Stage 1
Stage 2
Stage 3
Stage 4
Rubin et al. [59]
Portal inflammation and bile duct injury
Proliferation and destruction of bile ductules
Cirrhosis
Scheuer [60]
Florid duct lesion (portal hepatitis)
Ductular proliferation (periportal hepatitis)
Scarring (ductopenia and bridging fibrosis)
Nodular cirrhosis
Ludwig et al. [61]
Portal inflammation (portal stage)
Periportal inflammation with or without bile duct loss (periportal stage)
Bridging fibrosis (septal stage)
Cirrhosis
Liver biopsy is not required for clinical diagnosis in PBC, as the presence of AMA and cholestatic enzymes in a middle aged woman reportedly have a 98 % positive predictive value for the presence of PBC [62], obviating the need for a liver biopsy for diagnostic purposes in most cases. Biopsy is still essential for diagnosis in cases where the AMA is negative or in low titer, or if the patient has a biochemical picture with prominent elevation of the transaminase levels, i.e., hepatitic, or has been taking potentially hepatotoxic drugs [63]. Diagnosis of concurrent pathological processes is an invaluable consideration for liver biopsy; steatohepatitis has been documented in up to 5 % of other forms of chronic liver disease [64], and the presence of “overlap” features of autoimmune hepatitis are best documented by liver biopsy findings. Up to 20 % of otherwise typical PBC could be given a diagnosis of “probable” autoimmune hepatitis, according to the revised Autoimmune Hepatitis Group scoring system [65] and were thus considered as having PBC-autoimmune hepatitis overlap. The histological finding of interface hepatitis in biopsy was one of five features that distinguished between overlap and non-overlap patients. After six years of follow-up, the patients with overlap had significantly worse clinical outcomes than the non-overlap PBC patients, thus confirming the potential importance of using liver biopsy to establish the correct diagnosis [66]. Moreover, patients whose liver biopsies have interface hepatitis may have a more rapidly progressive disease than patients without this histologic feature [67], thus interface hepatitis is an important prognostic parameter. Other histological factors may also have prognostic significance, such as the degree of ductopenia [68].
Natural History and Prognosis
PBC is a slowly progressive disease that causes substantial loss of intrahepatic bile ducts, ultimately resulting in cholestasis, advanced fibrosis, cirrhosis, and liver failure. As such, PBC is an important indication for liver transplantation [1]. Cirrhosis may also lead to hepatocellular carcinoma in PBC, particularly in male patients and those with advanced histologic stages and evidence of portal hypertension [69, 70].
Progression of disease occurs at different rates and with varying degrees of severity in different patients [21]. The natural history of PBC can be divided in four phases. The silent or preclinical phase is characterized by isolated AMA positivity and normal serum biochemistries [71]; this phase may last many years. The next phase is characterized by gradual elevation of the serum AlkPhos levels. The vast majority of newly diagnosed patients with PBC presents without symptoms attributable to liver disease and are in this asymptomatic phase. Although this phase may last up to 20 years, only 30–50 % of patients remain asymptomatic after 5 years of follow-up [72]. As PBC is diagnosed increasingly earlier, this percentage may be increasing. Patients in the symptomatic phase will most often complain of fatigue and/or pruritus, but may also report abdominal pain. Symptoms related to portal hypertension usually appear later, with 20 % developing ascites and 10 % developing bleeding varices within a 10-year period [30]. Most patients who develop portal hypertension are often either anicteric or mildly jaundiced. If untreated, median survival ranges from 6 to 10 years, with an accelerated course after development of ascites and hepatic encephalopathy. Once progressive jaundice develops, patients enter a pre-terminal phase, which can last up to 4 years [30, 73]. Mean survival once the bilirubin is 2.0 mg/dL is 4 years, and when the bilirubin reaches 6.0 mg/dL, mean survival is only 2 years [74].
Natural history studies have identified numerous markers of progressive disease in PBC, including but not limited to: response to UDCA [75–78], histology (degree of interface hepatitis and features of overlap with autoimmune hepatitis) [66, 67], biochemical markers (serum bilirubin, albumin, and prothrombin time) [79], presence and/or degree of portal hypertension [80], certain genetic polymorphisms (apolipoprotein A, tumor necrosis factor [TNF]-alpha), specific autoantibodies (anti-gp210, anti-promyelocytic leukemia protein [PML], anti-sp100, anti-centromere) [56, 57], and serum markers of fibrosis (hyaluronic acid, procollagen III, tissue inhibitor metalloproteinase) [81].
