Primary biliary cholangitis: Difference between revisions
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The PBC Foundation is a UK-based international charity offering support and information to people with PBC, their families and friends.<ref name="AMRC">{{cite web|last1=Association of Medical Research Charities|title=The PBC Foundation|url=http://www.amrc.org.uk/our-members/member-directory/the-pbc-foundation|accessdate=12 July 2015}}</ref> It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK.<ref name=Scotsman2008/><ref>{{cite journal|author= Thain, Collette |journal = At Home Magazine| format = online | year = 2015 | title=Primary biliary cirrhosis: getting a diagnosis|url=http://www.athomemagazine.co.uk/primary-biliary-cirrhosis-getting-a-diagnosis/|accessdate=28 July 2015}}</ref> The Foundation has supported research into PBC including the development of the PBC-40 [[quality of life]] measure published in 2004<ref name="pmid15961522">{{cite journal | vauthors = Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, Jones DE | title = Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis | journal = Gut | volume = 54 | issue = 11 | pages = 1622–9 | date = Nov 2005 | pmid = 15961522 | pmc = 1774759 | doi = 10.1136/gut.2005.065862 }}</ref> and helped establish the PBC Genetics Study.<ref>{{cite journal | vauthors = Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, Heneghan MA, Neuberger JM, Donaldson PT, Day DB, Ducker SJ, Muriithi AW, Wheater EF, Hammond CJ, Dawwas MF, Jones DE, Peltonen L, Alexander GJ, Sandford RN, Anderson CA | title = Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis | journal = Nature Genetics | volume = 43 | issue = 4 | pages = 329–32 | date = Apr 2011 | pmid = 21399635 | pmc = 3071550 | doi = 10.1038/ng.789 | displayauthors = 6 }}</ref><ref name = "Liu_2012"/> It was founded by Collette Thain in 1996, after she was diagnosed with the condition.<ref name=Scotsman2008>Staff of The Scotsman, January 3, 2008. [http://www.scotsman.com/news/health/dealing-with-a-silent-killer-1-1239548 Dealing with a silent killer]</ref> Thain was awarded an MBE [[Order of the British Empire]] in 2004 for her work with the Foundation.<ref>Barry Gordon for The Scotsman. 31 December 2003 [http://www.scotsman.com/news/a-royal-seal-of-approval-1-898754 A royal seal of approval]</ref> |
The PBC Foundation is a UK-based international charity offering support and information to people with PBC, their families and friends.<ref name="AMRC">{{cite web|last1=Association of Medical Research Charities|title=The PBC Foundation|url=http://www.amrc.org.uk/our-members/member-directory/the-pbc-foundation|accessdate=12 July 2015}}</ref> It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK.<ref name=Scotsman2008/><ref>{{cite journal|author= Thain, Collette |journal = At Home Magazine| format = online | year = 2015 | title=Primary biliary cirrhosis: getting a diagnosis|url=http://www.athomemagazine.co.uk/primary-biliary-cirrhosis-getting-a-diagnosis/|accessdate=28 July 2015}}</ref> The Foundation has supported research into PBC including the development of the PBC-40 [[quality of life]] measure published in 2004<ref name="pmid15961522">{{cite journal | vauthors = Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OF, Jones DE | title = Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis | journal = Gut | volume = 54 | issue = 11 | pages = 1622–9 | date = Nov 2005 | pmid = 15961522 | pmc = 1774759 | doi = 10.1136/gut.2005.065862 }}</ref> and helped establish the PBC Genetics Study.<ref>{{cite journal | vauthors = Mells GF, Floyd JA, Morley KI, Cordell HJ, Franklin CS, Shin SY, Heneghan MA, Neuberger JM, Donaldson PT, Day DB, Ducker SJ, Muriithi AW, Wheater EF, Hammond CJ, Dawwas MF, Jones DE, Peltonen L, Alexander GJ, Sandford RN, Anderson CA | title = Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis | journal = Nature Genetics | volume = 43 | issue = 4 | pages = 329–32 | date = Apr 2011 | pmid = 21399635 | pmc = 3071550 | doi = 10.1038/ng.789 | displayauthors = 6 }}</ref><ref name = "Liu_2012"/> It was founded by Collette Thain in 1996, after she was diagnosed with the condition.<ref name=Scotsman2008>Staff of The Scotsman, January 3, 2008. [http://www.scotsman.com/news/health/dealing-with-a-silent-killer-1-1239548 Dealing with a silent killer]</ref> Thain was awarded an MBE [[Order of the British Empire]] in 2004 for her work with the Foundation.<ref>Barry Gordon for The Scotsman. 31 December 2003 [http://www.scotsman.com/news/a-royal-seal-of-approval-1-898754 A royal seal of approval]</ref> |
||
In 2014, the PBC Foundation, along with the US-based advocacy group, the PBCers, launched an initiative to change the name from "primary biliary cirrhosis" to "primary biliary cholangitis".<ref name="PBCFname"/><ref name="pbcers.org"/><ref>{{cite web|last1=PBC Foundation|title=EASL Name Change Presentation|url=http://www.pbcfoundation.org.uk/Home/BlogItem/12|accessdate=8 July 2015}}</ref> |
