Primary biliary cholangitis (PBC) is a slowly progressive autoimmune disease of the biliary system with a chronic course which may extend over many decades. It involves destruction of the small interlobular bile ducts (canals of Hering). This causes intrahepatic cholestasis which damages cells, leading to scarring, fibrosis and eventually cirrhosis. It is an insidious disease which progresses through the clinical phases: preclinical, asymptomatic, symptomatic, and finally liver insufficiency. The prognosis has improved significantly over a period of two decades because of earlier diagnosis and effective treatment which, whilst not curative, significantly slows progression if started in the early stages, and often does so sufficiently to allow a normal lifespan[1, 2, 3].
Nov 2017 - Dr Hayley Willacy draws your attention to the guidelines released this year on diagnosis and management. The key recommendations include taking a detailed history and physical examination when evaluating patients with biochemical tests that suggest cholestatic liver disease; using ultrasound as the first-line non-invasive imaging procedure, in order to differentiate intra- from extrahepatic cholestasis; performing serologic screening for AMA and PBC-specific-ANA by immunofluorescence in all patients with unexplained cholestasis; considering liver biopsy after serologic screening and extended imaging, in patients with ongoing unexplained intrahepatic cholestasis; considering genetic tests for inherited cholestatic syndromes in patients where clinically appropriate.
PBC is an autoimmune disease process and is often considered a model autoimmune disease because of its signature serology, the antimitochondrial antibody, and specific bile duct pathology. The aetiology is probably partly genetic and partly environmental: the disease is thought to be environmentally triggered in genetically predisposed individuals[5, 6, 7]. The rate of concordance amongst identical twins is amongst the highest of all autoimmune diseases. Families with a strong family history have been described.
- The prevalence of PBC has been estimated as 12.9 per 100,000 population in the UK with up to 90% of cases occurring in women.
- PBC 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 have been rising since 1980. This may be in part due to increased survival but is probably also due to better awareness of the disease, leading to more frequent and earlier diagnosis. Many patients are diagnosed when asymptomatic. Nevertheless, there does seem to be evidence of a true increase in incidence.
- About 25% of patients with PBC are diagnosed as a result of blood tests taken for other reasons and are asymptomatic at the time.
- The diagnosis of PBC should be suspected where chronic cholestasis is found after exclusion of other causes of liver disease.
- Fatigue: this is the most common symptom in PBC and occurs in 65-80% and is often the presenting symptom[11, 12, 13]. It appears to be associated with a higher mortality. It does not improve with treatment of depression and its aetiology is unknown.
- Pruritus: 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[14, 15].
- Right upper quadrant pain or discomfort: occurs in 10-15%.
- At a later stage the patient may present with jaundice of cholestatic origin with dark urine and pale stool.
- Sjögren's syndrome is commonly 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.
- In advanced disease cirrhosis eventually occurs, with associated features (including ascites, spider naevi and other features of portal hypertension).
There may be other diseases and conditions present, especially those of autoimmune origin. These include:
- Thyroid disease.
- Systemic sclerosis including its variant of CREST (calcinosis, Raynaud's phenomenon (o)esophageal motility disorder, sclerodactyly and telangiectasias).
- Coeliac disease.
- Extrahepatic malignancy.
- Hepatocellular carcinoma.
- Seropositive arthritis.
- Seronegative arthritis.
- Cholelithiasis (gallstones).
- Osteoporosis occurs in up to one third of patients. The cause is uncertain, as patients with PBC have normal vitamin D metabolism.
- Hyperlipidaemia is seen in many patients
- FBC is often normal but ESR is elevated.
- Abnormal LFTs are usual but not invariable:
- Alkaline phosphatase is usually elevated as PBC is a cholestatic condition.
- Less consistently, transaminases are raised.
- Bilirubin is often normal at first but rises as the disease progresses. Rising bilirubin demonstrates disease progression and heralds liver failure.
- Partial thromboplastin time (PTT) and albumin are normal until a late stage.
- IgM is raised.
