Historical timeline

The description of diseases similar to PBC extends back to 1851, when Addison and Gull reported a skin condition with a clinical relation to liver affection. Similar cases appeared in the literature until 1949, when Dauphinee and Sinclair coined the term PBC to distinguish the disease from obstructive biliary jaundice. In the 1950s, Ahrens and colleagues along with Sherlock reported the clinical spectrum of jaundice, pruritus, osteoporosis, xanthomas, portal hypertension, and liver failure.

In 1965 the hallmark of the disease, the AMA, was discovered via immunofluorescence by Walker and colleagues. Evaluation of this serum marker led to the recognition of a familial component in PBC. Immunofluorescence detection of AMA remains the most sensitive and specific marker for diagnosis of PBC.

The histologic continuum of PBC was first described in 1965 by Rubin and colleagues. Over time, genetic and environmental factors were considered to play an independent role in the development of PBC, with reports of case clustering. The association of PBC with other autoimmune conditions also led to the investigation of genetic polymorphisms, which may cause immune dysregulation, but the precise cause of PBC remains a mystery.

Epidemiology

PBC is a disease that is rare but universally present. It is most prevalent in Northern European countries (England and Scotland) and the Northern United States (Minnesota). In a recent systematic review by Prince and James, the prevalence of the disease ranged from 7 to 400 cases per million. Although it is a geographically variable disease, evidence suggests that both the prevalence and incidence are rising. The identification of geographic clusters of PBC has also raised the question of whether genetic and environmental factors are dominant factors in disease development.

Epidemiology

PBC is a disease that is rare but universally present. It is most prevalent in Northern European countries (England and Scotland) and the Northern United States (Minnesota). In a recent systematic review by Prince and James, the prevalence of the disease ranged from 7 to 400 cases per million. Although it is a geographically variable disease, evidence suggests that both the prevalence and incidence are rising. The identification of geographic clusters of PBC has also raised the question of whether genetic and environmental factors are dominant factors in disease development.

Cause

It is believed that PBC results when an individual with a susceptible genetic makeup encounters a superimposed environmental trigger that, in combination with other factors, leads to dysregulation of the immune system and an attack on target tissues within the liver. The genetic predisposition is shown by the high concordance rate among monozygotic twins, which is 63%. In this same study, dizygotic twins had a concordance rate of 0%, showing the complexity of genetic friability in patients who are susceptible. Approximately 6% of patients with PBC have a first-degree relative who suffers from PBC. The prevalence is nearly 100 times higher of developing PBC than in the general population if a first-degree relative suffers from the disease. There is a high female/male disease incidence ratio, which suggests a significant role for X chromosome defects in PBC. The increased risk of having PBC with genetic polymorphism of the vitamin D receptor is also of note. Allelic variations in the major histocompatibility complex along with innate and adaptive immunity have also been shown to increase genetic susceptibility for PBC.

Several etiologic environmental risk factors have been evaluated. One of the most widely studied environmental factors is a past history of infection. In an interview-based study, female patients with PBC had a history of increased number of genitourinary infections when compared with women without the disease. These findings were statistically significant, and PBC developing as a result of such infections is theorized under the mechanism of molecular mimicry. Infectious agents that have been studied in conjunction with PBC are Chlamydia pneumoniae , Escherichia coli , mouse mammary tumor virus, human betaretrovirus and Novosphingobium aromaticivorans .

Smoking consistently has been found to be a risk factor in the development of this disease and may also play a role in accelerating its progression. Toxin exposure by compounds such as halogenated hydrocarbons is also considered a potential risk factor for the development of PBC. Animal studies have shown that exposure to halogenated hydrocarbons can induce antimitochondrial antibodies but whether these lead to the development of liver disease is unclear. The role of the use of cosmetics, frequency of pregnancy, and hormone replacement therapy in contributing to disease development is unclear.