In 2014, the PBC Foundation, along with the US-based advocacy group, the PBCers, launched an initiative to change the name from "primary biliary cirrhosis" to "primary biliary cholangitis".<ref name="PBCFname"/><ref name="pbcers.org"/><ref>{{cite web|last1=PBC Foundation|title=EASL Name Change Presentation|url=http://www.pbcfoundation.org.uk/Home/BlogItem/12|accessdate=8 July 2015}}</ref> Clinician support for this name change has come from the [[American Association for the Study of Liver Diseases]]<ref name="AASLD-PBC"/> and the [[European Association for the Study of the Liver]], and it is proposed that this change be reflected in the [[International Classification of Disease]] ([[ICD11]]). |
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====PBCers==== |
====PBCers==== |
Revision as of 12:55, 4 August 2015
Primary biliary cholangitis | |
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Specialty | Gastroenterology ![]() |
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver.[1][2] It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts (Canals of Hering) affected early in the disease.[3] When these ducts are damaged, bile and other toxins build up in the liver (cholestasis) and over time damages the liver tissue in combination with ongoing immune related damage. This can lead to scarring, fibrosis and cirrhosis.
PBC was previously thought to be a rare disease, but more recent studies have shown that it may affect up to 1 in 3–4,000 people; the sex ratio is at least 9:1 female to male.[4]
As cirrhosis is only a feature of advanced disease, a change of name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.[5][6] It has not as of April 2015 been adopted in scientific publications but has been accepted by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.[7]
Signs and symptoms
Individuals with PBC with disease may present with the following:
- Fatigue
- Pruritus (itchy skin)
- Jaundice (yellowing of the eyes and skin), due to increased bilirubin in the blood in more advanced disease.
- Xanthoma (local collections of cholesterol in the skin, especially around the eyes (xanthelasma))
- Complications of cirrhosis and portal hypertension: in more advanced disease
- Fluid retention in the abdomen (ascites) in more advanced disease
- Enlarged spleen in more advanced disease
- Oesophageal varices in more advanced disease
- Hepatic encephalopathy, including coma in extreme cases in more advanced disease.
- Association with an extrahepatic autoimmune disorder such as rheumatoid arthritis or Sjögren's syndrome (in up to 80% of cases).
Causes
The cause of the disease is attributed to an immunological basis for the disease, making it an autoimmune disorder. Most of the patients (>90%) have anti-mitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme complex that is found in the mitochondria.
Many PBC patients have a concomitant autoimmune disease, including rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological conditions, which suggests shared genetic and immune abnormalities.[8] Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, SLE, hypothyroidism and gluten sensitive enteropathy.[8][9][10][11] In some cases of disease, protein expression may cause an immune tolerance failure, as might be the case with gp210 and p62, nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients.[12] Both proteins appear to be prognostic of liver failure relative to anti-mitochondrial antibodies.
A genetic predisposition to disease has been thought important for some time, as evident by cases of PBC in family members, concordance in identical twins, and clustering of autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study.[13][14] This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the etiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.[15][16]
In 2003 it was reported that an environmental Gram negative alphabacterium — Novosphingobium aromaticivorans[17] was strongly associated with this disease. Subsequent reports appear to have confirmed this finding suggesting an aetiological role for this organism.[18][19][20] The mechanism appears to be a cross reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells.[21] The gene encoding CD101 may also play a role in host susceptibility to this disease.[22]
Diagnosis
![](http://upload.wikimedia.org/wikipedia/commons/thumb/2/22/Primary_biliary_cirrhosis_intermed_mag.jpg/200px-Primary_biliary_cirrhosis_intermed_mag.jpg)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/d/d8/ANA_NUCLEAR_DOT_AND_AMA.jpg/220px-ANA_NUCLEAR_DOT_AND_AMA.jpg)
To diagnose PBC, distinctions should be established from other conditions with similar symptoms, such as autoimmune hepatitis or primary sclerosing cholangitis (PSC).