- 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:
- The most specific to PBC are antimitochondrial antibodies (AMAs), present in 90-95% of affected individuals (and 0.5% of normal controls, giving a specificity of over 98%.) Evidence suggests that this antibody is directly involved in the pathological process.
- Around 0.5% of the general population is positive for AMAs. Studies suggest that fewer than 10% of patients with positive AMAs will develop PBC, although almost all patients with PBC have positive AMAs.
- About 35% also have antinuclear antibodies.
- There may also be other autoantibodies, especially related to the thyroid.
- Thyroid function should be assessed and monitored.
- Imaging of the liver is useful to exclude 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.
- Cholangiography is occasionally helpful in order to exclude primary sclerosing cholangitis.
- Transient elastography is a non-invasive tool to evaluate the degree of liver fibrosis.
- Finally, liver biopsy is required to stage the disease. Histology will demonstrate chronic nonsuppurative cholangitis of the interlobular and septal bile ducts.
Diagnosis is based on two of the following three criteria being met:
- Biochemical evidence of cholestasis with evidence of alkaline phosphatase activity.
- Presence of AMAs.
- Histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts.
- 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.
Treatments are aimed at alleviation of symptoms and at slowing the disease. Measuring outcomes can be difficult. Only liver transplantation offers a cure but the disease can recur in the transplanted liver.
- Fatigue is a very common symptom and has an adverse effect on quality of life. It is difficult to treat. Modafinil has shown promise in this area, and trials suggest it produces benefits in energy, somnolence and sleep requirements. Modafinil has been proposed as a possible treatment.
- 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 one and four 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. However, 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[26, 27].
- 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.
- Oestrogens promote cholestasis and so combined oral contraceptives and HRT should be avoided.
- Pregnant women with PBC may develop worsening itching which does not fully resolve after pregnancy. They should be assessed during pregnancy for the presence of varices due to the marked blood volume increase during pregnancy. Treatment with beta-blockers is safe in pregnancy and prolonged pushing is to be avoided.
- 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 two to five 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.
- 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. Regular screening for the condition is advised for all patients with cirrhosis.
- There may be malabsorption of fats with steatorrhoea and fat-soluble vitamin deficiency
- Complications of cirrhosis are described in the separate Cirrhosis article.
- The Mayo Risk Score is a tool which stratifies prognosis in PBC using the patient’s age, their prothrombin time, bilirubin, albumin, their need for diuretics and the presence of peripheral oedema.
- The prognosis of 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 UDCA).
- New indicators of prognosis will be useful particularly for the increasing number of patients with less severe disease[3, 39].
- 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.
- One study suggests that the median time from the first positive AMA test to persistently abnormal LFTs is six years, with a range of 1-19 years. None of the patients in this study developed cirrhosis during follow-up and the study was small.
- This remains a serious disease and a worrying diagnosis. Affected patients will need information and support. Ten-year survival of asymptomatic patients in three studies ranged from 50-70%, whereas median duration of survival from the onset of symptoms ranged from 5-8 years.
Liver transplantation in PBC
- The outcome of liver transplantation for patients with PBC is more favourable than for nearly all other disease categories.
- Liver transplantation improves fatigue, pruritus, and Sjögren's syndrome. Bone disease worsens initially but then improves. AMA may persist or reappear but does not in itself signify a recurrence of PBC.
- In the mid 1980s PBC was the leading cause of liver transplantation but numbers have declined significantly in recent years. It is now the sixth leading indication for liver transplantation in the USA.
- 20-25% of patients with PBC who undergo transplantation develop recurrent disease over ten years; however, recurrent PBC does not appear to affect patient or graft (transplanted liver) survival.
- Long-term use of immunosuppressants seems to reduce recurrence rates.
Primary billiary cholangitis and primary sclerosing cholangitis
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are similarly named, so there is potential for confusion.
- Both involve primary sclerosis of bile ducts:
- PBC affects small interlobular bile ducts, PSC affects intrahepatic and extrahepatic bile ducts.
- PBC occurs predominantly in women, and PSC predominantly in men.
