Treatment of primary biliary cholangitis

Original link:〔学术园地〕原发性胆汁性胆管炎的治疗现状

Zhang Xinhe, Tian Haoyu, Li Yiling, the First Affiliated Hospital of China Medical University

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease caused by the destruction of small intrahepatic bile ducts and intrahepatic cholestasis caused by autoimmune response. The disease is common in middle-aged and elderly women, with elevated serum alkaline phosphatase (ALP) and glutamyltranspeptidase (GGT) [1], positive serum anti mitochondrial antibody (AMA), and positive anti nuclear antibody (ANA) in about 50% of patients. Generally, 15% ~ 40% of PBC patients have negative serum AMA, of which the positive rate of ANA is as high as 85%, and anti-sp100 and anti-gp210 can also be positive. Fatigue and skin pruritus are the most common clinical manifestations [2]. Once itching occurs, the disease progresses quickly. PBC is a disease caused by autoimmune reaction under the joint action of genetic factors and environmental factors. It can lead to liver fibrosis, liver cirrhosis and hepatocellular carcinoma due to bile acid toxicity and pericholangitis. This paper reviews the current drug and non drug measures for the treatment of PBC.

1. Drug treatment

1.1 ursodeoxycholic acid (UDCA) UDCA can increase the secretion of bile, reduce the damage of bile duct and hepatocytes, and play an anti-inflammatory and immunomodulatory role. It is the only first-line drug for the treatment of PBC at present. In addition to improving liver biochemical indexes in PBC patients, UDCA can also play an anti fibrosis role, but the detailed mechanism is not clear. A recent experimental study in rats found that UDCA plays an anti fibrotic role by inhibiting the production of collagen by hepatic stellate cells and inhibiting autophagy and cell activity [3]. Although UDCA can improve the prognosis of PBC patients, about 40% of patients have no response or poor response to UDCA treatment. The response criteria of UDCA include Barcelona, Paris, Rotterdam and Mayo criteria. Barcelona criteria is that the serum ALP decreases by 40% or returns to normal after one year of UDCA treatment. Paris criteria is that the serum ALP < 3 ULN, AST < 2 ULN and bilirubin ≤ 1 mg / dl after one year of UDCA treatment. Uk-pbc score and globe score are the common response prediction models of UDCA response. What factors are related to UDCA treatment response? A large number of literatures have confirmed that men have fewer related symptoms, longer diagnosis time, low response and poor prognosis than women, which may be related to the lower degree of autonomic symptoms and fatigue in men than women [4]. Age of onset is another self factor affecting treatment response. The response rate of patients younger than 45 years old is low [5]. ALP and bilirubin in liver function indexes are closely related to UDCA response [6]. The increase of bilirubin indicates that the bile discharge channel is blocked. Most copper is eliminated through bile, and the long-term retention of copper in the liver may be related to the poor bilirubin response rate after treatment. Most PBC patients are positive for autoantibody AMA, but with the deepening of understanding of PBC, more and more patients are AMA negative PBC, in which the positive anti gp210 is often closely related to the low response of UDCA [7]. A recent study in Korea found that in blood cell analysis, the ratio of neutrophils to lymphocytes greater than 2.46 will lead to low UDCA response, which may be because its ratio is related to systemic inflammatory response [8]. Subclinical PBC refers to patients with positive AMA and normal biochemical indexes. There is no consensus on whether these patients need UDCA treatment. Supporters believe that UDCA can not only improve biochemical indexes, but also delay histological progress. UDCA can improve the survival rate without liver transplantation, have a high response rate to early treatment, and preventive treatment can reduce the recurrence of PBC after liver transplantation, Opponents believe that the progress of subclinical stage is slow, and the therapeutic effect of UDCA on patients with normal biochemistry is not obvious. PBC patients with poor or no response to UDCA are called refractory PBC. At present, it is believed that there are many reasons that can lead to refractory PBC, including the dose used by UDCA, manufacturers, combined medication, patients' diet, compliance and environment. There may also be PBC-AIH overlap syndrome and other viral hepatitis, such as HBV / HCV infection, dyslipidemia, simultaneous fatty liver disease, genetic or metabolic liver disease At the same time, it is accompanied by a variety of autoimmune diseases, advanced PBC and so on. In addition to changing the therapeutic dose of UDCA, these patients are mainly treated with second-line drugs and other non drug methods.

