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

In the paper

“Again, pruritus was the most important adverse event, leading to discontinuation of 38% of study subjects in the 50-mg arm.”

What the sources say

• Disputed

  The Safety and Side Effects section confirms that pruritus was the most common adverse event, but reports discontinuation due to pruritus in 10% of the 10-mg group and 1% of the 5–10-mg group. This trial had no 50-mg arm; the 38% figure is the incidence of pruritus in the placebo group, not a discontinuation rate. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [160] 160. Kowdley KV, Luketic V, Chapman R, Hirschfield GM, Poupon R, Schramm C, et al. A randomized trial of obeti- cholic acid monotherapy in patients with primary biliary chol- angitis. Hepatology. 2018;67:1890-1902. 161 sourceExperimental — accuracy not yet measured

In the paper

“The indirect immunofluorescence method has the lowest sensitivity, with over 15% of AMA-negative sera by indirect immunofluorescence showing reactivity to MIT3, a combination of three mitochondrial antigens.(87)”

What the sources say

• ?Could not verify

  The indexed copy contains an IRIS repository listing and a PDF link, but no passage from the paper addressing assay sensitivity. Searches for MIT3, indirect immunofluorescence, and the claimed 15% figure found no relevant passage, so the claim cannot be checked against our copy. (LLM, conf=0.76)

  cites [87] 87. Bizzaro N, Covini G, Rosina F, Muratori P, Tonutti E, Villalta D, et al. Overcoming a "probable" diagnosis in antimitochon- drial antibody negative primary biliary cirrhosis: study of 100 sera and review of the literature. Clin Rev Allergy Immunol. 2012;42:288-297. sourceExperimental — accuracy not yet measured

In the paper

“The GLOBE score was developed from a retrospective cohort of 2,488 UDCA-treated patients and validated by a second cohort of 1,631 European and North American patients.(74)”

What the sources say

• Supported

  Statistical Analysis reports a derivation cohort of 2,488 patients and a separate validation cohort of 1,631, randomly split from the study population. Study Population and Design identifies the participants as UDCA-treated patients drawn from centers in North America and Europe. The validation cohort was a second group from the same database, not an independently recruited cohort. (LLM, conf=0.91)

  cites [74] 74. Lammers WJ, Hirschfield GM, Corpechot C, Nevens F, Lindor KD, Janssen HL, et al. Development and validation of a scoring system to predict outcomes of patients with pri- mary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149:1804-1812:e4. source

In the paper

“In addition to the high concordance among monozygotic twins compared with dizygotic twins with PBC (5) , the strong association with human leukocyte antigen alleles, which vary by ethnicity, supports a genetic cause of inherited risk.(12)(13)(14)(15)(16)(17)(18)(19)(20)”

What the sources say

• Supported

  The Results (p. 1) report PBC concordance in five of eight monozygotic twin pairs and none of eight dizygotic pairs; the Discussion (p. 6) says this suggests a major genetic role. In the citing sentence, this paper is citation (5) for the twin comparison. The HLA assertion has separate citations and is not attributed to this source. (LLM, conf=0.94)

  cites [5] 5. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish G, et al. Primary biliary cirrhosis in monzygotic and dizygotic twins: Genetics, epigenetics, and environment. Gastroenterology. 2004;127:485-492. source
• Supported

  The citation to this paper is attached to the HLA portion of the sentence, not the twin-concordance statement, which has a separate citation. In “Identification of multiple independent association signals at four PBC risk loci” (p. 5), the paper reports strong HLA class II allele associations with PBC and substantial allele-frequency differences between its Italian and Canadian/US cohorts. It says the associations’ direction and magnitude were generally consistent across those cohorts. (LLM, conf=0.87)

  cites [12] 12. Juran BD, Hirshfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, et al. Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q1, multiple independent associ- ations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum Mol Genet. 2012;21:5209-5221. source
• ?Not checked — no full text of the sourcecites [13] 13. Johnson PJ, Qin S, Park JW, Poon RTP, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: re- sults from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517-3524. source

In the paper

“Although AMA-negative PBC patients are nearly identical to AMA-positive PBC patients, minor differences have been noted, including a higher prevalence of antinuclear and anti-smooth muscle antibodies and lower serum IgM levels.(111)(112)(113)”

What the sources say

• Supported

  The discussion passage under “PBC=primary biliary cirrhosis” states that AMA-all negative patients were more likely than controls to have antinuclear and smooth muscle antibodies and had lower serum IgM. The Results passage also reports higher antibody prevalence in the AMA-negative group. Page numbers are not provided for these passages. (LLM, conf=0.94)

  cites [111] 111. Lacerda MA, Ludwig J, Dickson ER, Jorgensen RA, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Am J Gastroenterol. 1995;90:247-249. 112 source
• Supported

  The paper’s discussion states that, compared with AMA-positive controls, AMA-all-negative patients were more likely to have antinuclear and smooth muscle antibodies and had lower serum IgM concentrations. The Results section also reports higher antibody prevalence in the AMA-negative group. (LLM, conf=0.94)

  cites [112] 112. Michieletti P, Wanless IR, Katz A, Scheuer PJ, Yeaman SJ, Bassendine MF, et al. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis. Gut. 1994;35:260-265. 113 source
• ?Not checked — no full text of the sourcecites [113] 113. Invernizzi P, Crosignani A, Battezzati PM, Covini G, De Valle G, Larghi A, et al. Comparison of the clinical fea- tures and clinical course of antimitochondrial antibody-pos- itive and -negative primary biliary cirrhosis. Hepatology. 1997;25:1090-1095. 114 source

In the paper

“A number of studies have shown the benefit of UDCA in this context.(58)(59)(60)(61)(62)(63) Individual studies have demonstrated consistent evidence of improved liver biochemistries.”

