A Multicenter, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of Saroglitazar in Patients With Primary Biliary Cholangitis.

INTRODUCTION: Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC. METHODS: In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline. RESULTS: Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits. DISCUSSION: Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.

Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis.

Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.

Sildenafil protects against bile duct ligation induced hepatic fibrosis in rats: Potential role for silent information regulator 1 (SIRT1).

Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-ß content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1.

Role of Lipoylation of the Immunodominant Epitope of Pyruvate Dehydrogenase Complex: Toward a Peptide-Based Diagnostic Assay for Primary Biliary Cirrhosis.

Primary biliary cirrhosis is an immune-mediated chronic liver disease whose diagnosis relies on the detection of serum antimitochondrial antibodies directed against a complex set of proteins, among which pyruvate dehydrogenase complex is considered the main autoantigen. We studied the immunological role of the lipoyl domain of this protein using synthetic lipoylated peptides, showing that the lipoyl chain chirality does not affect autoantibody recognition and, most importantly, confirming that both lipoylated and unlipoylated peptides are able to recognize specific autoantibodies in patients sera. In fact, 74% of patients sera recognize at least one of the tested peptides but very few positive sera recognized exclusively the lipoylated peptide, suggesting that the lipoamide moiety plays a marginal role within the autoreactive epitope. These results are supported by a conformational analysis showing that the lipoyl moiety of pyruvate dehydrogenase complex appears to be involved in hydrophobic interactions, which may limit its exposition and thus its contribution to the complex antigenic epitope. A preliminary analysis of the specificity of the two most active peptides indicates that they could be part of a panel of synthetic antigens collectively able to mimic in a simple immunoenzymatic assay the complex positivity pattern detected in immunofluorescence.

Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.

Several lines of evidence show that serum alkaline phosphatase (AP) is not only a signpost of cholestasis but also a surrogate marker of the severity of primary biliary cirrhosis and primary sclerosing cholangitis. In the present opinion article, we review and discuss the putative role of liver AP in health and in cholestatic diseases. In inflammatory cholestatic conditions, loss of activity of liver AP (resulting from its relocation from canaliculi and the acidic milieu) might promote hyper-adenosine triphosphate-bilia, lipopolysaccharide overload, and subsequent exacerbation and perpetuation of inflammation. Drugs that can restore the polarity of hepatocytes and canalicular export of bile acids or act as bile alkalinity modifiers are predicted to exert anti-inflammatory effects and to benefit both primary biliary cirrhosis and primary sclerosing cholangitis. Oral administration of intestinal AP could be a valid therapeutic intervention that deserves further study under experimental conditions as well as in human diseases. Overall, the key role of the liver microenvironment that might shape the different facets of the inflammatory processes in fibrosing cholangiopathies is highlighted.

Pi*Z heterozygous alpha-1 antitrypsin states accelerate parenchymal but not biliary cirrhosis.

OBJECTIVE: The degree to which heterozygous forms of alpha-1 antitrypsin (A1AT), principally MZ, causes liver disease is uncertain. If heterozygosity is a relevant cofactor, over-representation in patients with end-stage liver disease would be predicted. We therefore assessed the prevalence and disease-related distribution of A1AT heterozygosity in the largest cohort to date for this purpose. METHODS: We retrospectively analysed 1036 patients assessed for liver transplantation at our unit between 2003 and 2010. A1AT heterozygotes were identified on the basis of isoelectric focusing and/or histology, showing A1AT globule deposition consistent with an abnormal phenotype. RESULTS: Z-allele frequency was the highest in patients with nonalcoholic steatohepatitis (NASH) cirrhosis (20.3%), followed by patients with 'other parenchymal' diseases (11.9%), alcohol-related liver disease (9.9%), autoimmune disease (8.6%), hepatitis C (6.1%), hepatitis B (3.0%) and biliary disease (1.9%). Compared with the heterozygote frequency in the general European population of 9.0%, the heterozygote frequency was significantly higher among patients with NASH cirrhosis (P≤0.0001) and lower in the biliary subgroup (P=0.004). The prevalence of MZ heterozygosity was significantly increased in cirrhosis because of both alcohol (9.9%) and NASH (17.3%) compared with the general European population (2.8%; P<0.0001). CONCLUSION: Accumulation of misfolded A1AT aggregates appears to accelerate progression, in which the hepatocyte is the key injured cell. Heterozygous A1AT states worsen prognosis, particularly in NASH and alcohol-related cirrhosis, and should be identified at presentation. In cases in which genetic screening is not readily available, a low threshold for isoelectric focusing and routine specific histochemical staining of liver biopsy specimens are warranted to identify these patients.

