Wang Qiong1 Wang Yiping2 1 Chengdu Third People’s Hospital 2 West China Hospital of Sichuan University Primary biliary cirrhosis (PBC) is an immune-mediated inflammatory disease of the small intrahepatic bile ducts, in which the bile ducts are destroyed by granulomas leading to bile duct occlusion and persistent cholangitis, causing liver fibrosis, cirrhosis, and eventually liver failure unless liver transplantation is performed. The disease is a common occurrence in middle-aged women. It is common in middle-aged women, without racial differences, with geographical differences, and is common in European women [1]. Wang Qiong, Department of Gastroenterology, Chengdu Third People’s Hospital I. Diagnosis of primary biliary cirrhosis Patients with early diagnosis almost always have jaundice and lid xanthomas. With the popularity of routine biochemical screening tests, primary biliary cirrhosis without jaundice is gradually being diagnosed. The natural course of asymptomatic PBC was first reported in the early 1970s, and patients with late confirmed positive AMA but normal liver function (due to other autoimmune diseases performed serologically) were likely to have histological changes of PBC, and most patients developed bilious or symptomatic PBC after 10 years of follow-up. due to errors in liver puncture biopsy sampling, there were differences in the staging of PBC, therefore In order to reduce the error, at least 20 confluent areas are required to be analyzed for staging, but a single liver puncture biopsy often fails to meet this criterion. Reference diagnostic points: 1. Jaundice, lid xanthoma, pruritus, liver function suggesting cholestasis, positive AMA and diagnostic liver puncture. In asymptomatic patients, liver function indicating cholestasis, positive AMA and diagnostic liver puncture are usually (about 60%) diagnostic of PBC. 2. Some asymptomatic patients with normal liver function, positive AMA and typical histological changes are also diagnostic of PBC. 3. Some patients with typical clinical symptoms, biochemical and histological features of PBC, combined with other autoimmune diseases, but with negative AMA and anti-nuclear antibody (PBC). The diagnosis of PBC can also be made in some patients who have the typical clinical symptoms, biochemical and histological features of PBC, combined with other autoimmune diseases, but negative AMA and positive anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). II. Natural course of primary biliary cirrhosis Metcalf et al. found [2] that serum AMA positivity seems to be followed by a longer subclinical period, but the study included more patients over middle age, even over 60 years. In contrast, asymptomatic patients are usually 2-10 years older than symptomatic patients, suggesting that asymptomatic patients do not necessarily progress to symptomatic. However, there was no significant difference in the natural course of disease between older and younger patients. Initial follow-up of asymptomatic patients showed that 50% of patients exhibited symptoms within 10 years. Another small sample of studies showed that the survival of asymptomatic patients was independent of age and gender. Numerous studies have shown that although asymptomatic patients progress more slowly than symptomatic patients, their survival is significantly shorter than the norm, regardless of whether they are asymptomatic or symptomatic, with an average survival time of 8 years for symptomatic patients and nearly 16 years for asymptomatic patients. Over the past 20 years, numerous randomized controlled trials have shown a wide variation in the natural course of PBC, with about 1/3 of asymptomatic patients showing symptoms within 5 years, while the remaining 2/3 do not show symptoms for a longer period of time. Once a patient develops hyperbilirubinemia, the natural course of disease is easily predicted. III. Treatment of primary biliary cirrhosis PBC is a relatively rare disease, and an increasing number of asymptomatic patients are being included in the study in order to increase the sample size. 1. Immunosuppression PBC is an autoimmune disease and can theoretically be treated with immunosuppression, but since PBC is mostly seen in women with osteoporosis, the use of corticosteroids is contraindicated. Randomized controlled trials of immunosuppressive drugs for PBC include azathioprine, cyclosporine, methotrexate, prednisone, nitrogen mustard phenylbutyrate, and reactive stop, but their use is limited because they either do not work or have high toxic side effects. 1.1 Azathioprine: Neither trial suggested that azathioprine improved patient survival. The first trial [3] had an inadequate sample size, no placebo control, no trial termination index, and no intention-to-treat was used to analyze the results. The second trial [4] included (248 patients), with a loss to follow-up rate of >20% in both the treatment and control groups, and despite a randomized approach, did not stratify factors affecting survival, did not perform a baseline comparability analysis of the two groups, and used only multiple regression analysis to adjust for baseline differences, with lower confidence than in the well-designed trial. The treatment group was observed for only a few months and should actually be followed for more than 10 years, while only a few people in the treatment group were followed for more than 10 years and no one in the control group met this criterion. 