Heterozygosity of the haemochromatosis mutation, C282Y, does not influence susceptibility to alcoholic cirrhosis.
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Chromosomes, Human, Pair 6↗
Biomedical subjects
I D Norton
Publications and source records attributed to I D Norton.
Cystic fibrosis genotypes and alcoholic pancreatitis.
Pancreatitis and pancreatic insufficiency are associated with both cystic fibrosis and alcoholism. The pathogenesis of alcoholic pancreatitis is unknown, but only a minority of alcoholics develop pancreatitis, and it has been suggested that a genetic predisposition may play a role in this disease. Two observations led to the hypothesis that this genetic predisposition could result from mutations in the cystic fibrosis gene. First, the prevalence of cystic fibrosis mutations in the Caucasian population (approximately 5%) is similar to the prevalence of pancreatitis among heavy drinkers. Second, in both diseases, pancreatic duct damage is a prominent feature and has been postulated to be the initial site of injury. Therefore, the aim of this study was to determine whether an increased frequency of mutations in the cystic fibrosis gene occurs in alcoholic pancreatitis. The 15 most common cystic fibrosis mutations in a Caucasian community were sought in 24 subjects with alcoholic pancreatitis. None were homozygous or heterozygous for these mutations. These findings suggest that cystic fibrosis mutations are not a major genetic factor predisposing to pancreatic injury in alcoholics.
Cystic Fibrosis↗
Cytochrome P4502E1 is present in rat pancreas and is induced by chronic ethanol administration.
BACKGROUND: The mechanisms responsible for the initiation of alcoholic pancreatitis remain elusive. However, there is an increasing body of evidence that reactive oxygen species play a role in both acute and chronic pancreatitis. In the liver, cytochrome P4502E1 (CYP2E1, the inducible ethanol metabolising enzyme) is one of the proposed pathways by which ethanol induces oxidative stress. AIMS: To determine whether CYP2E1 is present in the pancreas and, if so, whether it is inducible by chronic ethanol feeding. METHODS: Eighteen male Sprague-Dawley rats were pair fed liquid diets with or without ethanol as 36% of energy for four weeks. CYP2E1 levels were determined by western blotting of microsomal protein from both pancreas and liver. Messenger RNA (mRNA) levels for CYP2E1 were quantified using dot blots of total pancreatic RNA. RESULTS: CYP2E1 was found in the pancreas. Furthermore, the amount of CYP2E1 was greater in the pancreas of rats fed ethanol compared with controls (mean increase over controls 5.1-fold, 95% confidence intervals 2.4 to 7.7, p < 0.02). In the liver, induction by ethanol of CYP2E1 was similar (mean increase over controls 7.9-fold, 95% confidence intervals 5.2 to 10.6, p < 0.005). Pancreatic mRNA levels for CYP2E1 were similar in ethanol fed and control rats. CONCLUSIONS: CYP2E1 is present in the rat pancreas and is inducible by chronic ethanol administration. Induction of pancreatic CYP2E1 is not regulated at the mRNA level. The metabolism of ethanol via CYP2E1 may contribute to oxidative stress in the pancreas during chronic ethanol consumption.
Animals↗
Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture.
BACKGROUND: The pathogenesis of pancreatic fibrosis is unknown. In the liver, stellate cells (vitamin A storing cells) play a significant role in the development of fibrosis. AIMS: To determine whether cells resembling hepatic stellate cells are present in rat pancreas, and if so, to compare their number with the number of stellate cells in the liver, and isolate and culture these cells from rat pancreas. METHODS: Liver and pancreatic sections from chow fed rats were immunostained for desmin, glial fibrillary acidic protein (GFAP), and alpha smooth muscle actin (alpha-SMA). Pancreatic stellate shaped cells were isolated using a Nycodenz gradient, cultured on plastic, and examined by phase contrast and fluorescence microscopy, and by immunostaining for desmin, GFAP, and alpha-SMA. RESULTS: In both liver and pancreatic sections, stellate shaped cells were observed; these were positive for desmin and GFAP and negative for alpha-SMA. Pancreatic stellate shaped cells had a periacinar distribution. They comprised 3.99% of all pancreatic cells; hepatic stellate cells comprised 7.94% of all hepatic cells. The stellate shaped cells from rat pancreas grew readily in culture. Cells cultured for 24 hours had an angular appearance, contained lipid droplets manifesting positive vitamin A autofluorescence, and stained positively for desmin but negatively for alpha-SMA. At 48 hours, cells were positive for alpha-SMA. CONCLUSIONS: Cells resembling hepatic stellate cells are present in rat pancreas in a number comparable with that of stellate cells in the liver. These stellate shaped pancreatic cells can be isolated and cultured in vitro.
