There is scarce information about risk factors for exocrine pancreas insufficiency (EPI) in chronic pancreatitis (CP), and how it associates with other complications. The aim of the present study was ...to examine risk factors for EPI and associations to procedures and other CP related complications in a large, Northern European cohort.
We retrieved cross-sectional data on demographics, status on EPI, aetiological risk factors for CP, CP related complications as well as surgical and endoscopic treatment from the Scandinavian Baltic Pancreatic Club Database. Associations were assessed by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals.
We included 1869 patients with probable or definitive CP in the study. Exocrine pancreas insufficiency was present in 849 (45.4%) of patients. In multivariate analyses, EPI associated with smoking aetiology (OR 1.47 (1.20–1.79), p < 0.001), and nutritional/metabolic aetiology (OR 0.52 (0.31–0.87), p = 0.01) to CP. Pancreatic or common bile duct stenting procedure and pancreatic resection were both associated with EPI (ORs 1.44 (1.15–1.80), p = 0.002 and 1.54 (1.02–2.33), p = 0.04, respectively). The presence of diabetes mellitus (OR 2.45 (1.92–3.15), p < 0.001), bile duct stenosis (OR 1.48 (1.09–2.00), p = 0.02) and underweight (2.05 (OR 1.40–3.02), p < 0.001) were all associated with presence of EPI.
Smoking, bile duct stenosis, previous stenting and resection procedures are all associated with EPI in patients with CP. Presence of EPI were also associated with malnutrition and diabetes mellitus. Hence, intensive nutritional surveillance is needed in these patients.
Indications and diagnostic yield of small-bowel video capsule endoscopy (SB-VCE) are communicated in recent clinical academic guidelines. However, guidelines are based mainly on relatively few, ...small, selection-biased studies at experienced centers, and thus we lack information on indications and diagnostic yield of SB-VCE in the real-world community setting. The aim of the study was to evaluate indications and diagnostic yield of SB-VCE in the real-world community setting.
Our local VCE clinical database was used to identify patients undergoing SB-VCE procedures over a 7-year period (2011-2018). Patients were broadly referred and underwent SB-VCE using PillCam™ SB 2 and SB 3 capsule systems. Procedures were reviewed by local endoscopists, who had undergone similar formal SB-VCE review training. Medical reports of the procedures were composed as such. We retrospectively reviewed all reports and gathered data regarding indications and findings. Diagnostic yield was considered positive if SB-VCE visualized any type of clinically significant pathological finding.
536 SB-VCE procedures in 516 patients were included in final assessment. Patient mean (± SD) age was 50 ± 20 years with approximately even female/male ratio (275:241). The overall proportion of positive findings was 42% (225/536). The two main indications were obscure gastrointestinal bleeding (occult/anemia or overt/active, OGIB) of 46% (246/536) and definite/suspected Crohn's disease (CD) of 39% (210/536). Positive SB-VCE findings were obtained in 44% (108/246) of procedures with indication of OGIB and in 50% (104/210) of procedures with indication of CD.
The indications for SB-VCE are largely consistent with guidelines but with an apparently relatively low diagnostic yield in our real-world community setting.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AIM： To investigate the effects of troglitazone （TGZ）, an anti-diabetic drug which activates peroxisome proliferatoractivated receptor-y （PPAR-y）, for liver tissue repair, and the development of ...ductular reaction, following common bile duct ligation （BDL） in rats. METHODS： Rats were supplemented with TGZ （0.2% w/w in the pelleted food） for i wk before BDL or sham operation. Animals were killed at 1, 2, or 4 wk after surgery. RESULTS： The development of liver fibrosis was reduced in rats receiving TGZ, as indicated by significant decreases of procollagen type I gene expression and liver hydroxyproline levels. Accumulation of a-smooth-muscle actin （SMA）-expressing cells surrounding newly formed bile ducts following BDL, as well as total hepatic levels of SMA were partially inhibited by TGZ treatment, indicating the presence of a reduced number and/or activation of hepatic stellate cells （HSC） and myofibroblasts. Development of the ductular reaction was inhibited by TGZ, as indicated by histochemical evaluation and hepatic activity of γ-glutamyltransferase （GGT）. CONCLUSION： Treatment with thiazolidinedione reduces ductular proliferation and fibrosis in a model of chronic cholestasis, and suggests that limiting cholangiocyte proliferation may contribute to the lower development of scarring in this system.
