Hideo Harada

Clinical course and prognosis of chronic pancreatitis.

Course and prognosis of 125 patients with chronic pancreatitis (CP) were evaluated. Follow-up period ranged from 1–20 years with a median of 6.3 years. The following conclusions were obtained. Recent increase of CP in our clinics was ascribed to alcoholic CP and idiopathic CP in the aged. Of 106 patients with pain, 74 showed improvement or disappearance of pain. Drinking habit and observation period were the main factors determining the rate of pain relief. Serial endoscopic retrograde pancreatography (ERP) showed aggravation in 17/47 patients, cholecystokinin-pancreozymin (CCK-PZ) secretin test in 4/40 patients, and oral glucose tolerance test (OGTT) in 7/25 patients. Exocrine function showed improvement in five patients, whereas endocrine function showed none. Improvement or aggravation of exocrine function was closely related to drinking habit. Main complications included 15 cases of peptic ulcer, 19 of pancreatic pseudocyst, and 15 of bile duct stenosis. Twenty-six patients died, often due to malignant neoplasms and diabetic complications. Those who continued drinking as much showed a lower survival rate than those who discontinued or decreased alcohol intake. The socioeconomic status deteriorated often due to pain or alcoholism. Three patients had to degrade jobs and six fell into inactive social life.

Development and use of a new staging system for severe acute pancreatitis based on a nationwide survey in Japan.

Methodology In 1997, a cooperative nationwide survey of 192 patients diagnosed with severe acute pancreatitis in 1996 was carried out. Results Alcoholic pancreatitis was the major etiology (46%), and the male-to-female ratio was 2.6:1. Overall, the mortality rate was 27%, which was similar to the rate (30%) in the first nationwide survey of 1,219 patients diagnosed between 1982 and 1986 that was performed in 1987. A marked difference between the surveys was the early mortality rate within 2 weeks: 52% in the 1987 survey and 29% in the current survey. We devised a new stage classification system for acute pancreatitis. Stages 0 and 1 are equivalent to mild and moderate conditions, respectively, in the conventional classification, and stages 2 and higher correspond to severe acute pancreatitis. Severity scores of 2–8 are regarded as stage 2, scores of 9–14, as stage 3, and scores of ≥15, as stage 4. The mortality rates were as follows: 0, stages 0 and 1 at hospitalization; ≈10%, stage 2; ≈30–40%, stage 3; and ≈70–100%, stage 4. Conclusion We found that stage at hospitalization reflected the prognosis of acute pancreatitis.

Study on free radicals and pancreatic fibrosis-pancreatic fibrosis induced by repeated injections of superoxide dismutase inhibitor

The exact mechanisms of the development of pancreatic fibrosis are still unknown. To clarify the relationship between pancreatic fibrosis and free radicals, the effect of the administration of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC), on pancreatic fibrosis in rats was studied. A single intraperitoneal injection of 500 mg/kg of DDC significantly reduced SOD activity and significantly increased lipid peroxidation products in the pancreas, showing no histologic changes of inflammation or necrosis. Repeated administration of 500 mg/kg DDC, twice a week, caused inter-and intralobular fibrosis with atrophy of acinar cells in the pancreas for at least 2 weeks without fibrosis of the liver and kidney. Administration of allopurinol showed preventive effects against DDC-induced pancreatic fibrosis. In conclusion, repeated administration of DDC, which caused pancreatic fibrosis, is a new experimental model of pancreatic fibrosis from the viewpoint of oxidative stress.

Genotypes of Alcohol‐Metabolizing Enzymes in Relation to Alcoholic Chronic Pancreatitis in Japan