Animals↗
Chronic ethanol administration decreases rat pancreatic GP2 content.
Postulated mechanisms of alcoholic pancreatitis include (i) zymogen granule fragility facilitating intracellular activation of digestive enzymes and (ii) ductular obstruction by protein plugs. GP2, a pancreatic glycoprotein, stabilizes zymogen granule membranes and is an important constituent of pancreatic protein plugs. Therefore, this study examined the pancreatic content and messenger RNA levels of GP2 after chronic ethanol administration. Rats were fed liquid diets with or without ethanol, for four weeks. GP2 levels in pancreatic homogenates, crude zymogen granules and zymogen granule membrane fractions were assessed by immunoblotting. Messenger RNA levels for GP2 were measured by Northern and dot blotting of pancreatic RNA. Pancreatic GP2 levels were lower in ethanol-fed rats than in controls (GP2 levels expressed as % of control: 38.75 +/- 5.8, p < 0.001 in homogenate; 31.28 +/- 3.5, p < 0.0005 in crude zymogen granules and 22.89 +/- 5.4, p < 0.0005 in zymogen granule membranes). Messenger RNA levels for GP2 were unchanged after ethanol feeding. Chronic ethanol consumption decreases GP2 content of pancreatic homogenate and zymogen granules. This decrease could (i) result from an increased release into pancreatic juice thereby favouring protein plug formation and (ii) impair zymogen granule stability. Both these mechanisms could potentiate pancreatic damage.
Animals↗
Both ethanol and protein deficiency increase messenger RNA levels for pancreatic lithostathine.
Both ethanol abuse and protein deficiency are well known associations of chronic pancreatitis. An early event in chronic pancreatitis is the deposition of protein plugs in small pancreatic ducts, leading to ductular obstruction and acinar cell damage. Lithostathine, a pancreatic secretory protein, is a major organic component of protein plugs. The aim of this study was to determine the effect of chronic ethanol administration and dietary protein deficiency, separately and in combination, on messenger RNA (mRNA) levels for pancreatic lithostathine. Male Sprague-Dawley rats were fed in groups of four, for four weeks, protein sufficient and protein deficient diets with or without ethanol. Messenger RNA levels for pancreatic lithostathine were assessed in all four groups. Both ethanol and protein deficiency, separately and in combination, increased mRNA levels for lithostathine. Thus, both chronic ethanol consumption and dietary protein deficiency increase the capacity of the pancreatic acinar cell to synthesize lithostathine.
Alcoholism↗
Fraternal sisters with adult polycystic kidney disease and adenoma of the ampulla of Vater.
The cases of two fraternal sisters with symptomatic biliary obstruction due to adenomas of the ampulla of Vater are reported. Both sisters had autosomal dominant adult polycystic kidney disease. There are no previous reports of a familial occurrence of ampullary adenomas in the absence of familial adenomatous polyposis, nor has an association between autosomal dominant polycystic kidney disease and ampullary adenoma been described. The coexistence of both disorders in these sisters raises the possibility of a genetic link between autosomal dominant polycystic kidney disease and ampullary adenoma.
Adenoma↗
Upper gastrointestinal haemorrhage following coronary artery bypass grafting.
