Evidence-based clinical practice guidelines for chronic pancreatitis 2015.

Chronic pancreatitis is considered to be an irreversible progressive chronic inflammatory disease. The etiology and pathology of chronic pancreatitis are complex; therefore, it is important to correctly understand the stage and pathology and provide appropriate treatment accordingly. The newly revised Clinical Practice Guidelines of Chronic Pancreatitis 2015 consist of four chapters, i.e., diagnosis, staging, treatment, and prognosis, and includes a total of 65 clinical questions. These guidelines have aimed at providing certain directions and clinically practical contents for the management of chronic pancreatitis, preferentially adopting clinically useful articles. These revised guidelines also refer to early chronic pancreatitis based on the Criteria for the Diagnosis of Chronic Pancreatitis 2009. They include such items as health insurance coverage of high-titer lipase preparations and extracorporeal shock wave lithotripsy, new antidiabetic drugs, and the definition of and treatment approach to pancreatic pseudocyst. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the publication of the first edition.

An efficient laboratory-scale preparative method for [1-(13)C]glycocholic acid.

A breath test using [1-(13)C]glycocholic acid as a substrate is a potential diagnostic method for small intestinal bacterial overgrowth syndrome. [1-(13)C]Glycocholic acid has been thus synthesized in an excellent yield from ethyl [1-(13)C]glycinate hydrochloride in a one-pot reaction. This method is suitable for the preparation of the labeled compound on a laboratory scale, which helps to perform extensive clinical studies of the breath test.

Gastric emptying in patients with autoimmune pancreatitis.

OBJECTIVES: Autoimmune pancreatitis (AIP) and its extrapancreatic lesions seem to be clinical manifestations of organs involved in IgG4-related systemic disease. To clarify whether the stomach is a target organ, gastric function was evaluated in patients with AIP. METHODS: In 6 patients with AIP, gastric emptying was assessed by Carbon 13 (¹³C) acetate breath test before and after steroid therapy. Based on 4-hour breath samples, the half ¹³CO2 excretion time (T(1/2)) and the time of maximal excretion (T(max)) were calculated as gastric emptying parameters. Data of 20 healthy volunteers were used as controls. The number of IgG4-positive plasma cells in gastrofiberscopic biopsy specimens was counted before and after steroid therapy. RESULTS: Both T(1/2) and T(max) in patients with AIP decreased significantly after steroid therapy (T(1/2): 1.89 ± 0.21 hours vs 1.69 ± 0.15 hours, P = 0.046; and T(max): 1.1 ± 0.2 hours vs 0.96 ± 0.2 hours, P = 0.027), and became similar to those of the controls (T(1/2): 1.69 ± 0.32 hours and T(max): 0.98 ± 0.2 hour). The number of IgG4-positive plasma cells infiltrating the gastric mucosa decreased after steroid therapy. CONCLUSIONS: Gastric emptying was impaired in patients with AIP and improved to the reference range after steroid therapy. The stomach may be a target organ of IgG4-related systemic disease.

A brief outline of the history of the pancreatic anatomy.

In the middle of the 18th century, Kouan Kuriyama, a Japanese physician of the Choshu Domain, depicted the anatomy of the human pancreas in a report to his master, Toyo Yamawaki. This report is the first anatomical description of the pancreas in Japan. In the Mediterranean area, the pancreas was apparently first described about 2,000 years before his observation. Although there are quite a few reviews on the history of this complex organ, our brief essay offers a historical outline of the pancreas.

Serum cystatin C in diabetic patients. Not only an indicator for renal dysfunction in patients with overt nephropathy but also a predictor for cardiovascular events in patients without nephropathy.

Serum cystatin C (CysC) has been proposed as a potentially superior marker for the evaluation of renal function because it was more sensitive and accurate for the estimation of glomerular filtration rate (GFR) than other markers. We evaluated the clinical usefulness of CysC in diabetic nephropathy. The study was performed on 414 Japanese diabetic patients. We compared serum CysC levels with serum creatinine levels, urinary concentrations of albumin, transferrin and type IV collagen, and creatinine clearance (Ccr). Then, the correlation between serum CysC levels and high-sensitivity C-reactive protein (H-CRP) levels were examined. When the patients were classified by renal function, 19% of the patients were free from nephropathy, 49% had microalbuminuria, 28% had persistent proteinuria, and 4% had end stage renal disease. The serum CysC levels increased with the progression of nephropathy, and significantly higher in overt nephropathy, but not significant in early nephropathy. Serum CysC levels were well-correlated with H-CRP levels in the patients without nephropathy. These results indicate that serum CysC would be practical for the evaluation of renal function in diabetic patients with overt nephropathy but not early nephropathy and might be related with a risk for cardiovascular events in patients without nephropathy.

Carboxylester lipase gene polymorphism as a risk of alcohol-induced pancreatitis.

