BACKGROUND & AIMS: Long-term ursodeoxycholic acid (UDCA) therapy slows the progression of primary biliary cirrhosis. This study examined the effect of UDCA therapy on survival free of liver ...transplantation in a large group of patients.
METHODS: Data from three clinical trials were combined in which patients with primary biliary cirrhosis were randomly assigned to receive UDCA (n = 273) or placebo (n = 275). After 2 years, patients from French and Canadian studies received UDCA for up to 2 years. Patients from the American study remained on their assigned treatment for up to 4 years.
RESULTS: Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P < 0.001; relative risk, 1.9; 95% confidence interval, 1.3-2.8). Subgroup analyses showed that survival free of liver transplantation was significantly improved in medium- and high-risk groups (serum bilirubin level, 1.4 to 3.5 or > 3.5 mg/dL; P < 0.0001 and P < 0.03, respectively) and histological stage IV subgroup (P < 0.01).
CONCLUSIONS: Long-term UDCA therapy improves survival free of liver transplantation in patients with moderate or severe disease. An effect in patients with mild disease is probably not found because they do not progress to end-stage disease in 4 years. (Gastroenterology 1997 Sep;113(3):884-90)
Background & Aims:
We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains ...controversial.
Methods:
Our population included 262 patients with PBC who had received 13–15 mg/kg UDCA daily for a mean of 8 years (range, 1–22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population.
Results:
Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk RR, 1.4;
P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5;
P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8;
P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2;
P < .05).
Conclusions:
Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.
Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis (PBC). However, some UDCA-treated patients escape and progress toward cirrhosis and end-stage disease. This study aimed ...to assess the incidence of cirrhosis in UDCA-treated patients with PBC and to determine the predictive factors of cirrhosis development under this treatment.
A Markov model was used to describe the progression toward cirrhosis in 183 UDCA-treated patients with PBC. A total of 254 pairs of liver biopsy specimens collected during 655 patient-years were studied.
The incidence of cirrhosis after 5 years of UDCA treatment was 4%, 12%, and 59% among patients followed-up from stages I, II, and III, respectively. At 10 years, the incidence was 17%, 27%, and 76%, respectively. The median time for developing cirrhosis from stages I, II, and III was 25 years, 20 years, and 4 years, respectively. The independent predictive factors of cirrhosis development were serum bilirubin greater than 17 μmol/L, serum albumin less than 38 g/L, and moderate to severe lymphocytic piecemeal necrosis.
This study provides new data about the time course of PBC under UDCA and constitutes a rationale for the design and evaluation of clinical trials aimed to assess the efficacy of drugs associated with UDCA.
Ursodeoxycholic acid (UDCA) is the only approved treatment for primary biliary cirrhosis (PBC). However, the benefit from UDCA therapy on the progression of PBC from its early stage towards extensive ...fibrosis and cirrhosis has not been clearly shown. The aim of this study was to assess the effect of UDCA therapy on liver fibrosis progression in PBC. A Markov model was used to analyze the progression rates between early and late histologic stages in 103 patients with PBC enrolled in a randomized, double-blind, placebo-controlled trial of UDCA. Early stage was defined by the presence of portal and periportal lesions without extensive fibrosis, whereas late stage was defined by the presence of numerous septa, bridging fibrosis, or cirrhosis. A total of 162 pairs of liver biopsy specimens were studied. The model accurately described the observed data. UDCA therapy was associated with a 5-fold lower progression rate from early stage disease to extensive fibrosis or cirrhosis (7% per year under UDCA vs. 34% per year under placebo,
P <.002), but was not associated with a significant difference in regression rates (3% per year under both UDCA and placebo). At 4 years, the probability of UDCA-treated patients to remain in early stage disease is 76% (95% confidence interval: 58%-88%), as compared with 29% (15%-52%) in placebo-treated patients. In conclusion, UDCA therapy significantly delays the progression of liver fibrosis in PBC. Markov modeling should prove useful in assessing the efficacy of future medical treatments in clinical trials involving histologic endpoints. (Hepatology2000;32:1196-1199.)