What the sources say

• Supported

  The introductory passage indexed under Materials and Methods (page unavailable) describes several randomized trials of UDCA in PBC and reports biochemical improvement. A later passage indexed under Additional information (page unavailable) says longer-term follow-up studies found that improvements in liver biochemistries could be sustained. (LLM, conf=0.88)

  cites [58] 58. 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;19:1149-1156. sourceExperimental — accuracy not yet measured
• Supported

  The paper’s opening section reports that multiple UDCA trials in patients with PBC found improvements in biochemical measures of cholestasis. The Discussion likewise describes favorable biochemical effects across published trials, while noting that individual patients’ responses vary. (LLM, conf=0.91)

  cites [59] 59. Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology. 1996;110:1515-1518. sourceExperimental — accuracy not yet measured
• Supported

  The opening passage reports that several UDCA trials in patients with PBC, including six large trials, all found improvement in biochemical cholestasis. The Discussion likewise says most published trials found favorable effects on biochemical parameters, while distinguishing these from less certain survival benefits. (LLM, conf=0.92)

  cites [60] 60. Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006;130:715-720. source

In the paper

“Fatigue is the most common symptom in PBC; it has been found in 50% to 78% of patients and has a significant negative impact on quality of life.(95)(96)”

What the sources say

• Partly supported

  The Associations Between NHP Scores and the Characteristics of PBC section reports a significant association between fatigue and worse overall quality of life. The Discussion says fatigue was the finding most often associated with quality-of-life subscores, not that it was the most common symptom; it gives a prevalence range of 8%–80% across prior studies, not 50%–78%. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [95] 95. Newton JLJD. Modafinil is effective treatment for excessive daytime somnolence and fatigue in primary biliary cirrhosis [Abstract]. Hepatology. 2006;44:628A. sourceExperimental — accuracy not yet measured
• Partly supported

  The Associations Between NHP Scores and the Characteristics of PBC section reports a significant association between fatigue and worse overall quality of life. The Discussion calls fatigue the finding most often associated with quality-of-life scores, not the most common symptom, and reports prevalence across prior studies as 8%–80%, not 50%–78%. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [96] 96. Poupon RE, Chretien Y, Chazouilleres O, Poupon R, Chwalow J. Quality of life in patients with primary biliary cir- rhosis. Hepatology. 2004;40:489-494. sourceExperimental — accuracy not yet measured

In the paper

“A PBC/AIH overlap syndrome may also refer to patients with PBC followed sequentially by AIH or, less commonly, AIH followed by PBC.(119)(120)(121)”

What the sources say

• ?Not checked — no full text of the sourcecites [119] 119. Efe C, Ozaslan E, Heurgue-Berlot A, Kav T, Masi C, Purnak T, et al. Sequential presentation of primary biliary cirrho- sis and autoimmune hepatitis. Eur J Gastroenterol Hepatol. 2014;26:532-537. 120 source
• Supported

  The Frequency and Baseline Characteristics section identifies both sequential forms of PBC-AIH overlap syndrome: 12 patients developed AIH after PBC, while 5 developed PBC after AIH. The smaller second group supports the claim that AIH followed by PBC was less common in this cohort. (LLM, conf=0.94)

  cites [120] 120. Gossard AA, Lindor KD. Development of autoimmune hepa- titis in primary biliary cirrhosis. Liver Int. 2007;27:1086-1090. 121 source
• Supported

  The Results section (“Frequency and Baseline Characteristics”) includes sequential cases under PBC-AIH overlap syndrome: 12 patients developed AIH after PBC, while 5 developed PBC after AIH. This supports both sequences and the claim that the latter was less common in this cohort; page numbers were not supplied in our copy. (LLM, conf=0.94)

  cites [121] 121. Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology. 2006;44:85-90. 122 source

In the paper

“The symptoms of PBC significantly impair quality of life (182) and do not typically improve with UDCA or OCA treatment.”