Long-term consumption of large amounts of alcohol is the main cause of chronic pancreatitis. All heavy drinkers, however, do not contract chronic pancreatitis. Although genetic predisposition to alcoholism and alcoholic liver disease has been reported, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine the relation between genotypes of alcohol-metabolizing enzymes and chronic alcoholic pancreatitis, we examined genotype patterns of aldehyde dehydrogenase 2 (ALDH 2), alcohol dehydrogenase 2 (ADH 2) and cytochrome P-4502E1 (CYP2E1) in 54 patients with chronic alcoholic pancreatitis who were diagnosed in general hospitals in all over Japan and compared with those in 30 patients with chronic nonalcoholic pancreatitis or in 46 alcoholics with normal pancreatic function. There were no significant differences in the distribution of genotypes of ALDH 2 and CYP2E1 among those three groups. As for the ADH 2 genotype, distribution of 21 /21 ,21 /22 , and 22 /22 was 35%, 30%, and 35% in alcoholics with normal pancreatic function; 4%, 39%, and 57% in the chronic alcoholic pancreatitis group; and 0%, 50%, and 50% in the chronic nonalcoholic pancreatitis group, respectively. The frequency of ADH 22 allele was significantly higher in the chronic alcoholic pancreatitis group, compared with alcoholics with normal pancreatic function; but, it was not significantly different from that in the chronic nonalcoholic pancreatitis group. We also examined the relation between pancreatic fibrosis or pancreatitis histologically diagnosed and genotypes of alcohol-metabolizing enzymes in alcoholic autopsy cases. Twenty of 31 cases showed moderate or severe pancreatic fibrosis and showed intralobular + interlobular fibrosis, which is characteristic in alcoholic pancreatitis or intralobular fibrosis. ADH 22 allele tended to show a high frequency in the intralobular + interlobular fibrosis group, compared with that in the intralobular fibrosis group (75.0% vs. 41.7%, p < 0.1). The chronic pancreatitis group had a significantly higher frequency of the ADH 22 allele than that in cases without such findings (87.5% vs. 58.7%, p < 0.05). However, the ALDH 2 and CYP2E1 genotypes showed no significant relation to the findings of pancreatic fibrosis or histological pancreatitis. These data suggest that the risk of chronic alcoholic pancreatitis diagnosed clinically and pathologically seems to be associated with the ADH 22 allele in the genotypes of alcohol-metabolizing enzymes.

Clinical Trial with a Protease Inhibitor Gabexate Mesilate in Acute Pancreatitis

SummaryTo evaluate whether early administration of protease inhibitors could improve mortality and morbidity in acute pancreatitis (AP), we made a retrospective analysis of 23 patients with severe AP and 88 with mild to moderate AP who were treated in our institute and four affiliated medical centers during the 10-y period from 1980 to 1990. Intravenous infusion of a protease inhibitor, Gabexate Mesilate (FOY), was started within 24 h from onset of AP (early administration) in 17 patients with severe AP and 51 with mild to moderate AP. The remaining patients were put on FOY later than 24 h from onset of AP (late administration). Comparison of the mortality and morbidity between the two groups, early vs late administration of FOY, led to the following conclusions: (1) Early administration of FOY significantly improved mortality (29.4 vs 83.3%) in severe AP, although the improvement in mortality was not directly proportional to the shortening of the time lag between the onset of AP and the start of FOY, and (2) earlier administration of FOY brought about significantly earlier recovery of abdominal pain, hyperamylasemia, and leucocytosis in mild to moderate AP.

Analysis of pure pancreatic juice in patients with chronic alcoholism.

SummaryTo elucidate early biochemical changes of pancreatic juice and their reversibility in chronic alcoholics, pure pancreatic juice was collected from 23 chronic alcoholics by endoscopic retrograde catheterization of the papilla. Samples were collected at 1 minute intervals for 20 minutes after intravenous injection of secretin (Eisai, 1 U/kg) and for 10 minutes after CCK-PZ injection (Boots, 1 U/kg). Volume, bicarbonate concentration, protein concentration and three hydrolases were determined.Following results were obtained. (1) Five patients showed hypersecretory state. Four of the five patients showed hyperconcentration of protein. (2) Seventeen patients showed hyposecretory state. Lipase secretion was most frequently affected (94%). Maximal bicarbonate concentration was the next to be affected (82%). Amylase and chymotrypsinogen secretion were less frequently affected (65%). Flow rate was least frequently affected (24%). (3) It was suggested that exocrine dysfunction in chronic alcoholics is reversible in an early stage and that sequence of events with advancement of the stage is hypersecretion, hyperconcentration of protein, normalization of water secretion with a decrease in lipase secretion and maximal bicarbonate concentration, a decrease in amylase and chymotrypsinogen output, and finally a decrease in flow rate.