Gender in PBC

The ratio of women to men who have PBC is disproportionately 9:1. This ratio suggests the importance of gender in the development of PBC. This finding is supported by evidence that women with PBC have a significantly enhanced monosomy X frequency in peripheral white blood cells compared with age-matched healthy women and that the X chromosome loss is preferential. Recent data suggest that the role played by the X chromosome in immune function may be the critical factor. Studying the nature of autoimmunity that develops as a result of acquiring such monosomy is an important area of research.

The role of sex hormones is also a consideration in the cause of PBC. The higher prevalence of autoimmune conditions in women is believed to be secondary to the effect of sex hormones on the differentiation of immune responses. A recent study has shown pregnancy to be a precipitating factor associated with the development of PBC.

When comparing the presentation of PBC in men and women, studies have shown few, if any, differences. One study found that pruritus, and hyperpigmentation related to pruritus, was seen more frequently in women, most notably postmenopausal patients. Women were also found to have Sjögren syndrome more commonly than men.

Pathophysiology

Even although a definitive cause for PBC has not been explained, a multihit hypothesis leading to autoimmunity and subsequent disease is postulated. Although not yet clearly defined, genetic susceptibility is critical overall, and depends particularly on multiple inherited deficits in immune tolerance. Regardless of cause, the common pathway for injury is the hallmark of the disease and the development of antimitochondrial antibodies. Amongst the multiple antimitochondrial antigens, the so-called M2 antibody was shown to be the most specifically associated with PBC. These M2 antibodies target the 2-oxo-acid dehydrogenase complexes located on the inner mitochondrial membranes, and predominantly include the E2 binding protein components of the pyruvate dehydrogenase complex (PDC-E2). Recent evidence showed that CD4+ and CD8+ T cells reactive against PDC-E2 are found in higher titers in the livers of patients with PBC. The overexpression of PDC-E2 in biliary epithelial cells may also play a role in the recruitment of T cells to the liver.

The sequence of events in the initiation of PBC may begin with initiation by an autoantigenic stimulus provided either by a bacterial mimic of PDC-E2 or from a native mitochondrial antigen from apoptotic cells. This sequence of events in turn activates antigen-presenting cells, which present immunogenic peptides to autoreactive CD4+ T lymphocytes. These cells subsequently activate CD8+ cytotoxic T lymphocytes and B lymphocytes, which produce AMA. Regulatory T lymphocytes that normally restrain activated T cells are deficient in PBC, thus further augmenting T-cell proliferation and AMA production. Effector mechanisms converge on the target cell, the biliary epithelial cell, which can be damaged by injurious cytokines, direct cytotoxicity, or transcytosis of immunogenic peptides. A toxic effect might also be supplied by activated eosinophils and the release of eosinophil major basic protein. Biliary epithelial cells then undergo apoptosis and in doing so contribute immunogenic mitochondrial PDC-E2 antigen to sustain a self-perpetuating autoimmunization process. Destruction of biliary epithelial cells and bile ducts leads to chronic cholestasis and liver injury.

A patient with a susceptible genetic makeup undergoes an environmental insult, which then triggers AMA production. This production in turn leads to cholangiocyte apoptosis, inflammation, and cholestasis. Through a continued cycle of insult and injury, there is fibrosis, ductopenia, cirrhosis, and ultimately, liver failure.

Clinical presentation

The typical patient is a woman between the ages of 40 and 60 years who undergoes an investigation for PBC as a result of increased liver enzymes such as alkaline phosphatase and γ-glutamyl transpeptidase found on routine blood work. With progressively earlier diagnosis of PBC as a result of health maintenance blood work, most patients (nearly 60%) are diagnosed in the asymptomatic phase. Symptomatic patients generally present at a younger age, perhaps because of either a different clinical course or because their symptoms prompt an earlier clinical investigation. Early manifestations of the disease include symptoms of fatigue and pruritis followed by complications as a result of a long-standing history and progression of the disease such as osteoporosis, vitamin deficiencies, hyperlipidemia, and cirrhosis. These manifestations are discussed in further detail later.

