Primary biliary cholangitis

Primary biliary cholangitis, previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to build up in the liver, a condition called cholestasis. Further slow damage to the liver tissue can lead to scarring, fibrosis, and eventually cirrhosis.
Common symptoms are tiredness, itching, and in more advanced cases, jaundice. In early cases, the only changes may be those seen in blood tests.
PBC is a relatively rare disease, affecting up to one in 3,000–4,000 people. As with many other autoimmune diseases, it is much more common in women, with a sex ratio of at least 9:1 female to male. The reasons for this disparity are unclear, but may involve the expression of sex hormones such as estrogen, which impact immune system response.
The condition has been recognised since at least 1851, and was named "primary biliary cirrhosis" in 1949. Because cirrhosis is a feature only of advanced disease, a change of its name to "primary biliary cholangitis" was proposed by patient advocacy groups in 2014.

Signs and symptoms

People with PBC experience fatigue ; this is a nonspecific symptom and can be debilitating, with a huge impact on quality of life. Its pathogenesis is still unknown, and is quite challenging to explore its specificity and to treat. Comorbidities that could contribute to or worsen fatigue, such as depression, hypothyroidism, anaemia, obesity, or medication side effects, should be promptly identified and treated. Dry skin and dry eyes are also common. Itching occurs in 20–70% of cases, and can develop at any stage of the disease. Textbooks tend to describe itching in the feet and hands, but patients may also experience itching of the scalp, face, back, or other areas. The itching is typically mild-to-moderate in intensity. It may manifest as a tingling, crawling or burning sensation, and can develop even with normal liver function tests. It does not correlate with progression of liver disease, and may even improve or disappear as the disease advances. Given the impact on quality of life and night sleep, pruritus is also correlated with fatigue. It can rarely be severe, non-responsive to medical therapy, and requiring liver transplant. Pruritus is characteristically intermittent, worse at night, and improves during summer.
People with more severe PBC may have jaundice. PBC impairs bone density and the risk of fracture increases. Xanthelasma or other xanthoma may be present as a result of increased cholesterol levels.
PBC can eventually progress to cirrhosis of the liver. This, in turn, may lead to a number of symptoms or complications, including:

Fluid retention in the abdomen in more advanced disease
Enlarged spleen in more advanced disease
Oesophageal varices in more advanced disease
Hepatic encephalopathy, including coma in extreme cases in more advanced disease.

People with PBC may also sometimes have the findings of an associated extrahepatic autoimmune disorder such as thyroid disease or rheumatoid arthritis or Sjögren's syndrome.

Causes

PBC has an immunological basis, and is classified as an autoimmune disorder. It results from a slow, progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the canals of Hering being affected early in the disease.
Most people with PBC have antimitochondrial antibodies against pyruvate dehydrogenase complex, an enzyme complex found in the mitochondria. People who are negative for AMAs are usually found to be positive when more sensitive methods of detection are used.
People with PBC may also have been diagnosed with another autoimmune disease, such as a rheumatological, endocrinological, gastrointestinal, pulmonary, or dermatological condition, suggesting shared genetic and immune abnormalities.
Common associations include Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, lupus, hypothyroidism, and coeliac disease.
A genetic predisposition to disease has been thought to be important for some time. Evidence for this includes cases of PBC in family members, identical twins both having the condition, and clustering of PBC with other autoimmune diseases. In 2009, a Canadian-led group of investigators reported in the New England Journal of Medicine results from the first PBC genome-wide association study. This research revealed parts of the IL12 signaling cascade, particularly IL12A and IL12RB2 polymorphisms, to be important in the aetiology of the disease in addition to the HLA region. In 2012, two independent PBC association studies increased the total number of genomic regions associated to 26, implicating many genes involved in cytokine regulation such as TYK2, SH2B3 and TNFSF11.
A study of over 2,000 patients identified a gene, POGLUT1, that appeared to be associated with this condition. Earlier studies have also suggested that this gene may be involved. The implicated protein is an endoplasmic reticulum O-glucosyltransferase.
An environmental Gram-negative Alphaproteobacterium — Novosphingobium aromaticivorans has been associated with this disease, with several reports suggesting an aetiological role for this organism. The mechanism appears to be a cross-reaction between the proteins of the bacterium and the mitochondrial proteins of the liver cells. The gene encoding CD101 may also play a role in host susceptibility to this disease.
A failure of immune tolerance against the mitochondrial pyruvate dehydrogenase complex is a primary cause, with shedding of the antigen into apoptotic bodies or "apotopes" leading to the anatomic localization. Such autoreactivity may also be the case with other proteins, including the gp210 and p62 nuclear pore proteins. Gp210 has increased expression in the bile duct of anti-gp210 positive patients, and these proteins may be associated with prognosis.