Intraductal secretin test is as useful as duodenal secretin test in assessing exocrine pancreatic function

We assessed the clinical usefulness of theintraductal secretin test in order to ascertain whetherit can substitute for the conventional duodenal secretintest. Duodenal juice was obtained with a triple-lumen tube and pure pancreatic juice was obtained byretrograde cannulation of the main pancreatic duct usinga duodenofiberscope. Pancreatic secretion was stimulatedby a bolus intravenous injection of secretin (100 units). The two tests showed comparableinterindividual coefficients of variation, significantlygood correlations, and comparable diagnosticefficiencies. The intraductal secretin test showed noless reproducibility than that of the duodenalsecretin test as reported in the literature. In theintraductal secretin test, secretory volume, peak flowrate, bicarbonate output, and lipase output yielded the best diagnostic efficiency, followed by amylaseoutput and maximal bicarbonate concentration. In theintraductal secretin test, a 10-min collection providedas much information as a 20-min collection. We conclude, therefore, that the 10-minintraductal secretin test is as useful as theconventional duodenal secretin test in assessingexocrine pancreatic function and that the mostdiscriminatory parameters are secretory volume, bicarbonate output, andamylase (or lipase) output.

Detection of c-Ki-ras point mutation from pancreatic juice. A useful diagnostic approach for pancreatic carcinoma

SummaryCytological diagnosis of pancreatic carcinoma sometimes poses difficulties in distinguishing malignant from benign cells. Recent molecular study of pancreatic carcinoma has revealed a very high incidence of a point mutation of the c-Ki-ras oncogene at codon 12 in this neoplasm. To take advantage of this technique for the diagnosis of pancreatic carcinoma, we attempted to amplify the c-Ki-ras gene from endoscopically obtained pancreatic juice by isolation of DNA and polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). PCR was possible in approx 70% of the cases. A point mutation was nonradioisotopically detected in 4 of 6 pancreatic carcinomas and in one intraductal papillary neoplasm, whereas no mutation was detected in other cases. Thus, this method was thought to be useful for the diagnosis of pancreatic carcinoma.

Prevention of hyperlipidemic acute pancreatitis during pregnancy with medium-chain triglyceride nutritional support

SummaryConclusionA combination of diet therapy, nutritional support with medium-chain triglycerides (MCT), and well-planned preterm Cesarean delivery on demand is an effective measure to prevent gestational hyperlipidemic pancreatitis and leads to successful childbirth.BackgroundPrevention and therapy of gestational hyperlipidemic pancreatitis are important, although difficult, because the condition carries a high maternal and fetal morbidity and mortality.ResultsWe describe a 32-yr-old female with lipoprotein lipase-deficient familial hypertriglyceridemia who had recurrent episodes of acute pancreatitis. The third episode occurred with worsened hyperlipidemia 7 yr earlier at 32 wk of her first pregnancy and resulted in fetal death. The fourth and fifth episodes were also accompanied by marked hyperlipidemia probably caused by drug discontinuance and dietary noncompliance. She became pregnant. Serum triglyceride levels were controlled below 2000 mg/dL by strict monitoring with low-fat, low-calorie diet and MCT nutritional support. A premature but healthy infant was born by Cesarean delivery at 36 wk of gestation when the mother presented with mild abdominal pain and was found to have uterine contractions. The ensuing clinical course has been uneventful.

Evaluation of cytology and tumor markers of pure pancreatic juice for the diagnosis of pancreatic cancer at early stages

To evaluate the value of cytology of pure pancreatic juice (PPJ) and tumor marker determination in PPJ and serum for the diagnosis of early pancreatic cancer (EPC), PPJ was obtained endoscopically from 16 patients with EPC (<20 mm, confined to pancreas), 16 patients with chronic pancreatitis (CP), and 20 controls. Cutoff levels of CEA, CA19-9, and POA in PPJ were set from ROC curves at 40 ng/ml, 7,500 U/ml, and 1.5 U/ml, respectively. For the differentiation of EPC from CP, the sensitivity of CEA, CA19-9, and POA was 71.4, 42.9, and 5096, respectively; specificity was 93.3, 46.7, and 80%, respectively; and diagnostic accuracy was 82.8,44.8, and 65.5%, respectively. Determination of serum tumor markers was useless. Sensitivity of cytology was 75%, specificity was 93.8%, and diagnostic accuracy was 84.4%. Combined cytology and CEA determination in PPJ increased the diagnostic accuracy to 93.1%. The combination was useful in supporting and supplementing endoscopic retrograde cholangiopancreatography (ERCP) findings for the correct diagnosis in II and 4 patients, respectively, with EPC; in one patient EPC was correctly diagnosed on ERCP findings done. One of 16 patients with CP showed false-positive results. We conclude that cytology and CEA determination in PPJ with ERCP is a useful combination for the diagnosis of pancreatic cancer even in early stages.