Telomere dysfunction in peripheral blood mononuclear cells from patients with primary biliary cirrhosis.

BACKGROUND: Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence. AIM: To evaluate the clinical significance of telomerase activity and telomere length in peripheral blood mononuclear cells from patients with primary biliary cirrhosis. STUDY DESIGN: In this population-based case control study, 48 women with primary biliary cirrhosis (25 with cirrhosis), 12 with chronic hepatitis C matched by age and severity of disease, and 55 age-matched healthy women were identified. Mononuclear cells from the peripheral blood of patients and controls were isolated. Telomere length and telomerase activity were measured. RESULTS: Telomere length and telomerase activity did not differ between cases (5.9 ± 1.5 kb) and controls (6.2 ± 1.4 kb, pc=0.164). Telomere shortening and advanced-stage disease strongly correlated with telomerase activity. Patients with advanced disease retained significantly less telomerase activity than those with early-stage disease (0.6 ± 0.9 OD vs. 1.5 ± 3.7 OD, p=0.03). Telomere loss correlated with age, suggesting premature cellular ageing in patients with primary biliary cirrhosis. CONCLUSION: Our data strongly support the telomere hypothesis of human cirrhosis, indicating that telomere shortening and telomerase activity represent a molecular mechanism in the evolution of human cirrhosis in a selected population of patients.

Infiltration of inflammatory cells expressing mitochondrial proteins around bile ducts and in biliary epithelial layer may be involved in the pathogenesis in primary biliary cirrhosis.

AIMS: Serum antimitochondrial antibodies are characteristic in most patients with primary biliary cirrhosis (PBC); however, the significance of antimitochondrial antibodies in the pathogenesis of PBC remains unclear. We examined the extent and types of mitochondrial protein-expressing inflammatory cells and its association with deregulated autophagy of mitochondria in biliary epithelial lesions in PBC. METHODS: We examined the expression of pyruvate dehydrogenase complex-E2 component and a mitochondrial protein cytochrome c oxidase, subunit I in inflammatory cells in livers taken from patients with PBC (n=35) and control livers (n=64) including primary sclerosing cholangitis. Mitochondrial protein-expressing inflammatory cells were characterised by double immunofluorescence with surface markers. RESULTS: Infiltration of mitochondrial protein-expressing inflammatory cells was mainly observed in portal tracts and in the biliary epithelial layer and around the damaged small bile ducts in PBC. The extent of infiltration in portal tracts was significantly higher in PBC and early stage of chronic viral hepatitis than normal livers. The extent of infiltration around bile ducts and in biliary epithelial layer was significantly higher in early stage of PBC than control livers. Mitochondrial protein-expressing inflammatory cells included (1) CD68 and/or myeloperoxidase -positive monocytes/macrophages and (2) CD79a, CD38, CD138, IgM-positive and/or IgG-positive plasma cells. Colocalised expression of pyruvate dehydrogenase complex-E2 component and autophagy marker light chain 3ß was observed in the inflammatory cells. CONCLUSIONS: Mitochondrial protein-expressing inflammatory cells infiltrating around the damaged bile ducts and in biliary epithelial layers may be closely associated with the pathogenesis of bile duct lesion in PBC.

Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid.