32 patients were excluded due to incomplete information and the intention-to-treat could not be used to analyze the results. Therefore, the validity of its results in improving survival is questionable. 1.2 Cyclosporine: Several small sample trials and one large sample trial (enrolling 349 patients) were published, and these trials also had the same problems described above. However, renal failure occurred in 9% of patients in the treatment group and caused hypertension in 11%, compared with 1.7% and 1% in the treatment and control groups, two serious side effects that limit its use. 1.3 Methotrexate (Grade A): one systematic evaluation [5] included four randomized controlled trials that included 370 patients randomized to methotrexate or combined with ursodeoxycholic acid and placebo. methotrexate was not significantly different from placebo for relief of pruritus, malaise, improvement in liver function, and side effects, but serum alkaline phosphatase and immunoglobulin M levels were lower than in the control group, but this systematic evaluation was of low methodological quality. A randomized controlled trial [6] published in abstract form included 60 patients, 30 randomly assigned to the low-dose group (2.5 mg three times a week), with 6 years of follow-up, and serum bilirubin and Mayo risk factor scores were higher in the group receiving methotrexate than in the control group, considering a possible toxic effect of the drug on patients with PBC. A large US multicenter trial comparing ursodeoxycholic acid alone with ursodeoxycholic acid combined with methotrexate has not been completed. 1.4 Glucocorticoids (Grade A): a systematic evaluation [7] included 2 randomized controlled trials with 36 and 40 patients, respectively, using placebo control, but with different inclusion criteria and randomization methods hidden from view, resulting in no significant difference in mortality between the two groups, no description of serum proteins and bilirubin, and a significant increase in osteoporotic side effects in the glucocorticoid group. One small sample of randomized controlled trials with a 3-year follow-up [8] confirmed that prednisone significantly reduced serum bilirubin concentrations, but that osteoporosis worsened in one patient. Another trial showed that concomitant administration of diphosphonates in patients treated with prednisone stabilized vertebral bone mineral concentrations, so that the therapeutic value of corticosteroids in patients with PBC can be re-evaluated when appropriate prophylaxis is applied. 1.5 Phenylbutyrate (Grade A): a small sample trial [9] included 13 patients randomized to 0.5-4 mg/day of phenylbutyrate, and compared with placebo, patients in the treatment group had varying degrees of myelosuppression, and 4 patients withdrew from the study as a result, with a 30% loss to follow-up due to the toxic effects of the drug, which is no longer necessary for re-evaluation in patients with PBC. 1.6 Reactive stop (Grade A): a small sample of randomized controlled trials with a short period of observation (6 months) [10], 18 patients with PBC were treated with reactive stop, and the results showed some benefit to the patients, and serum bilirubin did not decrease, but the trial lacked sufficient convincing power and should be used with clinical caution. Other therapeutic measures, such as immunomodulation to influence the course of the disease, reduce liver fibrosis or mitigate the cholestatic process. Two anti-fibrotic drugs were evaluated, colchicine and D-penicillamine. 1.7 Colchicine (Grade A): one systematic evaluation [11] included 11 randomized controlled trials that included 716 patients randomized to colchicine and placebo treatment, with mortality or receipt of liver transplantation as endpoints, and showed that the colchicine and placebo groups were more effective in terms of the number of deaths (RR 1.21, 95% CI 0.71 to 2.06) or receipt of liver transplantation ( RR 1.00, 95% CI 0.67 to 1.49) were not statistically different. Using worst-event analysis, colchicine did not reduce mortality (RR 0.59, 95% CI 0.30 to 1.15) but improved pruritus symptoms and was not significantly different from coadministration of ursodeoxycholic acid. However, the methodological quality of this systematic evaluation was not high, and some studies had a high rate of missed visits. Three trials, all with less than 100 cases, used almost the same dose, so the results of the meta-analysis of the three trials may be valid, but were not published. The first trial used the composite “treatment failure” as an outcome measure, and there was no evidence that this indicator was valid, but several other clinical trials used similar indicators. Encouragingly, the results of the other two trials showed that colchicine improved liver function, serum bilirubin and albumin. None of the three trials improved symptoms or disease course, and one of them suggested that colchicine improved patient survival, although only 64 patients and 10 were lost to follow-up, 8 of whom were in the colchicine group. Another trial had a 32% lost-to-review rate. The last trial, with a follow-up of 8 years, showed that colchicine did not improve patient survival. Therefore, there are different opinions on the results of studies on colchicine for the treatment of PBC, and high-quality randomized controlled trials with large samples are needed. 