Diagnostic blood tests include:
- Elevated liver enzyme tests (elevated gamma-glutamyl transferase and alkaline phosphatase)
- Presence of certain antibodies: antimitochondrial antibody (AMA), antinuclear antibody (ANA)
Abdominal ultrasound, MR scanning (MRCP) or a CT scan is usually performed to rule out blockage to the bile ducts. Most suspected cases have a liver biopsy performed, and if uncertainty remains an is some patients, endoscopic retrograde cholangiopancreatography or ERCP, where an endoscopic investigation of the bile duct is performed. Most patients are diagnosed without invasive investigation, as the combination of anti-mitochondrial antibodies (see below) and typical (cholestatic) liver enzyme tests are considered diagnostic. However, a liver biopsy is necessary to determine the stage of disease.
Anti-nuclear antibodies appear to be prognostic agents in PBC. Anti-glycoprotein-210 antibodies, and to a lesser degree anti-p62 antibodies, correlate with the disease's progression toward end stage liver failure. Anti-centromere antibodies often correlate with developing portal hypertension.[23] Anti-np62[24] and anti-sp100 are also found in association with PBC.
-
Low magnification micrograph of PBC. H&E stain.
Biopsy
PBC is characterized by interlobular bile duct destruction. Histopathologic findings of primary biliary cholangitis include the following:[25]
- Inflammation of the bile ducts, characterized by intraepithelial lymphocytes, and
- Periductal epithelioid granulomata.
Summary of stages
- Stage 1 — Portal Stage: Normal sized triads; portal inflammation, subtle bile duct damage. Granulomas are often detected in this stage.
- Stage 2 — Periportal Stage: Enlarged triads; periportal fibrosis and/or inflammation. Typically characterized by the finding of a proliferation of small bile ducts.
- Stage 3 — Septal Stage: Active and/or passive fibrous septa.
- Stage 4 — Biliary Cirrhosis: Nodules present; garland or jigsaw puzzle pattern.
Treatment
There is no known cure, but medication may slow the progression so that a normal lifespan and quality of life may be attainable for many patients.[26][27]
- Ursodeoxycholic acid (Ursodiol) is the most frequently used treatment. This helps reduce the cholestasis and improves blood test results (liver function tests). It has a minimal effect on symptoms and whether it improves prognosis is controversial.[28]
- To relieve itching caused by bile acids in circulation, which would normally be removed by the liver, cholestyramine (a bile acid sequestrant) may be prescribed to absorb bile acids in the gut and be eliminated, rather than re-enter the blood stream. Alternative agents include stanozolol, naltrexone and rifampicin.[26][27][29]
- Specific treatment for fatigue, which may be debilitating in some patients, is limited and undergoing trials.[30] Some studies indicate that Provigil (modafinil) may be effective without damaging the liver.[31] Though off-patent, the limiting factor in the use of modafinil in the U.S. is cost. The manufacturer, Cephalon, has made agreements with manufacturers of generic modafinil to provide payments in exchange for delaying their sale of modafinil.[32] The FTC has filed suit against Cephalon alleging anti-competitive behavior.[33]
- Patients with PBC have poor lipid-dependent absorption of Vitamins A, D, E, K.[34] Appropriate supplementation is recommended when bilirubin is elevated.[35]
- Patients with PBC are at elevated risk of developing osteoporosis[36] and esophageal varices[37] as compared to the general population and others with liver disease. Screening and treatment of these complications is an important part of the management of PBC.
As in all liver diseases, consumption of alcohol is contraindicated.