BACKGROUND & AIMS: Ursodeoxycholic acid (UDCA) is the standard treatment for primary biliary cirrhosis (PBC) but excellent response is not observed in all cases. Since potential favourable effects of fibrates have been reported in short series with inconclusive results, we have carried out a pilot study to analyse the effects of bezafibrate in patients with suboptimal response to UDCA. METHODS: Thirty women (age 52.3 ± 2.3 years) treated with UDCA and abnormal alkaline phosphatase (AP) levels received bezafibrate (400 mg/d) for 1 year. Changes were measured every 3 months during the study period of 12 months, 3 months after discontinuation and 3 months after resuming bezafibrate. RESULTS: Two patients discontinued the treatment after few days, three at 6 and one at 9 months. Bezafibrate treatment resulted in a significant decrease in AP as early as 3 months. Normalization or decrease of AP below 1.5 times normal levels was observed in 13 and 4 patients respectively. There was also a significant decrease in γ-glutamyl transferase and alanine aminotransferase, cholesterol and triglyceride levels. Bezafibrate treatment resulted in significant improvement of pruritus. A rebound in liver biochemistries and pruritus occurred upon drug discontinuation, changes which improved again after resuming bezafibrate. Response to bezafibrate was associated with lower liver stiffness and severity of cholestasis. No severe adverse effects were observed. CONCLUSIONS: Combination treatment of bezafibrate and UDCA is associated with marked decrease or normalization of alkaline phosphatase as early as 3 months in patients with PBC. Better biochemical response was observed in patients with early disease and lower cholestasis.

Regulation of dipeptidyl peptidase 8 and 9 expression in activated lymphocytes and injured liver.

AIM: To investigate the expression of dipeptidyl peptidase (DPP) 8 and DPP9 in lymphocytes and various models of liver fibrosis. METHODS: DPP8 and DPP9 expression were measured in mouse splenic CD4⁺ T-cells, CD8⁺ T-cells and B-cells (B220⁺), human lymphoma cell lines and mouse splenocytes stimulated with pokeweed mitogen (PWM) or lipopolysaccharide (LPS), and in dithiothreitol (DTT) and mitomycin-C treated Raji cells. DPP8 and DPP9 expression were measured in epidermal growth factor (EGF) treated Huh7 hepatoma cells, in fibrotic liver samples from mice treated with carbon tetrachloride (CCl4) and from multidrug resistance gene 2 (Mdr2/Abcb4) gene knockout (gko) mice with biliary fibrosis, and in human end stage primary biliary cirrhosis (PBC). RESULTS: All three lymphocyte subsets expressed DPP8 and DPP9 mRNA. DPP8 and DPP9 expression were upregulated in both PWM and LPS stimulated mouse splenocytes and in both Jurkat T- and Raji B-cell lines. DPP8 and DPP9 were downregulated in DTT treated and upregulated in mitomycin-C treated Raji cells. DPP9-transfected Raji cells exhibited more annexin V⁺ cells and associated apoptosis. DPP8 and DPP9 mRNA were upregulated in CCl4 induced fibrotic livers but not in the lymphocytes isolated from such livers, while DPP9 was upregulated in EGF stimulated Huh7 cells. In contrast, intrahepatic DPP8 and DPP9 mRNA expression levels were low in the Mdr2 gko mouse and in human PBC compared to non-diseased livers. CONCLUSION: These expression patterns point to biological roles for DPP8 and DPP9 in lymphocyte activation and apoptosis and in hepatocytes during liver disease pathogenesis.

Apotopes and innate immune system: novel players in the primary biliary cirrhosis scenario.

Our understanding of primary biliary cirrhosis has been rapidly growing over the past decade and the disease is now regarded as a model for other female-predominant, organ-specific autoimmune conditions. Primary biliary cirrhosis ensues from a multi-lineage loss of tolerance to the E2 component of the pyruvate dehydrogenase complex. One of the major unanswered questions in the pathogenesis of primary biliary cirrhosis is the specificity of small intrahepatic bile ducts attack while PDC-E2 is present in mitochondria of all nucleated cells. Recent findings suggest that the uniqueness of the primary target tissue, biliary epithelium, may be of considerable importance for understanding primary biliary cirrhosis and that the biliary epithelial cell is more than an innocent victim. Rather, it attracts an immune attack by virtue of the unique apoptotic mechanisms and by the way it handles PDC-E2. Moreover, recent evidence suggests that apoptotic bodies of biliary epithelial cell are able to activate the innate immune system in the presence of anti-mitochondrial antibodies. This review article is intended to provide a critical overview of the role of apoptosis in biliary epithelial cells, the activation of the innate immune system, and its biological and clinical significance in primary biliary cirrhosis.

Approach to a patient with elevated serum alkaline phosphatase.

Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases.

Ursodeoxycholic acid is conjugated with taurine to promote secretin-stimulated biliary hydrocholeresis in the normal rat.

