Keratin 8 sequence variants in patients with pancreatitis and pancreatic cancer

Keratin 8 (KRT8) is one of the major intermediate filament proteins expressed in single-layered epithelia of the gastrointestinal tract. Transgenic mice over-expressing human KRT8 display pancreatic mononuclear infiltration, interstitial fibrosis and dysplasia of acinar cells resulting in exocrine pancreatic insufficiency. These experimental data are in accordance with a recent report describing an association between KRT8 variations and chronic pancreatitis. This prompted us to investigate KRT8 polymorphisms in patients with pancreatic disorders. The KRT8 Y54H and G62C polymorphisms were assessed in a cohort of patients with acute and chronic pancreatitis of various aetiologies or pancreatic cancer originating from Austria (n=16), the Czech Republic (n=90), Germany (n=1698), Great Britain (n=36), India (n=60), Italy (n=143), the Netherlands (n=128), Romania (n=3), Spain (n=133), and Switzerland (n=129). We also studied 4,234 control subjects from these countries and 1,492 control subjects originating from Benin, Cameroon, Ethiopia, Ecuador, and Turkey. Polymorphisms were analysed by melting curve analysis with fluorescence resonance energy transfer probes. The frequency of G62C did not differ between patients with acute or chronic pancreatitis, pancreatic adenocarcinoma and control individuals. The frequency of G62C varied in European populations from 0.4 to 3.8%, showing a northwest to southeast decline. The Y54H alteration was not detected in any of the 2,436 patients. Only 3/4,580 (0.07%) European, Turkish and Indian control subjects were heterozygous for Y54H in contrast to 34/951 (3.6%) control subjects of African descent. Our data suggest that the KRT8 alterations, Y54H and G62C, do not predispose patients to the development of pancreatitis or pancreatic cancer.

Neurokinin-2 receptor levels correlate with intensity, frequency, and duration of pain in chronic pancreatitis

OBJECTIVE: Generation and maintenance of pain in chronic pancreatitis (CP) have been shown to be partially attributable to neuroimmune interactions, which involve neuropeptides such as substance P (SP). So far, expression of SP receptors NK-2R, NK-3R, the SP-encoding gene preprotachykinin A (PPT-A), and the SP degradation enzyme neutral endopeptidase (NEP) and their relation to pain in CP have not been determined. METHODS: Tissue samples from patients with CP (n = 25) and from healthy donors (n = 20) were analyzed for PPT-A, NK-2R, NK-3R, and NEP expression using quantitative RT-PCR. NEP protein levels were examined by immunoblot analysis and its localization was determined using immunohistochemistry. A scoring system was used to grade the extent of fibrosis on hematoxylin and eosin- and Masson-Trichrome-stained sections. Messenger RNA levels and the extent of pain were analyzed for correlations. RESULTS: In CP tissues, NK-2R and PPT-A expression was increased, whereas NK-3R and NEP mRNA levels were comparable with normal pancreas. Overexpression of NK-2R was related to the intensity, frequency, and duration of pain in CP patients. NK-1R and NEP expression was significantly related to the extent of fibrosis. CONCLUSIONS: Expression of NK-2R and PPT-A is increased in CP and is associated with pain. Failure to up-regulate NEP may contribute to the disruption of the neuropeptides loop balance in CP and thus may exacerbate the severe pain syndrome.

Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations

BACKGROUND: Transforming growth factors betas (TGF-betas) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF-betas modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild-type (FVB-/-) and transgenic mice that are heterozygous (FVB+/-) for expression of a dominant negative type II TGF-beta receptor. METHODS: After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed. RESULTS: The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild-type mice resulted in 6- and 36-fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/- mice exhibited minimal alterations in response to caerulein with attenuated neutrophil-macrophage infiltrates. Moreover, acini from FVB+/- mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased. CONCLUSION: Our findings indicate that a functional TGF-beta signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.

