Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF. METHODS: We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated. CONCLUSION: In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.

Association of bezafibrate with transplant-free survival in patients with primary biliary cholangitis.

BACKGROUND & AIMS: A beneficial effect of bezafibrate (BZF) on symptoms and biochemical features of primary biliary cholangitis (PBC) has been reported in patients with an incomplete response to ursodeoxycholic acid (UDCA), but long-term effects on survival remain unknown. In Japan, BZF has been used as a de facto second-line therapy for PBC since 2000. Herein, we compared the survival rates between patients treated with and those without BZF in a large nationwide Japanese PBC cohort. METHODS: All consecutively registered patients of this cohort who started UDCA therapy from 2000 onwards and had a follow-up ≥1 year were included. Association between BZF exposure and mortality or need for liver transplantation (LT) was assessed using time-dependent, multivariable-and propensity score-adjusted Cox proportional hazards models. Clinical benefit was quantified using the number needed to treat (NNT). RESULTS: Of 3,908 eligible patients, 3,162 (81%) received UDCA only and 746 (19%) UDCA and BZF over 17,360 and 3,932 patient-years, respectively. During follow-up, 183 deaths (89 liver-related) and 21 LT were registered. Exposure to combination therapy was associated with a significant decrease in all-cause and liver-related mortality or need for LT (adjusted hazard ratios: 0.3253, 95% CI 0.1936-0.5466 and 0.2748, 95% CI 0.1336-0.5655, respectively; p <0.001 for both). This association was consistent across various risk groups at baseline. The NNTs with combination therapy to prevent 1 additional death or LT over 5, 10, and 15 years were 29 (95% CI 22-46), 14 (10-22), and 8 (6-15), respectively. CONCLUSIONS: In a large retrospective cohort study of treatment effects in patients with PBC, the addition of BZF to UDCA was associated with improved prognosis. LAY SUMMARY: The long-term efficacy of bezafibrate (BZF) on liver transplantation (LT) - free survival in patients with PBC and an incomplete response to ursodeoxycholic acid (UDCA) remains to be determined. In this Japanese nationwide retrospective cohort study, the use of UDCA-BZF combination therapy, compared to UDCA alone, was associated with a lower risk of all-cause and liver-related mortality or need for LT. These results indicate that BZF is so far the only drug in PBC to have demonstrated efficacy in improving symptoms, biochemical markers, and long-term outcomes.

Effect of deferred or no treatment with ursodeoxycholic acid in patients with early primary biliary cholangitis.

AIM: As primary biliary cholangitis (PBC) is a heterogeneous disease, we hypothesized that there is a population of patients with early PBC who do not require prompt treatment with ursodeoxycholic acid (UDCA). In this study, we analyzed data from a large-scale PBC cohort in Japan, and retrospectively investigated whether outcomes of early PBC patients were affected with prompt or deferred/no UDCA treatment. METHODS: We defined early PBC as asymptomatic, serum alkaline phosphatase <1.67-fold the upper limit of normal, normal bilirubin, and histological stages I-II at presentation. We compared the outcomes of early PBC patients between the treatment regimens; prompt treatment group (UDCA was initiated within 1 year after diagnosis) and deferred/no treatment group (UDCA initiated >1 year after diagnosis or never initiated). Furthermore, we examined the outcomes of early PBC patients alternatively defined only with symptomatology and biochemistry. RESULTS: We identified 562 early PBC patients (prompt: n = 509; deferred/no treatment: n = 53). Incidence rates (per 1000 patient-years) for liver-related mortality or liver transplantation and decompensating events were 0.5 and 5.4, respectively, in the prompt treatment group, and 0 and 8.7, respectively, in the deferred/no treatment group. Multivariate analyses showed that age and bilirubin were significantly associated with developing decompensating events, whereas the prompt and deferred/no treatments were not. We obtained similar results in early PBC patients defined without histological examination. CONCLUSIONS: We showed that deferred/no treatment for early PBC patients did not affect the outcomes. This study provides a rationale for a future prospective, randomized study.