- PBC is an autoimmune condition linked to the presence of antimitochrondrial antibodies.
- The cause of PSC is unclear, although the process is inflammatory and there is an association with inflammatory bowel disease.
- Mayo clinic scoring systems are used to assess prognosis; the two scoring systems differ.
- Liver transplantation can be curative for PBC and PSC. Each has a significant recurrence rate.
Further reading and references
Mayo MJ; Natural history of primary biliary cirrhosis. Clin Liver Dis. 2008 May12(2):277-88
Lee YM, Kaplan MM; The natural history of PBC: has it changed? Semin Liver Dis. 2005 Aug25(3):321-6.
Crosignani A, Battezzati PM, Invernizzi P, et al; Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008 Jun 714(21):3313-27.
EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis; European Association for the Study of the Liver (2017)
Selmi C; Environmental factors in primary biliary cirrhosis. Hepatol Res. 2007 Oct37 Suppl 3:S370-6.
Selmi C, Invernizzi P, Keeffe EB, et al; Epidemiology and pathogenesis of primary biliary cirrhosis. J Clin Gastroenterol. 2004 Mar38(3):264-71.
Kouroumalis E, Notas G; Pathogenesis of primary biliary cirrhosis: a unifying model. World J Gastroenterol. 2006 Apr 2112(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 Aug25(3):265-80.
Prince MI, James OF; The epidemiology of primary biliary cirrhosis. Clin Liver Dis. 2003 Nov7(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 Jun53(6):865-70.
Jones EA; Fatigue complicating chronic liver disease. Metab Brain Dis. 2004 Dec19(3-4):421-9.
Forton DM, Patel N, Oatridge A, et al; Fatigue in primary biliary cirrhosis. Gut. 2005 Mar54(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 Apr55(4):536-41. Epub 2005 Nov 18.
Bergasa NV; Pruritus and fatigue in primary biliary cirrhosis. Clin Liver Dis. 2003 Nov7(4):879-900.
Prince MI, Jones DE; Primary biliary cirrhosis: new perspectives in diagnosis and treatment. Postgrad Med J. 2000 Apr76(894):199-206.
Findor J, He XS, Sord J, et al; Primary biliary cirrhosis and hepatocellular carcinoma. Autoimmun Rev. 2002 Aug1(4):220-5.
Metcalf JV, Mitchison HC, Palmer JM, et al; Natural history of early primary biliary cirrhosis. Lancet. 1996 Nov 23348(9039):1399-402.
Stebbing J, Farouk L, Panos G, et al; A meta-analysis of transient elastography for the detection of hepatic fibrosis. J Clin Gastroenterol. 2010 Mar44(3):214-9. doi: 10.1097/MCG.0b013e3181b4af1f.
Lindor KD et al; Primary Biliary Cirrhosis, American Association for the Study of Liver Diseases, 2009
Gluud C, Brok J, Gong Y, et al; Hepatology may have problems with putative surrogate outcome measures. J Hepatol. 2007 Apr46(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 Aug40(2):489-94.
Ian Gan S, de Jongh M, Kaplan MM; Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience. Dig Dis Sci. 2009 Oct54(10):2242-6. doi: 10.1007/s10620-008-0613-3. Epub 2008 Dec 12.
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 1523(8):1113-6.
Bergasa NV; Medical palliation of the jaundiced patient with pruritus. Gastroenterol Clin North Am. 2006 Mar35(1):113-23.
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 Aug102(8):1799-807. Epub 2007 Apr 24.
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 Sep101(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 Oct97(10):2647-50.
Carithers RL Jr; Primary biliary cirrhosis: specific treatment. Clin Liver Dis. 2003 Nov7(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 Apr5 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.
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 Dec24(11-12):1535-44.
Angulo P, Dickson ER; The timing of liver transplantation in primary biliary cirrhosis. Baillieres Best Pract Res Clin Gastroenterol. 2000 Aug14(4):657-68.
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Prince M, Chetwynd A, Newman W, et al; Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002 Oct123(4):1044-51.