The aim of this study was to assess the incidence of decompensation (ascites, jaundice, variceal bleeding, and encephalopathy), hepatocellular carcinoma (HCC) and death or liver transplantation in ...patients with compensated hepatitis C virus (HCV)‐related cirrhosis, taking into account the viral genotype and interferon (IFN) therapy. Between 1989 and 1994, 668 patients with no clinical evidence of decompensation were referred to our department for liver biopsy because of positivity for anti‐HCV antibodies and elevated aminotransferase activity; 103 of these patients had cirrhosis. The median follow‐up was 40 months. Fifty‐nine patients were treated with IFN for a mean duration of 11 ± 6 months; 3 (5%) had a prolonged biochemical and virological response. Baseline characteristics of IFN‐treated and untreated patients were not significantly different. HCV genotypes (InnoLiPa) were predominantly 1b (48%) and 3a (20%). During follow‐up, complications of cirrhosis occurred in 26 patients, HCC in 11 patients, and decompensation not related to HCC in 19 patients. Sixteen patients died, 94% of liver disease. Three patients were transplanted for liver failure. The 4‐year risk of HCC was 11.5% (annual incidence 3.3%) and that of decompensation was 20%. Survival probability was 96% and 84% at 2 and 4 years, respectively. In multivariate analysis, the absence of IFN therapy was the only independent factor predictive both for HCC and decompensation. A low albumin level at entry and the absence of IFN therapy were the two independent factors predictive of death or liver transplantation. Probability of survival at 2 and 4 years was significantly different between IFN‐treated and untreated patients (respectively 97% and 92% vs 95% and 63%,P< .0001). In conclusion, in patients with compensated HCV‐related cirrhosis: 1) complications of cirrhosis are frequent, whatever the viral genotype; and 2) the severity of cirrhosis and the absence of IFN therapy are independently predictive of bad outcome
Serum bile acid levels and distributions were studied every 6 mo in patients with primary biliary cirrhosis who were randomly assigned to receive ursodeoxycholic acid (13 to 15 mg/kg/day) (n = 73) or ...a placebo (n = 73) over a 2-yr period. In the ursodeoxycholic acid group, ursodeoxycholic acid was the predominant serum bile acid at 6 mo and throughout the 2-yr treatment period. The total concentration of endogenous bile acids decreased with a reduction in cholic acid (in the ursodeoxycholic acid group and the placebo group, respectively mean +/- S.E.: 13.0 +/- 2.2 and 12.6 +/- 2.5 mumol/L at entry vs. 3.5 +/- 0.6 and 9.0 +/- 2.2 mumol/L at 2 yr; p < 0.002), chenodeoxycholic acid (in the ursodeoxycholic acid group and the placebo group, respectively: 12.1 +/- 1.7 and 12.7 +/- 2.3 mumol/L at entry vs. 5.8 +/- 0.8 and 10.7 +/- 2.2 mumol/L at 2 yr; p < 0.02) and 3 beta-hydroxy-delta 5-cholenoic acid. The concentration of deoxycholic acid did not change, whereas that of lithocholic acid increased significantly (in the ursodeoxycholic acid group and the placebo group, respectively: 0.63 +/- 0.06 and 0.81 +/- 0.12 mumol/L at entry vs. 1.26 +/- 0.12 and 0.90 +/- 0.15 mumol/L at 2 yr; p < 0.001). These changes were independent of the histological stage of the disease. Thus during ursodeoxycholic acid administration the liver was exposed to a lower level of endogenous bile acids and to an increased concentration of ursodeoxycholic acid.
Background/Aims: This study aimed at evaluating the effect of ursodeoxycholic acid (UDCA) treatment on histologic progression in primary biliary cirrhosis (PBC).
Methods: Using combined individual ...histologic findings from four clinical trials, we selected the patients in whom paired liver-biopsy specimens were available with a time interval of about 36 months between biopsies. A total of 367 patients were selected (UDCA: 200 vs. placebo: 167).
Results: Overall, there was no significant difference in the progression of the histologic stage between the two groups. By contrast, in the subgroup of patients with initial stages I–II (
n=177) there was a significant decrease in the histologic stage progression in the UDCA group relative to the placebo group (
P<0.03). Overall, there was a significant delay in the progression of periportal necroinflammatory lesions (
P=0.03), and an improvement in the degree of ductular proliferation (
P=0.02) in the UDCA group compared with the placebo group. There was no significant difference in the progression of other specific lesions.
