PBC is a chronic liver disease generally characterized by a slow progression but a highly variable clinical course. More than half of patients diagnosed today are asymptomatic at diagnosis 2122. They are generally identified by finding of an elevation of only serum alkaline phosphatase (ALP) or/and total serum cholesterol, often by chance through routine check up. The diagnosis may also be made in patients undergoing further investigation for an associated autoimmune disease such as scleroderma. It may take years before asymptomatic subjects develop symptoms of the disease. But asymptomatic disease is not synonymous with early liver disease. Little is known about why some patients remain asymptomatic and other progress rapidly and develop liver failure. The severity of the liver disease may be discordant with the severity of symptoms. In symptomatic patients, fatigue and pruritus are the most common presenting complaints 10. Patients with cirrhosis may present with ascites, hepatic encephalopathy and/or esophageal variceal hemorrhage. However, variceal hemorrhage is not limited to those with cirrhosis, as presinusoidal portal hypertension due to nodular regenerative hyperplasia (NRH) of the liver is sometimes present 23. Once jaundice is present, fat-soluble vitamin deficiency and malabsorption (e.g.: steatorrhea and weight loss) may occur.

The prevalence of fatigue has been reported to be as high as 80% 24. Fatigue does not correlate with the liver disease severity 25 and liver transplantation does not improve fatigue 26.

Pruritus, when present, may be a debilitating symptom that significantly impairs quality of life in PBC, just as may fatigue. Usually, pruritus occurs months to years earlier than jaundice, and may improve with progression of liver disease! It is usually less severe in sunny weather and, being worse at night, it may interfere with sleep. Severe pruritus causes sleep deprivation and may even lead to suicidal ideation 27. Sometimes PBC is initially diagnosed during pregnancy prompted by the symptom of pruritus that fails to disappear in the post partum period, unlike intrahepatic cholestasis of pregnancy.

Approximately 10% of patients complain of vague intermittent right upper quadrant pain or discomfort, which usually resolves spontaneously 28.

Physical examination may be normal in those with early-stage disease. As the disease progresses, patients may develop signs of portal hypertension such as splenomegaly and collateral vessels, and features of cholestasis such as skin pigmentation due to increased melanin deposition in the skin. In late stage disease, when both liver and spleen are enlarged, signs of liver failure such as ascites and encephalopathy are seen 22. However, there is no specific dermatological feature in PBC patients with pruritus other than diffuse pigmentation and scratch marks. Xanthelasma are seen in a minority of patients and xanthomas are rare nowadays, despite PBC related hypercholesterolemia being present. Signs and symptoms of scleroderma, particularly affecting the hands and swallowing, may be present.

Serum ALP and gamma-glutamyl transpeptidase (GGT) are raised and serum aminotransferase can also be elevated 29. Serum AMA are detected in more than 90% of affected individuals 20. Elevated levels of immunoglobulin M are common in PBC 3031. Titer of AMA does not carry any clinical significance nor do AMA profiles 32. Although rare findings in patients with PBC, "nuclear-rim" and "multiple nuclear-dot" patterns are highly specific for PBC irrespective of AMA status, and may provide supportive evidence for PBC especially in those who test AMA negative 33. Liver synthetic function, i.e.: changes in albumin and prothrombin time (PT) are observed with disease progression. But hyperbilirubinemia may be present earlier due to the cholestatic nature of this disease.

Lymphadenopathy in the abdomen is seen in 80% of patients with PBC 34. There is no specific feature on abdominal images in PBC although the intraabdominal lymph nodes may be so large as to suggest lymphoma. Abdominal images are not necessary to confirm the diagnosis of PBC in patients who test positive for AMA. However, those patients who are AMA negative and thought to nevertheless have PBC need radiographic demonstration of a normal biliary tree on cholangiography, either by magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP), to exclude other possible diagnoses, particularly primary sclerosing cholangitis (PSC). Findings from abdominal images in advanced PBC often resemble those seen in other forms of cirrhosis, with a heterogeneously attenuating liver, varices and splenomegaly.