1.2 Bates and PPAR α Receptor binding, reduce the production of leukocyte activators and inflammatory mediators, participate in PPAR mediated anti-inflammatory and immunomodulatory processes [9], reduce bile duct injury and improve bile acid metabolism. There are mainly two kinds of fibrates used in the second-line treatment of PBC, namely fenofibrate and bezafibrate. Bezafibrate can bind to three isoforms of PPAR, while fenofibrate only activates PPAR- α [10]。 Dohmen et al [11] early treated 9 PBC patients with fenofibrate for 12 weeks. The results showed that ALP, GGT and IgM decreased significantly, indicating that fenofibrate may be effective in the treatment of PBC patients. Subsequently, a large number of clinical trials confirmed that fenofibrate can be applied to PBC patients who do not respond to UDCA [12, 13]. In the two meta-analyses [14, 15], the analysis of a larger number of people confirmed that fenofibrate 100 ~ 200 mg · D-1 combined with UDCA can improve the biochemical indexes of PBC patients. Similarly, a large number of studies have confirmed that UDCA combined with bezafibrate can be used as a second-line treatment for PBC patients [16-18]. A recent meta-analysis [19] showed that the combination of the two can improve patients' biochemical indexes and pruritus score, but will not reduce adverse reactions and mortality. The primary endpoint of bezafibrate treatment was complete biochemical response, defined as normal serum total bilirubin, ALP, GGT, ALB and INR at 24 months. Dohmen et al [20] compared the efficacy of fenofibrate with bezafibrate, and found that compared with bezafibrate, fenofibrate can significantly reduce the levels of LDL and uric acid in patients. Therefore, fenofibrate may be better than bezafibrate in reducing cardiovascular and renal failure events. In addition, the use of fenofibrate should pay attention to the monitoring of potential liver injury and nephrotoxicity [21], and the use of bezafibrate should pay attention to the aggravation of pruritus, gastrointestinal discomfort and other adverse reactions [22]. There are not many reports on the effect of Bates on liver histology, which needs to be further explored.

1.3 the combined treatment of immunosuppressant UDCA and immunosuppressant is mainly used in patients with PBC-AIH overlap syndrome [23]. At present, immunosuppressants include corticosteroids, azathioprine, cyclosporine, methotrexate and mycophenolate mofetil, but their effects are not very ideal [24]. Budesonide is a representative drug of the second generation adrenocortical hormone. It has stronger effect than prednisone and less adverse reactions. It can reduce cholestasis by promoting the expression of bile acid transporter AE2. As early as 1999 [25], leuschner et al conducted a two-year prospective double-blind trial. The results showed that compared with UDCA plus placebo group, IgM and liver enzyme indexes decreased significantly, but bone mineral density decreased significantly. This conclusion was also reported in the study of Angulo and pagan B [26,27]. Subsequently, hempfling et al discussed the use of budesonide in detail. Compared with patients in phase I / II trial, patients in phase IV were more likely to have adverse reactions such as portal vein thrombosis. Therefore, it was concluded that budesonide was more suitable for patients with early PBC and not for patients with liver hardening PBC [28]. In liver histology, the combination of UDCA and budesonide can also improve the degree of liver inflammation and fibrosis [29]. However, the bone mineral density of patients should be closely monitored during the use of budesonide. Many studies have shown that budesonide is easy to reduce bone mineral density. It has also been confirmed in the randomized trial of rautiainen h that the combination of the two may reduce the bone mineral density of femoral neck and lumbar spine [30].

1.4 obecholate (OCA) OCA is a derivative of chenodeoxycholic acid, which was approved for second-line treatment of clinical patients in May 2017 [31]. The main mechanisms of OCA are: (1) inhibition of bile acid synthesis. OCA is a farnesol x (FXR) receptor agonist, which can induce the production of a heterodimer chaperone and intestinal hormone Fgf19 by binding to FXR receptor. The heterodimer chaperone can inhibit CYP7A1 activator, while the combination of Fgf19 and FGF receptor 4 can inhibit CYP7A1 mRNA level. Both of them can down regulate the main enzyme systems of bile acid synthesis, such as cytochrome P450, reduce the conversion of cholesterol to bile acid and inhibit the synthesis of bile acid; (2) Promote bile acid excretion. The heterodimer chaperone induced by FXR receptor activation can induce bile salt output pump and MDR 2 / 3 and promote the release of conjugated bile acids [32]; (3) Inhibit the enterohepatic circulation of bile acids. OCA activates FXR in ileum, which can down regulate transporters, reduce the reabsorption of bile acids by intestinal epithelium and increase the secretion of portal circulation [33]. Hirschfield et al [34] conducted a double-blind phase II clinical trial on 165 patients with PBC. The patients were randomly divided into four groups: placebo and OCA 10 mg.d-1, 25 mg.d-1 and 50 mg.d-1. All patients maintained the original dosage of UDCA. The researchers recorded and analyzed the changes of patients' condition after 3 months. The research results showed that ALP in OCA 10 mg.d-1, 25 mg.d-1 and 50 mg.d-1 decreased by 24% and 25% respectively 21%, the decrease was significantly greater than that in the comfort group. The decrease was the largest in each group at the end of 3 months, and alt, GGT and bilirubin in each OCA group were also significantly lower than those in the comfort group. Pruritus is the most common side effect of obecholate. The incidence of pruritus in OCA group is significantly higher than that in comfort group, and the incidence of pruritus also increases with the increase of dosage. It can be seen that the efficacy of 5-fold high-dose OCA group has no advantage and the side effects are greater. The study found that obecholic acid can reduce cholesterol and HDL levels, which may have a protective effect on the cardiovascular system of PBC patients. Nevens f et al [35] also conducted a 12-month phase III clinical trial on 217 patients by double-blind method. The patients were divided into three groups: OCA 10 mg.d-1, OCA 5 ~ 10 mg.d-1 and comfort group. The research results were basically consistent with Hirschfield's results. Compared with the placebo group, the liver function indexes such as ALP, GGT, alt, AST and bilirubin in each OCA group decreased significantly, However, the incidence of pruritus increased significantly. In addition to the above similar conclusions, the phase III trial also found that OCA can reduce IgM, CRP, interleukin-12 and TNF- α And other factors to regulate the patient's immune and inflammatory response. Obecholic acid will not aggravate the level of liver fibrosis in patients. This conclusion has been more accurately and rigorously confirmed in the Bowlus test. Bowlus [36] treated 17 patients with PBC with OCA for 3 years. Liver biopsy showed that OCA improved or stabilized the fibrosis in 71% of patients, and also reduced the loss of bile duct and improved the interface hepatitis in most patients. The end point of obecholic acid was ALP < 1.67 ×  ULN and / or bilirubin < 2 ×  ULN。 OCA can be used alone or in combination with UDCA. The initial dose is 5 mg, which can be increased to 10 mg after 6 months according to tolerance.