1. 8 D-penicillamine (Grade A): 8 randomized controlled trials with disappointing results [12], this drug is not recommended for the treatment of PBC due to the high side effects and high rate of missed visits. Recommendation: Given the limited number of studies or lack of evidence from randomized controlled trials for the above drug, it is not recommended . 2. Relief of cholestasis 2.1 Hydrophilic bile acids A 2-year pretrial [13], which included 15 patients, treated PBC with ursodeoxycholic acid (UDCA) 13-15 mg/kg/day and resulted in a significant decrease in serum bilirubin concentration. Subsequently, many randomized controlled trials of ursodeoxycholic acid in the treatment of PBC were conducted, and its mechanism has gradually become clear, mainly reducing the toxic effect of endogenous hydrophilic bile acids on hepatocyte membranes, inhibiting the reabsorption of endogenous bile acids in the terminal ileum, and possibly having immunomodulatory effects and improving cellular antioxidant activity. 2.2 Ursodeoxycholic acid (UDCA) (Grade A): 12 randomized controlled trials evaluated the efficacy of UDCA in the treatment of PBC, of which 11 trials with a follow-up of more than 6 months made a meta-analysis [14], but the results have not been published. However, these trials used small doses of UDCA, and some of them had short follow-up periods, and the results were not significant. The results of all trials showed that UDCA significantly reduced serum bilirubin levels in the first 3 months of treatment, and some trials suggested that bilirubin would be elevated in patients with end-stage disease, so that patients with decompensation should be closely monitored during treatment. None of the trials have adequately demonstrated improved patient survival. Three of the four large randomized, double-blind controlled trials used the same dose of UDCA (13-15 mg/kg/day) and analyzed the results according to the intention-to-treat principle, two of which used a “treatment failure” metric and one of which used a percentage change in serum bilirubin as an endpoint, and only this trial calculated sample Only this trial calculated sample content. All three trials had a failure rate of less than 20%, with few reported drug side effects. Raw data from the three trials were analyzed jointly [15] (non-systematic evaluation or meta-analysis), but in two of the trials, some patients were randomly assigned to the placebo group at the beginning and transferred to the treatment group after 24 months, and the results were analyzed according to the intention-to-treat principle; this group of patients remained in the placebo group at the time of outcome analysis and therefore may have reduced the treatment group efficiency. The results suggest that UDCA treatment for more than 4 years prolongs the time that patients need to undergo liver transplantation. Subgroup analysis showed that UDCA was not significantly effective in patients with early PBC and in patients in the compensated phase, so an extended follow-up with an expanded sample size is needed to determine its efficacy. A fourth trial using a small dose of UDCA (10-12 mg/kg/day), enrolling 151 patients with a 2-year follow-up, showed no improvement in patient survival in the treatment group, with 8 deaths in the treatment group and 12 in the placebo control group. A systematic evaluation [16] included 7 randomized controlled trials including 1,038 patients with PBC treated with moderate doses of UDCA and placebo, and showed that UDCA improved liver biochemical parameters but not malaise and pruritus; delayed the course of PBC, especially in early-stage patients; and Meta-analysis showed a reduction in the number of patients receiving liver transplants (OR 0.65, p = 0.01) and reduced mortality and liver transplantation rates (fixed-effects model: OR 0.76, p = 0.05; random-effects model: OR 0.77, p = 0.3). Sensitivity analysis showed that long-term treatment with UDCA reduced mortality and receipt of liver transplantation. Thus, if applied for a considerable period of time, UDCA can delay the progression of PBC, but so far there is no evidence that it can cure PBC. Recommendation: UDCA is recommended given that it is currently the only drug that can delay PBC and has few side effects . 3. Effect of specific treatment on other indicators of PBC 3.1 Portal hypertension (Grade A) Two randomized controlled trials [17, 18] evaluated the effect of ursodeoxycholic acid on varices and intrahepatic sinusoidal portal pressure and showed that the treatment group relieved esophageal varices but did not reduce the incidence of variceal rupture and bleeding. At 2-year follow-up, the increase in intrahepatic sinusoidal portal pressure in the ursodeoxycholic acid-treated group was less than that in the placebo control group. 