The characteristic lesion of PBC is the asymmetric destruction of the intralobular bile ducts within portal triads. Histological staging systems of PBC have been proposed and they have been divided into 3 or 4 distinct stages, according to the degree of fibrosis, inflammation and/or bile duct damage 4353637. According to the Ludwig's classification 37, stage 1 is defined by portal inflammation. Stage 2 is extension of this inflammation beyond portal tracts into the surrounding parenchyma, with or without associated duct loss. In stage 3, fibrous septa link adjacent portal triads. Stage 4 represents cirrhosis. On the other hand, with Scheuer's system 35, stage 1 is referred to as the florid duct lesion or chronic non-suppurative destructive cholangitis (Figure 1). In stage 2, there is proliferation of the small bile ductules (Figure 2). Stage 3 is characterized by fibrosis or scarring. Stage 4 is cirrhosis. However, the entire liver is not always uniformly involved, and a single biopsy may demonstrate the feature of all four stages simultaneously. Thus both under- and over-estimation may occur. It is crucial to have a sufficient size of specimen to minimize error 38. There should be a minimum of 10 portal tracts visualized before a confident diagnosis of bile duct loss can be established. Although liver biopsy is not always necessary to make a diagnosis of PBC, it does allow the severity of disease to be clarified. It also may indicate the need of specific therapeutic regimens or management (such as ultrasound screening for hepatocellular carcinoma, HCC, in PBC patients found to be cirrhotic) and, additionally, may be used as an objective way for evaluating the response to treatment.

In 2007, the majority of patients with PBC present without symptoms, most are identified with abnormal liver enzymes at the time of a regular check up or during work up for another disease. It is not difficult to diagnose PBC when the patients have typical features, particularly AMA positivity. However, 0.5% of people in general population are also positive for AMA 42. As obesity and non-alcoholic fatty liver disease (NAFLD) is becoming a serious issue worldwide, abnormal liver biochemical tests are not unusual in the general population. These factors all have to be taken into account in the differential diagnosis, especially when patients with abnormal liver enzymes are of a 'cholestatic nature', not unusual in NAFLD or drug induced liver injury.

All AMA negative patients with cholestatic liver disease should be carefully evaluated. In the differential diagnosis, the initial step is to clarify if the site of the damage is extra-hepatic, intra-hepatic or both. In addition to a carefully taken history, ultrasound (US) may help to differentiate these conditions. If abnormalities of the biliary tree are seen on US, cholangiography (MRCP) will help further differentiation, particularly in the diagnosis of PSC. The typical bile duct irregularities of PSC are demonstrated on cholangiography, but in early PSC as well as small duct PSC, the biliary tree may appear normal. Cholangiography may also help in the diagnosis of other bile duct lesions such as stones, cyst or tumor that may be not visualized on US 43. If the extra-hepatic biliary system appears normal, then liver biopsy is required. Liver biopsy allows differentiation between cholestatic disease (generally a "vanishing bile duct syndrome") and an infiltration in the liver, i.e.: lymphoma.

Secondary biliary cirrhosis is a biliary cirrhosis that develops secondary to a pathogenic process or injury of known cause (just as is the case for secondary sclerosing cholangitis 44) and may occur with chronic biliary obstruction of any cause (eg. hepatolithiasis or cystic fibrosis) 45.

It is also important to note that a possible change in diagnosis should continue to be considered during follow-up as well as at the time of initial diagnosis. Fatty liver and drug induced liver injury are the most common comorbidities that may "interfere" with the initial diagnosis or during follow up. These should be always considered if a patient with PBC has a sudden change in the liver enzyme pattern. Autoimmune hepatitis (AIH) is another disease that may develop subsequently 46, thus, it also should be considered in the differential diagnosis, particularly with a transaminitis. The most reliable feature to suggest development of AIH would be a further rise in serum IgG. Similarly, a co-existent untreated celiac disease (present in 7% of patients with PBC, particularly in Caucasians) may cause an increase in liver enzymes or a failure to normalize with UDCA 47. A recent general population-based study from Sweden has shown that odds ratio of PBC and fatty liver in celiac disease is 15.0 and 5.83, respectively 48. The anti-transglutaminase antibody test is specific and highly diagnostic for celiac disease. There are reports of improvement of liver enzymes or even reversal of hepatic failure after introducing gluten free diet in patients with PBC associated with celiac disease 49. Thyrotoxicosis may lead to the sudden onset of jaundice 50.

