Pancreatitis In Japan Research Articles

JPN Guidelines for the management of acute pancreatitis: treatment of gallstone-induced acute pancreatitis

Gallstones, along with alcohol, are one of the primary etiological factors of acute pancreatitis, and knowledge of the etiology as well as the diagnosis and management of gallstones, is crucial for managing acute pancreatitis. Because of this, evidence regarding the management of gallstone-induced pancreatitis in Japan was collected, and recommendation levels were established by comparing current clinical practices with optimal clinical practices. The JPN Guidelines for managing gallstone-induced acute pancreatitis recommend two procedures: (1) an urgent endoscopic procedure should be performed in patients in whom biliary duct obstruction is suspected and in patients complicated by cholangitis (Recommendation A); and (2) after the attack of gallstone pancreatitis has subsided, a laparoscopic cholecystectomy should be performed during the same hospital stay (Recommendation B).

Health insurance system and payments provided to patients for the management of severe acute pancreatitis in Japan

The health insurance system in Japan is based upon the Universal Medical Care Insurance System, which gives all citizens the right to join an insurance scheme of their own choice, as guaranteed by the provisions of Article 25 of the Constitution of Japan, which states: “All people shall have the right to maintain the minimum standards of wholesome and cultured living.” The health care system in Japan includes national medical insurance, nursing care for the elderly, and government payments for the treatment of intractable diseases. Medical insurance provisions are handled by Employee’s Health Insurance (Social Insurance), which mainly covers employees of private companies and their families, and by National Health Insurance, which provides for the needs of self-employed people. Both schemes have their own medical care service programs for retired persons and their families. The health care system for the elderly covers people 75 years of age and over and bedridden people 65 years of age and over. There is also a system under which the government pays all or part of medical expenses, and/or pays medical expenses not covered by insurance. This is referred to collectively as the “medical expenses payment system” and includes the provision of medical assistance for specified intractable diseases. Because severe acute pancreatitis has a high mortality rate, it is specified as an intractable disease. In order to lower the mortality rate of various diseases, including severe acute pancreatitis, the specification system has been adopted by the government. The cost of treatment for severe acute pancreatitis is paid in full by the government from the date the application is made for a certificate verifying that the patient has an intractable disease.

Consensus of primary care in acute pancreatitis in Japan

The incidence of acute pancreatitis in Japan is increasing and ranges from 187 to 347 cases per million populations. Case fatality was 0.2% for mild to moderate, and 9.0% for severe acute pancreatitis in Japan in 2003. Experts in pancreatitis in Japan made this document focusing on the practical aspects in the early management of patients with acute pancreatitis. The correct diagnosis of acute pancreatitis and severity stratification should be made in all patients using the criteria for the diagnosis of acute pancreatitis and the multifactor scoring system proposed by the Research Committee of Intractable Diseases of the Pancreas as early as possible. All patients diagnosed with acute pancreatitis should be managed in the hospital. Monitoring of blood pressure, pulse and respiratory rate, body temperature, hourly urinary volume, and blood oxygen saturation level is essential in the management of such patients. Early vigorous intravenous hydration is of foremost importance to stabilize circulatory dynamics. Adequate pain relief with opiates is also important. In severe acute pancreatitis, prophylactic intravenous administration of antibiotics at an early stage is recommended. Administration of protease inhibitors should be initiated as soon as the diagnosis of acute pancreatitis is confirmed. A combination of enteral feeding with parenteral nutrition from early stage is recommended if there are no clear signs and symptoms of ileus and gastrointestinal bleeding. Patients with severe acute pancreatitis should be transferred to ICU as early as possible to perform special measures such as continuous regional arterial infusion of protease inhibitors and antibiotics, and continuous hemodiafiltration. The Japanese Government covers medical care expense for severe acute pancreatitis as one of the projects of Research on Measures for Intractable Diseases.

Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity

Camostat mesilate (CM), an oral protease inhibitor, has been used clinically for the treatment of chronic pancreatitis in Japan. However, the mechanism by which it operates has not been fully understood. Our aim was to evaluate the therapeutic efficacy of CM in the experimental pancreatic fibrosis model induced by dibutyltin dichloride (DBTC), and we also determined the effect of CM on isolated monocytes and panceatic stellate cells (PSCs). In vivo, chronic pancreatitis was induced in male Lewis rats by single administration of 7 mg/kg DBTC and a special diet containing 1 mg/g CM was fed to the DBTC+CM-treated group from day 7, while the DBTC-treated group rats were fed a standard diet. At days 0, 7, 14 and 28, the severity of pancreatitis and fibrosis was examined histologically and enzymologically in both groups. In vitro, monocytes were isolated from the spleen of a Lewis rat, and activated with lipopolysaccharide stimulation. Thereafter, the effect of CM on monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) production from monocytes was examined. Subsequently, cultured rat PSCs were exposed to CM and tested to see whether their proliferation, MCP-1 production and procollagen α1 messenger RNA expression was influenced by CM. In vivo, the oral administration of CM inhibited inflammation, cytokines expression and fibrosis in the pancreas. The in vitro study revealed that CM inhibited both MCP-1 and TNF-α production from monocytes, and proliferation and MCP-1 production from PSCs. However, procollagen α1 expression in PSCs was not influenced by CM. These results suggest that CM attenuated DBTC-induced rat pancreatic fibrosis via inhibition of monocytes and PSCs activity.

Urinary Trypsin Inhibitor Protects against Systemic Inflammation Induced by Lipopolysaccharide

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis in Japan. Recent studies have demonstrated that serine protease inhibitors may play an anti-inflammatory role beyond merely an inhibitory action on neutrophil elastase at the site of inflammation at least in vitro. To clarify the direct contributions of UTI to inflammatory condition in vivo, we analyzed its roles in experimental systemic inflammatory response induced by intraperitoneal administration of lipopolysaccharide (LPS) using UTI deficient (-/-) mice and corresponding wild-type (WT) mice. After LPS (1 mg/kg) challenge, UTI (-/-) mice revealed a significant elevation of plasma fibrinogen and fibrinogen/fibrin degradation products and a decrease in white blood cell counts compared with WT mice. LPS treatment induced more severe neutrophilic inflammation in the lung and the kidney obtained from UTI (-/-) mice than in those from WT mice, which was confirmed by histological examination. The protein levels of proinflammatory mediators, such as macrophage chemoattractant protein (MCP)-1 in the lungs, MCP-1 and keratinocyte chemoattractant (KC) in the kidneys, and interleukin-1beta, macrophage inflammatory protein-2, MCP-1, and KC in the liver, were significantly greater in UTI (-/-) mice than in WT mice after LPS challenge. Our results suggest that UTI protects against systemic inflammatory response and subsequent organ injury induced by bacterial endotoxin, at least partly through the inhibition of the enhanced expression of proinflammatory cytokines and chemokines.

An update of endoscopic retrograde pancreatography-related pancreatitis in Japan

An update of endoscopic retrograde pancreatography-related pancreatitis in Japan

A Finger Sweat Chloride Test for the Detection of a High-Risk Group of Chronic Pancreatitis

Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with chronic pancreatitis in Caucasians. We developed a simple method for measuring finger sweat chloride concentration to test whether CFTR dysfunction underlies chronic pancreatitis in Japan where cystic fibrosis (CF) is rare. We studied 25 patients with chronic (21 alcoholic and 4 idiopathic) pancreatitis and 25 healthy volunteers. Sweat chloride concentrations were measured by a finger sweat chloride test. We analyzed DNA for 20 common CFTR mutations in Europeans, 9 CF-causing mutations in Japanese, and 2 polymorphic loci, a poly-T tract and (TG) repeats, at intron 8. Thirteen patients (52%) had sweat chloride levels >60 mmol/L, a level consistent with CF, while only 4 (16%) healthy subjects exceeded this level. The 29 CF mutations and the 5T allele were detected in neither the patients nor controls. The (TG) 12 allele was common in both the patients (58%) and controls (48%). The (TG) 12/12 genotype was common in alcoholic pancreatitis (29%) compared with the (TG) 11/11 (10%). Patients with the (TG) 12/12 genotype had significantly higher sweat chloride concentrations than the controls. CFTR dysfunction as evidenced by a finger sweat chloride test is present in about half of Japanese patients with chronic pancreatitis, suggesting that this test may be useful for detecting the high-risk group. A higher proportion of the (TG) 12 allele may be a genetic background for elevated sweat chloride concentrations in Japanese patients.

Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems

Chronic pancreatitis is a chronic clinical disorder characterized by irreversible damage to the pancreas and the development of histologic evidence of inflammation and fibrosis, and eventually the destruction and permanent loss of exocrine and endocrine tissue. A nationwide survey in Japan revealed an increase in the total number of patients treated for chronic pancreatitis from 32 000 in 1994 to 42 000 in 1999. The overall prevalence and the incidence rate of chronic pancreatitis also increased, from 28.5 and 5.4, respectively, in 1994 to 32.91 and 5.77 per 100 000 population, respectively, in 1999. Diagnostic criteria for chronic pancreatitis in Japan were proposed by the Japan Pancreas Society in 1995 and revised in 2001. The criteria were established to rule out false-positive cases and to confidently diagnose definite and probable cases of chronic pancreatitis, and thus easily detect advanced chronic pancreatitis, but the criteria are unable to lead to the early diagnosis of chronic pancreatitis. Cancer is the major cause of death in patients with chronic pancreatitis in Japan (49.6% of all deaths in patients with chronic pancreatitis). Clarification of the mechanisms by which possible chronic pancreatitis progresses to probable or definite chronic pancreatitis, and to pancreatic cancer, is an important research goal. Because even chronic pancreatitis defined as irreversible appears to be reversible for some time in its clinical course, there is an urgent need to develop methods for diagnosing reversible chronic pancreatitis, and to prevent the transition from chronic pancreatitis to pancreatic cancer.

Mutational analysis of the pancreatic secretory trypsin inhibitor gene in familial and juvenile pancreatitis in Japan.

Mutations in the pancreatic secretory trypsin inhibitor ( PSTI) gene have been reported in patients suffering from chronic pancreatitis. The aim of the present study was to investigate whether similar gene mutations are present in familial and juvenile pancreatitis patients in Japan. All four exons of the PSTI gene and their flanking intronic sequences were amplified by polymerase chain reaction and sequenced for 37 familial pancreatitis patients (24 families) and 15 juvenile pancreatitis patients, distributed throughout Japan. Three types of exonic mutation in the PSTI gene were observed. The N34S mutation was found in six familial pancreatitis patients (three families) and in one juvenile pancreatitis patient, and the R67C mutation was found in one familial pancreatitis patient and one juvenile pancreatitis patient. We also found a 272C>T mutation in the 3' untranslated region of exon 4 in one familial pancreatitis patient and four juvenile pancreatitis patients. It should be noted that the N34S mutation was cosegregated with two intronic mutations, specifically, IVS1-37T>C and IVS3-69insTTTT. The same set of N34S mutations (N34S + IVS1-37T>C + IVS3-69insTTTT) that exists in other countries was found in the PSTI gene in Japanese familial and juvenile pancreatitis patients. Another unique mutation (R67C) was also observed in two patients; 272C>T was suggested to be a normal polymorphism.

Different Effects of Oral Administration of Synthetic Trypsin Inhibitor on the Pancreas Between Cholecystokinin-A Receptor Gene Knockout Mice and Wild Type Mice

The synthetic trypsin inhibitor camostat has been used for the treatment of acute and chronic pancreatitis in Japan based on the evidences obtained from a rat experimental model. However, rats differ from other rodents and from humans in terms of lacking a gallbladder and no response of pancreatic bicarbonate secretion to cholecystokinin (CCK). In the present study, we determined whether oral administration of camostat showed a trophic effect in mice as observed in rats and whether the trophic effect, if substantial, was mediated via the CCK-A receptor, using CCK-A receptor gene targeting mice. The chow containing 0.1% camostat was fed to 8-month-old mice. Three- and seven-day treatments with camostat did not affect pancreatic wet weight in CCK-A receptor (+/-) mice. After 14-day treatment, the ratio of pancreatic wet weight /body weight was significantly lower in CCK-A receptor (-/-) than (+/+) mice. The protein and chymotrypsin contents were lower and amylase content was higher in CCK-A receptor (-/-) mice, compared to (+/+) mice. No pathological findings were observed by histological examination. Camostat has a trophic effect on the pancreas in mice and this effect is mediated via the CCK-A receptor, but is less potent than in rats.

Effects of synthetic serine protease inhibitors on proliferation and collagen synthesis of human pancreatic periacinar fibroblast-like cells.

