, when total bilirubin is shown to be better than monotherapy.81,82 greater than 6 mg/dl or if the Model for End-stage Liver Patients with decompensated disease will require Disease score is 12 or more.4 Rate of recurrence of PBC liver transplant. Cholestatic disease accounted for 8.3% in liver transplant recipients is about 25%.84 As AMA of all adult transplants in 2013, down from 11.1% in sometimes persists after liver transplantation, liver 2003.83 The use of UDCA has likely contributed to a biopsy is necessary for the definitive diagnosis of PBC decrease in the number of PBC patients with disease recurrence post transplantation. There is some evidence progression requiring transplant. Lee et al. conducted a that prophylactic UDCA after liver transplantation retrospective study evaluating liver transplants in PBC (continued on page 56)

54 Practical Gastroenterology • January 2016

Agrawal Jan 16.indd 54 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

(continued from page 54) vitamin deficiencies. Treatment is primarily UDCA might reduce the risk of recurrence.85 with strong data supporting benefits in mortality and progression of disease, especially when initiated early. Symptom Management Patients with advanced disease can develop cirrhosis Fatigue is a common symptom experienced by and its complications such as and varices. PBC patients. Unfortunately, there is no current These patients often require liver transplantation. recommendation in regards to managing fatigue. UDCA Further research is needed to better understand the has not been shown to be effective. Other medications etiology and pathogenesis in order to develop additional used to manage fatigue of such as management strategies. ondansetron and fluoxetine have also not been shown to be effective.86,87 Many PBC patients complain of References excessive daytime sleepiness and there is a strong 88 1. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, association with fatigue and altered sleep. Modafanil, Heathcote EJ. Primary biliary cirrhosis. (Baltimore, a medication used to mitigate daytime somnolence Md) 2009;50:291-308 [PMID: 19554543 DOI: 10.1002/hep.22906] 2. Talwalkar JA, Lindor KD. Primary biliary cirrhosis. Lancet (London, associated with shift work, has been shown to have England) 2003;362:53-61 [PMID: 12853201 DOI: 10.1016/s0140- some beneficial impact in treating fatigue in PBC 6736(03)13808-1] 89 3. Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary patients. sclerosing cholangitis and primary biliary cirrhosis: a systematic Pruritus is another common symptom experienced review. Journal of hepatology 2012;56:1181-8 [PMID: 22245904 by PBC patients. UDCA is not effective in managing DOI: 10.1016/j.jhep.2011.10.025] 4. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, pruritus. Cholestyramine is effective in alleviating Lindor KD, Kaplan MM, Vierling JM. Risk factors and comorbidi- pruritus at doses of 4g/day with a max dose of 16g/ ties in primary biliary cirrhosis: a controlled interview-based study 90,91 of 1032 patients. Hepatology (Baltimore, Md) 2005;42:1194-202 day. As mentioned earlier, it is important to separate [PMID: 16250040 DOI: 10.1002/hep.20907] the administration of binding sequesterants and 5. Kouroumalis E, Notas G. Pathogenesis of primary biliary cirrhosis: a unifying model. World