What the sources say

• Supported

  Citation (182) is attached to the claim that PBC symptoms significantly impair quality of life, not to the subsequent treatment claim. The Results report substantial quality-of-life impairment among PBC patients, and the Discussion says symptoms often had a dramatic impact on life quality. (LLM, conf=0.94)

  cites [182] 182. Mells GF, Pells G, Newton JL, Bathgate AJ, Burroughs AK, Heneghan MA, et al. Impact of primary biliary cirrho- sis on perceived quality of life: the UK-PBC national study. Hepatology. 2013;58:273-283. 183 source

In the paper

“Doubling the dose of UDCA and adding colchicine, methotrexate, or silymarin have not been found to be of benefit over and beyond that achieved with UDCA alone.(163,178,179)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [163] 163. Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrex- ate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology. 2004;39:915-923. 164
• ?Not checked — no full text of the sourcecites [178] 178. Angulo P, Patel T, Jorgensen RA, Therneau TM, Lindor KD. Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology. 2000;32:897-900. 179 source
• Partly supported

  The Discussion (page not specified) says adding colchicine showed no benefit for patients with a suboptimal response to UDCA. It also reports negative results from larger controlled trials of methotrexate, while acknowledging biochemical improvement in a few selected patients. Our copy does not establish the claimed lack of benefit from doubling the UDCA dose or adding silymarin. (LLM, conf=0.88)

  cites [179] 179. Angulo P, Jorgensen RA, Lindor KD. Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile? Am J Gastroenterol. 2001;96:3152-3157. 180 sourceExperimental — accuracy not yet measured

In the paper

“However, patients with earlier histologic stage usually respond more favorably to UDCA than patients with advanced disease, although patients with advanced disease may benefit in survival or avoid liver transplantation with this therapy.(63)”

What the sources say

• Partly supported

  The Discussion suggests UDCA might be less efficacious when introduced later in disease, but does not establish that earlier histologic stages usually respond more favorably. For the outcome this study measured, survival free of transplantation, the subgroup analysis found a significant benefit at stage IV but not at stages I–II or III (Figure 3, Discussion). The claim that patients with advanced disease may benefit is supported. (LLM, conf=0.87)

  cites [63] 63. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cir- rhosis. Gastroenterology. 1997;113:884-890. sourceExperimental — accuracy not yet measured

In the paper

“As with the phase 2 studies, pruritus was the most common adverse event, but it was less common in patients undergoing dose titration starting at 5 mg/day.”

What the sources say

• Supported

  The Trial Design section (p. 2) identifies this as a phase 3 trial and says the 5–10 mg group started at 5 mg daily, with an increase to 10 mg if appropriate. The Discussion (p. 10) calls pruritus the most common adverse event and reports a lower incidence in that group (56%) than in the group starting at 10 mg (68%). (LLM, conf=0.94)

  cites [161] 161. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeti- cholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631-643. 162 source

In the paper

“After 1 year, this primary endpoint was met by 46% of patients in the titration group, 47% in the 10 mg/day group, and 10% of patients in the placebo group.(161)”

What the sources say

• Supported

  The Primary End Point section (p. 4) reports that at month 12 the endpoint was met by 46% in the 5–10-mg titration group, 47% in the 10-mg group, and 10% in the placebo group. These are the figures and time point attributed to the source in the citing sentence. (LLM, conf=0.95)

  cites [161] 161. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeti- cholic acid in primary biliary cholangitis. N Engl J Med. 2016;375:631-643. 162 source

In the paper

“However, UDCA therapy does not improve fatigue, pruritus, associated bone disease, or autoimmune features found in association with PBC.(69,89,153,154)”

What the sources say

• ?Not checked — no full text of the sourcecites [69] 69. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER. Ursodeoxycholic acid delays the onset of esoph- ageal varices in primary biliary cirrhosis. Mayo Clin Proc. 1997;72:1137-1140. source
• ?Could not verify

  The paper’s ‘Effect of UDCA Therapy on Histological Progression’ and ‘UDCA Therapy and Histology Progression’ sections assess liver-biopsy findings, not whether UDCA improves fatigue, pruritus, bone disease, or associated autoimmune features. Searches for those symptoms and conditions found no passage addressing the claimed lack of improvement; page numbers were not supplied for the passages. (LLM, conf=0.75)

  cites [89] 89. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology. 1999;29:1007-1012. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [153] 153. Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. Mayo Clin Proc. 1994;69:923-929. 154 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [154] 154. Lindor KD, Janes CH, Crippin JS, Jorgensen RA, Dickson ER. Bone disease in primary biliary cirrhosis: Does ursodeoxy- cholic acid make a difference? Hepatology. 1995;21:389-392. 155

In the paper

“Although uncommon, drug-induced liver injuries-sometimes progressing to acute liver failure, hemolysis, renal impairment, and alteration in drug metabolism-have all been reported with rifampicin use such that use is avoided in patients with bilirubin levels greater than 2.5 mg/dL, with close follow-up warranted.(195,199)”

What the sources say

• ?Not checked — no full text of the sourcecites [195] 195. Bachs L, Pares A, Elena M, Piera C, Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet. 1989;1:574-576. 196 source
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [199] 199. Prince MI, Burt AD, Jones DE. Hepatitis and liver dysfunc- tion with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut. 2002;50:436-439. 200 sourceExperimental — accuracy not yet measured

In the paper

“Etidronate was ineffective compared with placebo”