Protease inhibitors are currently used as therapeutic agents for chronic pancreatitis in Japan. We previously reported that human pancreatic periacinar fibroblast-like cells (hPFCs) could be cultured from isolated pancreatic acini, and those are thought to play a crucial role in pancreatic fibrosis correlating with platelet-derived growth factor (PDGF) and transforming growth factor beta1 (TGF-beta1) (Pancreas 1997;14: 373-82). The present study was designed to examine the effects of synthetic serine protease inhibitors (FOY-007 and FOY-305) on proliferation and collagen synthesis of hPFCs under cytokine stimulation. The cell proliferation and collagen synthesis were evaluated using assays of [3H]-thymidine incorporation and procollagen type I c-terminal peptide (PIP), and [14C]-proline incorporation to de novo synthesized collagen, respectively. The cell proliferation stimulated by PDGF was inhibited by the application of FOY-007 dose dependently (1-100 microM) and FOY-305 at 100 microM. FOY-007 attenuated the collagen synthesis and PIP production stimulated by TGF-beta1 dose dependently, but FOY-305 inhibited only PIP production. Both protease inhibitors demonstrated no effect on the proliferation and collagen synthesis of hPFCs when they were not stimulated by PDGF or TGF-beta1. Thus, serine protease inhibitors act on hPFCs to diminish the effects of PDGF on proliferation and the effects of TGF-beta1 on collagen synthesis.

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 2(1)/2(1), 2(1)/2(2), and 2(2)/2(2) 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 2(2) 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 2(2) 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 2(2) 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 2(2) allele in the genotypes of alcohol-metabolizing enzymes.

Acute Pancreatitis

In this article we describe the current status of treatment of acute pancreatitis in Japan and the guidelines established for the treatment of severe acute pancreatitis. In 1987 the Research Committee for Intractable Diseases of the Pancreas of the Ministry of Health and Welfare conducted a nationwide survey on acute pancreatitis to determine the prevalence of the disease between 1982 and 1986 and the treatment modalities used. Based on a detailed assessment of the results of the survey, the Committee developed criteria for rating the severity of acute pancreatitis and guidelines for the treatment of acute pancreatitis, which was revised in 1995. The five points cited as the principal aspects of treatment of severe acute pancreatitis in Japan include (a) rating the severity of the disease according to the severity rating criteria; (b) differentiating between edematous and necrotic pancreatic lesions and performing dynamic CT of the pancreas to define the extent of pancreatic necrosis; (c) performing ultrasonography to determine whether there are gallstones; (d) in principle, not performing surgery except in patients who clearly have early infection or complications after the onset; and (e) providing conservative intensive care immediately after the onset. In the absence of complications, the treatment of acute pancreatitis in Japan is primarily medical. In contrast to other countries, however, administration of antiprotease agents has become an important method of treating acute pancreatitis in Japan. Special treatment modalities, such as peritoneal lavage, blood purification, and continuous arterial infusion of protease inhibitor, are being performed in severe acute pancreatitis, in addition to intensive care.

Surgical aspects and management of acute necrotizing pancreatitis: recent results of a cooperative national survey in Japan.

A cooperative national survey between 1991 and 1994 recently clarified the status of acute necrotizing pancreatitis in Japan. The overall mortality rate was 20.8%; however, the mortality rate in patients with infection was 33.3%, and the mortality rate in patients who underwent surgery was 27.4%. With regard to surgical procedures, drainage procedures (mobilization of the pancreatic bed and retroperitoneal drainage) were performed most frequently, and one third of the patients who underwent drainage procedures needed reoperation. Although debridement of the necrotic tissue (necrosectomy or resection of the pancreas) was performed in 33.3%, the mortality rate was 35.3%. There was no difference in the mortality rate between early and delayed operation. Recently two new modalities have been advocated for the management of severe acute pancreatitis in Japan. One is continuous regional arterial infusion of protease inhibitor and antibiotics, and the other is continuous hemodiafiltration. Further work is needed to establish the most effective procedures for the management of acute necrotizing pancreatitis and debridement of pancreatic infection.

The epidemiology of pancreatic diseases in Japan.