journal of gastroenterology 2006;12:2320-7 UDCA as the interaction can decrease the absorption [PMID: 16688819 DOI: of UDCA. A separation of at least 2-4 hours is 6. Invernizzi P, Battezzati PM, Crosignani A, Perego F, Poli F, Morabito 1 A, De Arias AE, Scalamogna M, Zuin M, Podda M. Peculiar HLA recommended. Rifampicin has also been shown to be polymorphisms in Italian patients with primary biliary cirrhosis. effective in the management of pruritus.92-95 Current Journal of hepatology 2003;38:401-6 [PMID: 12663229 DOI: guidelines recommend a dose of 150mg daily for 7. Mullarkey ME, Stevens AM, McDonnell WM, Loubiere LS, Brackensick JA, Pang JM, Porter AJ, Galloway DA, Nelson JL. bilirubin less than 3mg/dL and 150mg twice daily if the Human leukocyte antigen class II alleles in Caucasian women with bilirubin is greater.1 Chronic use of rifampicin has been primary biliary cirrhosis. Tissue antigens 2005;65:199-205 [PMID: 15713222 DOI: 10.1111/j.1399-0039.2005.00351.x] associated with serious side effects such as hepatic or 8. Onishi S, Sakamaki T, Maeda T, Iwamura S, Tomita A, Saibara renal injury and hemolysis. Furthermore rifampicin has T, Yamamoto Y. DNA typing of HLA class II genes; DRB1*0803 increases the susceptibility of Japanese to primary biliary cirrhosis. been shown to decrease the effectiveness of serotonin Journal of hepatology 1994;21:1053-60 [PMID: 7699227 DOI: reuptake inhibition leading to serotonin withdrawal 9. Selmi C, Lleo A, Pasini S, Zuin M, Gershwin ME. Innate immu- 96 nity and primary biliary cirrhosis. Current molecular medicine syndrome. Close monitoring of liver function and 2009;9:45-51 [PMID: 19199941 DOI: blood counts is recommended for any patient on 10. McNally RJ, James PW, Ducker S, Norman PD, James OF. No rise rifampicin.1 Opiate antagonists, such as , in incidence but geographical heterogeneity in the occurrence of primary biliary cirrhosis in North East England. American journal 97 have also been shown to ameliorate pruritus. of epidemiology 2014;179:492-8 [PMID: 24401563 DOI: 10.1093/ aje/kwt308] 11. Ala A, Stanca CM, Bu-Ghanim M, Ahmado I, Branch AD, Schiano TD, Odin JA, Bach N. Increased prevalence of primary biliary cir- Conclusion rhosis near Superfund toxic waste sites. Hepatology (Baltimore, Md) 2006;43:525-31 [PMID: 16496326 DOI: 10.1002/hep.21076] Primary biliary cholangitis is a chronic progressive 12. Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis. Lancet cholestatic disease that results in autoimmune mediated (London, England) 2015 [PMID: 26364546 DOI: 10.1016/s0140- 6736(15)00154-3] hepatic damage. Patients present with non-specific 13. Leung PS, Park O, Tsuneyama K, Kurth MJ, Lam KS, Ansari AA, symptoms of fatigue and pruritus. Positive AMA is a Coppel RL, Gershwin ME. Induction of primary biliary cirrhosis in hallmark of PBC. PBC is often associated with other guinea pigs following chemical xenobiotic immunization. Journal of immunology (Baltimore, Md : 1950) 2007;179:2651-7 [PMID: autoimmune mediated disease such as Sjogren’s disease 17675529 DOI: and autoimmune hepatitis. Common complications 14. Lleo A, Invernizzi P, Mackay IR, Prince H, Zhong RQ, Gershwin ME. Etiopathogenesis of primary biliary cirrhosis. World journal of of PBC include hyperlipidemia, osteoporosis, and gastroenterology 2008;14:3328-37 [PMID: 18528930 DOI:

