Primary biliary cholangitis

Notes

Overview

Primary biliary cholangitis is an autoimmune cholestatic liver disease that can lead to cirrhosis.

Primary biliary cholangitis (PBC) is an autoimmune liver disorder. It causes autoimmune destruction of the small, intrahepatic bile ducts that leads to poor bile flow (i.e. cholestasis), progressive fibrosis, and eventually cirrhosis.

Epidemiology

PBC is a rare disease that affects approximately 35/100,000 people in the UK.

PBC is more commonly diagnosed in older women over the age of 50. The female to male ratio approaches 10:1. The median age at diagnosis is 65 years old. There is known to be genetic susceptibility (increased risk of a family member getting the condition) in some families with PBC.

Aetiology & pathophysiology

PBC is an autoimmune biliary disorder but the precise aetiology is unknown.

The exact cause of PBC remains unknown. It is an autoimmune condition leading to bile duct injury. There is evidence of genetic susceptibility with first-degree relatives at increased risk of developing the condition. In addition, a number of environmental factors have been identified that increase the risk of PBC including recurrent urinary tract infections, cigarette smoking, and pregnancy-related cholestasis.

PBC is characterised by T-cell mediated attack to small bile ducts within the liver. Autoreactive T cells seem to target the E2 subunit of the pyruvate dehydrogenase complex, which is expressed on the luminal surface of bile duct epithelial cells in PBC. Chronic inflammation leads to bile duct destruction and loss. This leads to cholestasis (poor bile flow), which causes the build-up of potentially toxic substances at high concentrations, such as bile acids, that can lead to damage to hepatocytes. Over time, this leads to chronic liver disease.

Autoantibodies

The hallmark of PBC is the formation of specific autoantibodies known as anti-mitochondrial (AMA) autoantibodies. These antibodies are used for the diagnosis of PBC due to their high specificity. They are present in ~95% of patients.

Other autoantibodies include:

  • Anti-nuclear antibody (ANA): non-specific autoantibody found in many autoimmune diseases
  • Anti-gp210 and anti-sp100: these are antibodies directed against specific nuclear antigens that may be found in some patients with PBC

Other autoimmune diseases

There is an increased incidence of other autoimmune disorders in patients, and their relatives, with PBC (e.g. autoimmune thyroiditis, coeliac disease). These are estimated to occur in >50% of patients with PBC.

Clinical features

The cardinal features of PBC are fatigue and pruritus.

An estimated 50-60% of patients with PBC are asymptomatic and identified by abnormalities in liver function tests. The most commonly observed symptoms when present are pruritus and fatigue.

Symptoms

  • Fatigue
  • Pruritus
  • Right upper quadrant pain
  • Features of chronic liver disease (advanced disease)

Signs

  • Hepatomegaly
  • Excoriation marks
  • Xanthomas (deposition of cholesterol in the skin causing a nodule)
  • Xanthelasmas (deposition of cholesterol in the skin causing a papule or plaque)
  • Xerosis (dry skin)
  • Hyperpigmentation of skin: due to melanin deposition but reason unknown
  • Jaundice: more common as disease advances
  • Features or chronic liver disease (advanced disease)

Diagnosis & investigations

Diagnosis of PBC is based on the presence of cholestatic liver enzymes and positive anti-mitochondrial antibodies.

PBC should be considered in any patient with an unexplained rise in alkaline phosphatase (ALP), which can be requested as part of ‘liver function tests’ (LFTs). The key investigation in PBC is an anti-mitochondrial antibody, which is positive in ~95% of patients. A formal diagnosis of PBC can be made based on the presence of cholestatic liver enzymes and positive anti-mitochondrial antibodies without an alternative explanation.

Liver function tests

A rise in ALP alongside gamma-glutamyl transferase (gGT) is consistent with a ‘cholestatic’ derangement in LFTs. This should prompt investigation into the possible causes of cholestatic liver enzyme derrangement including biliary obstruction (e.g. gallstones, strictures) and cholestatic liver disease (e.g. PBC, PSC).