Incidence of and risk factors for hepatocellular carcinoma in primary biliary cirrhosis: national data from Japan.

UNLABELLED: Primary biliary cirrhosis (PBC) primarily affects females and is rarely complicated by hepatocellular carcinoma (HCC). Although the HCC incidence in PBC patients is low, several characteristics and risk factors associated with its development have been reported. In this study, national data concerning the current status of carcinogenesis in PBC patients in Japan are reviewed. Using data from two national questionnaire surveys, we investigated the clinicopathological findings associated with HCC in PBC patients. According to the data of all reviewed PBC patients, the HCC incidence was 2.4% (71/2946). The HCC incidence by gender was 5.1% (19/370) in males and 2.0% (52/2576) in females, and the proportion of males was 26.7%. Prognosis was significantly poorer in the PBC patients with HCC than in those without. Multivariate analysis of risk factors associated with HCC by gender revealed histological stage at the time of PBC diagnosis as an independent risk factor associated with the development of HCC in females, but not in males. Furthermore, data from another national survey of 178 PBC patients with HCC (male/female = 49/129; proportion of males 27.5%) revealed that the duration between the diagnosis of PBC and that of HCC was significantly shorter in males than in females. In addition, histological stage at the time of HCC diagnosis was an independent risk factor for HCC in females, whereas no risk factors were identified in males. CONCLUSION: these data indicate that males are at risk of developing HCC at any histological stage of PBC. Therefore, male PBC patients in particular should be carefully screened for HCC from the early stages of PBC.

Detection of Portal Vein Stenosis by Technetium-99m-Diethylenetriaminepentaacetic Acid-Galactosyl Human Serum Albumin Liver Scintigraphy after Living-Donor Liver Transplantation.

BACKGROUND/AIM: To investigate portal vein stenosis after living-donor liver transplantation by liver scintigraphy. METHODOLOGY: A 63-year-old woman with hepatic cirrhosis due to autoimmune hepatitis underwent living-donor liver transplantation using a graft donated by her daughter. Technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-99m-GSA) scintigraphy was used to determine the maximum rate of Tc-99m-GSA removal (GSA-Rmax) by hepatocytes, as a parameter of hepatic functional reserve. RESULTS: Conventional liver function parameters on laboratory tests and graft volume on computed tomography (CT) were almost unchanged at postoperative month (POM) 12. GSA-Rmax was 0.11 mg/min before surgery and increased 5-fold to approximately 0.5 mg/min at POM 1 and 3, followed by a decrease to 0.25 mg/min at POM 6 and 12. Enhanced CT did not detect blood flow in the intra- or extrahepatic portions of the portal vein at POM 12. The portal vein stenosis was dilated with a balloon catheter, followed by deployment of a self-expanding stent across the stenotic segment via the transileocolic vein. GSA-Rmax recovered to 0.5 mg/min at POM 15, and subsequently remained high. CONCLUSIONS: Decreased GSA-Rmax at POM 6 indicated that the portal vein stenosis was affecting graft function. Tc-99m-GSA liver scintigraphy may be a useful noninvasive method for evaluation of graft functional reserve.

Prognostic utility of albumin-bilirubin grade in Japanese patients with primary biliary cholangitis.