56 Practical Gastroenterology • January 2016

Agrawal Jan 16.indd 56 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

15. Alempijevic T, Krstic M, Jesic R, Jovanovic I, Sokic Milutinovic A, Sarrazin C. Assessment of liver fibrosis and steatosis in PBC with Kovacevic N, Krstic S, Popovic D. Biochemical markers for non- FibroScan, MRI, MR-spectroscopy, and serum markers. Journal of invasive assessment of disease stage in patients with primary biliary clinical gastroenterology 2010;44:58-65 [PMID: 19581812 DOI: cirrhosis. World journal of gastroenterology 2009;15:591-4 [PMID: 10.1097/MCG.0b013e3181a84b8d] 19195061 DOI: 29. Oude Elferink RP, Kremer AE, Martens JJ, Beuers UH. The 16. Amano K, Leung PS, Rieger R, Quan C, Wang X, Marik J, Suen YF, molecular mechanism of cholestatic pruritus. Digestive diseases Kurth MJ, Nantz MH, Ansari AA, Lam KS, Zeniya M, Matsuura E, (Basel, Switzerland) 2011;29:66-71 [PMID: 21691108 DOI: Coppel RL, Gershwin ME. Chemical xenobiotics and mitochondrial 10.1159/000324131] autoantigens in primary biliary cirrhosis: identification of antibod- 30. Gatselis NK, Zachou K, Norman GL, Gabeta S, Papamichalis P, ies against a common environmental, cosmetic, and food additive, Koukoulis GK, Dalekos GN. Clinical significance of the fluctuation 2-octynoic acid. Journal of immunology (Baltimore, Md : 1950) of primary biliary cirrhosis-related autoantibodies during the course 2005;174:5874-83 [PMID: 15845458 DOI: of the disease. Autoimmunity 2013;46:471-9 [PMID: 23777462 17. Frazer IH, Mackay IR, Jordan TW, Whittingham S, Marzuki DOI: 10.3109/08916934.2013.801461] S. Reactivity of anti-mitochondrial autoantibodies in primary 31. Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor biliary cirrhosis: definition of two novel mitochondrial polypep- KD, Janssen HL, Floreani A, Ponsioen CY, Mayo MJ, Invernizzi tide autoantigens. Journal of immunology (Baltimore, Md : 1950) P, Battezzati PM, Pares A, Burroughs AK, Mason AL, Kowdley 1985;135:1739-45 [PMID: 2410503 DOI: KV, Kumagi T, Harms MH, Trivedi PJ, Poupon R, Cheung A, Lleo 18. Baum H, Palmer C. The PBC-specific antigen. Molecular aspects of A, Caballeria L, Hansen BE, van Buuren HR. Development and medicine 1985;8:201-34 [PMID: 3913830 DOI: Validation of a Scoring System to Predict Outcomes of Patients With 19. Gershwin ME, Mackay IR, Sturgess A, Coppel RL. Identification Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. and specificity of a cDNA encoding the 70 kd mitochondrial antigen Gastroenterology 2015;149:1804-12.e4 [PMID: 26261009 DOI: recognized in primary biliary cirrhosis. Journal of immunology 10.1053/j.gastro.2015.07.061] (Baltimore, Md : 1950) 1987;138:3525-31 [PMID: 3571977 DOI: 32. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The 20. Moteki S, Leung PS, Dickson ER, Van Thiel DH, Galperin C, Buch effect of ursodeoxycholic acid therapy on liver fibrosis progres- T, Alarcon-Segovia D, Kershenobich D, Kawano K, Coppel RL, et sion in primary biliary cirrhosis. Hepatology (Baltimore, Md) al. Epitope mapping and reactivity of autoantibodies to the E2 com- 2000;32:1196-9 [PMID: 11093724 DOI: 10.1053/jhep.2000.20240] ponent of 2-oxoglutarate dehydrogenase complex in primary biliary 33. Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson cirrhosis using recombinant 2-oxoglutarate dehydrogenase complex. ER. Effects of ursodeoxycholic acid on survival in patients with pri- Hepatology (Baltimore, Md) 1996;23:436-44 [PMID: 8617422 mary biliary cirrhosis. Gastroenterology 1996;110:1515-8 [PMID: DOI: 10.1002/hep.510230307] 8613058 DOI: 21. Tanaka A, Nalbandian G, Leung PS, Benson GD, Munoz S, 34. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Findor JA, Branch AD, Coppel RL, Ansari AA, Gershwin ME. Heathcote EJ. Combined analysis of randomized controlled trials of Mucosal immunity and primary biliary cirrhosis: presence of anti- ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology mitochondrial antibodies in urine. Hepatology (Baltimore, Md) 1997;113:884-90 [PMID: 9287980 DOI: 2000;32:910-5 [PMID: 11050038 DOI: 10.1053/jhep.2000.19254] 35. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treat- 22. Nakamura M. Clinical significance of autoantibodies in primary ment of primary biliary cirrhosis. The UDCA-PBC Study Group. biliary cirrhosis. Seminars in liver disease 2014;34:334-40 [PMID: The New England journal of medicine 1994;330:1342-7 [PMID: 25057956 DOI: 10.1055/s-0034-1383732] 8152446 DOI: 10.1056/nejm199405123301903] 23. Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, 36. Pares A, Caballeria L, Rodes J. Excellent long-term survival in Takii Y, Koyabu M, Yokoyama T, Migita K, Daikoku M, Abiru S, patients with primary biliary cirrhosis and biochemical response to Yatsuhashi H, Takezaki E, Masaki N, Sugi K, Honda K, Adachi H, ursodeoxycholic Acid. Gastroenterology 2006;130:715-20 [PMID: Nishi H, Watanabe Y, Nakamura Y, Shimada M, Komatsu T, Saito A, 16530513 DOI: 10.1053/j.gastro.2005.12.029] Saoshiro T, Harada H, Sodeyama T, Hayashi S, Masumoto A, Sando 37. Ungprasert P, Wijarnpreecha K, Ahuja W, Spanuchart I, T, Yamamoto T, Sakai H, Kobayashi M, Muro T, Koga M, Shums Z, Thongprayoon C. Coronary artery disease in primary biliary cirrho- Norman GL, Ishibashi H. Anti-gp210 and anti-centromere antibod- sis: A systematic review and meta-analysis of observational studies. ies are different risk factors for the progression of primary biliary Hepatology research : the official journal of the Japan Society of cirrhosis. Hepatology (Baltimore, Md) 2007;45:118-27 [PMID: Hepatology 2014 [PMID: 25689394 DOI: 10.1111/hepr.12452] 17187436 DOI: 10.1002/hep.21472] 38. Ungprasert P, Wijarnpreecha K, Thongprayoon C. Risk of cere- 24. Ludwig J, Dickson ER, McDonald GS. Staging of chronic non- brovascular accident in patients with primary biliary cirrhosis: a suppurative destructive cholangitis (syndrome of primary biliary systematic review and meta-analysis. European journal of gastro- cirrhosis). Virchows Archiv A, Pathological anatomy and histology enterology & hepatology 2015 [PMID: 26473301 DOI: 10.1097/ 1978;379:103-12 [PMID: 150690 DOI: meg.0000000000000493] 25. Gaiani S, Gramantieri L, Venturoli N, Piscaglia F, Siringo S, 39. Lanspa SJ, Chan AT, Bell JS, 3rd, Go VL, Dickson ER, DiMagno EP. D’Errico A, Zironi G, Grigioni W, Bolondi L. What is the criterion Pathogenesis of steatorrhea in primary biliary cirrhosis. Hepatology for differentiating chronic hepatitis from compensated cirrhosis? (Baltimore, Md) 1985;5:837-42 [PMID: 2411648 DOI: A prospective study comparing ultrasonography and percutane- 40. Raszeja-Wyszomirska J, Miazgowski T. Osteoporosis in primary bil- ous liver biopsy. Journal of hepatology 1997;27:979-85 [PMID: iary cirrhosis of the liver. Przeglad gastroenterologiczny 2014;9:82-7 9453422 DOI: [PMID: 25061487 DOI: 10.5114/pg.2014.42502] 26. Iwao T, Toyonaga A, Oho K, Tayama C, Masumoto H, Sakai T, Sato 41. Corpechot C, Chretien Y, Chazouilleres O, Poupon R. Demographic, M, Tanikawa K. Value of Doppler ultrasound parameters of portal lifestyle, medical and familial factors associated with primary biliary vein and hepatic artery in the diagnosis of cirrhosis and portal hyper- cirrhosis. Journal of hepatology 2010;53:162-9 [PMID: 20471130 tension. The American journal of gastroenterology 1997;92:1012-7 DOI: 10.1016/j.jhep.2010.02.019] [PMID: 9177521 DOI: 42. Lammert C, Nguyen DL, Juran BD, Schlicht E, Larson JJ, Atkinson 27. Corpechot C, Carrat F, Poujol-Robert A, Gaouar F, Wendum D, EJ, Lazaridis KN. Questionnaire based assessment of risk factors Chazouilleres O, Poupon R. Noninvasive elastography-based assess- for primary biliary cirrhosis. Digestive and liver disease : official ment of liver fibrosis progression and prognosis in primary biliary journal of the Italian Society of Gastroenterology and the Italian cirrhosis. Hepatology (Baltimore, Md) 2012;56:198-208 [PMID: Association for the Study of the Liver 2013;45:589-94 [PMID: 22271046 DOI: 10.1002/hep.25599] 23490343 DOI: 10.1016/j.dld.2013.01.028] 28. Friedrich-Rust M, Muller C, Winckler A, Kriener S, Herrmann 43. Parikh-Patel A, Gold EB, Worman H, Krivy KE, Gershwin ME. E, Holtmeier J, Poynard T, Vogl TJ, Zeuzem S, Hammerstingl R, Risk factors for primary biliary cirrhosis in a cohort of patients