What the sources say

• ?Could not verify

  The introduction mentions trials of etidronate in patients with primary biliary cirrhosis, including bisphosphonate comparisons with placebo, but gives no result for etidronate versus placebo. The Results report outcomes for ibandronate and alendronate only. Searches for etidronate’s effectiveness versus placebo found no passage establishing the claimed lack of benefit. (LLM, conf=0.74)

  cites [239] 239. Guanabens N, Monegal A, Cerda D, Muxi A, Gifre L, Peris P, et al. Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with pri- mary biliary cirrhosis. Hepatology. 2013;58:2070-2078. 240 sourceExperimental — accuracy not yet measured

In the paper

“Although the itch in cholestasis does not appear to be histamine-related, antihistamines may be beneficial in patients with cholestasis, probably because of their sedative properties.(214,215)”

What the sources say

• Partly supported

  The indexed Abstract (page unavailable) reports that patients with primary biliary cirrhosis most commonly associated antihistamines with itch relief. It does not establish that cholestatic itch is unrelated to histamine or attribute the reported relief to antihistamines’ sedative properties. (LLM, conf=0.84)

  cites [214] 214. Rishe E, Azarm A, Bergasa NV. Itch in primary bili- ary cirrhosis: a patients' perspective. Acta Derm Venereol. 2008;88:34-37. 215) sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [215] 215. Greaves MW. Antihistamines in dermatology. Skin Pharmacol Physiol. 2005;18:220-229. 216

In the paper

“This helps detect patients who are inadequate responders to UDCA after 12 months of therapy, lack of adherence, and the rare patients who go on to develop AIH.(121,135,224,225)”

What the sources say

• Supported

  This source supports the AIH portion of the multiply cited sentence. In the Results (pp. 85–90), 12 of 282 patients with PBC developed AIH during follow-up; the Clinical and Laboratory Assessments section describes examinations at follow-up visits, and the Discussion cautions that the condition should not be missed. The paper does not establish the separate claims about 12-month UDCA response or adherence. (LLM, conf=0.88)

  cites [121] 121. Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology. 2006;44:85-90. 122 source
• ?Not checked — no full text of the sourcecites [135] 135. Chazouilleres O, Wendum D, Serfaty L, Rosmorduc O, Poupon R. Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syn- drome. J Hepatol. 2006;44:400-406. 136 source
• ?Not checked — no full text of the sourcecites [224] 224. Colombato LA, Alvarez F, Cote J, Huet PM. Autoimmune cholangiopathy: the result of consecutive primary bili- ary cirrhosis and autoimmune hepatitis? Gastroenterology. 1994;107:1839-1843. 225 source
• ?Not checked — no full text of the sourcecites [225] 225. Weyman RL, Voigt M. Consecutive occurrence of primary biliary cirrhosis and autoimmune hepatitis: a case report and review of the literature. Am J Gastroenterol. 2001;96:585-587. 226 source

In the paper

“both drugs have a comparable efficacy and safety profile.(239)”

What the sources say

• Supported

  The Discussion reports that both drugs increased bone mass and were well tolerated in postmenopausal women with primary biliary cirrhosis and osteoporosis or severe osteopenia. The Results report similar overall adverse-event rates, and the study found no significant difference between groups in lumbar-spine bone-density gains. The comparison is supported for the population studied. (LLM, conf=0.90)

  cites [239] 239. Guanabens N, Monegal A, Cerda D, Muxi A, Gifre L, Peris P, et al. Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with pri- mary biliary cirrhosis. Hepatology. 2013;58:2070-2078. 240 source

In the paper

“Some 20% to 30% of patients with PBC who undergo transplantation develop recurrent disease over 10 years, and up to 50% do so by 20 years of follow-up.”

What the sources say

• ?Not checked — no full text of the sourcecites [256] 256. Duclos-Vallee JC, Sebagh M. Recurrence of autoimmune dis- ease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation. Liver Transpl. 2009;15(Suppl 2):S25-S34. 257 source
• Partly supported

  The Recurrence Rate section reports recurrent PBC in 17% of patients using strict histologic criteria; Table 4 gives an estimate of 26% using expanded criteria. Neither is a 10-year estimate: the Patient Groups section reports mean follow-up of 4.7 years and a maximum of 13.8 years. The paper does not support the claim of up to 50% recurrence by 20 years. (LLM, conf=0.88)

  cites [257] 257. Bosch A, Dumortier J, Maucort-Boulch D, Scoazec JY, Wendum D, Conti F, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol. 2015;63:1449-1458. 258 sourceExperimental — accuracy not yet measured

In the paper

“Several randomized trials, combined analyses, and long-term observational studies have shown that UDCA not only improves biochemical indices but also delays histologic progression and improves survival without transplantation.(53,(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)”

What the sources say

• ?Not checked — no full text of the sourcecites [53] 53. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibro- sis progression in primary biliary cirrhosis. Hepatology. 2000;32:1196-1199. source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [56] 56. Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histo- logical progression in primary biliary cirrhosis. Hepatology. 1999;29:644-647.
• ?Not checked — no full text of the sourcecites [57] 57. Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, et al. A randomized, double-blind, place- bo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology. 1995;22:759-66. source

In the paper

“The bilirubin level is the best predictor of survival and is the most important component in all mathematical models of prognosis in PBC.(71,76)”

What the sources say

• ?Not checked — no full text of the sourcecites [71] 71. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology. 1989;10:1-7. source
• ?Not checked — no full text of the sourcecites [76] 76. Grambsch PM, Dickson ER, Kaplan M, LeSage G, Fleming TR, Langworthy AL. Extramural cross-validation of the Mayo primary biliary cirrhosis survival model establishes its generalizability. Hepatology. 1989;10:846-850. source

In the paper

“The UK-PBC score involved a cohort of 3,165 patients and found that serum ALP, amino transferases, and bilirubin after 12 months of therapy-as well as albumin and platelets at baseline-predicted the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years.(75)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [75] 75. Carbone M, Sharp SJ, Flack S, Paximadas D, Spiess K, Adgey C, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2016;63:930-950.