Models using time-fixed Cox proportional hazards regression analysis have been developed to predict survival in PBC. Among several well-validated models (European, Mayo, Oslo, Barcelona, Newcastle) [30, 79, 82, 83], the Mayo risk score is the most widely used, at least in the USA, and includes the following variables: age, total bilirubin, prothrombin time, albumin and presence/absence of peripheral edema, and response to diuretics [79]. This model has been used as a historical control to estimate the benefits of treatment, including pharmacological therapy and liver transplantation [84], as well as in everyday practice to counsel patients and help make clinical management decisions. This model has the disadvantage of overestimating the survival in patients with poor short-term survival.
Of all the serum markers studied to date, serum bilirubin is the best independent predictor of survival [74, 85, 86], but it only becomes abnormal in late stages of the disease and therefore is less useful in assessing improvement in patients with mild-moderate disease. Response of AlkPhos to therapy has been shown to be a good correlate of both survival [76] and liver histology [62] in PBC and is used globally in clinical practice to predict the progression of the disease; it is therefore an acceptable therapeutic criterion to monitor PBC treatment. Analysis of UDCA trials demonstrated that normalization of AlkPhos, when assessing a large group, was associated with better survival than expected [75, 77].
Treatment
UDCA has been the drug most widely evaluated in the treatment of PBC. At least four mechanisms of action are involved in the beneficial therapeutic effects of UDCA in PBC, including an increased hydrophilicity index of the circulating bile acid pool, stimulation of hepatocellular and ductular secretions, cytoprotection against bile acid and cytokine-induced injury, and immunomodulation and anti-inflammatory effects [87]. Currently, treatment with UDCA in a dose of 13–15 mg/kg/day is recommended as therapy for PBC by the American Association for the Study of Liver Diseases (AASLD) [88] and is approved for this indication by the US Food and Drug Administration (FDA).
Early trials have clearly shown that UDCA improves serum liver tests including bilirubin and other markers of cholestasis [89–93]. Long-term follow-up studies show that improvement in liver biochemistries can be sustained, however, interruption of UDCA therapy is associated with a deterioration in liver biochemistries, indicating that the treatment is needed indefinitely [94]. Biochemical response to UDCA at one year is a strong predictor of long-term prognosis [75–78]. Indeed, patients with PBC who have achieved a biochemical response to UDCA have been shown to survive just as long as the normal population [95]. Biochemical response has been be defined by numerous criteria (summarized in Table 3.2): the Mayo criteria [75] (AlkPhos <2 times the upper limits of normal [ULN]), the French criteria [77] (AlkPhos < 3 times ULN, aspartate aminotransferase [AST] <2 times ULN, and bilirubin <1.0 mg/dL), the Spanish criteria [76] (decline in AlkPhos of more than 40 % of baseline or to a normal value), or the Dutch (Rotterdam) criteria [78] (normalization of bilirubin and/or albumin after treatment if one or both were abnormal at baseline) have been most commonly used. Around 50 % of patients fulfill at least one criterion of incomplete biochemical response to USDA. These patients have an increased risk of adverse events during the course of their disease.
Table 3.2
Biochemical response to treatment with ursodeoxycholic acid
Angulo et al. [75]a |
AlkPhos < 2 times ULN |
Pares et al. [76]b |
AlkPhos < 40 % from baseline or to normal value |
Corpechot et al. [77] b |
AlkPhos < 3 times ULN |
AST < 2 times ULN |
Bilirubin < 1.0 mg/dL |
Kuiper et al. [78]b |
Normal bilirubin and albumin (if one or both were abnormal before treatment) |
Normal bilirubin or albumin (if both were abnormal before treatment) |
Kumagi et al. [134]c |
AlkPhos ≤ 1.67 times ULN |
Bilirubin < 1.0 mg/dL |
Momah et al. [135]b |
AlkPhos ≤ 1.67 times ULN |
Bilirubin < 1.0 mg/dL |
None of the studies that evaluated the effect of UDCA treatment on the symptoms of fatigue and pruritus [90–93, 96, 97] showed any significant effect on fatigue and only one study reported a significant reduction of pruritus in the UDCA group compared with the placebo group [96]. There was no effect of UDCA on autoimmune conditions [98] or on bone disease in PBC [99]. Therapy with UDCA appears to reduce the onset and severity of portal hypertension, including the development of ascites [90, 91, 93, 97] and esophageal varices [100].