Practical Gastroenterology • January 2016 57

Agrawal Jan 16.indd 57 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

from the united states. Hepatology (Baltimore, Md) 2001;33:16-21 58. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, [PMID: 11124815 DOI: 10.1053/jhep.2001.21165] controlled trial of ursodiol for the treatment of primary biliary 44. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc cirrhosis. UDCA-PBC Study Group. The New England journal O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis over- of medicine 1991;324:1548-54 [PMID: 1674105 DOI: 10.1056/ lap syndrome: clinical features and response to therapy. Hepatology nejm199105303242204] (Baltimore, Md) 1998;28:296-301 [PMID: 9695990 DOI: 10.1002/ 59. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. hep.510280203] Transplantation trends in primary biliary cirrhosis. Clinical gas- 45. Neuhauser M, Bjornsson E, Treeprasertsuk S, Enders F, Silveira troenterology and hepatology : the official clinical practice journal M, Talwalkar J, Lindor K. Autoimmune hepatitis-PBC overlap of the American Gastroenterological Association 2007;5:1313-5 syndrome: a simplified scoring system may assist in the diagnosis. [PMID: 17900996 DOI: 10.1016/j.cgh.2007.07.015] The American journal of gastroenterology 2010;105:345-53 [PMID: 60. Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid 19888204 DOI: 10.1038/ajg.2009.616] for patients with primary biliary cirrhosis: an updated system- 46. Jung HE, Jang JY, Jeong SW, Kim JN, Jang HY, Cho YJ, Woo atic review and meta-analysis of randomized clinical trials using SA, Lee SH, Kim SG, Cha SW, Kim YS, Cho YD, Kim HS, Kim Bayesian approach as sensitivity analyses. The American journal BS. Prognostic indicators in primary biliary cirrhosis: significance of gastroenterology 2007;102:1799-807 [PMID: 17459023 DOI: of revised IAHG (International Autoimmune Hepatitis Group) 10.1111/j.1572-0241.2007.01235.x] score. Clinical and molecular hepatology 2012;18:375-82 [PMID: 61. Goulis J, Leandro G, Burroughs AK. Randomised controlled tri- 23323253 DOI: 10.3350/cmh.2012.18.4.375] als of ursodeoxycholic-acid therapy for primary biliary cirrhosis: 47. Silveira MG, Talwalkar JA, Angulo P, Lindor KD. Overlap of a meta-analysis. Lancet (London, England) 1999;354:1053-60 autoimmune hepatitis and primary biliary cirrhosis: long-term out- [PMID: 10509495 DOI: 10.1016/s0140-6736(98)11293-x] comes. The American journal of gastroenterology 2007;102:1244- 62. Angulo P, Dickson ER, Therneau TM, Jorgensen RA, Smith C, 50 [PMID: 17319931 DOI: 10.1111/j.1572-0241.2007.01136.x] DeSotel CK, Lange SM, Anderson ML, Mahoney DW, Lindor KD. 48. Purohit T, Cappell MS. Primary biliary cirrhosis: Pathophysiology, Comparison of three doses of ursodeoxycholic acid in the treatment clinical presentation and therapy. World journal of hepatology of primary biliary cirrhosis: a randomized trial. Journal of hepatol- 2015;7:926-41 [PMID: 25954476 DOI: 10.4254/wjh.v7.i7.926] ogy 1999;30:830-5 [PMID: 10365809 DOI: 49. Inoue K, Hirohara J, Nakano T, Seki T, Sasaki H, Higuchi K, Ohta 63. Angulo P, Jorgensen RA, Lindor KD. Incomplete response to ursode- Y, Onji M, Muto Y, Moriwaki H. Prediction of prognosis of primary oxycholic acid in primary biliary cirrhosis: is a double dosage worth- biliary cirrhosis in Japan. Liver 1995;15:70-7 [PMID: 7791541 DOI: while? The American journal of gastroenterology 2001;96:3152-7 50. Marasini B, Gagetta M, Rossi V, Ferrari P. Rheumatic disorders and [PMID: 11721764 DOI: 10.1111/j.1572-0241.2001.05270.x] primary biliary cirrhosis: an appraisal of 170 Italian patients. Annals 64. Jorgensen RA, Dickson ER, Hofmann AF, Rossi SS, Lindor KD. of the rheumatic diseases 2001;60:1046-9 [PMID: 11602476 DOI: Characterisation of patients with a complete biochemical response 51. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, Podda M, Xu to ursodeoxycholic acid. Gut 1995;36:935-8 [PMID: 7615288 DOI: C, Xie G, Macciardi F, Selmi C, Lupoli S, Shigeta R, Ransom M, 65. