PBC in Depth
PBC is an autoimmune liver disease characterised by auto-reactive T-cells and B-cells, typically with specificity for the E2-domain of pyruvate dehydrogenase complex (PDC-E2), which is part of a multi-enzyme complex located on the inner mitochondrial membrane. The autoimmune injury is focussed on the biliary epithelial cells (BEC) of the small, interlobular bile ducts, causing a non-suppurative destructive cholangitis that eventually leads to biliary cirrhosis. A proportion of cases eventually develop end-stage liver disease (ESLD) with attendant need for liver transplantation. PBC occurs globally but it is most common in Northern Europe and North America. It is more common in women, with a female to male ratio of approximately 9:1. The median age at diagnosis is 55 years.
PBC is a complex disorder, meaning the autoimmune process results from a complex interaction of genetic and environmental factors. Large-scale genetic studies have identified several genetic risk factors for PBC. However, understanding of the genetic basis of PBC remains incomplete. Several environmental risk factors have been proposed, including urinary tract infections, especially by Escherichia coli; colonisation of the bowel by Novosphingobium aromaticivorans, and xenobiotics derived from foodstuffs, cosmetics or industrial pollutants. It has also been suggested that PBC may result from direct infection of biliary epithelial cells by a human beta-retrovirus resembling mouse mammary tumour virus. Understanding of environmental risk factors for PBC is also incomplete.
Clinical features
Up to 60% of patients are entirely asymptomatic at the time of diagnosis. In these patients, the disease may be detected following an incidental finding of abnormal liver biochemistry (LFT). Symptoms of PBC that may occur at any stage of the liver disease include fatigue, pruritus, pain in the right upper quadrant, indigestion and bone pain. Sicca symptoms and Raynaud’s phenomenon are common and may reflect an additional autoimmune disorder. Xanthelasma are frequently observed.
Patients with advanced disease may suffer the usual manifestations of portal hypertension or hepatocellular failure, such as variceal haemorrhage, ascites, jaundice or hepatic encephalopathy. PBC-related cirrhosis may be complicated by hepatocellular carcinoma. In patients with marked ductopenia, severe cholestasis may lead to malabsorption; deficiencies of fat-soluble vitamins; steatorrhoea, and weight loss.
Patients with PBC may also have features of associated conditions. Conditions associated with PBC include osteoporosis and other autoimmune disorders. Up to 50% of PBC patients have at least one additional autoimmune condition, most commonly Sjögren’s syndrome (~25%), Raynaud’s phenomenon (~25%), autoimmune thyroid disease (~25%), rheumatoid arthritis (~20%) or systemic sclerosis (~10%).
Laboratory features
Course and Prognosis
In some but not all PBC patients, the liver disease progresses over several years to cirrhosis and eventually to end-stage liver disease (ESLD), with the usual manifestations of chronic liver failure and portal hypertension. Clinical features of ESLD include jaundice, ascites, variceal haemorrhage and hepatic encephalopathy. PBC patients with cirrhosis also have increased risk of hepatocellular carcinoma (HCC).
Many studies have been undertaken to identify variables that predict outcome. Recent studies have shown that the biochemical response to ursodeoxycholic acid (UDCA) is an important prognostic variable. UDCA is a hydrophilic bile acid used for treatment of PBC. In some PBC patients, treatment with UDCA brings about substantial improvement in the liver biochemistry; these patients are known as UDCA responders. In other patients, there is little change in the liver biochemistry with treatment; these patients are known as UDCA non-responders. Several definitions of UDCA response have been published – but irrespective of how it is defined, survival free from liver transplantation (LT) is much better in UDCA responders compared to UDCA non-responders. Evaluation of the UDCA response is an important part of patient management. Independent risk factors for HCC in PBC include advanced stage, older age, male sex and evidence of portal hypertension. The risk of HCC is also increased in UDCA non-responders. Surveillance for HCC by means of six-monthly ultrasound scan of the liver is recommended for PBC patients with cirrhosis.
Management of PBC
There is no cure for PBC. General health measures are important. Medications for PBC may be classified as disease-modifying or symptom-modifying. Patients with ESLD should be considered for liver transplantation.