In the paper

“Compared with AMA-positive PBC patients, AMAnegative PBC patients have more nonhepatic autoimmune conditions (114)(115) and worse health-related quality of life in social and emotional domains.(116)”

What the sources say

• ?Not checked — no full text of the sourcecites [114] 114. Sakauchi F, Mori M, Zeniya M, Toda G. Antimitochondrial antibody negative primary biliary cirrhosis in Japan: utiliza- tion of clinical data when patients applied to receive public financial aid. J Epidemiol. 2006;16:30-34. 115 source
• ?Not checked — no full text of the sourcecites [115] 115. Juliusson G, Imam M, Bjornsson ES, A. TJ, Lindor KD. Long- term outcomes in antimitochondrial antibody negatve primary biliary cirrhosis. Scand J Gastroenterol. 2016;51:745-752. 116 source
• ?Not checked — no full text of the sourcecites [116] 116. Raszeja-Wyszomirska J, Wunsch E, Krawczyk M, Rigopoulou EI, Kostrzewa K, Norman GL, et al. Assessment of health related quality of life in polish patients with primary biliary cirrhosis. Clin Res Hepatol Gastroenterol. 2016;40:471-479. 117 source

In the paper

“These criteria have been met in 1% to 14.2% of PBC patients, with higher rates found in Hispanic PBC patients.(128)(129)(130)(131)(132)(133)”

What the sources say

• ?Not checked — no full text of the sourcecites [128] 128. Lohse AW, zum Buschenfelde KH, Franz B, Kanzler S, Gerken G, Dienes HP. Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals. Hepatology. 1999;29:1078-1084. 129 source
• ?Not checked — no full text of the sourcecites [129] 129. Joshi S, Cauch-Dudek K, Wanless IR, Lindor KD, Jorgensen R, Batts K, et al. Primary biliary cirrhosis with additional fea- tures of autoimmune hepatitis: response to therapy with ur- sodeoxycholic acid. Hepatology. 2002;35:409-413. 130 source
• ?Not checked — no full text of the sourcecites [130] 130. Heurgue A, Vitry F, Diebold MD, Yaziji N, Bernard-Chabert B, Pennaforte JL, et al. Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Clin Biol. 2007;31:17-25. 131 source

In the paper

“The proposed mechanisms of action of UDCA are multiple and include choleretic, cytoprotective, anti-inflammatory, and immunomodulatory properties.(141)”

What the sources say

• ?Not checked — no full text of the sourcecites [141] 141. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revis- ited. Hepatology. 2002;36:525-531. 142 source

In the paper

“However, the International Autoimmune Hepatitis Group score was designed for the diagnosis of AIH with the exclusion of other liver diseases, including PBC, and therefore positive points are given for the absence of factors unrelated to a diagnosis of PBCe.g., viral hepatitis and alcohol abuse-and negative scores are given for AMA and/or biochemical/histologic features of biliary disease.”

In the paper

“These patients may no longer have AMA seropositivity, and liver histology becomes more typical of AIH that responds to immunosuppressive therapy.”

In the paper

“UDCA is widely used and has demonstrated the ability to produce a reduction in need for liver transplantation for PBC.(144)”

What the sources say

• ?Not checked — no full text of the sourcecites [144] 144. Lee J, Belanger A, Doucette JT, Stanca C, Friedman S, Bach N. Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5:1313-1315. 145 source

In the paper

“However, treatment response to UDCA appears similar in AMA-negative and AMA-positive PBC patients, and whether there are differences in clinical outcomes has not been resolved.(113,115)”

What the sources say

• ?Not checked — no full text of the sourcecites [113] 113. Invernizzi P, Crosignani A, Battezzati PM, Covini G, De Valle G, Larghi A, et al. Comparison of the clinical fea- tures and clinical course of antimitochondrial antibody-pos- itive and -negative primary biliary cirrhosis. Hepatology. 1997;25:1090-1095. 114 source
• ?Not checked — no full text of the sourcecites [115] 115. Juliusson G, Imam M, Bjornsson ES, A. TJ, Lindor KD. Long- term outcomes in antimitochondrial antibody negatve primary biliary cirrhosis. Scand J Gastroenterol. 2016;51:745-752. 116 source

In the paper

“The wide variability among studies may be due to a variety of genetic and environmental factors as well as the nonuniform collection of biochemical, serological, immunological, and histological data.”

In the paper

“However, an estimated 50% of patients in either group had received treatment with UDCA, and some in both groups had received a variety of other therapies.”