Pancreatitis preceding acute episodes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: report of five patients with a systematic review of published reports

BACKGROUND AND OBJECTIVES: The thrombotic thrombocytopenic purpura-hemolytic uremic syndromes (TTP-HUS) have diverse etiologies, clinical manifestations, and risk factors, but the events that may trigger acute episodes are often unclear. We describe the occurrence of TTP-HUS following pancreatitis and consider whether pancreatitis may be a triggering event for acute episodes of TTP-HUS. DESIGN AND METHODS: We report on three patients from the Oklahoma Registry and two patients from Northwestern University who had an acute episode of TTP-HUS following pancreatitis. A systematic review of published case reports was performed to identify additional patients who had TTP-HUS following pancreatitis. RESULTS. In each of our five patients there was an apparent etiology of alcoholism or common bile duct obstruction for the pancreatitis and no evidence of TTP-HUS when the pancreatitis was diagnosed. Two patients had severe ADAMTS13 deficiency with an inhibitor; in one of these patients TTP-HUS recurred following a subsequent recurrent episode of pancreatitis. The systematic review identified 16 additional patients who had TTP-HUS following pancreatitis; recurrent TTP-HUS occurred in three of these patients following a subsequent episode of recurrent pancreatitis. In all 21 patients, the interval between the diagnosis of pancreatitis and TTP-HUS was short (1-13 days; median, 3 days). The three Oklahoma patients represent approximately 1% of the 356 patients in the Registry. INTERPRETATION AND CONCLUSIONS: These observations suggest that in some patients pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP-HUS.

Genetic polymorphisms of manganese-superoxide dismutase and glutathione-S-transferase in chronic alcoholic pancreatitis

Chronic alcohol consumption is a major risk factor for the development of chronic pancreatitis. However, chronic pancreatitis occurs only in a minority of heavy drinkers. This variability may be due to yet unidentified genetic factors. Several enzymes involved in the degradation of reactive oxidants and xenobiotics, such as glutathione-S-transferase P1 (GSTP1) and manganese-superoxide dismutase (MnSOD) reveal functional polymorphisms that affect the antioxidative capacity and may therefore modulate the development of chronic pancreatitis and long-term complications like endocrine and exocrine pancreatic insufficiency. Two functional polymorphisms of the MnSOD and the GSTP1 gene were assessed by polymerase chain reaction and restriction fragment length polymorphism in 165 patients with chronic alcoholic pancreatitis, 140 alcoholics without evidence of pancreatic disease and 160 healthy control subjects. The distribution of GSTP1 and MnSOD genotypes were in Hardy-Weinberg equilibrium in the total cohort. Genotype and allele frequencies for both genes were not statistically different between the three groups. Although genotype MnSOD Ala/Val was seemingly associated with the presence of exocrine pancreatic insufficiency, this subgroup was too small and the association statistically underpowered. None of the tested genotypes affected the development of endocrine pancreatic insufficiency. Polymorphisms of MnSOD and GSTP1 are not associated with chronic alcoholic pancreatitis. The present data emphasize the need for stringently designed candidate gene association studies with well-characterized cases and controls and sufficient statistical power to exclude chance observations.

Corticosteroid-binding globulin: a possible early predictor of infection in acute necrotizing pancreatitis

OBJECTIVE: Infected pancreatic necrosis is the main cause of death in patients with acute pancreatitis, and therefore its early prediction is of utmost importance. Endogenous cortisol metabolism plays a basic role both in the course of acute pancreatitis and in the process of infection. The purpose of this study was to analyze corticosteroid-binding globulin (CBG), total cortisol, calculated free cortisol and adrenocorticotropic hormone as potential early predictors in order to differentiate between infected pancreatic necrosis and sterile pancreatic necrosis in patients with acute pancreatitis. MATERIAL AND METHODS: Serum levels of CBG, total cortisol, calculated free cortisol, and plasma levels of adrenocorticotropic hormone were determined in 109 consecutive patients with acute pancreatitis. C-reactive protein was measured as the control parameter. Thirty-five patients developed necrotizing pancreatitis and 10 developed infection of the necrosis. Blood was monitored for 6 days after the onset of pain; 30 healthy individuals served as controls. RESULTS: Of all parameters only CBG showed a significant difference (p = 0.0318) in its peak levels measured in the first 48 h in patients with sterile (26.5 microg/ml, range 21.3-34.7) and infected (16.0 microg/ml, range 15.2-25.0) necrosis at a cut-off level of 16.8 microg/ml. That difference was further preserved for the first 6 days after onset of pain. CONCLUSIONS: In our group of patients, a decreased CBG level below 16.8 g/ml within the initial 48 h of acute pancreatitis was an early predictor of later infected pancreatic necrosis, with a positive predictive value of 100% and a negative predictive value of 87.5%.