Diagnosis

Most patients are currently diagnosed when asymptomatic, having been referred to the hepatologist for abnormal liver function tests performed for annual screening blood tests. Other frequent scenarios include screening of patients with nonliver autoimmune diseases, e.g. rheumatoid arthritis, or investigation of elevated cholesterol, evaluation of itch or unresolved cholestasis post partum. Diagnosing PBC is generally straightforward. The basis for a definite diagnosis are:

Abnormalities in liver enzyme tests are usually present and elevated gamma-glutamyl transferase and alkaline phosphatase are found in early disease. Elevations in bilirubin occur in advanced disease.
Antimitochondrial antibodies are the characteristic serological marker for PBC, being found in 90–95% of patients and only 1% of controls. PBC patients have AMA against pyruvate dehydrogenase complex, an enzyme complex that is found in the mitochondria. Those people who are AMA negative but with disease similar to PBC have been found to have AMAs when more sensitive detection methods are employed.
Other auto-antibodies may be present:
Abdominal ultrasound, magnetic resonance cholangiopancreatography or a CT scan is usually performed to rule out blockage to the bile ducts. This may be needed if a condition causing secondary biliary cirrhosis, such as other biliary duct disease or gallstones, needs to be excluded. A liver biopsy may help, and if uncertainty remains as in some patients, an endoscopic retrograde cholangiopancreatography, an endoscopic investigation of the bile duct, may be performed.

Given the high specificity of serological markers, liver biopsy is not necessary for the diagnosis of PBC; however, it is still necessary when PBC-specific antibodies are absent, or when co-existent autoimmune hepatitis or nonalcoholic steatohepatitis is suspected. Liver biopsy can be useful to stage the disease for fibrosis and ductopenia. Finally, it may also be appropriate in the presence of other extrahepatic comorbidities.

Liver biopsy

On microscopic examination of liver biopsy specimens, PBC is characterized by chronic, nonsuppurative inflammation, which surrounds and destroys interlobular and septal bile ducts. These histopathologic findings in primary biliary cholangitis include:

Inflammation of the bile ducts, characterized by intraepithelial lymphocytes
Periductal epithelioid granulomas.
Proliferation of bile ductules
Fibrosis

The Ludwig and Scheuer scoring systems have historically been used to stratify four stages of PBC, with stage 4 indicating the presence of cirrhosis. In the new system of Nakanuma, the stage of disease is based on fibrosis, bile duct loss, and features of cholestasis, i.e. deposition of orcein-positive granules, whereas the grade of necroinflammatory activity is based on cholangitis and interface hepatitis. The accumulation of orcein-positive granules occurs evenly across the PBC liver, which means that staging using the Nakanuma system is more reliable regarding sampling variability.
Liver biopsy for the diagnosis and staging of PBC lost favour after the evidence of a patchy distribution of the duct lesions and fibrosis across the organ. The widespread availability of noninvasive measures of fibrosis means that liver biopsy for staging of PBC is somewhat obsolete.
Liver biopsy does, however, remain useful in certain settings. The main indications are to confirm the diagnosis of PBC when PBC-specific antibodies are absent and confirm a diagnosis of PBC with AIH features. Liver biopsy is also useful to assess the relative contribution of each liver injury when a comorbid liver disease is present, such as non-alcoholic steatohepatitis. In patients with inadequate response to UDCA, liver biopsy may provide the explanation and could undoubtedly inform risk stratification. For example, it may identify a previously unsuspected variant syndrome, steatohepatitis, or interface hepatitis of moderate or greater severity. It is also useful in AMA and ANA-specific antibody negative cholestatic patients to indicate an alternative process, e.g. sarcoidosis, small duct PSC, adult idiopathic ductopenia.