Primary biliary cirrhosis (PBC) is a slowly progressive disease of the liver and biliary system, with destruction of the small interlobular bile ducts, cholestasis, fibrosis and eventually cirrhosis. Cirrhosis is a late feature. In the light of earlier diagnosis and better treatment it is perhaps misnamed because many patients today do not develop cirrhosis.
There is much to suggest an autoimmune aetiology. The aetiology is probably partly genetic and partly environmental. A popular hypothesis is that the disease is environmentally triggered in genetically predisposed individuals. The rate of concordance amongst identical twins is amongst the highest of all autoimmune diseases. Families with a strong family history have been described.
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- The prevalence has been estimated as 12.9 per 100,000 population in the UK with up to 90% being women.
- It is more common amongst those of northern European descent and less common amongst those of African origin.
- Diagnosis is usually between about 45 and 55 years old.
- The prevalence appears to be rising since 1980. This may be in part due to increased survival but also to better awareness of the disease, leading to more frequent and earlier diagnosis. Nevertheless, there does seem to be evidence of a true increase in incidence.
About 25% are diagnosed as a result of blood tests taken for other reasons and are asymptomatic at the time.
- Fatigue is the most common symptom in primary biliary cirrhosis (PBC) and occurs in 65% and is often the presenting symptom. It appears to be associated with a higher mortality.
- Around 55% report pruritus and in 10% this is severe. It is usually assumed to be due to deposition of bile pigments in skin although evidence is lacking and it may be due to central opioid neurotransmission.
- Right upper quadrant pain or discomfort occurs in 10 to 15%.
- At a later stage the patient may present with jaundice of cholestatic origin with dark urine and pale stool.
- Sjögren's syndrome may be present with dry eyes and dry mouth.
- Hepatomegaly occurs in 25%.
- Hyperpigmentation occurs in 25%.
- Splenomegaly occurs in 15%.
- Jaundice occurs in 10%.
- Xanthelasma may occur in the later stages.
- Only in advanced disease will there be cirrhosis with associated features (including ascites, spider naevi and other features of portal hypertension).
There may be other diseases present too, especially those of autoimmune origin. These include:
- Thyroid disease.
- Systemic sclerosis including its variant of CREST (c alcinosis, R aynaud's phenomenon (o)e sophageal motility disorder, s clerodactyly and t elangiectasiae).
- Coeliac disease.
- Extrahepatic malignancy.
- Hepatocellular carcinoma.
- Seropositive arthritis.
- Seronegative arthritis.
- Cholelithiasis (gallstones).
- FBC is often normal but ESR is elevated
- Abnormal LFTs are to be expected but are not invariable. Alkaline phosphatase is usually elevated as it is a cholestatic condition and, less consistently, transaminases are raised. Bilirubin is often normal at first but rises as the disease progresses whilst partial thromboplastin time (PTT) and albumin are normal until a late stage. IgM is raised.
- When bilirubin rises this suggests disease progression and it heralds liver failure.
- Lipid levels and cholesterol levels are raised in 85% but risk of coronary heart disease (CHD) is not raised as high-density lipoprotein (HDL) cholesterol is elevated.
- Autoantibodies are characteristic and in this disease the most specific are antimitochondrial antibodies that are present in 90 to 95% with a specificity of 98%. About 35% also have antinuclear antibodies. There may well be other autoantibodies, especially related to the thyroid.
- Monitor thyroid function.
- Imaging of the liver excludes causes of obstruction like stones. Ultrasound is most commonly used but CT and MRI scanning may be employed. As the disease progresses there may be features suggestive of portal hypertension and cirrhosis.
- Finally, liver biopsy is required to stage the disease.
- Portal stage with portal inflammation and bile duct abnormalities.
- Periportal stage with periportal fibrosis, with or without periportal inflammation.
- Septal stage with septal fibrosis and active inflammation.
- Cirrhotic stage with nodules with various degrees of inflammation.
Treatment can aim to alleviate symptoms or to slow the disease. Measuring outcomes in clinical trials involving patients with liver disease can be difficult. Only liver transplantation offers a cure but the disease has been reported in the transplanted liver.
- Fatigue is a very common symptom and has an adverse effect on quality of life. It is difficult to treat.
- Pruritus may be treated with sedating antihistamines in the early stages but later colestyramine or colestipol are used. They sequester bile salts but it takes between 1 and 4 days before there is any effect. Again it is a very difficult symptom to treat.
- Rifampicin has helped some patients unresponsive to colestyramine but its mode of action is unknown. Plasmapheresis is also effective but for severe, intractable pruritus a liver transplant offers the only hope.