Familial predisposition to PBC is not rare, its prevalence rate among first-degree relatives has been estimated to be approximately 5% 51, which is more common than in unrelated persons. It has been reported that familial PBC is related to maternally inherited factors, and that the disease tends to present earlier in the second generation 52, and is most common in mother-daughter and sister-sister combinations 53. Familial cohort studies have shown that the concordance rate of PBC in monozygotic twins was 63% versus 0% among dizygotic twins. Among monozygotic twins, the age of disease onset was similar, but there were differences in the natural history and disease severity, emphasizing the role of epigenetic factors or simply environmental factors 54. Although the disease is virtually identical in women and men, recent data suggest that X-chromosome monosomy in lymphoid cells is common in women with PBC 55. Genes governing immune tolerance are carried on the X gene. Case reports of PBC in patients with Turner syndrome also support the possible role of genes on the X chromosome in the genetic predisposition to PBC 56.

Several environmental factors have been suggested as potential causative initial agents, particularly bacteria. Escherichia coli and their "rough" mutant have been reported in excess in the stools of patients with PBC; in addition, the incidence of urinary tract infections is high in PBC patients 5758. Recently, Novosphingobium aromaticivorans, a ubiquitous organism that metabolizes organic compounds and estrogens, has been proposed as a candidate for the induction of PBC 59. The titers of antibody against the lipoylated bacterial proteins of N. aromaticivorans were 1,000-fold higher than those to E. coli, in patients with PBC including patients in early stage of disease.

Various other bacteria, such as Chlamydia pneumoniae, Helicobacter pylori and Mycobacterium gordonae have also been implicated as putative pathogens 60616263. However, no compelling data have been provided to show that any individual agent can be reproducibly detected in the liver of patients with PBC 64.

Recently, it has been reported that human betaretrovirus (that shares marked genetic homology with the mouse mammary tumor virus) infection may be detected in approximately 75% of patients with PBC (by reverse transcription polymerase chain reaction and immunochemistry) 65. This has been supported by histological and biochemical endpoints achieved in a pilot study of an antiretroviral agent 66. However, other studies have not been able to reproduce these data 67.

Surgeries including appendectomy, other abdominal surgeries and tonsillectomy are significantly increased in patients with PBC in an epidemiological study in North America 68. However, an earlier population-based case-control study conducted in England did not show any association with surgical procedures 69. More recently, a case-control study provided evidence that there was no association between PBC and the occurrence of appendectomy, and pointed out the selection bias present in the previous study done in North America 70. However, the observation of a PBC-specific immune response to the highly conserved caseinolytic protease P of Yersinia enterocolitica in 40% of patients with PBC may support the link with past appendenctomy 71, where infection with Y. enterocolitica is one of the major causes of acute terminal ileitis mimicking acute appendicitis 72.

A recent experiment demonstrated that circulating antibodies isolated from the serum of PBC patients recognized artificially altered (by environmental chemicals) the lipoic acid component of the pyruvate dehydrogenase complex (PDC) epitope 73. This same group of investigators has shown that 2-octynoic acid, which is widely used in the manufacture of perfumes, lipstick and many common food flavorings, have the potential to modify E2 subunit of PDC (PDC-E2) in vivo 74. The frequent use of nail polish has been linked to risk of having PBC 75. Smoking has been demonstrated to accelerate the progression of PBC and to be a risk factor for PBC 7576, possibly due to exposure to chemicals in cigarette smoke. Apparent clusters of populations and a group of individuals living close to toxic waste or specific reservoirs have been reported to have higher rate of incidence or prevalence of PBC and this suggests toxic waste as a risk factor or trigger of the disease 777879.

UDCA is a bile acid, which naturally comprises 2% of human bile. Treatment with UDCA improves serum biomarkers such as bilirubin, ALP, GGT, alanine aminotransferase, aspartate aminotransferase, cholesterol and IgM levels 99100101.

According to the combined data from three controlled trials, UDCA between 13 and 15 mg/kg body weight is considered the preferred treatment for PBC 102. It is safe and the side effects are few. Some patients suffer from hair thinning, gain in weight and/or diarrhea. Significant weight gain that occurs in the first 12 months of treatment persists for the duration of treatment and occurs independent of baseline body mass index (BMI) 103.