As part of the work-up to determine the cause of abnormal LFTs, patients will usually undergo a ‘liver screen’. A non-invasive liver screen refers to screening questions, biochemical tests, and imaging to assess patients with suspected liver disease. For more information see notes on Chronic liver disease.

Imaging

Liver ultrasound is usually performed as a first-line imaging modality to investigate abnormal liver function tests. It is typically normal in PBC but useful to exclude an alternative cause and/or biliary dilatation. This will usually suffice to enable a diagnosis of PBC. If there is concern about another diagnosis (e.g. PSC) or a patient is seronegative (i.e. absence of anti-mitochondrial antibodies) then a magnetic resonance cholangiopancreatography (MRCP) is typically recommended.

Liver biopsy

Liver biopsy is not routinely required for the diagnosis. It may be completed if there is concern about an overlap syndrome (the presence of more than one liver disease such as PBC and autoimmune hepatitis), co-existing liver disease, or alternative diagnosis.

Other diagnoses

It is reasonable to screen patients for other autoimmune diseases at diagnosis including coeliac disease, thyroid disease, and Sjögren’s syndrome.

Management

The principal treatment for PBC is ursodeoxycholic acid (UDCA).

Treatment of PBC aims to slow the progression of the disease and lead to normalisation in liver enzymes.

Primary treatment

The primary treatment for PBC is ursodeoxycholic acid (UDCA). UDCA is a normally occurring bile acid that makes up ~4% of the bile acid pool. With treatment, UDCA becomes the primary bile acid and has been shown to improve transplant-free survival. UDCA should be given at 13–15 mg/kg/day and continued life-long if tolerated.

The response to UDCA should be assessed after 12 months using a well-validated prognostic score (discussed below).

Secondary treatments

Patients who fail to respond to UDCA (based on prognostic scores) should be considered for second-line treatments. The main second-line treatment is obeticholic acid (OCA), which is a semi-synthetic hydrophobic bile acid analogue that is highly selective for farnesoid X receptors.

Liver transplantation

Unfortunately, PBC does progress to chronic liver disease in some patients with the development of cirrhosis and features of decompensation including jaundice, ascites, hepatic encephalopathy, and GI bleeding. Patients may be suitable for liver transplantation and those with a bilirubin > 50 umol/L or evidence of decompensation should be referred to a transplant centre for assessment.

Symptom management

Fatigue and pruritus can be particularly troubling in PBC. Several drugs may be used to help treat pruritus, which includes:

  • Cholestyramine: bile acid sequestrant
  • Rifampicin: antibiotic commonly used to treat mycobacterium
  • Gabapentin: neuropathic pain agent
  • Naltrexone: long-acting opioid antagonist
  • Sertraline: selective serotonin reuptake inhibitor (SSRI)

Prognostic scores

Most patients with PBC are asymptomatic at diagnosis and ~90% do not have features of liver scarring (i.e. fibrosis). However, over 10 years, it is estimated that 50% become symptomatic and it is important to recognise the patients at higher risk of disease progression.

A number of prognostic models have been developed that look at clinical features and blood tests to help determine response to treatment. Two commonly used scores include the GLOBE score and the UK-PBC score.

Patients treated with UDCA who have an ALP >1.67x upper limit of normal (ULN) and/or elevated bilirubin < 2x ULN should be considered for the addition of second-line therapies.

Complications

Complications in PBC are due to cirrhosis and cholestasis.

PBC is a slowly progressive disease that can lead to cirrhosis. Patients with cirrhosis are at risk of many complications (e.g. variceal bleeding, hepatocellular carcinoma) that is thoroughly discussed in our notes on Chronic liver disease.

Many of the complications seen in PBC relate to cholestasis, which includes:

  • Hypercholesterolaemia: due to a decrease in functional low-density lipoprotein (LDL) receptors and an increase in lipoprotein X.
  • Malabsorption of fat-soluble vitamins (A, D, E, K)
  • Malabsorption of fat
  • Osteoporosis: cause multifactorial

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