- Ursodeoxycholic acid (UDCA) slows progression of the disease. Patients with early disease have clinical, biochemical, and histological improvement but its value in late disease is dubious. Any benefit in improving mortality is not supported in a 2007 Cochrane review. However, there are studies which appear to show improved mortality.
- Drugs are used to inhibit the autoimmune process:
- Methotrexate is well established although its basis has been criticised as anecdotal rather than based on randomised controlled trials. It is not recommended for use outside clinical trials and appears to increase mortality.
- Steroids may help but osteoporosis is a concern.
- Ciclosporin may be beneficial. However it is recommended that it should only be used in the context of a clinical trial. It has a high rate of complications, such as renal dysfunction and hypertension.
- A 2007 Cochrane review found inadequate evidence of the effectiveness of colchicine and found that it may increase mortality.
- Azathioprine was recommended after a large international trial in 1985 showed beneficial effects and few adverse effects. However, a Cochrane review from 2007 does not support this, demonstrating adverse effects and no demonstrable benefits.
- D-penicillamine does not appear to reduce morbidity or mortality and causes significant adverse effects.
- As liver failure sets in, a transplant offers the only hope for cure. Increasing prothrombin time, elevated bilirubin and decreased albumin all point to the time being due. After 2 to 5 years from the transplant, between 8 and 16% will have recurrence of the disease, as the underlying autoimmune process remains. This figure may rise to 50% by 10 years. There also tend to be more problems of chronic rejection than with other indications for transplantation.
- Although osteoporosis is often cited as a complication of primary biliary cirrhosis (PBC), the risk of osteoporosis is no more than for other women of that age unless they have cirrhosis that is a risk irrespective of aetiology.
- Renal tubular acidosis occurs in around half of patients with PBC. Copper deposition in the renal tubules or an autoimmune phenomenon may be the mechanism.
- Around 20% develop hypothyroidism.
- Hepatocellular carcinoma develops in about 6% but this represents about 4% of women with the disease and 20% of men.
- There may be malabsorption of fats with steatorrhoea and fat-soluble vitamin deficiency
- Complications of cirrhosis are described in the article
The prognosis of primary biliary cirrhosis (PBC) has improved considerably in recent years. This is because of both earlier diagnosis (and particularly a recognition of asymptomatic, indolent cases) and probably because of use of ursodeoxycholic acid (UDCA). New indicators of prognosis will be useful particularly for the increasing number of patients with less severe disease. Development of such indicators is complex and highlights how calculations of prognosis can vary according to a variety of individual factors. The relatively poor figures for prognosis quoted before recent trends in early diagnosis can be both alarming and misleading.
Further reading & references
- Crosignani A, Battezzati PM, Invernizzi P, et al; Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008 Jun 7;14(21):3313-27.; good review article
- Selmi C; Environmental factors in primary biliary cirrhosis. Hepatol Res. 2007 Oct;37 Suppl 3:S370-6.
- Selmi C, Invernizzi P, Keeffe EB, et al; Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol. 2004 Mar;38(3):264-71.
- Kouroumalis E, Notas G; Pathogenesis of primary biliary cirrhosis: a unifying model. World J Gastroenterol. 2006 Apr 21;12(15):2320-7.
- Selmi C, Invernizzi P, Zuin M, et al; Genetics and geoepidemiology of primary biliary cirrhosis: following the footprints to disease etiology. Semin Liver Dis. 2005 Aug;25(3):265-80.
- Brind AM, Bray GP, Portmann BC, et al; Prevalence and pattern of familial disease in primary biliary cirrhosis. Gut. 1995 Apr;36(4):615-7.
- Prince MI, James OF; The epidemiology of primary biliary cirrhosis. Clin Liver Dis. 2003 Nov;7(4):795-819.
- Prince MI, Chetwynd A, Craig WL, et al; Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut. 2004 Jun;53(6):865-70.
- Jones EA; Fatigue complicating chronic liver disease. Metab Brain Dis. 2004 Dec;19(3-4):421-9.
- Fahey S; The experience of women with primary biliary cirrhosis: a literature review. J Adv Nurs. 1999 Aug;30(2):506-12.
- Forton DM, Patel N, Oatridge A, et al; Fatigue in primary biliary cirrhosis. Gut. 2005 Mar;54(3):438.
- Jones DE, Bhala N, Burt J, et al; Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut. 2006 Apr;55(4):536-41. Epub 2005 Nov 18.
- Bergasa NV; Pruritus and fatigue in primary biliary cirrhosis. Clin Liver Dis. 2003 Nov;7(4):879-900.