In advanced cases, a liver transplant, if successful, results in a favorable prognosis.[38]
The farnesoid X receptor agonist, obeticholic acid, which is a modified bile acid, is in phase III clinical trials for PBC.[39]
Epidemiology
PBC is a chronic autoimmune liver disease with a female gender predominance with female:male ratio is at least 9:1 and a peak incidence in the fifth decade of life.[40] In some areas of the US and UK the prevalence is estimated to be as high as 1 in 4000. This is much more common than in South America or Africa, which may be due to better recognition in the US and UK. First-degree relatives may have as much as a 500 times increase in prevalence, but there is debate if this risk is greater in the same generation relatives or the one that follows.[4]
Prognosis
The serum bilirubin level is an indicator of the prognosis of PBC, with levels of 2–6 mg/dL having a mean survival time of 4.1 years, 6–10 mg/dL having 2.1 years and those above 10 mg/dL having a mean survival time of 1.4 years.[41]
After liver transplant, the recurrence rate may be as high as 18% at 5 years, and up to 30% at 10 years. There is no consensus on risk factors for recurrence of the disease.[42]
Patients with PBC have an increased risk of hepatocellular carcinoma compared to the general population, as is found in other cirrhotic patients. In patients with advanced disease, one series found an incidence of 20% in men and 4% in women.[43]
History
Addison and Gull in 1851 described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. Ahrens et al in 1950 coined the term primary biliary cirrhosis for this disease. The association with anti-mitochondrial antibodies was first reported in 1965[44] and their presence was recognized as a marker of early, pre-cirrhotic disease.[45]
Society and culture
Patient support groups
The PBC Foundation
The PBC Foundation is a UK-based international charity offering support and information to people with PBC, their families and friends.[46] It campaigns for increasing recognition of the disorder, improved diagnosis and treatments, and estimates over 8000 people are undiagnosed in the UK.[47][48] The Foundation has supported research into PBC including the development of the PBC-40 quality of life measure published in 2004[49] and helped establish the PBC Genetics Study.[50][15] It was founded by Collette Thain in 1996, after she was diagnosed with the condition.[47] Thain was awarded an MBE Order of the British Empire in 2004 for her work with the Foundation.[51]
In 2014, the PBC Foundation, along with the US-based advocacy group, the PBCers, launched an initiative to change the name from "primary biliary cirrhosis" to "primary biliary cholangitis".[5][6][52] Clinician support for this name change has come from the American Association for the Study of Liver Diseases[7] and the European Association for the Study of the Liver, and it is proposed that this change be reflected in the International Classification of Disease (ICD11).
PBCers
This is a US-based patient support group which also has a strong on-line presence.[53] It was founded in 1996 and advocates for greater awareness of the disease and new treatments.[54] It has been a major force behind the initiative for a change in name.[6]
References
- ^ Hirschfield GM, Gershwin ME (Jan 2013). "The immunobiology and pathophysiology of primary biliary cirrhosis". Annual Review of Pathology. 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352.
- ^ Dancygier, Henryk (2010). Clinical Hepatology Principles and Practice of. Springer. pp. 895–. ISBN 978-3-642-04509-7. Retrieved 29 June 2010.
- ^ Saxena R, Theise N (Feb 2004). "Canals of Hering: recent insights and current knowledge". Seminars in Liver Disease. 24 (1): 43–8. doi:10.1055/s-2004-823100. PMID 15085485.
- ^ a b Clavien, Pierre-Alain; Killenberg, Paul G. (2006). Medical Care of the Liver Transplant Patient: Total Pre-, Intra- and Post-Operative Management. Wiley-Blackwell. p. 155. ISBN 1-4051-3032-6.
{{cite book}}
: Invalid|ref=harv
(help); Unknown parameter|name-list-format=
ignored (|name-list-style=
suggested) (help) - ^ a b PBC Foundation (UK). "PBC Name Change Press Release". Retrieved 8 July 2015.
- ^ a b c PBCers Organization. "Primary Biliary Cirrhosis Name Change Initiative" (PDF).
- ^ a b AASLD. "A name change for PBC: cholangitis replacing cirrhosis". Retrieved 6 July 2015.
- ^ a b Floreani A, Franceschet I, Cazzagon N (Aug 2014). "Primary biliary cirrhosis: overlaps with other autoimmune disorders". Seminars in Liver Disease. 34 (3): 352–60. doi:10.1055/s-0034-1383734. PMID 25057958.
- ^ Watt FE, James OF, Jones DE (Jul 2004). "Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study". Qjm. 97 (7): 397–406. PMID 15208427.