Conclusions: A 2-year UDCA treatment reduces periportal necroinflammation and improves ductular proliferation, and when initiated at the earlier stages I–II of the disease also delays the progression of histologic stage. These data support the early initiation of the drug to prevent these histologic features of PBC.
The semiquantitative histopathological analysis of the liver biopsies obtained before and after 4 years of ursodeoxycholic acid (UDCA) therapy in a cohort of primary biliary cirrhosis (PBC) patients ...is reported. The relationships between elementary histological lesions before treatment and their progression under therapy were assessed. At baseline, two independent groups of lesions, each of which participate in the development of fibrosis, were individualized,i.e., florid bile duct lesions and ductopenia on one hand and lymphocytic piecemeal necrosis, ductular proliferation, and lobular necroinflammatory changes on the other hand. Four years of UDCA therapy were associated with a significant decrease in the prevalence of florid interlobular bile duct (ILBD) lesions, of epithelioid granuloma (P < .001) without any aggravation in the severity of bile duct paucity. Lobular inflammation and necrosis markedly improved (P < .001) whereas the degree of severity of the lymphocytic piecemeal necrosis and ductular proliferation at entry and at 4 years were similar. Worsening of fibrosis was observed in 14 patients (12 of them had a one grade progression) whereas stabilization was noted in 30 of the remaining patients. Severity of both the lymphocytic piecemeal necrosis and lobular inflammation and necrosis at entry was significantly associated with the progression of fibrosis. The results suggest that UDCA therapy influences the process leading to bile duct destruction. Patients with severe lymphocytic piecemeal necrosis and lobular inflammation may need additional therapeutic intervention because they have increased risk of fibrosis progression
Chronic cholestatic diseases, whether occurring in infancy, childhood or adulthood, are characterized by defective bile acid transport from the liver to the intestine, which is caused by primary ...damage to the biliary epithelium in most cases. In this article, approaches to diagnosis and management of the main specific disorders are provided and some of the recent developments in this field are discussed. Major advances in the understanding of the cellular and molecular physiology of bile secretion have led to identification of genetic defects responsible for the different types of progressive familial intrahepatic cholestasis (PFIC). The potential role of the genes involved in PFIC in some adult cholestatic disorders remains to be determined. The majority of adult patients with chronic cholestasis have primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Recently, variant forms of PBC have been described. The term autoimmune cholangitis is used to describe patients having chronic non-suppurative cholangitis with negative antimitochondrial antibodies (AMA) but positive antinuclear and/or antismooth muscle antibodies. Autoimmune cholangitis and AMA-positive PBC are quite similar in terms of clinical presentation, survival and response to ursodeoxycholic acid (UDCA) therapy. In contrast, autoimmune cholangitis must be distinguished from PBC-autoimmune hepatitis (AIH) overlap syndrome in which biochemical and histological characteristics of both PBC and AIH coexist. Combination of UDCA and corticosteroids is required in most patients with overlap syndrome to obtain a complete clinical and biochemical response. Long-term UDCA treatment improves survival without liver transplantation in PBC patients. Among the putative mechanisms of the beneficial effects of UDCA, description of anti-apoptotic properties and effect on endotoxin disposal in biliary cells have provided new insights. In patients with incomplete response to UDCA, combination of UDCA with antiinflammatory or immunosuppressive drugs is under evaluation. Variant forms of PSC have also been described, including PSC-AIH overlap syndrome, especially in children or young adults, and small-duct PSC, which is characterized by normal cholangiogram in patients having chronic cholestasis, histologic features compatible with PSC and inflammatory bowel disease. Development of cholangiocarcinoma (CC) is a major feature of PSC, occurring in 10–15% of patients. Early diagnosis of CC is a difficult challenge, although positron emission tomography seems a promising tool. Unlike PBC, effective medical therapy is not yet available in PSC, reflecting the lack of knowledge about the exact pathogenesis of the disease. Currently, liver transplantation is the only effective therapy for patients with advanced disease, although recurrence of PSC in the graft may occur.
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