Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.Financial support has been received by National Institute of Health Research (RD-TRC and Birmingham Biomedical Research Centre), Isaac Newton Trust, Addenbrooke’s charitable trust, Norwegian PSC Research Center and PSC Support. GMH is supported by the Lily and Terry Horner Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease, Toronto

Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young).

CEL-MODY is a monogenic form of diabetes with exocrine pancreatic insufficiency caused by mutations in CARBOXYL-ESTER LIPASE (CEL). The pathogenic processes underlying CEL-MODY are poorly understood, and the global knockout mouse model of the CEL gene (CELKO) did not recapitulate the disease. We therefore aimed to create and phenotype a mouse model specifically over-expressing mutated CEL in the pancreas.We established a monotransgenic floxed (flanking LOX sequences) mouse line carrying the human CEL mutation c.1686delT and crossed it with an elastase-Cre mouse to derive a bitransgenic mouse line with pancreas-specific over-expression of CEL carrying this disease-associated mutation (TgCEL). Following confirmation of murine pancreatic expression of the human transgene by real-time quantitative PCR, we phenotyped the mouse model fed a normal chow and compared it with mice fed a 60% high fat diet (HFD) as well as the effects of short-term and long-term cerulein exposure.Pancreatic exocrine function was normal in TgCEL mice on normal chow as assessed by serum lipid and lipid-soluble vitamin levels, fecal elastase and fecal fat absorption, and the normoglycemic mice exhibited normal pancreatic morphology. On 60% HFD, the mice gained weight to the same extent as controls, had normal pancreatic exocrine function and comparable glucose tolerance even after resuming normal diet and follow up up to 22 months of age. The cerulein-exposed TgCEL mice gained weight and remained glucose tolerant, and there were no detectable mutation-specific differences in serum amylase, islet hormones or the extent of pancreatic tissue inflammation.In this murine model of human CEL-MODY diabetes, we did not detect mutation-specific endocrine or exocrine pancreatic phenotypes, in response to altered diets or exposure to cerulein

Bile Acid Profiles in Primary Sclerosing Cholangitis and their Ability to Predict Hepatic Decompensation

Background and Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. Approach and Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials

Pancreatic exocrine function in chow-fed TgCEL and control mice at 7 months of age.

<p>Values are mean ± SEM; ns, not significant; NA, not available.</p

Characteristics of mice subjected to the short-term cerulein protocol.

<p>(A) Serum amylase levels by the time of sacrification of the mice. (B) Pancreatic weight (grams) by the time of sacrification of the mice. (C) Pancreatic morphology in TgCEL or Control mice injected with cerulein or with PBS (HE staining).</p

Characteristics of mice subjected to the long-term cerulein protocol.

<p>(A) Weight (grams) development during the chronic cerulein protocol in TgCEL mice and control mice subjected to cerulein or PBS. (B). Serum glucose levels during an intraperitoneal glucose tolerance test at the time of completion of the chronic cerulein protocol. (C) Pancreatic morphology in TgCEL or control mice injected with cerulein or with PBS (HE staining).</p

Weight and glucose homeostasis in TgCEL and control mice.

<p>Controls, white bars or open circles; TgCEL mice, black bars or filled circles. Results are given as mean ± SEM. Tail or hind leg vein blood was drawn in after an overnight fast and glucose was measured by glucometer. The characteristics were assessed in chow-fed mice at 7 and 9 months of age, at 12 months of age following 12 weeks on a 60% HFD (all tests: n = 4 [males] and n = 5 [females]), and at 22 months of age in mice that had been chow-fed after the HFD challenge (n = 2 controls, 1 TgCEL [males] and n = 3 controls, 5 TgCEL [females]). There were no statistical differences in body weight between male (A) and female (B) mice. Body weights increased during a 12-week challenge with a 60% HFD, but there were no differences in body weight development between TgCEL and control mice in male (C) and female mice (D). Fasting blood glucose levels also increased after 12 weeks of HFD but there were no differences in fasting blood glucose levels between TgCEL and control mice at any age in male (E) and female mice (F). A glucose tolerance test was performed in male mice (G, H, I, J) and female mice (K, L, M, N) after a 12–14 hr fast by i.p. injection of glucose (2 g per kg bodyweight). The test was performed in chow-fed mice at 7 months (G, K) and 9 months (H, L) of age, at 12 months (I, M) of age following 12 weeks of a 60% HFD. Although the 60% HFD increased glucose intolerance compared to baseline (9 months), there were no differences between TgCEL mice and controls in any of the groups.</p

Serum levels of insulin, C-peptide, glucagon, GLP-1, amylin and leptin after long-term cerulein exposure.

<p>Serum levels of insulin, C-peptide, glucagon, GLP-1, amylin and leptin after long-term cerulein exposure.</p

Insulin homeostasis and pancreatic morphology in TgCEL and control mice.

<p>Controls, white bars or open circles; TgCEL mice, black bars or filled circles. Results are given as mean ± SEM. Insulin was measured by ELISA. An insulin tolerance test was performed by i.p. injection of insulin (1.5 [males] or 1.0 [females] U/kg b.wt.) in 12 months old male (A) and female (B) mice. No differences were detected between the TgCEL and control mice. For 7 months old chow-fed mice, there were no statistical differences in fed or fasting plasma insulin levels in male (C) or (D) female mice. Similarly, we observed no differences in stimulated plasma insulin levels in female mice as demonstrated by a glucose-stimulated insulin secretion test by actual insulin values (E) or by percent change after glucose injection (F). Islet size and number as well as the organization of the exocrine pancreatic tissue were normal in HE-stained sections from TgCEL mice (G) and not different from controls (H) at 8 months of age.</p