BACKGROUND & AIMS: Secretin induces bicarbonate-rich hydrocholeresis in healthy individuals, but not in untreated patients with primary biliary cirrhosis (PBC). Ursodeoxycholic acid (UDCA)--the first choice treatment for PBC--restores the secretin response. Compared with humans, secretin has poor effect in experimental normal-rat models with biliary drainage, although it may elicit hydrocholeresis when the bile-acid pool is maintained. In view of the benefits of UDCA in PBC, we used normal-rat models to unravel the acute contribution of UDCA (and/or taurine-conjugated TUDCA) for eliciting the biliary secretin response. METHODS: Intravascular and/or intrabiliary administration of agonists and inhibitors was performed in normal rats with biliary monitoring. Secretin/bile-acid interplay was analyzed in 3D cultured rat cholangiocytes that formed expansive cystic structures with intralumenal hydroionic secretion. RESULTS: In vivo, secretin stimulates hydrocholeresis upon UDCA/TUDCA infusion, but does not modify the intrinsic hypercholeretic effect of dehydrocholic acid (DHCA). The former effect is dependent on microtubule polymerization, and involves PKCα, PI3K and MEK pathways, as shown by colchicine (i.p.) and retrograde biliary inhibitors. In vitro, while secretin alone accelerates the spontaneous expansion of 3D-cystic structures, this effect is enhanced in the presence of TUDCA, but not UDCA or DHCA. Experiments with inhibitors and Ca(2+)-chelator confirmed that the synergistic effect of secretin plus TUDCA involves microtubules, intracellular Ca(2+), PKCα, PI3K, PKA and MEK pathways. Gene silencing also demonstrated the involvement of the bicarbonate extruder Ae2. CONCLUSIONS: UDCA is conjugated in order to promote secretin-stimulated hydrocholeresis in rats through Ae2, microtubules, intracellular Ca(2+), PKCα, PI3K, PKA, and MEK.

Causes and evaluation of mildly elevated liver transaminase levels.

Mild elevations in levels of the liver enzymes alanine transaminase and aspartate transaminase are commonly discovered in asymptomatic patients in primary care. Evidence to guide the diagnostic workup is limited. If the history and physical examination do not suggest a cause, a stepwise evaluation should be initiated based on the prevalence of diseases that cause mild elevations in transaminase levels. The most common cause is nonalcoholic fatty liver disease, which can affect up to 30 percent of the population. Other common causes include alcoholic liver disease, medication-associated liver injury, viral hepatitis (hepatitis B and C), and hemochromatosis. Less common causes include α(1)-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) can also cause elevated liver transaminase levels. Initial testing should include a fasting lipid profile; measurement of glucose, serum iron, and ferritin; total iron-binding capacity; and hepatitis B surface antigen and hepatitis C virus antibody testing. If test results are normal, a trial of lifestyle modification with observation or further testing for less common causes is appropriate. Additional testing may include ultrasonography; measurement of α(1)-antitrypsin and ceruloplasmin; serum protein electrophoresis; and antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody type 1 testing. Referral for further evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for six months or more.

[No complaints, but constantly elevated cholestatic serum liver tests]. / (Fast) beschwerdefreie Patientin, aber konstant erhöhte Cholestaseparameter.

A 75 year old woman presented with long-lasting pruritus and elevation of serum levels of alkaline phosphatase and gamma-glutamyl transpeptidase (GGT). Potentially hepatotoxic drugs were stopped; an abdominal ultra-sonography was normal. Antimitochondrial antibodies were elevated and are the serologic hallmark of primary biliary cirrhosis. The disease can progress from an asymptomatic inflammation to a cirrhosis. The disease-modifying treatment consists in ursodeoxycholic acid 13-15 mg/kg per day. Concomitant to the primary biliary cirrhosis hypothyroidism, osteoporosis, malabsorption and dyslipidemia can occur.

When and how to evaluate mildly elevated liver enzymes in apparently healthy patients.

Because 1% to 9% of people without symptoms have elevated liver enzymes, extensive evaluation of all abnormal test results would expose many patients to undue risks and expenses. On the other hand, failure to evaluate minor liver enzyme elevations could mean missing the early diagnosis of potentially treatable disorders. This review discusses likely causes of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase levels and provides algorithms for evaluating high liver enzyme values in apparently healthy patients in the primary care setting.

Pharmacological treatment of biliary cirrhosis with ursodeoxycholic acid.