What the sources say

• ?Not checked — no full text of the sourcecites [134] 134. Silveira MG, Talwalkar JA, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes. Am J Gastroenterol. 2007;102:1244-1250. 135 source

In the paper

“Some meta-analyses have questioned these results.(142) Often, these meta-analyses include studies of short duration and those that have used what is now known to be an inadequate dose of UDCA.(143)”

What the sources say

• ?Not checked — no full text of the sourcecites [142] 142. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cir- rhosis: a meta-analysis. Lancet. 1999;354:1053-1060. 143 source
• ?Not checked — no full text of the sourcecites [143] 143. Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses. Am J Gastroenterol. 2007;102:1799-1807. 144 source

In the paper

“Early studies reported that pruritus (itching) occurs in 20% to 70% of patients with PBC.It is now less common because of the growing number of patients with PBC who are diagnosed in the early, asymptomatic phase.(100)(101)(102)”

What the sources say

• ?Not checked — no full text of the sourcecites [100] 100. Prince MI, Chetwynd A, Craig WL, Metcalf JV, James OF. Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 2004;53:865-870. 101 source
• ?Not checked — no full text of the sourcecites [101] 101. Talwalkar JA, Souto E, Jorgensen RA, Lindor KD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2003;1:297-302. 102 source
• ?Not checked — no full text of the sourcecites [102] 102. Pares A, Rodes J. Natural history of primary biliary cirrhosis. Clin Liver Dis. 2003;7:779-794. 103 source

In the paper

“Right upper quadrant pain is found in approximately 17% of patients with PBC.It is typically nonspecific in character, not progressive in nature, not well correlated with disease stage or hepatomegaly, and often disappears spontaneously.Its etiology is unknown.(108)”

What the sources say

• ?Not checked — no full text of the sourcecites [108] 108. Laurin JM, DeSotel CK, Jorgensen RA, Dickson ER, Lindor KD. The natural history of abdominal pain asso- ciated with primary biliary cirrhosis. Am J Gastroenterol. 1994;89:1840-1843. 109

In the paper

“This score was subsequently revised (122) and, when applied to PBC cohorts, revealed that less than 1% of PBC patients met definite AIH diagnostic criteria, while 8% to 19% met probable AIH criteria.(123)(124)”

What the sources say

• ?Not checked — no full text of the sourcecites [122] 122. Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929-938. 123 source
• ?Not checked — no full text of the sourcecites [123] 123. Talwalkar JA, Keach JC, Angulo P, Lindor KD. Overlap of auto- immue hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system. Am J Gastroenterol. 2002;97:1191-1197. 124 source
• ?Not checked — no full text of the sourcecites [124] 124. Suzuki Y, Arase Y, Ikeda K, Saitoh S, Tsubota A, Suzuki F, et al. Clinical and pathological characteristics of the auto- immune hepatitis and primary biliary cirrhosis overlap syn- drome. J Gastroenterol Hepatol. 2004;19:699-706. 125 source

In the paper

“UDCA with or without immunosuppressive therapy has been used, but no clear consensus on optimal therapy for these patients exists.(129)(130)(134)(135)”

What the sources say

• ?Not checked — no full text of the sourcecites [129] 129. Joshi S, Cauch-Dudek K, Wanless IR, Lindor KD, Jorgensen R, Batts K, et al. Primary biliary cirrhosis with additional fea- tures of autoimmune hepatitis: response to therapy with ur- sodeoxycholic acid. Hepatology. 2002;35:409-413. 130 source
• ?Not checked — no full text of the sourcecites [130] 130. Heurgue A, Vitry F, Diebold MD, Yaziji N, Bernard-Chabert B, Pennaforte JL, et al. Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Clin Biol. 2007;31:17-25. 131 source
• ?Not checked — no full text of the sourcecites [134] 134. Silveira MG, Talwalkar JA, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes. Am J Gastroenterol. 2007;102:1244-1250. 135 source

In the paper

“Budesonide may be helpful, although this is controversial.(180)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [180] 180. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ur- sodeoxycholic acid. Hepatology. 2000;31:318-323. 181

In the paper

“A 5-pound weight gain over the first year of therapy has been reported and is not progressive.(155)”

What the sources say

• ?Not checked — no full text of the sourcecites [155] 155. Siegel JL, Jorgensen R, Angulo P, Lindor KD. Treatment with ur- sodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis. J Clin Gastroenterol. 2003;37:183-185. 156 source

In the paper

“Altered serotonin neurotransmission may mediate fatigue in chronic liver disease (183) ; however, ondansetron, an antagonist to serotonin receptor, did not relieve fatigue in a clinical trial.(184)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [183] 183. Jones EA. Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet. 1999;354:397. 184
• ?Not checked — no full text of the sourcecites [184] 184. Theal JJ, Toosi MN, Girlan L, Heslegrave RJ, Huet PM, Burak KW, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fa- tigue. Hepatology. 2005;41:1305-1312. 185 source

In the paper

“Modafinil, a stimulant used for narcolepsy, was originally reported to lessen fatigue in PBC in open-label studies.(186,187) However, a subsequent placebo-controlled trial failed to show benefit.(188)”