UDCA improves 10-year survival 104 and/or delays the progression of hepatic fibrosis in early-stage disease 105, and the development of esophageal varices in patients with PBC 106. Recently, the Spanish group has shown that a good biochemical response to UDCA (defined by an alkaline phosphatase decrease greater than 40% of baseline values or to normal levels) within 1 year of starting treatment is associated with a similar survival to a matched Spanish control populations but this is not so for those patients who show no biochemical response following introduction of UDCA 107. However, these findings are not seen in patients with advanced stage disease at baseline. Non-randomized controlled studies from Greece and the Netherlands indicate that in most patients with PBC (particularly those who are in early stage of disease), the 10-year survival is comparable to that in the general population 108109.

A recent meta-analysis has shown that long-term treatment with mid-dose UDCA (10–20 mg/kg/day) improves the liver biochemistry and survival free of liver transplantation, and delays histological progression in the early-stage patients 110. But whether there is a survival benefit of treatment with UDCA in PBC still remains controversial. The most recent meta-analysis from Cochrane group included 6 trials of short duration, some of them non-randomized studies, and there were some data collection errors with varying doses of UDCA. Thus, their results suggesting no survival benefit with UDCA treatment need to be questioned 111.

There is no data indicating that UDCA is teratogenic but if a pregnancy can be planned then it may be wise to stop any medication before and during the first trimester. UDCA is used to treat intrahepatic cholestasis of pregnancy 112 and has not been shown to be toxic to the fetus if given during the second or third trimester.

Budesonide (a glucocorticoid with high receptor activity and high first-pass metabolism in liver) combined with UDCA has been shown to improve liver histology in 2–3 years in a patient population with or without failure of UDCA monotherapy 113114. Rautiainen et al. have shown that the plasma concentrations of budesonide do not differ when the patients were randomized to receive either budesonide and UDCA, or budesonide alone for 3 years, at least in early PBC 115. But the combination of budesonide and UDCA has been shown to be associated with decreased bone mass density in the femoral neck and lumbar spine in some patients (probably those with cirrhosis) 116. This combination therapy is promising but the observation period for side effects is too short at present, thus, studies with longer follow-up using a combination of budesonide and UDCA are necessary to confirm that the benefit outweighs the risks.

Various adjuvant medications have been used alone or in combination with UDCA in PBC, particularly in patients with an incomplete response to UDCA monotherapy. These include systemic corticosteroids 117, azathioprine 118, cyclosporine 119, mycophenolate mofetil 120, methotrexate 121, chlorambucil 122, penicillamine 123, colchicine 124, silymarin 125 and bezafibrate 126. Some of the studies have shown a benefit in terms of improving biochemical markers, decreasing the intensity of pruritus, improving liver histology, reducing the incidence of major complications of cirrhosis and delaying the need for liver transplantation. However, neither the large trials nor the pilot studies have indicated any survival benefit from these additional agents.

PBC used to be a common indication for liver transplantation in adults. However, the proportion of patients with PBC who undergo liver transplantation has recently decreased, most probably because of the marked increase of transplantation for cirrhosis due to viral hepatitis, alcoholic liver disease and HCC. The assessment for liver transplantation in PBC is indicated when the patients show features of end-stage liver failure such as profound jaundice with or without intractable ascites, episodes of spontaneous bacterial peritonitis, and/or encephalopathy resistant to appropriate treatment, i.e. situations with expected survival less than 1 year. The Mayo Risk Score, which calculates 2-year survival rate is useful in this regard. Even though this calculation was developed before UDCA treatment was introduced, it appears valid even when UDCA is used 127.

Recently, the MELD (model for end-stage liver disease) score has been found helpful to decide organ allocation of patients who are already on the waiting list. The score includes bilirubin, creatinine and INR (international normalized ratio). The height of the serum bilirubin level alone is a very important factor when considering the appropriate timing of referral for liver transplantation assessment for patients with PBC. One study has shown that patients should be referred when their serum bilirubin level reaches to 100 μmol/l (5.9 mg/dl) and that the outcome post transplantation is better than without transplantation when the serum bilirubin level is less than 170 μmol/l (10 mg/dl) 128. The 5-year survival rate after orthotopic liver transplantation (OLT) in PBC may be as high as 85%, one of the best outcomes of any liver diseases.