- ^ Logan RF, Ferguson A, Finlayson ND, Weir DG (Feb 1978). "Primary biliary cirrhosis and coeliac disease: an association?". Lancet. 1 (8058): 230–3. doi:10.1016/S0140-6736(78)90480-4. PMID 74661.
- ^ Volta U, Rodrigo L, Granito A, Petrolini N, Muratori P, Muratori L, Linares A, Veronesi L, Fuentes D, Zauli D, Bianchi FB (Oct 2002). "Celiac disease in autoimmune cholestatic liver disorders". The American Journal of Gastroenterology. 97 (10): 2609–13. doi:10.1111/j.1572-0241.2002.06031.x. PMID 12385447.
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: Unknown parameter|displayauthors=
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: Unknown parameter|displayauthors=
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suggested) (help) - ^ Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, Lu Y, Gu X, Walker EJ, Jing K, Juran BD, Mason AL, Myers RP, Peltekian KM, Ghent CN, Coltescu C, Atkinson EJ, Heathcote EJ, Lazaridis KN, Amos CI, Siminovitch KA (Jun 2009). "Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants". The New England Journal of Medicine. 360 (24): 2544–55. doi:10.1056/NEJMoa0810440. PMC 2857316. PMID 19458352.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ http://www.uk-pbc.com
- ^ a b Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, Ducker SJ, Day DB, Heneghan MA, Neuberger JM, Donaldson PT, Bathgate AJ, Burroughs A, Davies MH, Jones DE, Alexander GJ, Barrett JC, Sandford RN, Anderson CA (Oct 2012). "Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis". Nature Genetics. 44 (10): 1137–41. doi:10.1038/ng.2395. PMC 3459817. PMID 22961000.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ Juran BD, Hirschfield GM, Invernizzi P, Atkinson EJ, Li Y, Xie G, Kosoy R, Ransom M, Sun Y, Bianchi I, Schlicht EM, Lleo A, Coltescu C, Bernuzzi F, Podda M, Lammert C, Shigeta R, Chan LL, Balschun T, Marconi M, Cusi D, Heathcote EJ, Mason AL, Myers RP, Milkiewicz P, Odin JA, Luketic VA, Bacon BR, Bodenheimer HC, Liakina V, Vincent C, Levy C, Franke A, Gregersen PK, Bossa F, Gershwin ME, deAndrade M, Amos CI, Lazaridis KN, Seldin MF, Siminovitch KA (Dec 2012). "Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants". Human Molecular Genetics. 21 (23): 5209–21. doi:10.1093/hmg/dds359. PMC 3490520. PMID 22936693.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ Selmi C, Balkwill DL, Invernizzi P, Ansari AA, Coppel RL, Podda M, Leung PS, Kenny TP, Van De Water J, Nantz MH, Kurth MJ, Gershwin ME (Nov 2003). "Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium". Hepatology. 38 (5): 1250–7. doi:10.1053/jhep.2003.50446. PMID 14578864.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ Mohammed JP, Mattner J (Jul 2009). "Autoimmune disease triggered by infection with alphaproteobacteria". Expert Review of Clinical Immunology. 5 (4): 369–379. doi:10.1586/ECI.09.23. PMC 2742979. PMID 20161124.
- ^ Kaplan MM (Nov 2004). "Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis". The American Journal of Gastroenterology. 99 (11): 2147–9. doi:10.1111/j.1572-0241.2004.41121.x. PMID 15554995.
- ^ Selmi C, Gershwin ME (Jul 2004). "Bacteria and human autoimmunity: the case of primary biliary cirrhosis". Current Opinion in Rheumatology. 16 (4): 406–10. doi:10.1097/01.bor.0000130538.76808.c2. PMID 15201604.
- ^ Mattner J, Savage PB, Leung P, Oertelt SS, Wang V, Trivedi O, Scanlon ST, Pendem K, Teyton L, Hart J, Ridgway WM, Wicker LS, Gershwin ME, Bendelac A (May 2008). "Liver autoimmunity triggered by microbial activation of natural killer T cells". Cell Host & Microbe. 3 (5): 304–15. doi:10.1016/j.chom.2008.03.009. PMC 2453520. PMID 18474357.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
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{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M, Takii Y, Koyabu M, Yokoyama T, Migita K, Daikoku M, Abiru S, Yatsuhashi H, Takezaki E, Masaki N, Sugi K, Honda K, Adachi H, Nishi H, Watanabe Y, Nakamura Y, Shimada M, Komatsu T, Saito A, Saoshiro T, Harada H, Sodeyama T, Hayashi S, Masumoto A, Sando T, Yamamoto T, Sakai H, Kobayashi M, Muro T, Koga M, Shums Z, Norman GL, Ishibashi H (Jan 2007). "Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis". Hepatology. 45 (1): 118–27. doi:10.1002/hep.21472. PMID 17187436.