BACKGROUND: Upper gastrointestinal (UGI) bleeding is a relatively common and potentially fatal complication of coronary artery bypass graft (CABG) surgery. However, little is known of this problem, including its incidence, predisposing factors and safety of endoscopy in these patients. AIM: To document the incidence, site, predisposing factors and outcome of UGI bleeding following CABG surgery. Also, to assess the safety of UGI endoscopy in these patients. METHOD: Retrospective study of UGI haemorrhage following CABG at one institution between 1976 and 1991. RESULTS: Fifty-five of 10,573 patients (0.5%) suffered a major UGI haemorrhage (as defined by need for transfusion or presence of melaena or haematemesis associated with hypotension). Of 51 patients undergoing endoscopy or laparotomy, 42 (82%) bled from duodenal ulceration. Five patients bled from gastric ulcers and one each from oesophagitis and Mallory Weiss tear. Nine patients underwent endoscopic therapy, which initially arrested haemorrhage in eight patients. However, three patients rebled and required surgery. Eight patients underwent surgery as initial therapy, resulting in an overall surgical rate of 20%. One patient died due to multi system failure following surgery. There were no complications from endoscopy. Patients who bled were more likely to have received inotropic support post-operatively prior to the haemorrhage (p < 0.05) and tended to be older than controls (mean age 65.6 years vs 58.7 years, p < 0.01). Twenty-one of the patients (38%) who bled had a past history of peptic ulceration or dyspepsia compared with 9% of controls (p < 0.001). Seven (12.5%) had previously bled from peptic ulceration. Patients who bled were less likely to have received H2-receptor antagonists in the perioperative period than controls (4% vs 20%, p < 0.05). CONCLUSION: Upper GI haemorrhage following CABG is relatively frequent. It is usually secondary to duodenal ulceration. Endoscopy is a safe procedure in this patient group. Mortality did not differ between index patients who suffered a UGI haemorrhage and controls undergoing CABG who did not bleed.
Aged↗
Ethanol-induced alterations in messenger RNA levels correlate with glandular content of pancreatic enzymes.
Ethanol abuse is a well-known association of pancreatitis. The effects of chronic ethanol consumption on pancreatic digestive and lysosomal enzymes may be relevant to the pathogenesis of alcoholic pancreatitis, because pancreatic enzymes play an important role in the development of pancreatic injury. The aims of this study were to determine the effects of ethanol on gene expression and glandular content of pancreatic digestive enzymes and on gene expression of the lysosomal enzyme cathepsin B (known to be capable of activating trypsinogen). Pancreatic content and mRNA levels for lipase, trypsinogen, and chymotrypsinogen were determined in rats that were pair-fed a nutritionally adequate liquid diet with or without ethanol for 4 weeks. mRNA levels for the lysosomal enzyme cathepsin B were also assessed in this model. Ethanol significantly increased the content of lipase in the pancreas. There was a trend toward an increase in trypsinogen and chymotrypsinogen levels; however, these differences were not statistically significant. mRNA levels for lipase, trypsinogen, and chymotrypsinogen were raised in ethanol-fed rats. Ethanol feeding also increased mRNA levels for the lysosomal enzyme cathepsin B. Furthermore, there was a close, statistically significant correlation between changes in mRNA levels and tissue activities of pancreatic digestive and lysosomal enzymes after ethanol consumption. These results suggest that ethanol increases the capacity of the pancreatic acinar cell to synthesize digestive and lysosomal enzymes, thereby increasing the susceptibility of the gland to enzyme-related injury.
Acetaldehyde↗
Ethanol induced acinar cell injury.
Ethanol abuse is a well known association of pancreatitis. Research into the pathogenesis of alcoholic pancreatitis has generally followed two directions. Firstly, factors which may predispose alcoholics to pancreatitis have been examined. To date, these studies have been negative and the predisposing factor(s) remain unknown. The second approach has involved studies on the constant metabolic effects of ethanol on the pancreas which may render the acinar cell susceptible to digestive enzyme induced injury. Recently developed models of experimental pancreatitis have implicated intracellular activation of digestive enzymes by lysosomal enzymes as an early event. Using the Lieber-DeCarli model of ethanol administration to rats, a number of changes have been described in pancreatic acinar cells which may predispose the gland to autodigestion. These changes include: (1) increased glandular content of digestive enzymes as a result of increases in mRNA levels for these enzymes; (2) increased glandular content of the lysosomal enzyme cathepsin B (known to be capable of activating trypsinogen); (3) increased fragility of lysosomes possibly mediated by cholesteryl esters and fatty acid ethyl esters; and (4) increased fragility of zymogen granules. These effects of ethanol constitute a "primed" setting (the "Drinker's Pancreas") for autodigestion. Triggering factors for autodigestion in this setting have not yet been identified.
Animals↗
Endoscopic ultrasound: diagnostic and therapeutic applications.
