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.)
Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever ...case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease.
We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease.
In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5–1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer.
In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer.
In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.
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•Low-phospholipid-associated cholelithiasis (LPAC) syndrome affects approximately 1% of adults with symptomatic cholelithiasis.•Normal weight, common bile duct stones, and lack of cholecystitis are clinical features significantly associated with this syndrome.•ABCB4 variants in patients with LPAC may be associated with an increased personal or family risk of hepato-biliary cancer.
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
The association of primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) is thought to be rare, and its optimal treatment is unknown. Of 130 consecutive patients with a diagnosis of PBC, we ...identified 12 cases (9.2%) of overlap syndrome (10 females, 2 males; median age, 50 years) strictly defined by the presence of at least two of the three recognized biochemical, serological, and histological criteria of each disease. One patient had initially pure PBC and developed AIH characterized by a flare of alanine transaminase (ALT) (1,330 IU/L; N < 35), elevated immunoglobulin G (IgG) (42 g/L; N < 14.0), and presence of anti‐smooth muscle antibodies (ASMA) after 20 months of ursodeoxycholic acid (UDCA) therapy. A complete clinical and biochemical remission was achieved under combination of corticosteroids and UDCA. Eleven patients had features of both diseases at presentation: high serum levels of alkaline phosphatase (AP) (median: 280 IU/L; N < 100), ALT (140 IU/L), and IgG (30.8 g/L), presence of mitochondrial antibodies (n = 9) or ASMA (n = 9), florid bile duct lesions (n = 8), and moderate or severe periportal or periseptal lymphocytic piecemeal necrosis (n = 11). UDCA (13‐15 mg/kg/d) given alone in 5 patients induced a significant decrease in biochemical cholestasis but not in ALT levels, and liver fibrosis progressed in 3 patients. Corticosteroids given alone in 6 patients induced a significant decrease in ALT, IgG, and AP levels, but none had a biochemical normalization. The patients with persistently abnormal liver tests under either UDCA or corticosteroids received both UDCA and corticosteroids. A further marked biochemical improvement was observed, and all patients became asymptomatic. We conclude that, in patients with PBC: 1) overlap syndrome with AIH is not rare; 2) flares of AIH may occur either spontaneously or under UDCA; and 3) combination of UDCA and corticosteroids is required in most patients to obtain a complete biochemical response. Overlap syndrome may represent an important and unrecognized cause of resistance to UDCA in patients with PBC.
The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of ...hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle α-actin–immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle α-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle α-actin, α1 (I) collagen mRNA, and PDGF receptor-β subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle α-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct–ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle α-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.
Background & Aims Chronic, progressive hepatobiliary disease is the most severe complication of erythropoietic protoporphyria (EPP) and can require liver transplantation, although the mechanisms that ...lead to liver failure are unknown. We characterized protoporphyrin-IX (PPIX)-linked hepatobiliary disease in BALB/c and C57BL/6 (Fechm1Pas) mice with mutations in ferrochelatase as models for EPP. Methods Fechm1Pas and wild-type (control) mice were studied at 12–14 weeks of age. PPIX was quantified; its distribution in the liver, serum levels of lipoprotein-X, liver histology, contents of bile salt and cholesterol phospholipids, and expression of genes were compared in mice of the BALB/c and C57BL/6 backgrounds. The in vitro binding affinity of PPIX for bile components was determined. Results Compared with mice of the C57BL/6 background, BALB/c Fechm1Pas mice had a more severe pattern of cholestasis, fibrosis with portoportal bridging, bile acid regurgitation, sclerosing cholangitis, and hepatolithiasis. In C57BL/6 Fechm1Pas mice, PPIX was sequestrated mainly in the cytosol of hepatocytes and Kupffer cells, whereas, in BALB/c Fechm1Pas mice, PPIX was localized within enlarged bile canaliculi. Livers of C57BL/6 Fechm1Pas mice were protected through a combination of lower efflux of PPIX and reduced synthesis and export of bile acid. Conclusions PPIX binds to bile components and disrupts the physiologic equilibrium of phospholipids, bile acids, and cholesterol in bile. This process might be involved in pathogenesis of sclerosing cholangitis from EPP; a better understanding might improve diagnosis and development of reagents to treat or prevent liver failure in patients with EPP.
Background: Antibodies to soluble liver antigen (SLA)/liver pancreas (LP) are generally considered as highly specific diagnostic markers of type 1 auto‐immune hepatitis (AIH‐1), and are particularly ...useful in patients without conventional antibodies. However, the presence of anti‐SLA/LP in type 2 auto‐immune hepatitis (AIH‐2), primary sclerosing cholangitis (PSC) and hepatitis C has recently been reported. The aim was thus to describe the characteristics of anti‐SLA/LP‐positive patients in the largest series reported to date.
Methods: Sera were selected from the period between 1998 and 2005, based on the presence of antibodies to SLA/LP detected by two methods. The clinical status of patients was determined from their medical records.
Results: Eighty‐one anti‐SLA/LP‐positive patients with available clinical data were included: 89% (72/81) had a diagnosis of AIH‐1, including 10 (12%) associated with cholestatic diseases (primary biliary cirrhosis in seven cases and PSC in three cases). Six patients (7%) suffered from another liver disease: hepatitis C (n=3) and drug‐induced hepatitis (n=3). No specific diagnosis was made in three patients.
Conclusions: Antibodies to SLA/LP are of a major diagnostic value for AIH‐1, including paediatric forms and overlap syndromes with cholestatic diseases, but are not found in association with anti‐liver/kidney/microsome type 1 or antibodies to liver cytosol type 1. They are rarely present in other liver diseases such as hepatitis C and drug‐induced hepatitis.
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