What the sources say

• ?Not checked — no full text of the sourcecites [186] 186. Kaplan MM, Bonis PA. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med. 2005;143:546-547. 187 source
• ?Not checked — no full text of the sourcecites [187] 187. Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary bili- ary cirrhosis. Aliment Pharmacol Ther. 2007;25:471-476. 188 source
• ?Not checked — no full text of the sourcecites [188] 188. Silveira MG, Gossard AA, Stahler AC, Jorgensen RA, Petz JL, Ali AH, et al. A randomized, placebo-controlled clini- cal trial of efficacy and safety: modafinil in the treatment of fatigue in patients with primary biliary cirrhosis. Am J Ther. 2017;24:e167-e76. 189 source

In the paper

“Finally, fibrates can cause elevation of transaminases, which is also typically reversible.”

In the paper

“Improvement in liver tests are typically observed within a few weeks, and 90% of the improvement usually occurs within 6 to 9 months.”

In the paper

“The use of UDCA has been associated with a reduction of serum low-density lipoprotein cholesterol levels, a reduced risk of developing varices, and slower histologic progression.”

In the paper

“This is typically reversible and not associated with a decline in glomerular filtration rate, but it is attributed to an increase in creatinine production.(167)”

What the sources say

• ?Not checked — no full text of the sourcecites [167] 167. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99:3C-18C. 168 source

In the paper

“Furthermore, improvement in pruritus and beneficial effects on markers of fibrosis were also observed.”

What the sources say

• ?Not checked — no full text of the sourcecites [94] 94. Corpechot C, Chazouillères O, Rousseau A, Guyader D, Habersetzer F, Mathurin P, et al. A 2-year multicenter, double-blind, randomized, placebo-controlled study of be- zafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxy- cholic acid therapy (Bezurso). J Hepatol. 2017;66:S89. source

In the paper

“OCA is a farnesoid X receptor (FXR) agonist that is 100 times more potent than the endogenous ligand, chenodeoxycholic acid.(156)”

What the sources say

• ?Not checked — no full text of the sourcecites [156] 156. Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. 6α-ethyl-chenodeoxycholic acid (6- ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002;45:3569-3572. 157 source

In the paper

“Notably, use of fibrates can be associated with myalgias and heartburn, and an elevation in serum creatinine is frequently observed.”

In the paper

“Older patients and those with lower fibrosis scores were more likely to respond.”

What the sources say

• ?Not checked — no full text of the sourcecites [166] 166. Reig A, Sese P, Pares A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with subopti- mal ursodeoxycholic acid response. Am J Gastroenterol. 2018;113:49-55. 167 source

In the paper

“These comorbidities both promote disease progression and may put the individual at risk of not being accepted for a liver transplant should the latter become necessary.”

In the paper

“Estrogens promote cholestasis, so oral contraceptive pills and estrogen supplements may induce or worsen pruritus.”

In the paper

“Intractable fatigue is not a valid indication for liver transplantation because fatigue usually persists post transplant.(189)”

What the sources say

• ?Not checked — no full text of the sourcecites [189] 189. Carbone M, Bufton S, Monaco A, Griffiths L, Jones DE, Neuberger JM. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol. 2013;59:490-494. 190 source

In the paper

“At this time, there is no recommended therapy for the fatigue resulting from PBC.”

In the paper

“A short second stage of labor is optimal because the Valsalva maneuver may precipitate variceal hemorrhage.”

In the paper

“It is not known which substance in the gut they may be binding to that leads to improved cholestatic itching, and clinical trials proving their efficacy are limited, but they have a long track record of clinical use.(190,191)”

What the sources say

• ?Not checked — no full text of the sourcecites [190] 190. Datta DV, Sherlock S. Cholestyramine for long term re- lief of the pruritus complicating intrahepatic cholestasis. Gastroenterology. 1966;50:323-332. 191 source
• ?Not checked — no full text of the sourcecites [191] 191. Van Itallie TB, Hashim SA, Crampton RS, Tennent DM. The treatment of pruritus and hypercholesteremia of pri- mary biliary cirrhosis with cholestyramine. N Engl J Med. 1961;265:469-474. 192 source

In the paper

“There are limited data about fertility or infant outcome in PBC patients.”

In the paper

“The majority of individuals currently have no symptoms referable to their liver disease when diagnosed with PBC.”

In the paper

“This lack of symptoms makes it particularly difficult for an individual to recognize the importance of preventive strategies in PBC.”

In the paper

“Colesevalam was not effective in a single placebo-controlled trial of cholestatic pruritus.(192) However, only patients who had already failed other resins were enrolled.”