Acute pancreatitis and thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) has multiple clinical manifestations and risk factors, but the events that actually trigger acute episodes of TTP are often unclear. We describe the case of a 56-year-old woman who presented with clinical signs and symptoms of TTP and acute pancreatitis. We discuss whether pancreatitis was due to ischemic pancreatic damage caused by microvascular platelet clumping in the frame of TTP, or whether acute pancreatitis, a disorder that results in an intense systemic inflammatory response, may be a triggering event for acute episodes of TTP.

Basic and clinical immunology of Siglecs

Siglecs are cell-surface proteins found primarily on hematopoietic cells. By definition, they are members of the immunoglobulin gene super-family and bind sialic acid. Most contain cytoplasmic tyrosine motifs implicated in cell signaling. This review will first summarize characteristics common and unique to Siglecs, followed by a discussion of each human Siglec in numerical order, mentioning in turn its closest murine ortholog or paralog. Each section will describe its pattern of cellular expression, latest known immune functions, ligands, and signaling pathways, with the focus being predominantly on CD33-related Siglecs. Potential clinical and therapeutic implications of each Siglec will also be covered.

Differential expression of chemokines in normal pancreas and in chronic pancreatitis

Cellular infiltrates are present already in early stages of chronic pancreatitis. The mechanisms responsible for their recruitment are unknown. Hence, we determined the differential expression of chemokine genes and their cellular sources in normal and affected pancreatic tissues.

Management of chronic pancreatitis

Chronic pancreatitis (CP) is an inflammatory disorder that results in permanent impairment of the glandular anatomy of the pancreas with or without functional abnormalities. The pathogenesis of CP is usually unclear, except in the case of alcohol-induced disease. The most common symptoms of CP are abdominal pain, diarrhea, and weight loss often requiring recurring hospitalization. Over time, pancreatic endocrine and exocrine dysfunction may develop as the disease progresses, and a variety of complications can occur. Among the possible complications are nutrient malabsorption and diabetes mellitus. The treatment of CP is difficult and challenging for every physician. Relieving pain is the first step in treating CP. This symptom needs to be controlled, often with narcotics, which can cause dependence. Diarrhea usually indicates the presence of steatorrhea, which is often treated with a high-calorie, high-protein, and low-fat diet to minimize symptoms of the underlying disease and to promote weight retention or gain. Pancreatic replacement therapy is used to combat maldigestion and malabsorption. Patients with diabetes may need insulin therapy for glycemic control. The use of parenteral nutrition for bowel rest is a standard approach in patients with symptomatic CP. The use of jejunal enteral feeding recently has been evaluated for efficacy in CP patients. The role of pancreatic endotherapy in the management of CP is evolving. Several reports have suggested that endoscopic therapy aimed at decompressing the obstructed pancreatic duct can be associated with pain relief in some patients. Surgery should be considered in patients who fail medical therapy.

Effect of jejunal long-term feeding in chronic pancreatitis

In the late course of chronic pancreatitis (CP), weight loss is often seen because of reduced caloric intake and a reduction of pancreatic enzyme secretion, resulting in maldigestion. Most of these patients can be managed by dietary recommendations and pancreatic enzyme supplementation. However, approximately 5% of these patients are reported to be candidates for enteral nutrition support during their course of CP. Although small bowel access for enteral feeding can be easily obtained by percutaneous endoscopic gastrojejunostomy (PEG/J) or direct percutaneous endoscopic jejunostomy (DPEJ), to date there are no data regarding clinical outcome and safety of long-term jejunal feeding in CP.

Evaluation of endosonography as a new diagnostic tool for feline pancreatitis

The purpose of this study was to evaluate endosonography (EUS) as a potential diagnostic tool for feline pancreatitis. Eleven healthy cats and six cats diagnosed with pancreatitis based on an increased serum feline pancreatic lipase immunoreactivity (fPLI) concentration were included. Transabdominal ultrasound (AUS) and EUS were performed in all cats. The widths of both pancreatic limbs and echogenicity and homogenicity were assessed by AUS and EUS. Finally, findings from both modalities were subjectively compared. In the healthy cats, the right pancreatic limb was significantly smaller on EUS compared to AUS. Also, subjectively, general visualization of the normal pancreas was superior with EUS and, the pancreatic margins and parenchyma could be resolved better with EUS in all sick patients. In this study, EUS findings did not alter the diagnosis in six cats with pancreatitis when compared to AUS. However, EUS may be useful in cases where AUS fails due to obesity, hyperechoic mesentery, or excessive intestinal gas.