1.5 Taurodeoxycholic acid (TUDCA) TUDCA is a binding bile acid formed by the carboxyl group of ursodeoxycholic acid and the amino dehydration of taurine. It has strong hydrophilicity, can reduce the toxicity of bile acids and protect hepatocytes from apoptosis [37], and has been approved by FDA for the treatment of primary biliary cholangitis. Ma et al [38] The efficacy of TUDCA and UDCA were compared. The results showed that both were equally effective in reducing biochemical indexes of PBC patients, but TUDCA seemed to be better than UDCA in alleviating pruritus. In addition, some researchers [39] It is found that in the mouse model of cholestatic liver disease, TUDCA can reduce the expression of chop, reduce chop induced apoptosis, and significantly reduce the degree of liver fibrosis. However, whether TUDCA can also inhibit the process of liver fibrosis in PBC patients needs further experimental exploration.

1.6 traditional Chinese medicine in addition to traditional western medicine treatment, Chinese researchers try to explain PBC with traditional Chinese medicine theory and explore whether traditional Chinese medicine treatment is effective. Traditional Chinese medicine theory holds that the main syndrome type of PBC is liver depression and spleen deficiency. Chen et al found that the combination of traditional Chinese medicine and UDCA is significantly better than UDCA alone in reducing GGT and TBIL, and can improve the 1-year response rate of patients with UDCA [40] Therefore, whether the combination of traditional Chinese medicine and Western medicine can be widely used needs more standardized experimental design and larger population trials.

2 non drug treatment

2.1 biotherapy rituximab is an anti-CD20 monoclonal antibody, which can selectively eliminate B cells to treat autoimmune mediated liver diseases [41]. In previous studies, rituximab can significantly reduce the production of autoantibodies, but has limited effect on the recovery of liver function [42] Recently, experts have devoted themselves to studying whether rituximab can treat the fatigue response caused by PBC. In the latest phase 2 randomized controlled trial, the research results found that both groups can reduce the fatigue degree, but the difference is not statistically significant. Therefore, it can not explain that rituximab can treat the fatigue caused by PBC [43].

2.2 mesenchymal stem cells (MSc) MSc is a potential method to treat PBC. At present, the therapeutic mechanisms are as follows: (1) inhibit the production of T cells and promote their apoptosis through PGE2, no and Ido pathways [44]; (2) in mouse experiments, it was found that MSC can reduce the production of Th1 and Th17 through Gal-9 [45]; (3) Autophagy dysfunction of intrahepatic bile duct epithelium is the main pathogenesis of PBC. MSC may regulate autophagy function of intrahepatic bile duct epithelium by inhibiting STAT3 activity [46]; (4) bone marrow mesenchymal stem cells can also resist the progress of liver fibrosis [47]. The clinical efficacy and safety of MSc in the treatment of PBC need exploration and research of a large number of randomized trials.

3 others

Some PBC patients need some adjuvant treatment to deal with their extrahepatic manifestations. Colerenium, opioid receptor antagonist naltrexone and rifampicin can be used to improve their pruritus. If the treatment is ineffective, they can choose ultraviolet irradiation, plasma exchange, in vitro albumin dialysis or transnasal biliary drainage. PBC patients can prevent osteoporosis by supplementing calcium and vitamin D , for patients with osteoporosis, bisphosphonates such as alendronate can be used to treat fatigue