Endoscopic ultrasound (EUS) comprises several techniques of performing high-frequency ultrasound via an endoscope placed in the gastrointestinal tract (oesophagus, stomach, duodenum and pancreaticobiliary tree and rectum). It has rapidly become an important tool in the investigation of a variety of lumenal disorders as well as locoregional staging of gastrointestinal malignancies. Needle biopsy of peri-intestinal structures, such as lymph nodes and pancreatic masses, can also be performed under real-time ultrasound control. To date, the utilization of this technology in Australia has been limited by cost constraints and a paucity of training opportunities. EUS continues to be a rapidly growing area in clinical gastroenterology. Recent studies continue to define its role, particularly in the loco-regional staging of a variety of malignancies. In addition, new instruments permit tissue sampling and a variety of therapeutic manoeuvres under direct ultrasound guidance.33; 26-32)
Biopsy↗
Anti-neutrophil cytoplasmic antibody: a prognostic indicator in primary sclerosing cholangitis.
Considerable variability has been reported in the frequency and specificity of anti-neutrophil cytoplasmic antibody with a perinuclear staining pattern (pANCA) in patients with chronic liver disease, especially in primary sclerosing cholangitis (PSC), and in inflammatory bowel disease. This study examines the presence of pANCA in patients with these disorders, in particular those with PSC complicated by other biliary disease, and also patients who had undergone orthotopic liver transplantation. An indirect immunofluorescent technique was used to measure pANCA with serum diluted 1:20. Ten of 39 (26%) patients with PSC had detectable pANCA, as did two of nine (22%) with autoimmune chronic active hepatitis (AICAH) but none of the 51 patients with other forms of chronic liver disease. The presence of pANCA was significantly more frequent in patients who had PSC with biliary tract complications, in particular calculi (seven of 16 with vs three of 23 without; P = 0.03). Eight of the 12 pANCA-positive patients with PSC or AICAH had undergone hepatic transplantation. This was more likely than in patients with PSC or AICAH who were pANCA negative (10 of 36; P = 0.02). To date, pANCA has been detected after transplantation in four patients with PSC and one with AICAH. In patients with PSC or AICAH, pANCA should be sought as a marker of prognosis.
Adult↗
Management of periampullary adenoma.
The periampullary region is the most common site of adenomatous change in the small bowel, particularly in patients with familial adenomatous polyposis (FAP) syndromes. These lesions have been shown to progress to malignancy in a manor analogous to colonic polyps. Following colectomy, the periampullary region is the commonest site of gastrointestinal malignancy in FAP patients. The periampullary region is within easy reach of forward- and side-viewing endoscopes and therefore endoscopic surveillance in FAP patients is both easy and prudent. Furthermore, there is accumulating evidence that endoscopic resection and/or ablation are the treatment of choice for periampullary adenomas. However, the optimal timing of surveillance and best methods of ablation remain to be determined. This paper reviews the literature on the endoscopic management of periampullary adenoma as well as outlining our current approach to this challenging problem.
Adenoma↗
Bacteremia and bacterascites after endoscopic sclerotherapy for bleeding esophageal varices and prevention by intravenous cefotaxime: a randomized trial.
Thirty-one patients were randomized during 39 episodes of bleeding to receive either 1 g of intravenous cefotaxime (19 patients) or no antibiotic (20 patients) immediately before emergency endoscopic sclerotherapy. Blood was obtained for culture before and at 5 minutes, 4 hours, and 24 hours after the procedure. Specimens for culture were taken from the endoscope tip and channel, water bottle, and injection needle after sclerotherapy. When ascites was present (5 patients in the antibiotic group, 7 in the control group), fluid was obtained by paracentesis before endoscopy and at 4 and 24 hours. Bacteremia occurred in 1 of 19 patients in the antibiotic group (5.3%), compared with 6 of 19 in the control group (31.6%; p = .04). The cultured organisms were oral flora and usually also contaminated the endoscope and needle. No bacteria were cultured from ascitic fluid in any patient nor was the ascitic fluid white cell count elevated. Clinical infection attributable to sclerotherapy did not develop in any patient. In conclusion, the frequency of bacteremia after endoscopic sclerotherapy for bleeding esophageal varices can be reduced by prophylactic administration of intravenous cefotaxime. However, this may not be clinically relevant, given the absence of bacterascites and infection in this study. These findings do not support the routine use of antibiotics before sclerotherapy.
Ascites↗