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson Lleo A, Lee AT, Mason AL, Myers RP, Peltekian KM, Ghent CN, ER. Ursodeoxycholic acid delays the onset of esophageal varices in Bernuzzi F, Zuin M, Rosina F, Borghesio E, Floreani A, Lazzari R, primary biliary cirrhosis. Mayo Clinic proceedings 1997;72:1137-40 Niro G, Andriulli A, Muratori L, Muratori P, Almasio PL, Andreone [PMID: 9413293 DOI: 10.1016/s0025-6196(11)63676-8] P, Margotti M, Brunetto M, Coco B, Alvaro D, Bragazzi MC, Marra 66. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon F, Pisano A, Rigamonti C, Colombo M, Marzioni M, Benedetti R. Histopathological study of primary biliary cirrhosis and the A, Fabris L, Strazzabosco M, Portincasa P, Palmieri VO, Tiribelli effect of ursodeoxycholic acid treatment on histology progression. C, Croce L, Bruno S, Rossi S, Vinci M, Prisco C, Mattalia A, Hepatology (Baltimore, Md) 1999;29:1007-12 [PMID: 10094939 Toniutto P, Picciotto A, Galli A, Ferrari C, Colombo S, Casella G, DOI: 10.1002/hep.510290444] Morini L, Caporaso N, Colli A, Spinzi G, Montanari R, Gregersen 67. Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of ursode- PK, Heathcote EJ, Hirschfield GM, Siminovitch KA, Amos CI, oxycholic acid on serum lipids of patients with primary biliary cirrho- Gershwin ME, Seldin MF. Genome-wide meta-analyses identify sis. Mayo Clinic proceedings 1994;69:923-9 [PMID: 7934188 DOI: three loci associated with primary biliary cirrhosis. Nature genetics 68. Lindor KD, Janes CH, Crippin JS, Jorgensen RA, Dickson ER. Bone 2010;42:658-60 [PMID: 20639880 DOI: 10.1038/ng.627] disease in primary biliary cirrhosis: does ursodeoxycholic acid make 52. Kar SP, Seldin MF, Chen W, Lu E, Hirschfield GM, Invernizzi P, a difference? Hepatology (Baltimore, Md) 1995;21:389-92 [PMID: Heathcote J, Cusi D, Gershwin ME, Siminovitch KA, Amos CI. 7843710 DOI: Pathway-based analysis of primary biliary cirrhosis genome-wide 69. Hoofnagle JH, Davis GL, Schafer DF, Peters M, Avigan MI, Pappas association studies. Genes and immunity 2013;14:179-86 [PMID: SC, Hanson RG, Minuk GY, Dusheiko GM, Campbell G, et al. 23392275 DOI: 10.1038/gene.2013.1] Randomized trial of chlorambucil for primary biliary cirrhosis. 53. Mells GF, Kaser A, Karlsen TH. Novel insights into autoimmune Gastroenterology 1986;91:1327-34 [PMID: 3533699 DOI: liver diseases provided by genome-wide association studies. Journal 70. Wiesner RH, Ludwig J, Lindor KD, Jorgensen RA, Baldus WP, of autoimmunity 2013;46:41-54 [PMID: 23931959 DOI: 10.1016/j. Homburger HA, Dickson ER. A controlled trial of cyclosporine in jaut.2013.07.004] the treatment of primary biliary cirrhosis. The New England journal 54. Shizuma T. Clinical Characteristics of Concomitant Systemic Lupus of medicine 1990;322:1419-24 [PMID: 2184355 DOI: 10.1056/ Erythematosus and Primary Biliary Cirrhosis: A Literature Review. nejm199005173222003] Journal of immunology research 2015;2015:713728 [PMID: 71. Christensen E, Neuberger J, Crowe J, Altman DG, Popper H, 26090497 DOI: 10.1155/2015/713728] Portmann B, Doniach D, Ranek L, Tygstrup N, Williams R. 55. Floreani A, Franceschet I, Cazzagon N. Primary biliary cirrhosis: Beneficial effect of azathioprine and prediction of prognosis in overlaps with other autoimmune disorders. Seminars in liver disease primary biliary cirrhosis. Final results of an international trial. 2014;34:352-60 [PMID: 25057958 DOI: 10.1055/s-0034-1383734] Gastroenterology 1985;89:1084-91 [PMID: 3899841 DOI: 56. Heathcote J. The clinical expression of primary biliary cirrhosis. 72. Kaplan MM, Alling DW, Zimmerman HJ, Wolfe HJ, Sepersky RA, Seminars in liver disease 1997;17:23-33 [PMID: 9089908 DOI: Hirsch GS, Elta GH, Glick KA, Eagen KA. A prospective trial of 10.1055/s-2007-1007180] colchicine for primary biliary cirrhosis. The New England journal 57. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, of medicine 1986;315:1448-54 [PMID: 3537784 DOI: 10.1056/ Ghent CN, Michieletti P, Minuk GY, Pappas SC, Scully LJ, et al. The nejm198612043152304] Canadian Multicenter Double-blind Randomized Controlled Trial 73. Dickson ER, Fleming TR, Wiesner RH, Baldus WP, Fleming CR, of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology Ludwig J, McCall JT. Trial of penicillamine in advanced primary bili- (Baltimore, Md) 1994;19:1149-56 [PMID: 8175136 DOI: ary cirrhosis. The New England journal of medicine 1985;312:1011-5