- Prince MI, Jones DE; Primary biliary cirrhosis: new perspectives in diagnosis and treatment. Postgrad Med J. 2000 Apr;76(894):199-206.
- Bergasa NV, Jones EA; The pruritus of cholestasis: evolving pathogenic concepts suggest new therapeutic options. Clin Liver Dis. 1998 May;2(2):391-405, x.
- Culp KS, Fleming CR, Duffy J, et al; Autoimmune associations in primary biliary cirrhosis. Mayo Clin Proc. 1982 Jun;57(6):365-70.
- Floreani A, Baragiotta A, Baldo V, et al; Hepatic and extrahepatic malignancies in primary biliary cirrhosis. Hepatology. 1999 May;29(5):1425-8.
- Findor J, He XS, Sord J, et al; Primary biliary cirrhosis and hepatocellular carcinoma. Autoimmun Rev. 2002 Aug;1(4):220-5.
- Gluud C, Brok J, Gong Y, et al; Hepatology may have problems with putative surrogate outcome measures. J Hepatol. 2007 Apr;46(4):734-42. Epub 2007 Jan 26.
- Poupon RE, Chretien Y, Chazouilleres O, et al; Quality of life in patients with primary biliary cirrhosis. Hepatology. 2004 Aug;40(2):489-94.
- Jones EA; Personal view: a potential novel treatment for fatigue complicating chronic liver disease--how should its efficacy be evaluated? Aliment Pharmacol Ther. 2006 Apr 15;23(8):1113-6.
- Bergasa NV; Medical palliation of the jaundiced patient with pruritus. Gastroenterol Clin North Am. 2006 Mar;35(1):113-23.
- Poupon RE, Poupon R, Balkau B; Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med. 1994 May 12;330(19):1342-7.
- Gong Y, Huang Z, Christensen E, et al; 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 Aug;102(8):1799-807. Epub 2007 Apr 24.
- van Hoogstraten HJ, Hansen BE, van Buuren HR, et al; Prognostic factors and long-term effects of ursodeoxycholic acid on liver biochemical parameters in patients with primary biliary cirrhosis. Dutch Multi-Centre PBC Study Group. J Hepatol. 1999 Aug;31(2):256-62.
- Poupon RE, Bonnand AM, Chretien Y, et al; Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology. 1999 Jun;29(6):1668-71.
- ter Borg PC, Schalm SW, Hansen BE, et al; Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol. 2006 Sep;101(9):2044-50. Epub 2006 Jul 18.
- Jorgensen R, Angulo P, Dickson ER, et al; Results of long-term ursodiol treatment for patients with primary biliary cirrhosis. Am J Gastroenterol. 2002 Oct;97(10):2647-50.
- Carithers RL Jr; Primary biliary cirrhosis: specific treatment. Clin Liver Dis. 2003 Nov;7(4):923-39.
- Gong Y, Gluud C; Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004385.
- Bray GP, Williams R; Immunointervention in primary biliary cirrhosis: an overview. J Autoimmun. 1992 Apr;5 Suppl A:293-300.
- Gong Y, Christensen E, Gluud C; Cyclosporin A for primary biliary cirrhosis. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD005526.
- Gong Y, Gluud C; Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev. 2004;(2):CD004481.
- Christensen E, Neuberger J, Crowe J, et al; Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology. 1985 Nov;89(5):1084-91.
- Gong Y, Christensen E, Gluud C; Azathioprine for primary biliary cirrhosis. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006000.
- Gong Y, Klingenberg SL, Gluud C; Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis--Cochrane Hepato-Biliary Group. Aliment Pharmacol Ther. 2006 Dec;24(11-12):1535-44.
- Angulo P, Dickson ER; The timing of liver transplantation in primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol. 2000 Aug;14(4):657-68.
- Batts KP, Wang X; Recurrence of primary biliary cirrhosis, autoimmune cholangitis and primary sclerosing cholangitis after liver transplantation. Clin Liver Dis. 1998 May;2(2):421-35, xi.
- MacQuillan GC, Neuberger J; Liver transplantation for primary biliary cirrhosis. Clin Liver Dis. 2003 Nov;7(4):941-56, ix.
- Floreani A, Mega A, Camozzi V, et al; Is osteoporosis a peculiar association with primary biliary cirrhosis? World J Gastroenterol. 2005 Sep 14;11(34):5347-50.
- Jones DE, Metcalf JV, Collier JD, et al; Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology. 1997 Nov;26(5):1138-42.
|Original Author: Dr Richard Draper||Current Version: Dr Richard Draper|
|Last Checked: 16/07/2010||Document ID: 2664 Version: 22||© EMIS|
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