Background/Aims
: Little is known about the role of fractalkine (CX3CL1) in the liver. The aim of this study was to investigate the expression patterns of fractalkine and its receptor CX3CR1 in ...normal human liver and in conditions of injury.
Methods
: Distribution and expression of fractalkine and its receptor were investigated using immunohistochemistry, in situ hybridization, flow cytometry and reverse transcriptase–polymerase chain reaction. In vitro experiments were conducted in HepG2 cells.
Results
: Both fractalkine and CX3CR1 were up-regulated during chronic injury, in areas of portal and lobular inflammation. In severe acute hepatitis, fractalkine and CX3CR1 were expressed at high levels not only in areas of inflammation but also in regenerating epithelial cells within bile duct-like structures, which showed co-expression of fractalkine and cytokeratin-7 or CX3CR1. The human hepatocarcinoma cell line HepG2 expressed fractalkine at the gene and protein level, and HepG2-conditioned medium was chemotactic for cells overexpressing CX3CR1. Transcripts for CX3CR1 were detected in HepG2, and exposure of these cells to recombinant fractalkine induced cell migration.
Conclusions
: This study shows that the fractalkine system is up-regulated during liver damage, and suggests that fractalkine may play a role in the recruitment and adhesion of inflammatory cells and in the biology of liver epithelial cells.
We aimed to describe a cohort of hereditary hemochromatosis (HH) patients from a single urban center in Copenhagen.
Retrospectively, data from patients with HH from the years 2009-2020 were ...collected.
A total of 203 patients was recorded. Males constituted 65.0% of the patients. Homozygous HH (HHH)/compound heterozygous HH (CHH) accounted for 69.4%/30.6%. HHH patients had significantly higher ferritin and transferrin saturation (TS) levels at debut than CHH patients. Fifty-five HHH patients (39.0%) had ferritin >1000 ug/L versus 9 (14.5%) in the CHH group (p < .001). Age at debut did not differ between female and male patients. Ferritin (but not TS) levels were significantly higher in male patients. The proportion of patients with ferritin >1000 did not differ between males and females. One-hundred patients (49.3%) had one or more symptoms at the time of diagnosis; arthralgias of the metacarpophalangeal joints and/or ankles (n = 46 (22.7%)), fatigue (n = 67 (33.0%)) and decreased libido (n = 20 (9.9%)). The proportion of patients with symptoms did not differ between HHH and CHH or between male and female patients. Severe organ complications (cardiomyopathy, late onset type 1 diabetes or cirrhosis) were present in 14 patients (6.9%).
We report a high proportion of compound HH, constituting almost one-third of patients. We found that the proportion of patients with symptoms did not differ between HHH and CHH and recommend that CHH should be treated and examined in the same way as HHH.
Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological ...response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO was associated with a dose-dependent increase in cell migration and chemoinvasion through Matrigel-coated filters. A checkerboard analysis showed that the effects of TPO on cell migration were dependent on both chemotaxis and chemokinesis. Exposure of HepG2 cells to TPO resulted in the activation of different members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated with increased activation of nuclear factor-kappaB. With the use of specific inhibitors, tyrosine phosphorylation and activation of PI3K were found to be required for the induction of migration in response to TPO. We conclude that TPO exerts biological actions on cultured hepatoblastoma cells via activation of c-Mpl and its downstream signaling.
Background & Aims: Proliferation and migration of hepatic stellate cells (HSCs) and expression of chemokines are involved in the pathogenesis of liver inflammation and fibrogenesis. Peroxisome ...proliferator–activated receptor (PPAR)-γ is a receptor transcription factor that controls growth and differentiation in different tissues. We explored the effects of PPAR-γ agonists on the biological actions of cultured human HSCs. Methods: HSCs were isolated from normal human liver tissue and used in their myofibroblast-like phenotype or immediately after isolation. Activation of PPAR-γ was induced with 15-deoxy-Δ12,14-prostaglandin J2 or with troglitazone. Results: PPAR-γ agonists dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signaling or expression of c-fos and c-myc and was associated with inhibition of cell cycle progression beyond the G1 phase. Activation of PPAR-γ also resulted in a complete inhibition of the expression of monocyte chemotactic protein 1 at the gene and protein levels. Comparison of quiescent and culture-activated HSCs revealed a marked decrease in PPAR-γ expression in activated cells. Conclusions: Activation of PPAR-γ modulates profibrogenic and proinflammatory actions in HSCs. Reduced PPAR-γ expression may contribute to confer an activated phenotype to HSCs.