PBC recurs post-OLT in about 20% of patients, usually between 3 and 7 years post-OLT 129130131. There is no correlation between AMA titer and clinical or histological recurrence of PBC post-OLT. The hallmark feature of recurrence is granulomatous bile duct destruction seen on liver biopsy. A plasma cell infiltrate also characterizes recurrent PBC and distinguishes it from other processes such as drug induced liver injury and acute or chronic rejection 132. Optimal immunosuppression needs to be provided to prevent recurrence of PBC. It is still controversial as to whether to use cyclosporine or tacrolimus 131132. Disease progression after recurrence is slow and retransplantation is rarely necessary. However, there is a report of graft failure due to recurrent disease 133.

Very recent meta-analysis has shown that there are insufficient data to evaluate the efficacy of cholestyramine 140. However, the first choice in the treatment of pruritus in cholestatic patients is cholestyramine (4–12 g/d) because it is safe. This agent seems to bind bile that contains the unknown pruritogen of cholestasis in the gastrointestinal tract. Usually it is helpful and effective when taken properly, i.e. at the time gallbladder empties (thus it should be taken before and after breakfast). It also has to be taken 4 hours apart from any other medications to avoid their binding. Patients need to appreciate that cholestyramine should be used for long-term prevention of pruritus. It may cause abdominal bloating and constipation.

Rifampin would be the second choice when cholestyramine is not effective, starting at 150 mg twice daily. Usually, its benefit is appreciated in the first week to month of treatment and increasing the dose may help further in those patients who initially fail to respond. A recent meta-analysis indicates that treatment with rifampin leads to complete or partial resolution of pruritus in 77% of patients as compared with 20% treated with placebo or alternative 141. Rifampin may be considered the first-line therapy for pruritus, but this has not been the case since its efficacy is not widely appreciated, and because of certain untoward side effects and contraindications. Rifampin is an enzyme inducer, hence the potential to cause clinically relevant drug interactions should always be considered, i.e. it may inactivate the effect of certain antidepressants. Rifampin may cause hepatitis, hemolytic anemia and renal dysfunction, usually within the initial few weeks of therapy. Patients treated with rifampin need to be monitored closely in this regard.

The precise mechanism of pruritus remains unclear. However, the efficacy of partial external biliary diversion, biliary drainage and plasmapheresis for intractable pruritus in patients with intrahepatic cholestasis suggest that pruritogen(s) such as circulating endogeneous opioids are present in both bile and blood 142143144, and increased levels are reported in patients with PBC 145. The efficacy of naloxone, an opioid antagonist, for the pruritus of chronic cholestasis supports this hypothesis and may be one of the alternatives when the patients have failed other treatments 146. Symptoms suggestive of narcotic withdrawal may develop in some patients, thus naloxone should be introduced at very low dose and be built up gradually, ideally by an experienced physician. Attention to the chronic pain syndrome should be paid with long-term use 147.

A recent randomized control trial has shown that sertraline (75–100 mg/day), a serotonine reuptake inhibitor, seems to be an effective and well-tolerated treatment for pruritus caused by chronic cholestasis. This suggests that serotonergic pathways are important in the perception of pruritus 148.

Plasmapheresis should be considered when treatment of pruritus is urgently required, for example when the patient is suicidal due to severe and uncontrollable pruritus. Treatment with ultraviolet light may be beneficial, particularly when the symptom worsens during the winter.

Fatigue is one of the most common presenting complaints in patients with PBC. There is no known treatment for fatigue in PBC. However, complications such as hypothyroidism, anemia, depression or any other reasons for fatigue have to be carefully excluded rather than assuming PBC to be the cause, particularly as these complications may be treatable. Many drugs such as UDCA 149, cyclosporine 119, thalidomide 150 and antioxidants 151 have been investigated previously but failed to show any efficacy in controlling this debilitating symptom. Even though the cause of fatigue in PBC remains unclear, it may be related to dysfunction of either the corticotrophin-releasing hormone or serotonergic neurotransmitter systems 152. However, a randomized, controlled crossover trial of ondansetron (a serotonin receptor antagonist) did not confer clinically significant fatigue reduction 153. In a case series of 8 patients, methotrexate was shown to be efficacious for fatigue in PBC 154. More recent data suggest a possibility that fatigue is associated with excessive daytime somnolence and altered autonomic function 155156. Open label modafinil therapy (a central nervous system stimulant used to treat narcolepsy) was associated with improvement in excessive daytime somnolence and associated fatigue in PBC 157.