58 Practical Gastroenterology • January 2016

Agrawal Jan 16.indd 58 1/11/16 11:28 AM Primary Biliary Cholangitis

LIVER DISORdERS, SERIES #4 LIVER DISORdERS, SERIES #4

[PMID: 3885033 DOI: 10.1056/nejm198504183121602] lower risk of disease recurrence. Journal of hepatology 2015 [PMID: 74. Lombard M, Portmann B, Neuberger J, Williams R, Tygstrup 26282232 DOI: 10.1016/j.jhep.2015.07.038] N, Ranek L, Ring-Larsen H, Rodes J, Navasa M, Trepo C, et al. 86. Theal JJ, Toosi MN, Girlan L, Heslegrave RJ, Huet PM, Burak KW, Cyclosporin A treatment in primary biliary cirrhosis: results of a Swain M, Tomlinson GA, Heathcote EJ. A randomized, controlled long-term placebo controlled trial. Gastroenterology 1993;104:519- crossover trial of ondansetron in patients with primary biliary cir- 26 [PMID: 8425695 DOI: rhosis and fatigue. Hepatology (Baltimore, Md) 2005;41:1305-12 75. Talwalkar JA, Angulo P, Keach JC, Petz JL, Jorgensen RA, Lindor [PMID: 15915460 DOI: 10.1002/hep.20698] KD. Mycophenolate mofetil for the treatment of primary biliary cir- 87. Talwalkar JA, Donlinger JJ, Gossard AA, Keach JC, Jorgensen RA, rhosis in patients with an incomplete response to ursodeoxycholic Petz JC, Lindor KD. Fluoxetine for the treatment of fatigue in pri- acid. Journal of clinical gastroenterology 2005;39:168-71 [PMID: mary biliary cirrhosis: a randomized, double-blind controlled trial. 15681915 DOI: Digestive diseases and sciences 2006;51:1985-91 [PMID: 17053955 76. Neuberger J, Christensen E, Portmann B, Caballeria J, Rodes J, DOI: 10.1007/s10620-006-9397-5] Ranek L, Tygstrup N, Williams R. Double blind controlled trial 88. Newton JL, Gibson GJ, Tomlinson M, Wilton K, Jones D. Fatigue of d-penicillamine in patients with primary biliary cirrhosis. Gut in primary biliary cirrhosis is associated with excessive daytime 1985;26:114-9 [PMID: 3881323 DOI: somnolence. Hepatology (Baltimore, Md) 2006;44:91-8 [PMID: 77. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record 16800007 DOI: 10.1002/hep.21230] CO, James OF. A controlled trial of prednisolone treatment in 89. Ian Gan S, de Jongh M, Kaplan MM. Modafinil in the treatment of primary biliary cirrhosis. Three-year results. Journal of hepatology debilitating fatigue in primary biliary cirrhosis: a clinical experience. 1992;15:336-44 [PMID: 1447500 DOI: Digestive diseases and sciences 2009;54:2242-6 [PMID: 19082890 78. Hendrickse MT, Rigney E, Giaffer MH, Soomro I, Triger DR, DOI: 10.1007/s10620-008-0613-3] Underwood JC, Gleeson D. Low-dose methotrexate is ineffective in 90. Datta DV, Sherlock S. Cholestyramine for long term relief of the primary biliary cirrhosis: long-term results of a placebo-controlled pruritus complicating intrahepatic cholestasis. Gastroenterology trial. Gastroenterology 1999;117:400-7 [PMID: 10419922 DOI: 1966;50:323-32 [PMID: 5905351 DOI: 79. Giljaca V, Poropat G, Stimac D, Gluud C. Methotrexate for primary 91. Van Itallie TB, Hashim SA, Crampton RS, Tennent DM. The biliary cirrhosis. The Cochrane database of systematic reviews treatment of pruritus and hypercholesteremia of primary bili- 2010:Cd004385 [PMID: 20464729 DOI: 10.1002/14651858. ary cirrhosis with cholestyramine. The New England journal CD004385.pub3] of medicine 1961;265:469-74 [PMID: 13779996 DOI: 10.1056/ 80. Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. The nejm196109072651004] Cochrane database of systematic reviews 2004:Cd004481 [PMID: 92. Hoensch HP, Balzer K, Dylewizc P, Kirch W, Goebell H, Ohnhaus 15106254 DOI: 10.1002/14651858.CD004481.pub2] EE. Effect of rifampicin treatment on hepatic drug metabolism and 81. Angulo P, Patel T, Jorgensen RA, Therneau TM, Lindor KD. serum bile acids in patients with primary biliary cirrhosis. European Silymarin in the treatment of patients with primary biliary cirrhosis journal of clinical pharmacology 1985;28:475-7 [PMID: 4029252 with a suboptimal response to ursodeoxycholic acid. Hepatology DOI: (Baltimore, Md) 2000;32:897-900 [PMID: 11050036 DOI: 10.1053/ 93. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary jhep.2000.18663] cirrhosis with rifampin. Results of a double-blind, crossover, ran- 82. Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled domized trial. Gastroenterology 1988;94:488-93 [PMID: 3275568 trial of colchicine plus ursodiol versus methotrexate plus ursodiol in DOI: primary biliary cirrhosis: ten-year results. Hepatology (Baltimore, 94. Podesta A, Lopez P, Terg R, Villamil F, Flores D, Mastai R, Udaondo Md) 2004;39:915-23 [PMID: 15057894 DOI: 10.1002/hep.20103] CB, Companc JP. Treatment of pruritus of primary biliary cirrhosis 83. Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP, Edwards with rifampin. Digestive diseases and sciences 1991;36:216-20 EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BL. [PMID: 1988266 DOI: OPTN/SRTR 2013 Annual Data Report: liver. American journal 95. Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to of transplantation : official journal of the American Society of chronic cholestasis: a meta-analysis of prospective randomized-con- Transplantation and the American Society of Transplant Surgeons trolled trials. Liver international : official journal of the International 2015;15 Suppl 2:1-28 [PMID: 25626341 DOI: 10.1111/ajt.13197] Association for the Study of the Liver 2006;26:943-8 [PMID: 84. Invernizzi P, Selmi C, Gershwin ME. Update on primary bili- 16953834 DOI: 10.1111/j.1478-3231.2006.01326.x] ary cirrhosis. Digestive and liver disease : official journal of the 96. Markowitz JS, DeVane CL. Rifampin-induced selective serotonin Italian Society of Gastroenterology and the Italian Association reuptake inhibitor withdrawal syndrome in a patient treated with for the Study of the Liver 2010;42:401-8 [PMID: 20359968 DOI: sertraline. Journal of clinical psychopharmacology 2000;20:109-10 10.1016/j.dld.2010.02.014] [PMID: 10653222 DOI: 85. Bosch A, Dumortier J, Maucort-Boulch D, Scoazec JY, Wendum 97. Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, D, Conti F, Morard I, Rubbia-Brandt L, Terris B, Radenne S, Turner ML, Schmitt JM, Walker EC, Jones EA. Effects of naloxone Abenavoli L, Poupon R, Chazouilleres O, Calmus Y, Boillot O, infusions in patients with the pruritus of cholestasis. A double- Giostra E, Corpechot C. Preventive administration of UDCA after blind, randomized, controlled trial. Annals of internal medicine liver transplantation for primary biliary cirrhosis is associated with a 1995;123:161-7 [PMID: 7598296 DOI:

practicalgastro.com

Practical Gastroenterology • January 2016 59

Agrawal Jan 16.indd 59 1/11/16 11:28 AM