The biochemical response to ursodeoxycholic acid (UDCA)—so‐called “treatment response”—strongly predicts long‐term outcome in primary biliary cholangitis (PBC). Several long‐term prognostic models ...based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long‐term prognostic models of PBC using data from the UK‐PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA‐treated participants. We used nonautomatic backward selection to derive the best‐fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver‐related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA‐treated participants. The best‐fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5‐, 10‐, and 15‐year risk scores were highly accurate (areas under the curve: >0.90). Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK‐PBC risk scores. They may be used to identify high‐risk patients for closer monitoring and second‐line therapies, as well as low‐risk patients who could potentially be followed up in primary care. (Hepatology 2016;63:930–950)
Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide ...association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.
Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical ...response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters.
We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples.
2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p<0·0001), higher total bilirubin concentration (p=0·0003), lower aminotransferase concentration (p=0·0012), younger age (p<0·0001), longer interval from diagnosis to the start of UDCA treatment (treatment time lag, p<0·0001), and worsening of alkaline phosphatase concentration from diagnosis (p<0·0001). Based on these variables, we derived a predictive score of UDCA response. In the external validation cohort, 460 patients diagnosed with primary biliary cholangitis were treated with UDCA, with follow-up data until May 31, 2016. In this validation cohort, the area under the receiver operating characteristic curve for the score was 0·83 (95% CI 0·79-0·87). In 20 liver biopsy samples from patients with primary biliary cholangitis, the UDCA response score was associated with ductular reaction (r=-0·556, p=0·0130) and intermediate hepatocytes (probability of response was 0·90 if intermediate hepatocytes were absent vs 0·51 if present).
We have derived and externally validated a model based on pretreatment variables that accurately predicts UDCA response. Association with histological features provides face validity. This model provides a basis to explore alternative approaches to treatment stratification in patients with primary biliary cholangitis.
UK Medical Research Council and University of Milan-Bicocca.
To assess the changing distribution of disease within the large bowel in patients presenting with ulcerative proctitis or proctosigmoiditis. To evaluate the influence of clinical exacerbations, ...smoking, parity and family history in disease extension.
Retrospective single-centre study in a university hospital.
Case records of patients presenting over a 40-year period were examined to evaluate the clinical course and disease distribution from initial presentation to final follow-up. For each patient whose disease extended to the more proximal colon, an age- and sex-matched control patient was identified whose disease remained confined to the original site. Patients completed a questionnaire to provide information on family history, smoking and parity. The differences in clinical exacerbations, family history, smoking and parity were then compared between the two groups.
Among 145 patients presenting with proctitis or proctosigmoiditis followed prospectively for a median period of 10.9 years, the disease extended in 53 patients. Using actuarial methods the disease progressed beyond the rectosigmoid area in 16% of patients at 5 years and 31% at 10 years. Among the patients whose disease progressed, progression was preceded in 68% of cases by a clinical exacerbation of the colitis. When patients whose disease progressed were compared with those whose disease remained confined to the original site, no differences were detected in the number of clinical exacerbations, smoking habit, family history or parity.
The factors that are associated with the extension of colitis are probably different from those that predisposed an individual to develop inflammatory bowel disease initially.
Background. Emergency admissions account for 40% of National Health Service bed usage. Recent policy is to increase the role of intermediate care, which includes the use of community hospitals (CHs). ...However, the proposed expansion presumes that CH care is as effective as acute hospital care. No direct comparison of outcomes between CHs and district general hospitals (DGHs) has been undertaken. Objectives. The aim of this study was to compare patient-based outcomes at 6 months following emergency admission to a DGH or CH. Methods. We designed a prospective cohort study, with strict eligibility criteria. The study was set in one DGH and five CHs in Devon, UK. Study participants were people aged >70 years with an acute illness requiring hospital admission, but whose condition could have been treated in either hospital setting. A cohort of people admitted to each setting was identified and followed-up for 6 months. The primary outcome measure was change in quality of life 6 months after admission, as measured by SF-36 and EuroQol. Secondary outcome measures were death, readmission and place of residence at 6 months. The use of drugs and investigations during the hospital stay were also measured. Results. A total of 376 patients were recruited and completed baseline measures, 254 of whom were followed-up at the 6-month stage (136 CH, 118 DGH). There were no differences in outcome between settings, with a small increase in quality of life scores at 6 months in both cohorts: the mean change in EuroQol 5D in CH was 6.6 points (95% confidence interval, 2.8–10.4) and in DGH was 6.5 (2.4–10.7); P = 0.97. Mortality and place of residence at 6 months were similar in the two groups. The numbers of investigations (median CH four investigations, DGH 22; P < 0.001) and of prescribed medications during the hospital stay (median CH eight drugs, DGH 11; P < 0.001) were significantly higher in the DGH. Conclusions. The quality of life and mortality in the CH cohort was similar to those in the DGH cohort. CH care can be used as an alternative to DGH care for a wide range of conditions requiring emergency admission.