Treatment with UDCA may delay disease progression and prolong survival free of liver transplantation [101]. No single randomized controlled trial has demonstrated a survival benefit using UDCA versus placebo. However, most of the trials of UDCA have not recruited sufficient patients to have the power to show an effect of therapy on survival. Therefore, the evidence that UDCA inhibits the progression of the disease has been delayed until long after the completion of the trials that demonstrated improvement in markers of cholestasis. Analysis of the combined data from three large, well-designed, controlled trials that used adequate UDCA doses up to four years, including a total of 548 patients, showed that UDCA significantly reduced the likelihood of liver transplantation or death [101]. Several studies evaluating long-term survival of patients have been published and uniformly they indicate that those who demonstrated biochemical response to adequate doses of UDCA for prolonged periods of time have longer survival free of liver transplantation and longer overall survival [75–78]. Additional indirect support for a long-term beneficial effect of UDCA in PBC might come from retrospective studies of transplantation trends among patients with PBC [102]. Several studies evaluating large series of patients in Europe and in the USA indicate that the proportion and the absolute number of patients transplanted for PBC are decreasing [102–104] while the incidence of the disease appears to be stable [105] and the prevalence, rising [106].
A variety of immunosuppressive medications have been used alone or with UDCA in patients with PBC, particularly those with incomplete response to UDCA monotherapy. Medications evaluated include azathioprine, budesonide, chlorambucil, cyclosporine, methotrexate, mycophenolate mofetil, prednisone, prednisolone, and tacrolimus. Some small studies have suggested that combination therapy may be superior to UDCA monotherapy [107–109], but further studies are necessary. At present, there are insufficient data to support the use of immunosuppressive therapy for PBC [110].
Additional treatments are needed for patients who have an incomplete response to UDCA. Drugs that are directed at reducing the presence of autoantibodies, such as rituximab, have led to some benefit in two small studies [111, 112]. New therapies are being directed at NF-κB using various activators of peroxisome proliferator-activated receptor (PPAR) α including the fibrates with some evidence of benefit [113–117], but larger studies are needed. Preliminary phase II studies of obeticholic acid, a farnesoid X receptor, in patients with PBC have demonstrated marked biochemical improvement in patients with PBC when administered in combination with UDCA and alone [118, 119], and is a promising agent for treatment for PBC. Pruritus is the most common side effect, limiting treatment when obeticholic acid is administered at higher doses. The discovery that mutations in the interleukin 12 (IL-12) pathway are associated with PBC [5] may lead to immunotherapy directed at this pathway.
Liver Transplantation
As patients with PBC progress to end-stage liver disease, liver transplantation (LT) remains their only therapeutic option. PBC is one of the top six indications for LT in the USA and Europe. To date, over 6,000 liver transplants have been performed for PBC in both regions combined [120]. Over time, however, a notable decline in the number of liver transplantations and waiting list additions for PBC has been observed [103, 121, 122]. Patient and graft survival for PBC are excellent compared to other indications. One, five, and ten-year survival rates for PBC are estimated at 83 %, 77 %, and 69 %, respectively [120]. At selected centers, the 1 and 5-year survival rates may exceed 90 % and 80 %, respectively [123, 124].
With prolonged survival, recurrent disease becomes a major problem in this patient population. The prevalence rates for recurrent PBC reported by individual LT programs range between 9 and 35 % [103, 125–131]. The cumulative incidence rate, which better describes the risk of recurrent disease, varies between 21 and 37 % at 10 years [103, 125, 130], and maybe as high as 43 % at 15 years [130]. Among centers with over 100 patients transplanted for PBC, the average time to recurrence ranges between 3 and 5.5 years [103, 125, 127, 130, 132]. Though an increased risk for advanced liver disease in patients with recurrent PBC has been described—cirrhosis was observed in 25 % of patients in one study [128], and hepatic retransplantation or death due to organ dysfunction related to recurrent PBC remains an uncommon scenario [133].
No standard approach exists for the treatment of recurrent PBC. Dose modification or re-institution of corticosteroids, azathioprine, and/or mycophenolate mofetil has not been formally reported as an interventional strategy. Given the near universal presence of early stage disease at diagnosis, a potential role for UDCA therapy exists [103, 127, 128, 130, 132]. Though improvements in serum liver biochemistries are reported in patients with recurrent PBC treated with UDCA [129, 130], significant differences in histologic progression rate or the probability of death or liver retransplantation for patients treated with UDCA when compared to untreated patients have not been described.
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