Background & Aims: The albumin-bilirubin (ALBI) score is calculated using serum levels of total bilirubin and albumin as a simple method to assess liver function. This study investigated the ability of baseline ALBI score/grade measurements to assess histological stage and disease progression in individuals with primary biliary cholangitis (PBC) in a large Japanese nationwide cohort. Methods: A total of 8,768 Japanese patients with PBC were enrolled between 1980 and 2016 from 469 institutions, among whom 83% received ursodeoxycholic acid (UDCA) only, 9% received UDCA and bezafibrate, and 8% were given neither drug. Baseline clinical and laboratory parameters were retrospectively retrieved and reviewed from a central database. Associations of ALBI score/grade with histological stage, mortality, and need for liver transplantation (LT) were evaluated using Cox proportional hazards models. Results: During the median follow-up period of 5.3 years, 1,227 patients died (including 789 from liver-related causes) and 113 underwent LT. ALBI score and ALBI grade were significantly associated with Scheuer's classification (both p <0.0001). ALBI grade 2 or 3 had significant associations with all-cause mortality or need for LT as well as liver-related mortality or need for LT according to Cox proportional hazards regression analysis (hazard ratio 3.453, 95% CI 2.942-4.052 and hazard ratio 4.242, 95% CI 3.421-5.260, respectively; both p <0.0001). Cumulative LT-free survival rates at 5 years in the ALBI grade 1, 2, and 3 groups were 97.2%, 82.4%, and 38.8%, respectively, while respective non-liver-related survival rates were 98.1%, 86.0%, and 42.0% (both p <0.0001, log-rank test). Conclusions: This large nationwide study of patients with PBC suggested that baseline measurements of ALBI grade were a simple non-invasive predictor of prognosis in PBC. Impact and implications: Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by progressive destruction of intrahepatic bile ducts. This study examined the ability of albumin-bilirubin (ALBI) score/grade to estimate histological findings and disease progression in PBC by means of a large-scale nationwide cohort in Japan. ALBI score/grade were significantly associated with Scheuer's classification stage. Baseline ALBI grade measurements may be a simple non-invasive predictor of prognosis in PBC.

A prospective randomized controlled trial of preoperative whole-liver chemolipiodolization for hepatocellular carcinoma.

BACKGROUND: We previously reported that preoperative chemolipiodolization of the whole liver is effective for reducing the incidence of postoperative recurrence and prolonging survival in patients with resectable hepatocellular carcinoma (HCC). The present randomized controlled trial was performed to evaluate the influence of preoperative transcatheter arterial chemoembolization (TACE) on survival after the resection of HCC. METHODS: Operative results and long-term outcome were prospectively compared among 42 patients who received only selective TACE targeting the tumor (selective group), 39 patients who received TACE targeting the tumor plus chemolipiodolization of the whole liver (whole-liver group), and 43 patients without preoperative TACE or chemolipiodolization (control group). RESULTS: There were no serious side effects of TACE or chemolipiodolization and the operative outcomes did not differ among the three groups. Even though preoperative TACE induced complete tumor necrosis, there were no significant differences in the pattern of intrahepatic recurrence or the time until recurrence among the three groups. There were also no significant differences in disease-free survival or overall survival among the three groups, even among patients with larger tumor size. CONCLUSION: These results indicate that preoperative selective TACE and whole-liver chemolipiodolization plus TACE do not reduce the incidence of postoperative recurrence or prolong survival in patients with resectable HCC.

Phospho-Smad3 signaling is predictive biomarker for hepatocellular carcinoma risk assessment in primary biliary cholangitis patients.

INTRODUCTION: Patients with primary biliary cholangitis (PBC) are at increased risk for development of hepatocellular carcinoma (HCC), particularly in the presence of comorbidities such as excessive alcohol consumption. Although liver fibrosis is an important risk factor for HCC development, earlier predictors of future HCC development in livers with little fibrosis are needed but not well defined. The transforming growth factor (TGF)-ß/Smad signaling pathway participates importantly in hepatic carcinogenesis. Phosphorylated forms (phospho-isoforms) in Smad-related pathways can transmit opposing signals: cytostatic C-terminally-phosphorylated Smad3 (pSmad3C) and carcinogenic linker-phosphorylated Smad3 (pSmad3L) signals. METHODS AND RESULTS: To assess the balance between Smad signals as a biomarker of risk, we immunohistochemically compared Smad domain-specific Smad3 phosphorylation patterns among 52 PBC patients with various stages of fibrosis and 25 non-PBC patients with chronic hepatitis C virus infection. HCC developed in 7 of 11 PBC patients showing high pSmad3L immunoreactivity, but in only 2 of 41 PBC patients with low pSmad3L. In contrast, 9 of 20 PBC patients with minimal Smad3C phosphorylation developed HCC, while HCC did not occur during follow-up in 32 patients who retained hepatic tumor-suppressive pSmad3C. Further, PBC patients whose liver specimens showed high pSmad3L positivity were relatively likely to develop HCC even when little fibrosis was evident. CONCLUSION: In this study, Smad phospho-isoform status showed promise as a biomarker predicting likelihood of HCC occurrence in PBC. Eventually, therapies to shift favorably Smad phospho-isoforms might decrease likelihood of PBC-related HCC.

Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA.

BACKGROUND: Bezafibrate is reported to have biochemical efficacy for patients with primary biliary cirrhosis (PBC) refractory to ursodeoxycholic acid (UDCA), yet the long-term effect is still unknown. In Japan, nationwide surveys of PBC have been performed since 1980. In the current study, we retrospectively examined whether response to bezafibrate treatment is associated with the long-term outcomes using this large-scale database. METHODS: Among 7,376 patients in the database, we enrolled patients who were treated with UDCA at 13-15 mg/kg per day and followed up for at least 2 years after diagnosis. Bezafibrate (400 mg/day) was administered in addition to UDCA when biochemical response to UDCA was not optimal. Response to bezafibrate treatment was determined by serum alanine transaminase (ALT) levels within 2-3 years or at the earliest point thereafter from the commencement of bezafibrate treatment. RESULTS: We enrolled 1,121 PBC patients, and the observational period was 6.1 ± 3.4 years. Among the PBC patients, 835 were asymptomatic, defined as no liver-related symptoms at the baseline. In asymptomatic PBC patients, multivariate analysis indicated that ALT response to bezafibrate treatment was significantly associated with the presence of liver-related symptoms at the end of observation [hazard ratio 1.46 (95 % confidence interval 1.01-2.13), P = 0.048]. The cumulative liver-related-symptoms-free rate of patients treated with bezafibrate and who had a normal ALT level was significantly higher than that of those treated with bezafibrate and who had an elevated ALT level (P < 0.001), and was comparable to that of those who received UDCA monotherapy. CONCLUSION: These results suggested that normalization of ALT levels with additional bezafibrate treatment significantly decreased the rate of occurrence of liver-related symptoms in asymptomatic PBC patients with suboptimal response to UDCA.

Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate.

Bezafibrate has been empirically used for the treatment of primary biliary cirrhosis. Although its clinical efficacy has been demonstrated, the therapeutic mechanism of action of this drug remains unclear. We suggested that multi-drug resistance (MDR) 3 plays an important role as a mediator of bezafibrate. We adopted a human hepatoma cell line to elucidate the up-regulating effect of bezafibrate. To analyze the effects on mRNA, the dose effect was assessed by slot-blot study, the time course by real time PCR, and the subcellular location was determined by in situ hybridization. The results revealed that MDR3 mRNA reached a peak level 12h after the administration of bezafibrate, and dose dependency was observed. We also investigated the interaction of bile acid and bezafibrate. A low dose of chenodeoxycholic acid could become a co-effecter of bezafibrate. In the protein analysis, a precursor protein was induced by bezafibrate. Even in the cell line endogenously expressing MDR3, the expression of the protein was found to be modulated. We identified MDR3 mRNA in the livers of PBC patients using a sensitive in situ hybridization study. The present findings indicate that PBC patients can respond to bezafibrate, and therefore receive clinical benefits from this medication.

Long-term prognosis of primary biliary cirrhosis (PBC) in Japan and analysis of the factors of stage progression in asymptomatic PBC (a-PBC).