{{cite journal}}
: Unknown parameter|displayauthors=
ignored (|display-authors=
suggested) (help) - ^ Nesher G, Margalit R, Ashkenazi YJ (Apr 2001). "Anti-nuclear envelope antibodies: Clinical associations". Seminars in Arthritis and Rheumatism. 30 (5): 313–20. doi:10.1053/sarh.2001.20266. PMID 11303304.
- ^ Nakanuma Y, Tsuneyama K, Sasaki M, Harada K (Aug 2000). "Destruction of bile ducts in primary biliary cirrhosis". Baillière's Best Practice & Research. Clinical Gastroenterology. 14 (4): 549–70. doi:10.1053/bega.2000.0103. PMID 10976014.
- ^ a b Levy C, Lindor KD (Apr 2003). "Treatment Options for Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis". Current Treatment Options in Gastroenterology. 6 (2): 93–103. doi:10.1007/s11938-003-0010-0. PMID 12628068.
- ^ a b Oo YH, Neuberger J (2004). "Options for treatment of primary biliary cirrhosis". Drugs. 64 (20): 2261–71. doi:10.2165/00003495-200464200-00001. PMID 15456326.
- ^ Gluud C, Christensen E (2002). "Ursodeoxycholic acid for primary biliary cirrhosis". The Cochrane Database of Systematic Reviews (1): CD000551. doi:10.1002/14651858.CD000551. PMID 11869580.
- ^ Walt RP, Daneshmend TK, Fellows IW, Toghill PJ (Feb 1988). "Effect of stanozolol on itching in primary biliary cirrhosis". British Medical Journal. 296 (6622): 607. PMC 2545238. PMID 3126923.
- ^ Abbas G, Jorgensen RA, Lindor KD (Jun 2010). "Fatigue in primary biliary cirrhosis". Nature Reviews. Gastroenterology & Hepatology. 7 (6): 313–9. doi:10.1038/nrgastro.2010.62. PMID 20458334.
- ^ Modafinil#Primary biliary cirrhosis
Ian Gan S, de Jongh M, Kaplan MM (Oct 2009). "Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience". Digestive Diseases and Sciences. 54 (10): 2242–6. doi:10.1007/s10620-008-0613-3. PMID 19082890.
Kumagi T, Heathcote EJ (2008). "Primary biliary cirrhosis". Orphanet Journal of Rare Diseases. 3: 1. doi:10.1186/1750-1172-3-1. PMC 2266722. PMID 18215315.Ref 157 viz:
{{cite journal}}
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Jones DE, Newton JL (Feb 2007). "An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis". Alimentary Pharmacology & Therapeutics. 25 (4): 471–6. doi:10.1111/j.1365-2036.2006.03223.x. PMID 17270003. - ^ Modafinil#Patent protection and antitrust litigation
Carrier MA (2011). "Provigil: A Case Study of Anticompetitive Behavior" (PDF). Hastings Science & Technology Law Journal. 3 (2): 441–452. - ^ "Cephalon, Inc" (PDF). Federal Trade Commission.
- ^ Bacon, Bruce R.; O'Grady, John G. (2006). Comprehensive clinical hepatology. Elsevier Health Sciences. pp. 283–. ISBN 978-0-323-03675-7. Retrieved 29 June 2010.
{{cite book}}
: Unknown parameter|name-list-format=
ignored (|name-list-style=
suggested) (help) - ^ Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ (Jul 2009). "Primary biliary cirrhosis". Hepatology. 50 (1): 291–308. doi:10.1002/hep.22906. PMID 19554543.
- ^ "Guidelines on the management of osteoporosis associated with chronic liver disease". Gut. 50 Suppl 1 (Suppl 1): i1-9. Feb 2002. doi:10.1136/gut.50.suppl_1.i1. PMC 1867644. PMID 11788576.
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(help);|first3=
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