OBJECTIVES: Alcohol abuse causes pancreatic damage in humans. However, only 5% of alcoholic patients have a clinical manifestation of pancreatitis, and the genetic predisposition of alcohol-associated pancreatitis remains elusive. Nonoxidative metabolites of ethanol, fatty acid ethyl esters (FAEEs), might play an important role in pancreatic damage. Carboxylester lipase (CEL) has been known to catalyze FAEE synthesis from fatty acids and ethanol. METHODS: The variable number of tandem repeat (VNTR) polymorphism in the coding region of the CEL gene was studied in patients with alcoholic pancreatitis (n = 100), in alcoholics without pancreatitis (n = 52), in patients with nonalcoholic pancreatitis (n = 50), in hyperlipidemia patients (n = 96), and control subjects (n = 435). RESULTS: The frequency of the NN-type (wild-type) gene was significantly decreased in patients with alcoholic pancreatitis than in other groups. The frequency of subjects who had the L allele in patients with alcoholic pancreatitis was significantly higher than in other groups. The distribution of the CEL gene polymorphism was not different among the control subjects, alcoholics without pancreatitis, patients with nonalcoholic pancreatitis, and patients with hyperlipidemia. CONCLUSIONS: The CEL gene polymorphism, especially an increase in the frequency of the L allele, was found to be associated with alcohol-induced pancreatitis.

Acute experimental pancreatitis and NF-kappaB/Rel activation.

Acute pancreatitis is a serious disease with a high morbidity and an overall mortality rate of about 10%. However, in its most severe form, which is characterized by pancreatic necrosis, 20-30% of the patients die. Death is often the result of multiorgan dysfunction, including acute respiratory, kidney, and hepatic failure as well as generalized diffuse capillary leak water retention, hypoxia, and acid/base disturbance. The mechanisms by which distant organ systems are involved still remain obscure, but several lines of evidence suggest the participation of cytokines (IL-1, IL-6, and TNF-alpha) as a response to local tissue damage. A series of studies have now shed new light on the pivotal pathogenic role of the transcription factor NF-kappaB/Rel that binds to the promoter regions of many proinflammatory genes and regulates their transcription.

Different modes of NF-kappaB/Rel activation in pancreatic lobules.

The eukaryotic transcription factor nuclear factor-kappaB (NF-kappaB)/Rel is activated by a large variety of stimuli. It has been demonstrated that NF-kappaB/Rel is induced during the course of cerulein pancreatitis. Here, we show that NF-kappaB/Rel is differentially activated in pancreatic lobules. Cerulein induces NF-kappaB/Rel via activation of IkappaB kinase (IKK), which causes degradation of IkappaBalpha but not IkappaBbeta. Tumor necrosis factor-alpha-mediated IKK activation leads to IkappaBalpha and IkappaBbeta degradation. In contrast, oxidative stress induced by H(2)O(2) activates NF-kappaB/Rel independent of IKK activation and IkappaBalpha degradation; instead IkappaBalpha is phosphorylated on tyrosine. H(2)O(2) but not cerulein-mediated NF-kappaB/Rel activation can be blocked by stabilizing microtubules with Taxol. Inhibition of tubulin polymerization with nocodazole causes NF-kappaB/Rel activation in pancreatic lobules. These results propose three different pathways of NF-kappaB/Rel activation in pancreatic acinar cells. Furthermore, these data demonstrate that microtubules play a key role in IKK-independent NF-kappaB/Rel activation following oxidative stress.

Induction of IkappaB-kinase by cholecystokinin is mediated by trypsinogen activation in rat pancreatic lobules.

BACKGROUND AND AIMS: Supramaximal concentrations of cholecystokinin (CCK) or cerulein induce the intracellular activation of trypsinogen and the transcription factor NF-kappaB, a key regulator of inflammatory gene expression. Both events occur early in the development of an acute pancreatitis. The aim of this study was to examine the relationship between intracellular trypsinogen and NF-kappaB activation. METHODS: We detected NF-kappaB-binding activity in electromobility shift assays, IkappaB proteolysis in Western analysis and endogenous IkappaB-kinase (IKKalpha and beta) activation using immune complex kinase assays following treatment with CCK in rat pancreatic lobules. To block intrapancreatic trypsinogen activation, a potent and cell-permeable serine-protease inhibitor, Pefabloc, was used. RESULTS: CCK-induced IkappaBalpha degradation and subsequent NF-kappaB activation correlated closely with the catalytic activity of IKKs to phosphorylate IkappaBalpha in vitro. Activation is dose-dependent and peaked at 30 min. Doses of Pefabloc sufficient to inhibit trypsin activation reduced CCK-induced activation of NF-kappaB whereas TNF-alpha-induced NF-kappaB activation was not blocked but slightly increased. Moreover, treatment with Pefabloc as well as another serine protease inhibitor, FUT175, inhibited CCK-induced IKK activation. CONCLUSION: These results suggest that intrapancreatic activation of trypsinogen may contribute to NF-kappaB signaling via IKK activation in cerulein pancreatitis. This also explains the fact that only doses of CCK which activate trypsinogen induce NF-kappaB activation in pancreatic acinar cells. Thus, trypsinogen activation is likely to modulate signaling events in acinar cells in the initial phase of acute pancreatitis.