In most asymptomatic patients afflicted with PBC, the physical examination is normal. A few patients may have hepatomegaly (4%–52%), splenomegaly (6%–24%), and abdominal pain in the right upper quadrant. Jaundice is seen in only 3% to 8% of patients at the time of diagnosis, and is a marker for advanced disease and poor prognosis. Routine blood work may reveal increased alkaline phosphatase and γ-glutamyl transpeptidase levels. In addition, hypercholesterolemia with an increase in low-density lipoprotein cholesterol is found in nearly 20% of patients with PBC. If the bilirubin is greater than 3 mg/L, patients are likely to have advanced fibrosis and less likely to respond to medical treatment and require liver transplantation. An ultrasound of the abdomen is of paramount importance to evaluate the liver parenchyma and biliary tree. The typical cholestatic liver profile can also be seen in biliary obstruction. Identification of antimitochondrial antibodies by indirect immunofluorescence and immunoblotting, and/or investigation by liver biopsy, leads to the eventual diagnosis of PBC.

Associated diseases

About 5% of patients with PBC may present with an AMA-negative PBC (also known as autoimmune cholangitis [AIC]). These patients have the same clinical presentation and histology findings as AMA-positive patients but lack AMA by indirect immunofluorescence and immunoblotting. Such a presentation illustrates the multifactorial, and still not fully understood, nature of this illness. A liver biopsy, along with other serologic tests including PBC-specific antinuclear antibodies should be performed to confirm PBC in patients who are suspected of having the disease, but are negative for AMA.

Furthermore, an overlap syndrome between PBC and autoimmune hepatitis has also been described and exists in about 5% to 19% of patients. In all patients with PBC, regardless of the AMA status, a polyclonal increase of serum IgM levels can also be found. Although PBC primarily involves intrahepatic bile ducts, the salivary and lacrimal glands may also be involved because of cells phenotypically similar to biliary epithelia. This finding explains why PBC is associated with other autoimmune conditions such as Sjögren syndrome (70%–100% of patients), scleroderma, CREST syndrome, systemic lupus erythematosis, autoimmune hepatitis, rheumatoid arthritis, and Hashimoto thyroiditis. Evaluation should also include anticentromere, Ro/SSA, La/SSB, Scl-70, and histone antibodies.

Other diseases associated with PBC include Raynaud disease, arthropathy/arthritis, glomerulonephritis, cutaneous disorders, celiac disease, ulcerative colitis, pulmonary fibrosis, and gallstones. There may also be an increased risk of breast cancer in women who have PBC. Although there is no consensus in this regard and this observation needs further study, it is prudent to reinforce the need for mammograms and breast cancer screening tests in accordance with standard guidelines.

Histology

The sentinel lesion in PBC on a liver biopsy specimen is damage to epithelial cells of the small bile ducts. The most important and only diagnostic clue in many cases is ductopenia, defined as the absence of interlobular bile ducts in greater than 50% of portal tracts. The florid duct lesion, in which the epithelium of the interlobular and segmental bile ducts degenerates segmentally, with formation of poorly defined, noncaseating epithelioid granulomas, is nearly diagnostic of PBC but is found in few cases, mainly in the early stages.

The histology can be divided into 4 stages as described by Ludwig. Ludwig stage 1 disease is characterized by inflammatory destruction of the intrahepatic, septal, and interlobular bile ducts. The disease is limited to the portal triad and the tracts are usually expanded by lymphocytes. In stage 2 disease the inflammation extends from the portal tract into the hepatic parenchyma, also known as interface hepatitis or, formerly, piecemeal necrosis. Destruction of bile ducts with proliferation of bile ductules can be seen. Stage 3 disease is characterized by scarring and fibrosis. Lymphocytic involvement of the portal and periportal areas, as well as the hepatic parenchyma, can be seen, but the hallmark of this stage is the presence of fibrosis. Stage 4 disease is characterized by cirrhosis with fibrous septa and regenerative nodules.

Although a liver biopsy is not necessary for the diagnosis of PBC, most patients eventually receive a liver biopsy, which may be of use in staging the disease and may also help in guiding management. An instance in which a liver biopsy may be necessary is in the setting of suspected PBC in a patient lacking antimitochondrial antibodies.