Objective: Based on data from a national survey of primary biliary cirrhosis (PBC), the pathology and prognosis of PBC in Japan were clarified. In particular, we tried to perform multivariate analysis of factors useful in determining prognosis of asymptomatic PBC (a-PBC). Methods: The survey was performed 10 times. Responses from 3778 of 4361 registered patients (416 institutions) were investigated (survey period: January 1968-December 1998). At the time of diagnosis, patients were classified as a-PBC or symptomatic PBC (s1-PBC; pruritus only, s2-PBC; jaundice and serum bilirubin level above 2 mg/dl). The survival rate was obtained by the Kaplan-Meier method. Logistic regression analysis was used in multivariate analysis of prognostic factors of a-PBC. Results: There were no significant differences in clinical findings from those in previous reports. The 5-year survival rates of patients with a-PBC, s1-PBC, and s2-PBC at the time of diagnosis were 97, 88, and 53%, respectively. Patients with a-PBC at the time of diagnosis were divided into groups: those in whom the disease progressed to s2-PBC (8%) and did not progress to s2-PBC (92%) at the final examination, and the prognosis was compared between groups. The prognosis was significantly poorer in the s2-PBC progression group. As a result of multivariate analysis for prediction of prognosis, levels at diagnosis of total serum bilirubin (T-Bil), albumin (Alb), total cholesterol (T-Cho), histological stage, and presence or absence of ursodeoxycholic acid (UDCA) administration were selected as significant factors (P<0.00001). Conclusion: Serum T-Bil, Alb, T-Cho, and histological stage at the time of diagnosis and presence or absence of UDCA administration were considered useful early prognostic indicators in patients diagnosed as having a-PBC whose prognosis may deteriorate with progression to s2-PBC.

Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases.

OBJECTIVES: Patients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct. METHODS: Laboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed. RESULTS: The ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation. CONCLUSIONS: The IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).

Liver regeneration in donors evaluated by Tc-99m-GSA scintigraphy after living donor liver transplantation.

The impact of hepatic steatosis on regeneration of the remnant liver after living donor liver transplantation is unclear. We evaluated the impact of steatosis on regeneration and function of the remnant liver by using technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy. Twelve living donors were classified into groups with or without mild hepatic steatosis according to the liver-to-spleen attenuation ratio on computed tomography: 6 donors had a ratio >or= 1.20 (control group) and 6 donors had a ratio < 1.20 (fatty liver group). Scintigraphy was performed to determine the hepatic uptake ratio of the tracer (corrected for disappearance from the blood) and the maximum removal rate of the tracer by hepatocytes as parameters of the hepatic functional reserve. The fatty liver group had a significantly lower corrected hepatic uptake ratio and removal rate compared with the control group at 6 and 12 months after partial hepatectomy. These parameters were decreased at 1 month after surgery in both groups. However, both parameters returned more rapidly to prehepatectomy levels in the control group. The regenerated liver volume estimated by scintigraphy did not differ significantly between the two groups at any time. Liver scintigraphy may be useful for evaluating the regeneration of functioning hepatocytes. Because donors with mild hepatic steatosis showed impaired liver regeneration at 1 year after partial hepatectomy, management of these donors requires more care.

Recurrent hepatitis C after living donor liver transplantation detected by Tc-99m GSA liver scintigraphy.

Recurrence of hepatitis C virus (HCV) after living donor liver transplantation was investigated using technetium-99m- diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-99m-GSA) liver scintigraphy. Four patients with decompensated cirrhosis due to HCV infection were retrospectively reviewed in this study. Scintigraphy was performed to determine the hepatic uptake ratio of the tracer corrected for disappearance from the blood, as well as the maximal removal rate of the tracer by hepatocytes, as parameters of hepatic functional reserve. In all patients, serum HCV ribonucleic acid (RNA) was detected 3 months after transplantation. The corrected hepatic uptake ratio and removal rate showed little change after transplantation in two patients without the recurrence of HCV infection. In another two patients, these levels were decreased at 3 months after transplantation. In one patient, recurrent HCV infection was diagnosed by confirmatory histologic examination at 12 months after transplantation. In the other patient, both levels declined further at 8 months. Although treatment was initiated with a combination of interferon plus ribavirin, this patient died of progressive hepatic failure. In conclusion, a decrease in scintigraphic parameters at 3 months after transplantation suggests recurrent HCV infection affecting the graft. Tc-99m-GSA liver scintigraphy is a useful noninvasive method for evaluating graft functional reserve.