GASTROENTEROLOGY 2000;119:466-478
Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue-specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this ...study, we explored the signal transduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes. In HSC, interaction of CXCR3 with its ligands resulted in increased chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 also stimulated Src phosphorylation and kinase activity and increased the activity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. The increase in ERK activity was inhibited by genistein and PP1, but not by wortmannin, indicating that Src activation is necessary for the activation of the Ras/ERK pathway by CXCR3. Inhibition of ERK activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation resulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferation. These data characterize CXCR3 signaling in pericytes and clarify the relevance of downstream pathways in the modulation of different biologic responses.
Objectives
Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. ...Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence‐based guidelines treatment of CP.
Patients and methods
Patients with definitive or probable CP according to M‐ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase <200 μg/g was defined as a marker for PEI. Enzyme replacement therapy of 100,000 lipase units or more was defined as adequate treatment.
Results
We included 1006 patients from 8 centers in five countries. Sixty‐four percent of the patients were correctly treated. Twenty‐five per cent of PEI patients were not taking enzymes at all, and 20% of PEI patients were undertreated with insufficient PERT doses according to the guidelines. Fourteen percent of patients with sufficient pancreatic function were receiving enzymes despite normal exocrine pancreatic function. There were center differences. Current smoking was associated with lack of treatment and alcohol abuse was associated with under‐treatment. There were no associations between “no treatment” or “under‐treatment” for underweight or vitamin D deficiency.
Conclusion
In our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence.
: Increased expression of matrix metalloproteinase (MMP)‐2, ‐3 and ‐9 has been demonstrated in Crohn’s disease fistulas, but it is unknown whether these enzymes are biologically active and represent ...a therapeutic target. Therefore, we investigated the proteolytic activity of MMPs in fistula tissue and examined the effect of inhibitors, including clinically available drugs that beside their main action also suppress MMPs. Fistula specimens were obtained by surgical excision from 22 patients with Crohn’s disease and from 10 patients with fistulas resulting from other causes. Colonic endoscopic biopsies from six controls were also included. Total functional MMP activity was measured by a high‐pressure liquid chromatography (HPLC)‐based, fluorogenic MMP‐substrate cleavage assay, and the specific activity of MMP‐2, ‐3 and ‐9 by the MMP Biotrak Activity Assay. The MMP inhibitors comprised ethylene‐diamine‐tetraacetic acid (EDTA), the synthetic broad‐spectrum inhibitor, GM6001, the angiotensin‐converting enzyme (ACE) inhibitor, ramiprilate, and the tetracycline, doxycycline. In Crohn’s disease fistulas, about 50% of the total protease activity was attributable to MMP activity. The average total MMP activity was significantly higher (about 3.5‐times) in Crohn’s fistulas (471 FU/μg protein, range 49–2661) compared with non‐Crohn’s fistulas 134 FU/μg protein, range 0–495, (p < 0.05) and normal colon 153 FU/μg protein, range 77–243, (p < 0.01). MMP‐3 activity was increased in Crohn’s fistulas (1.4 ng/ml, range 0–9.83) compared with non‐Crohn’s fistulas, 0.32 ng/ml, range 0–2.66, (p < 0.02). The same applied to MMP‐9 activity 0.64 ng/ml, range 0–5.66 and 0.17 ng/ml, range 0–1.1, respectively (p < 0.04). Ramiprilate significantly decreased the average total MMP activity level by 42% and suppressed the specific MMP‐3 activity by 72%, which is comparable to the effect of GM6001 (87%). Moreover, MMP‐9 activity was completely blunted by ramiprilate. Doxycycline had no effect on MMP activity. Increased functional MMP activity, notably MMP‐3 and ‐9, is present in Crohn’s fistulas and may be inhibited by ramiprilate, a widely available ACE inhibitor.
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