IMPORTANCE OF THE FIELD: Primary biliary cirrhosis is a cholestatic liver disease that at one time was the leading indication for liver transplantation. Treatment with ursodeoxycholic acid has clearly improved the natural history of primary biliary cirrhosis. AREAS COVERED IN THIS REVIEW: The treatment of primary biliary cirrhosis with a focus on ursodeoxycholic acid is covered. Papers related to treatment of primary biliary cirrhosis and associated conditions, using a variety of drugs but with a focus on ursodeoxycholic acid, are included. The papers reviewed date from 1984 - 2009. WHAT WILL THE READER GAIN: The reader will gain an up-to-date understanding of current treatment strategies for primary biliary cirrhosis using ursodeoxycholic acid and an appreciation of what conditions are improved with this therapy and what associated conditions are not. TAKE-HOME MESSAGE: Ursodeoxycholic acid in a dose of 13 - 15 mg/kg/day should be considered in all patients with primary biliary cirrhosis who have abnormal liver enzymes.

Predictive value of aspartate aminotransferase to alanine aminotransferase ratio for hepatic fibrosis and clinical adverse outcomes in patients with primary biliary cirrhosis.

BACKGROUND: The aspartate aminotransferase to alanine aminotransferase ratio (AAR) was seldom applied for fibrosis assessment in primary biliary cirrhosis (PBC) patients. GOALS: To validate the AAR for evaluating hepatic fibrosis, disease severity, and prognosis in patients with PBC. STUDY: Ninety-two consecutive PBC patients were retrospectively evaluated to validate the AAR for assessing the severity of liver function, the degrees of hepatic fibrosis, and predicting outcomes. RESULTS: AAR showed modest correlations to Mayo score, model for end-stage liver disease score, and Child-Pugh score (r2=0.156,P<0.001; r2=0.084, P=0.005; r2=0.142, P<0.001, respectively)in evaluating the severity of liver function. For 46 patients who underwent liver biopsy, 35 were in early stage fibrosis and the other 11 were in advanced fibrosis. AAR was significantly higher in patients with advanced fibrosis than those with early fibrosis (mean+/-standard deviation; 1.40+/-0.44 vs. 0.98+/-0.65,P=0.001). The AAR yielded the highest area under the receiver operating curve of 0.847 than Mayo score, model for end-stage liver disease score, and Child-Pugh score in predicting advanced fibrosis. During a median follow-up of 44.5 months, 24 patients expired and 68 patients were alive. Patients with an AAR of 1 or less had significantly better prognosis than their counterparts(P=0.043). CONCLUSIONS: AAR is a simple and reliable marker to assess liver function and hepatic fibrosis as well as to predict outcomes in PBC patients.

Portal hypertension and primary biliary cirrhosis: effect of long-term ursodeoxycholic acid treatment.

BACKGROUND & AIMS: Portal hypertension can complicate primary biliary cirrhosis, but studies evaluating the direct measurement of the portohepatic gradient (PHG) are rare. The aim of the study was to determine the prevalence and prognostic value of portal hypertension in patients treated with ursodeoxycholic acid. METHODS: A total of 132 patients from a local "PBC clinic" were enrolled in this cohort study. The PHG and biochemical values were measured at inclusion and every 2 years. Factors associated with survival were analyzed. RESULTS: Mean PHG at inclusion was 7.2 +/- 5.8 mm Hg. It was higher than normal (6 mm Hg) in 46 patients (34.9%) and higher than 12 mm Hg (variceal bleeding risk limit) in 26 patients (19.7%). There was a difference between the 3 subgroups in the probability of survival free of liver transplantation (P < .0003). After 2 years of treatment, a decreased or stable PHG (hazard ratio, 4.64; 95% confidence interval, 2.01-10.72) and normalization of aspartate aminotransferase (AST) level (hazard ratio, 2.89; 95% confidence interval, 1.03-8.05) were predictive of better survival on multivariate analysis. "Responders" (stable or improved PHG and normalized AST level at 2 years) have a 15-year survival similar to that of a control Quebec female population. CONCLUSIONS: Significant portal hypertension is a common complication of primary biliary cirrhosis. Changes in the PHG and normalized AST level after 2 years of ursodeoxycholic acid treatment can be used to identify a subgroup of responders with survival comparable to that of a control population.