What the sources say

• ?Not checked — no full text of the sourcecites [192] 192. Kuiper EM, van Erpecum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, et al. The potent bile acid sequestrant cole- sevelam is not effective in cholestatic pruritus: results of a dou- ble-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:1334-1340. 193 source

In the paper

“Sertraline, given at a dose of 75 to 100 mg, helped relieve pruritus in a single, small, placebo-controlled trial and in a retrospective case series.The effect was independent from an improvement in depression.(209)”

What the sources say

• ?Not checked — no full text of the sourcecites [209] 209. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666-674. 210 source

In the paper

“Phenobarbital can improve cholestatic pruritus but is a strong sedative that worsens or initiates fatigue, increases vitamin D deficiency, and has been associated with troublesome gingival hyperplasia.(213)”

What the sources say

• ?Not checked — no full text of the sourcecites [213] 213. Bloomer JR, Boyer JL. Phenobartial effectis in cholestatic liver disease. Ann Intern Med. 1975;82:310-317. 214 source

In the paper

“Patients with PBC may develop portal hypertension as a result of biliary cirrhosis or, in the precirrhotic stage of the disease, in association with nodular regenerative hyperplasia.(232,233)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [232] 232. Kew MC, Varma RR, Santos HAD, Scheuer PJ. Portal hyper- tension in primary biliary cirrhosis. Gut. 1971;12:830-834. 233
• ?Not checked — no full text of the sourcecites [233] 233. Abraham SC, Kamath PS, Eghtesad B, Demetris AJ, Krasinskas AM. Liver transplantation in precirrhotic bili- ary tract disease: Portal hypertension is frequently associated with nodular regenerative hyperplasia and obliterative portal venopathy. Am J Surg Pathol. 2006;30:1454-1461. 234 source

In the paper

“Similarly, during pregnancy, itching may become severe even early on in the pregnancy, and it may fail to resolve completely after delivery in patients with PBC.”

In the paper

“Ondansetron, a serotonin antagonist, was initially reported to decrease cholestatic itch but was later found to be no better than placebo in more rigorous trials.(210)(211)(212)”

What the sources say

• ?Not checked — no full text of the sourcecites [210] 210. Raderer M, Muller C, Scheithauer W. Ondansetron for pruri- tus due to cholestasis. N Engl J Med. 1994;330:1540. 211 source
• ?Not checked — no full text of the sourcecites [211] 211. Schworer H, Ramadori G. Improvement of cholestatic pruri- tus by ondansetron. Lancet. 1993;341:1277. 212 source
• ?Not checked — no full text of the sourcecites [212] 212. Jones EA, Molenaar HA, Oosting J. Ondansetron and pruritus in chronic liver disease: a controlled study. Hepatogastroenterology. 2007;54:1196-1199. 213

In the paper

“Patients with dry mouth are at increased risk of dental caries and should receive regular professional dental cleanings and check-ups.”

In the paper

“Treatment with beta blockers is safe in pregnancy.”

In the paper

“This has been challenged by a meta-analysis that identified a pooled risk of 1.57 (95% CI, 1.21-2.06)(247)”

What the sources say

• ?Not checked — no full text of the sourcecites [247] 247. Ungprasert P, Wijarnpreecha K, Ahuja W, Spanuchart I, Thongprayoon C. Coronary artery disease in primary biliary cirrhosis: A systematic review and meta-analysis of observa- tional studies. Hepatol Res. 2015;45:1055-1061. 248 source

In the paper

“Long-term immunosuppression with a cyclosporine-based regimen seems to be associated with reduced incidence of recurrent PBC, but this is not proven.(259)”

What the sources say

• ?Not checked — no full text of the sourcecites [259] 259. Charatcharoenwitthaya P, Pimentel S, Talwalkar JA, Enders FT, Lindor KD, Krom RA, et al. Long-term survival and im- pact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl. 2007;13:1236-1245. 260 source

In the paper

“Osteopenia may worsen for the first 6 months after transplantation, but bone mineral density returns to baseline after 12 months and improves thereafter.(254)”

What the sources say

• ?Not checked — no full text of the sourcecites [254] 254. Eastell R, Dickson ER, Hodgson SF, Wiesner RH, Porayko MK, Wahner HW, et al. Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis. Hepatology. 1991;14:296-300. 255 source

In the paper

“Fatigue improves in a subset of patients with PBC, but moderate to severe fatigue continues to affect nearly half of patients 2 years after liver transplantation.(189)”

What the sources say

• ?Not checked — no full text of the sourcecites [189] 189. Carbone M, Bufton S, Monaco A, Griffiths L, Jones DE, Neuberger JM. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol. 2013;59:490-494. 190 source

In the paper

“In the same study, the 1-, 3-, 5-, and 10-year graft survival rates were 85%, 80%, 78.1%, and 71.9%, and the 1-, 3-, 5-, and 10-year patient survival rates were 90.2%, 86.7%, 84.4%, and 79%, respectively.(253)”

What the sources say

• ?Not checked — no full text of the sourcecites [253] 253. Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver trans- plantation based on etiology of liver disease. Transplantation. 2013;95:755-760. 254 source

In the paper

“Hormone replacement therapy has led to some improvement in bone mineral density, but these agents are seldom used because of safety concerns.(243)”

What the sources say

• ?Not checked — no full text of the sourcecites [243] 243. Boone RH, Cheung AM, Girlan LM, Heathcote EJ. Osteoporosis in primary biliary cirrhosis: a randomized trial of the efficacy and feasibility of estrogen/progestin. Dig Dis Sci. 2006;51:1103-1112. 244 source