Primary biliary cholangitis

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 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 lifespan¹ .

Primary biliary cholangitis used to be called primary biliary cirrhosis, a term now confined to the late stage of PBC in which cirrhosis actually occurs.

Aetiology

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. The triggers have yet to be determined² . The rate of concordance amongst identical twins is amongst the highest of all autoimmune diseases³ . Families with a strong family history have been described.

Epidemiology¹

• A large study in the north east of England reported a prevalence of definite or probable disease of 35/100,000, with an annual incidence of 2-3/100,000. This is similar to figures reported in studies of cohorts in northern Europe.

• The rate in women is 10-fold higher than that in men.

• PBC is less common amongst those of African origin.

• The median age at diagnosis is 65 years. The condition has never been reported under the age of 15 years.

• The prevalence appears to have stabilised after an observed increase since 1980. This may be in part due to increased survival but is probably also due to changes in diagnostic practice and clinician perception becoming fully evolved.

Presentation

History

• About 25% of patients with PBC are diagnosed as a result of blood tests taken for other reasons and are asymptomatic at the time⁴ .

• 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, occurring in 50% and often the presenting symptom. In 20% of cases it is severe enough to be life-changing⁵ . It appears to be associated with higher liver-related mortality but not non-liver-related mortality⁶ . There is lack of evidence about whether or not it improves with antidepressants and its aetiology is unknown⁷ .

• Pruritus: around 55% report pruritus and in 10% this is severe⁸ . 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 neurotransmission⁹ .

• Right upper quadrant pain or discomfort: occurs in 17%³ .

• 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.

Examination¹⁰

• Hepatomegaly occurs in 44%.

• Hyperpigmentation occurs in up to 40%.

• Splenomegaly is more common in the later stages.

• Jaundice occurs in 40%.

• 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).
  

Associations

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

The link with extrahepatic malignancy has been disputed; however, there is an association between cirrhosis secondary to primary biliary cholangitis and hepatocellular carcinoma¹¹ .

Investigations¹

• 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 may be raised 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.

• Liver biopsy may be required if liver tests show a cholestatic picture but autoantibody results are not diagnostic. It may also be required to differentiate PBC from autoimmune hepatitis or overlap syndrome. Histology will demonstrate chronic nonsuppurative cholangitis of the interlobular and septal bile ducts. In autoimmune hepatitis the histological picture is of interface hepatitis.

• Genetic studies are currently in the research phase and have no impact on clinical management.

Diagnostic criteria¹

A diagnosis of PBC can be confidently made if the presence of antimitochondrial antibodies (>1 in 40) or highly PBC-specific antinuclear antibodies can be demonstrated, combined with cholestatic liver biochemistry, without other explanation. Occasionally, histological confirmation may be required, if autoimmune hepatitis is suspected. Rarely, the features of both conditions may be incorporated ('overlap syndrome')³ .

Staging¹

Traditionally, staging has relied on the histological analysis of liver biopsy, resulting in the following stages:

• 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.

However, it has subsequently been found that the use of liver biopsy adds little to the management of the condition, and its use in recent times has been confined to cases of diagnostic difficulty. Disease stratification is a more appropriate means of determining progression. This relies on the response of the individual patient to treatment with ursodeoxycholic acid (UDCA) as determined by biochemical response indices.

Differential diagnosis

• Autoimmune hepatitis

• Reaction to phenothiazines

• Sarcoidosis

Treatment

Treatments are aimed at alleviation of symptoms and at slowing the disease. Measuring outcomes can be difficult¹² . Only liver transplantation offers a cure but the disease can recur in the transplanted liver.

A Cochrane review determined that the evidence base for the medical treatment of PBC was limited and there was no convincing evidence of beneficial effects on any clinical outcomes¹³ . The following - principally based on the British Society of Gastroenterology guidelines - reflects current best practice in the UK¹ :

• Cochrane studies have not found definitive evidence that UDCA improves mortality rates or reduces the need for transplants, but current British guidelines recommend its first-line use for all patients with PBC.

• Fatigue is a very common symptom and has an adverse effect on quality of life. It is difficult to treat. Studies suggest that modafinil has a significant effect on daytime somnolence. Rituximab is also showing promise in this area¹⁴ .

• Pruritus:

  • Sedating antihistamines are used in the early stages but later colestyramine or colestipol are employed. They sequester bile salts but it takes between one and four days before there is any effect. Colesevelam is a newer drug in this group which may be better tolerated.

  • Rifampicin has helped some patients unresponsive to colestyramine but its mode of action is unknown. Other drugs which have been tried empirically include SSRIs (eg, sertraline), gabapentin and naltrexone,

  • Plasmapheresis is also effective. However, for severe, intractable pruritus a liver transplant offers the only hope.

• Drugs are used to inhibit the autoimmune process:
  

  • Steroids and azathioprine are not recommended for PCB per se but British guidelines suggest they may be of use in overlap syndrome.

  • Ciclosporin may be of value in PBC recurring after an allograft but is otherwise not advocated.

  • Methotrexate, D-penicillamine and colchicine are no longer considered to have a role in the management of PBC.

• Oestrogens promote cholestasis and so combined oral contraceptives and HRT should be avoided. However, oestrogen cream may be helpful if vaginal dryness is a problem.

• Pregnant women with PBC may develop worsening itching which does not fully resolve after pregnancy. UDCA is considered safe in pregnancy, as are cholestyramine and rifampicin (second trimester onwards), Pregnant women should be assessed by endoscopy 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. A variety of risk score systems are available (eg, the Mayo Risk Score - see below ) which predict the prognosis if surgical management is not undertaken. There also tend to be more problems of chronic rejection than with other indications for transplantation.

Complications

• 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 mainly in PBC patients with cirrhosis. Non-response to medical treatment increases the risk. The condition is much more common in men than in women. There are no consensus UK guidelines with respect to screening but the current best practice approach is to screen male PBC patients who have advanced histological changes. Abdominal ultrasound is the principal investigation. Alpha-fetoprotein (AFP) is also used, although supportive evidence is limited.

• 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 oedema¹⁵ . More recent score systems include resistance to UDCA treatment as a predictive factor (eg, GLOBE score, UK-PBC risk score)¹⁶ .

Prognosis

• 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)¹⁷ . However, up to 40% of patients are UDCA non-responders and require second-line treatment or transplantation¹⁸ .

• 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.

• 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 small¹⁹ .

• This remains a serious disease and a worrying diagnosis. Affected patients will need information and support. In patients with low serum albumen, the survival range is 3-6 years. Persistently high bilirubin levels equate to a mean survival of 1.7 years²⁰ .

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 pruritus. It is less successful in improving fatigue and should not be performed for this indication alone²¹ . Bone disease worsens initially but then improves²² . AMA may persist or reappear and may indicate a recurrence of PBC²³ .

• In the mid 1980s PBC was the leading cause of liver transplantation but numbers have declined significantly in recent years. However, the numbers are falling in Northern Europe and America³ .

• 20% of patients with PBC who undergo transplantation develop recurrent disease over ten years. This normally occurs within 3-5.5 years¹ .

• There is no convincing evidence that the use of immunosuppressants reduces recurrence rates, although there is some support for the use of UDCA¹ .

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 AMAs.

• 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.

Dr Mary Lowth is an author or the original author of this leaflet.