Chronic cholestasis is associated with an increased risk of osteopenia and osteoporosis. In the development of osteoporosis in PBC, there are two mechanisms that are commonly used to classify primary osteoporosis: "low-turnover" with normal resorption but reduced synthesis and slow mineralization of matrix and "high-turnover" with increased resorption due to reduced osteoblast function or increased activity of osteoclast 158159. Commonly associated risk factors for primary osteoporosis such as postmenopausal status, cigarette smoking and alcohol consumption as well as malabsorption (co-existent celiac disease and/or jaundice) of calcium and vitamin D may be also contributing factors in patients with PBC 160161. Inherited predisposition to deficiency of vitamin D associated with particular genetic polymorphisms has been also reported 162. However, whether patients with PBC are at higher risk of developing osteoporosis than general population is controversial 163164. Menopausal status and/or severity of liver disease may be independent factors for osteoporosis development 165166. One study does suggest that osteoporosis is a feature of PBC, especially in those patients who are older, thinner and with more advanced liver disease 164. Recently, it has been confirmed in a population-based study that there is a modest increase in both the absolute fracture risks (12.5 per 1000 person-years for any fracture, and 1.9 per 1000 person-years and 3.4 per 1000 person-years for hip fracture and for ulna/radius fracture, respectively) and the relative fracture risks (approximately 2-fold increased) in patients with PBC, with the excess risk similar in those with more severe disease 167. Additionally, bone fracture post-OLT occurs due to the combination of preexisting low bone mineral density and early post-OLT bone loss 168. Therefore, we should consider that all patients with PBC are at risk of osteoporosis, and prophylactic and therapeutic measures need to be undertaken. Screening regularly for bone mineral density using non-invasive, dual energy X-ray absorptiometry (DEXA scan), may identify bone changes prior to bone fractures.

It is difficult to prevent osteoporosis, but both calcium supplements (1500 mg/d) and vitamin D (400–1200 IU/d) are advised. Patients should be encouraged to take exercise on regular basis and be in the sunlight to activate vitamin D. The use of hormone replacement is controversial for postmenopausal patients since it may provide protection against bone loss, but may worsen cholestasis 169. Recently, alendronate has been demonstrated be more effective than bisphosphonate for the treatment of osteoporosis in PBC 170. A small pilot trial of vitamin K2 (a fat-soluble vitamin that modulates bone metabolism similarly to vitamin D) has shown the efficacy of vitamin K for treatment of osteoporosis in PBC patients 171.

Nodular regenerative hyperplasia (NRH) is a condition characterized by hepatocytic nodules distributed throughout the liver without perinodular fibrosis and caused by occlusion of small portal veins in the portal tracts. In patients with PBC, NRH may contribute to development of non-cirrhotic portal hypertension 23. We have shown that patients with PBC and PSC that have a platelet count <200,000/mm³, an albumin level <40 g/l, and a bilirubin level >20 micromol/l should be screened for esophageal varices 172. Once patients are found to have moderate to large esophageal varices, beta-blockers and/or endoscopic variceal ligation (EVL) should be instituted for primary prevention of variceal bleeding 173. However, nonselective beta-blockers are ineffective in preventing the development of varices in unselected patients with cirrhosis 174. There is a report showing earlier recurrence of esophageal varices, following endoscopic therapy, in patients with PBC compared with non-PBC patients 175.

One large retrospective study has shown that there is an increased risk for development of hepatobiliary malignancies in PBC 176. Hepatocellular carcinoma (HCC) is the most common malignancy in PBC, particularly in cirrhotic patients. When compared to the rate of HCC in patients with chronic hepatitis C, the relative risks for HCC were similar 177. Older age, male sex and portal hypertension and/or cirrhosis indicate higher likelihood of HCC 178179180. Therefore, screening for HCC, for instance, ultrasound at 6 months interval, might be beneficial in these patients.