In previous studies, intrahepatic human biliary epithelial cells (BEC) were isolated in high purity. However, these cells demonstrated only limited growth responses. Here we report that human BEC ...proliferate in response to human hepatocyte growth factor (hHGF), retain BEC-specific phenotype, and can be serially passaged. BEC showed dose-dependent growth in response to 0.01-100 ng/ml hHGF. The maximum S-phase labeling index reached 40% with half-maximal stimulation at 1 ng/ml. The response of cells from normal and primary biliary cirrhotic liver to hHGF was similar. Cultures were immunostained with specific antibodies and then processed for 3Hthymidine autoradiography. Proliferating cells expressed BEC-specific markers (HEA125 and CK-19), but were negative for desmin and factor VIII-related antigen. Occasional vimentin-positive cells were observed, but these were nonproliferative. In conclusion, cells responding to hHGF were clearly BEC in origin. The observation that HGF is mitogenic for BEC as well as hepatocytes has important implications. First, greater yields of intrahepatic BEC are available for subsequent studies of the pathogenesis and etiology of diseases of the biliary epithelium. Secondly, some means of regulating the cellular response to HGF in vivo must operate, in that HGF levels rise early after partial hepatectomy and yet BEC proliferate 24 h later than hepatocytes.
The leucocyte adhesion molecule intercellular adhesion molecule–1 is induced on bile ducts in patients with primary biliary cirrhosis and primary sclerosing cholangitis and may be involved in ...targeting immune damage to these structures. It has recently been reported that, when activated, in vitro lymphocytes release a soluble form of intercellular adhesion molecule–1 that can also be detected in human serum. Because it is functionally active, this circulating intercellular adhesion molecule–1 might play a role in regulating inflammation by blocking adhesion. We used an enzyme‐linked immunosorbent assay to detect circulating intercellular adhesion molecule‐1 in the serum of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Levels of circulating intercellular adhesion molecule–1 were markedly elevated in primary biliary cirrhosis and primary sclerosing cholangitis when compared with other chronic liver diseases. Circulating intercellular adhesion molecule–1 is probably derived from activated lymphocytes rather than from bile ducts because biliary epithelial cells from patients with primary biliary cirrhosis did not release circulating intercellular adhesion molecule–1 when stimulated to express the membrane‐bound molecule in vitro. These studies are the first to demonstrate circulating intercellular adhesion molecule–1 in chronic inflammatory diseases that are characterized by strong tissue expression of intercellular adhesion molecule–1 and as such suggest a potential immunoregulatory role for circulating adhesion molecules. The very high levels detected in primary biliary cirrhosis and primary sclerosing cholangitis probably reflect lymphocyte activation, which is further evidence of immune pathogeneses for these diseases. (HEPATOLOGY 1992;16:810–814.)
Previous human studies in renal transplant recipients have shown a lower incidence of acute rejection and cyclosporine-associated acute nephrotoxicity when prostaglandins are administered in ...conjunction with standard immunosuppressants. This study evaluates the effects of enisoprost (EP), a synthetic PGE methyl ester analog, in a single-center, prospective, randomized, double-blind, placebo-controlled, parallel group trial in 81 consecutive adult patients undergoing orthotopic liver transplantation (OLT). The subjects received EP 100 mg p.o. t.i.d. (n = 40) or placebo (n = 41) for the first 12 weeks after OLT. Immunosuppression was based on cyclosporine, azathioprine, and corticosteroids. Effective renal plasma flow and glomerular filtration rate were determined at 4 and 12 weeks after OLT. Eighty-one patients entered the study; sixty-six patients completed the 16-week study period. There were no statistically significant differences between EP- and placebo-treated groups at 12 weeks for creatinine clearance, glomerular filtration rate, and effective renal plasma flow. At least 1 episode of cyclosporine nephrotoxicity occurred in 7/40 patients (17.5%) in the EP group compared with 9/41 patients (20.0%) in the placebo group (P = 0.781). There was no significant difference in the incidence of graft rejection episodes in the 2 groups. Enisoprost, as used in this study, does not have any beneficial effect on renal function or incidence of rejection in OLT recipients.
From the New York Gazette, Nov. 20 Wagstaff, David; Haines, Reuben; Israel, Dean ...
American farmer (Baltimore, Md. : 1819),
12/1820, Letnik:
2, Številka:
39
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