3.2 Osteoporosis (Grade A) The results of a randomized controlled trial [19] showed no significant effect of ursodeoxycholic acid on bone mineral density. A small sample of randomized controlled trials comparing the effects of cyclosporine and placebo on bone mineral density and lumbar fractures in patients with PBC showed that cyclosporine reduced bone loss. 3.3 Malaise and pruritus (Grade C) There are no randomized controlled trials evaluating the effect of this symptom, and only some cases have reported that ursodeoxycholic acid improves or worsens malaise and pruritus. Pre-tests of methotrexate have shown significant relief of malaise and pruritus, but there is insufficient evidence from uncontrolled trials. Drug side effects Most trials have not described drug toxicity to the liver, although the effects of ursodeoxycholic acid on bone marrow suppression, methotrexate on the lungs, cyclosporine affecting renal function and causing hypertension, and colchicine causing neuropathy have been described. At present, the safest and most effective drug is ursodeoxycholic acid. III. Prospects for the treatment of PBC Ursodeoxycholic acid does not cure PBC, but only delays the development of some patients, and the evidence is not conclusive. Small sample trials of ursodeoxycholic acid in combination with methotrexate, colchicine, and prednisolone have been conducted, but large sample trials and randomized controlled trials are lacking. A current study [20] evaluating survival after liver transplantation and Mayo risk score to predict liver transplantation survival showed that liver transplantation significantly improves survival in patients with PBC and is the only possible cure for PBC. IV. Indicators of endpoint events The severity of PBC is judged by serum bilirubin or Mayo risk score and is not proportional to symptoms such as malaise and pruritus. In fact, pruritus decreases rather during PBC loss of compensation, just as skin xanthomas disappear with disease progression. Unlike other chronic liver diseases, PBC is pre-sinusoidal portal hypertension, pseudobulbar and cirrhosis are not evident, while the chances of complicating variceal bleeding are significantly less due to liver ischemia, while intractable coagulation dysfunction can be used as an end-stage indicator. Patients in the compensated stage are often asymptomatic, and it has been suggested that the prognosis may be worse with concomitant autoimmune disease, but this does not seem to hold true in the present time. The degree of high serum bilirubin is significantly correlated with survival time. Serum bilirubin is a valid endpoint indicator before liver failure requiring liver transplantation (e.g. death), while conventional liver biochemical indicators such as alkaline phosphatase and transaminases are not related to the prognosis of PBC. Risk factor scores (of which serum bilirubin is an important indicator) are of some value in evaluating prognosis, with the Mayo risk score being the most commonly used and appearing to determine prognosis since few invasive manipulations are involved, including age, serum albumin, clotting time, presence of water and sodium retention and/or use of diuretics. Another small sample of studies has proposed that liver biopsy reveals fibrosis or cirrhosis with a poor prognosis, but liver fibrosis or cirrhosis is not an endpoint indicator. The recent marked decrease in serum bilirubin levels due to the use of ursodeoxycholic acid does not indicate that serum bilirubin or Mayo risk score cannot be used as indicators of prognosis, at least within 6 months of treatment. It is not clear whether bilirubin can be used as an indicator to evaluate survival time in end-stage patients treated with ursodeoxycholic acid. mayo risk score is also used as an indicator in end-stage patients before liver transplantation. Since liver transplantation has been used as an effective treatment in recent years, the Mayo risk score has also been re-evaluated for the assessment of survival time after transplantation. Only clinical trials with large numbers of liver biopsy samples can reduce sample error, and only liver biopsy can accurately determine the degree of bile duct agenesis, liver inflammation and fibrosis. There is no evidence that the titer of AMA is positively correlated with the course of PBC. The only biochemical indicator that is valid for determining prognosis is serum bilirubin, and no other indicator has been found for determining prognosis. But it is difficult to use death as an endpoint indicator, because most of the decompensated PBC are converted to liver transplantation. Valid indicators are needed to judge the treatment measures. V. Period of liver transplantation Liver transplantation as the ultimate feasible treatment for liver failure in patients with PBC, but it is difficult to determine effective indicators for liver transplantation because liver transplantation is often performed in additional patients, such as intractable pruritus and severe osteoporosis. Even when liver transplantation is performed in patients with decompensated liver function, the period of liver transplantation may vary depending on blood type, donor, duration of health insurance, and distance from the medical center, so the period of liver transplantation is highly variable. What is currently being studied and evaluated 1. 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