89 research outputs found
Monogenic diabetes and pancreatic exocrine dysfunction in mouse and man
No full textExocrine and endocrine pancreatic disease is often observed to occur together. The close colocalization of the endocrine and exocrine tissues within one organ, as well as their common embryological ancestry, have given rise to hypotheses concerning the pathogenesis of such diseases. However, often two questions remain: Which cell type is the origin of the disease? And what is the fundamental pathological process? Principally, there are three possible sites of action in combined exocrine and endocrine pancreatic disease: The exocrine cells, the endocrine cells, or the common progenitor cells. In order to investigate the association between exocrine function and diabetes further, we studied exocrine and endocrine function as well as pancreatic structure in three different contexts: HNF1A-MODY, HNF1B-MODY and CEL-MODY. Exocrine dysfunction and a striking association with pancreatic atrophy have been reported in HNF1B mutation carriers. Mouse studies have revealed an essential function of Hnf1b in pancreatic development and mouse embryos deficient of Hnf1b exhibit a rudimentary dorsal pancreatic bud. In Paper III, we describe exocrine dysfunction and absence of tissue corresponding to the pancreatic body and tail as evaluated by CT and MRCP in five individuals from two families with HNF1B mutations. Our observations strengthen the evidence for a critical role of HNF1B in the normal development and differentiation of the pancreas and support the notion that HNF1B mutations cause diabetes and exocrine dysfunction based on congenital malformation. HNF1A and HNF1B encode closely related transcription factors, and a similar phenotype for exocrine dysfunction and pancreas structure could be expected. Furthermore, exocrine dysfunction has been observed in 10-30 % of type 1 and 2 diabetes patients, and reduced pancreatic volume has been well described in type 1 diabetes and to some degree in type 2 diabetes. In Paper I we describe for the first time the prevalence of pancreatic exocrine dysfunction in a cohort of patients with HNF1A-MODY. The data in Paper I indicate that 13 % of adult HNF1A-MODY patients had exocrine dysfunction. This was similar to results from the type 1 diabetes control group (19 %) and in line with previous findings in type 1 and 2 diabetic patients, but three times higher than that in nondiabetic controls (4 %). The strong association between endocrine and exocrine dysfunctions as that observed in HNF1BMODY was not paralleled in HNF1A-MODY. In Paper II, we showed that HNF1A-MODY patients had reduced pancreatic volume compared to non-diabetic controls, mimicking the pancreatic volume reduction in type 1 diabetes. Taken together, the findings in Papers I and II indicate that the prevalence of exocrine dysfunction and the structural changes of the pancreas in HNF1A-MODY are different from that characterizing HNF1B-MODY, but similar to that observed in type 1 diabetes, and likely due to insulinopenia. Pancreatic exocrine dysfunction as expressed by fecal elastase deficiency in subjects with diabetes has been claimed to be moderate and clinically irrelevant. This is contradicted by our finding of pathologically high fat excretion in all of the available six patients with fecal elastase deficiency and HNF1A-MODY, 14 out of 17 type 1 diabetes subjects, one of three available type 2 diabetes subjects (Papers I and II), and in seven out of nine subjects with CEL-MODY (Paper IV). Our results support previous observations of a high prevalence of steatorrhea in subjects with diabetes and fecal elastase deficiency. All of our CEL-MODY patients had pathologically low vitamin E levels. Osteopenia or osteoporosis was frequently found, possibly as sequela of undiagnosed exocrine dysfunction. Pancreatic enzyme supplements constitute the main treatment of maldigestion in pancreatic exocrine insufficiency, but the effect on glycemic control in the presence of diabetes has been debated. We studied the effects of enzyme replacement therapy in nine subjects with diabetes and exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL). They experienced immediate alleviation of symptoms, fecal fat excretion was reduced, and vitamin E levels increased. We found no effect of pancreatic enzyme supplements on glycemic control, suggesting that such treatment is safe in a context of diabetes. CEL-MODY is a syndrome of monogenic diabetes and pancreatic dysfunction due to CEL mutations. Diabetes is believed to arise secondary to exocrine dysfunction in CEL-MODY, but the pathogenetic processes are unclear. Investigating a loss-of-function mechanism, we studied the global knockout model (CELKO; Paper V). Female CELKO mice developed mild random fed hyperglycemia and islet hyperplasia; however, no clear phenotype resembling CEL-MODY was demonstrated. In order to explore the hypothesis that disease develop due to an altered cellular function of the mutant protein, we created and studied the TgCEL mouse line expressing the Del1 disease-associated human CEL allele (Paper VI). The mice did not exhibit any endocrine or exocrine dysfunction, however. Further studies remain to be done, particularly to explore the effects of mutant human CEL in a transgenic mouse line
Når veien må tilpasses målet: Bakgrunn, plan og evaluering for revidert studieplan i propedeutikk for medisinstudentutdanningen
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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities
No full textPrimary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics
Liver Elastography in Primary Sclerosing Cholangitis Patients Using Three Different Scanner Systems
No full textThe aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE
In Vitro Comparison of Five Different Elastography Systems for Clinical Applications, Using Strain and Shear Wave Technology
No full textAbstractSeveral different platforms providing ultrasound elastography have emerged in recent years. In this in vitro study on a single tissue-mimicking phantom (CIRS Model 49), we aimed to compare the performance of quantitative elastography measurements from platforms running strain elastography and others running shear wave elastography. We evaluated five different elastography platforms using both linear and curvilinear probes. All measurements were performed in parallel by two independent investigators who recorded the elasticity quantitatively. We investigated intra- and inter-observer agreement by intra-class correlation analysis and coefficient of variation, by correlation and limits of agreement. The reproducibility of elasticity measurements was good to excellent for shear wave and strain elastography. All five elastography platforms had high intra-observer (intra-class correlation coefficient: 0.932–1.0) and inter-observer correlation (intra-class correlation coefficient: 0.845–0.996). All inclusions could be differentiated by quantitative elastography by all systems (p < 0.001). The use of a linear probe yielded more reproducible measurements compared with use of a convex probe in 3/4 platforms
Whole blood RNA sequencing identifies transcriptional differences between primary sclerosing cholangitis and ulcerative colitis
No full textBackground & Aims: Genetic and microbiome studies across patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) have indicated that UC in PSC is a separate disease entity to primary UC, but expression studies for PSC are lacking.
Methods: We conducted whole blood RNA sequencing experiments for 495 patients with UC, 220 patients with PSC (including 177 with UC), and 320 healthy controls from Germany and Norway. Differential expression analyses, gene ontology and coexpression analyses and random forest machine learning were performed to identify genes, ontologies and transcriptional features that discriminate diagnoses.
Results: The blood transcriptome in UC and PSC is dominated by neutrophil activation genes (e.g. S100A12). In UC, but not in PSC (neither PSC alone nor patients with an additional diagnosis of UC [PSC/UC]), ribosomal, mitochondrial, and energy metabolism genes are upregulated in conjunction with antibody transcript expression (MZB1, IGJ). In PSC, there is an increase in modules related to apoptosis and expression of genes of interferon-I-related ontologies. Random forest analysis could poorly discriminate PSC alone from PSC/UC (AUROC 0.56), but could discriminate PSC, UC, and controls with high accuracy (AUROC UC vs. controls 0.95, PSC vs. controls 0.88, UC vs. PSC 0.986). The main coexpression modules relevant for distinguishing PSC, UC, and controls are enriched in neutrophil degranulation and antibody production genes.
Conclusions: Supported by machine learning results, PSC and UC appear to be separate entities on a molecular level, while PSC/UC and PSC are indistinguishable.
Impact and implications: Clinical and genetic studies suggest that the colitis-like symptoms in primary sclerosing cholangitis (PSC) represent a different disease entity from primary ulcerative colitis (UC). The present study supports this assumption with transcriptomic data from whole blood and describes notable differences in gene expression between primary UC and PSC, providing insights into the still unclear pathophysiology of both diseases. These findings are of interest to scientists seeking to decipher the molecular pathophysiology of both diseases and provide evidence that a redefinition of the PSC-UC phenotype should be considered. The study practically supports future molecular research by providing a large transcriptomic whole blood reference cohort.publishedVersio
Ultrasound and Point Shear Wave Elastography in Livers of Patients with Primary Sclerosing Cholangitis
No full textAbstractPoint shear wave elastography (pSWE) is an ultrasound-based method for non-invasive quantification of liver fibrosis. The objective of this study was to explore liver pSWE in patients with primary sclerosing cholangitis (PSC) for assessment of fibrosis. Fifty-five non-transplant patients with PSC (38 males, 17 females; mean age: 46.4 y) were included and compared with 24 matched controls. Median (range) PSC duration was 8.1 (0–33) y. Ultrasonographic scanning followed by liver stiffness measurement by pSWE was performed using a conventional ultrasound system (Philips iU22). Signs of liver fibrosis on B-mode were identified in 21 patients (38%). Splenomegaly was found in 19 patients (35%) and ascites in two patients (4%). Successful pSWE measurements were achieved in the right liver lobe of all individuals and in the left liver lobe of 36 patients (65.5%). PSC patients had significantly higher median shear wave velocity (SWV) than controls in the right liver (median [range] SWV 1.26 [0.73–2.57] m/s vs. 1.09 [0.88–1.25] m/s, p < 0.001). SWV measured in the left liver lobe and spleen did not differ between PSC patients and controls. Our findings indicate that PSC patients have increased median SWV, indicating more fibrosis compared with controls; however, a wide range of SWV values were obtained among PSC patients, possibly reflecting the various stages in disease development
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