We reviewed the trends and death rates of pancreatic cancer and pancreatitis in Japan over the past four decades. It is a disturbing fact that the death rate due to pancreatic cancer is rising, parallel to that of lung cancer and colon cancer and that it is affecting primarily the elderly 65 years and older in both sexes. The cause of this increase is partially attributable to improvements in the diagnosis, changes in life-style, and smoking. The death rate due to chronic and acute pancreatitis has remained constant during the past four decades.

Current surgical trends in Japan for managing chronic pancreatitis.

The main aims of surgery for treating chronic pancreatitis are to relieve the patient's persistent pain and to preserve pancreatic functioning. The indications for surgery include treating complications, such as the presence of pancreatic pseudocysts or biliary stenosis associated with chronic pancreatitis or both. A resection, ductal drainage, or both, may commonly be required. Furthermore, some surgeons recommend pancreatic denervation. We analyze the details of 2,936 patients with chronic pancreatitis who were treated surgically and were listed in the 1985 National Statistics in Japan. We have also evaluated the present surgical methods for treating chronic pancreatitis in Japan. In addition, we discuss a new surgical method being used to treat chronic pancreatitis. This is a recently improved technique involving a complete duodenum-preserving resection of the head of the pancreas, which also preserves the biliary and alimentary tracts.

Criteria for diagnosis of acute pancreatitis in Japan and clinical implications.

The Japanese grading system for severity of acute pancreatitis has evolved from results of a national survey on 2,553 patients managed in 523 major medical centers in Japan between 1982 and 1986. It was devised to embrace the predictive factors that would offer high sensitivity and specificity in rendering an accurate diagnosis. In this system, computed tomographic (CT) examination is used for estimating the severity of acute pancreatitis. Combining criteria from laboratory data, clinical signs, and CT findings, the system appears cumbersome. However, it is actually more flexible in that only few criteria, from the wide range of findings actually covered, are needed to predict severity. Its rationale stems from a national effort to improve the outcome of this life-threatening disease. Further prospective studies are needed to determine its accuracy and superiority.

Criteria for pancreatic disease diagnosis in Japan: diagnostic criteria for chronic pancreatitis.

Chronic pancreatitis was not a clinical entity until around 1960 in Japanese gastroenterology. The diagnosis of chronic pancreatitis had been vague and difficult to ascertain. The diagnostic criteria for chronic pancreatitis were first proposed in 1971, and they were subsequently revised in 1983. Patient numbers of chronic pancreatitis were summed by national surveys under each of the common diagnostic criteria. Total patient number and incidence rate of chronic pancreatitis are recognized as increasing throughout Japan, based on results of two national surveys of chronic pancreatitis. The diagnostic criteria for chronic pancreatitis in Japan were again revised in 1995, because the 1983 criteria were too complicated, and there had been more recent progress in clinical investigations of the pancreas. The essential revised points of the Diagnostic Criteria, 1995, are introduced in this review along with some discussion.

Severe acute pancreatitis in Japan

The status of severe acute pancreatitis in Japan has been clarified by a series of surveys of the disease carried out by the Research Committee of Intractable Diseases of the Pancreas under the aegis of the Japanese Ministry of Health and Welfare. The severity of disease classification systems, consisting of: clinical signs and symptoms, laboratory data, and computed tomographic grading, have led to early detection of severe disease with precise assessment and the potential to screen for local complications. Early mortality has been markedly reduced by intensive care, with specific treatment modalities, while there has been an increase in late mortality caused by severe infection. Indications for surgery have been changed: to debridement for infected pancreatic necrosis and drainage of abscess although the timing of surgery is still controversial.

Evaluation of specific treatment for severe acute pancreatitis based on the results of the cooperative national survey in Japan

A cooperative national survey on acute pancreatitis in Japan was conducted by the Research Committee for Intractable Diseases of the Pancreas. Between January 1952 and December 1986, 2533 cases of acute pancreatitis, including 1219 severe and 1285 moderate cases, diagnosed according to the criteria of the Ministry of Health and Welfare of Japan, were collected from 523 institutions. Peritoneal lavage, plasma exchange, and artifical kidney therapy, that is, hemodialysis and hemofiltration, were employed as specific treatments for severe acute pancreatitis. We have attempted to evaluate the efficacy of these treatments based on the results of this survey. Peritoneal lavage, employed to treat 57 patients, was effective when performed within 3 days of the onset of symptoms and more than six times a day. Plasma exchange, employed in 20 patients, was effective when performed within 5 days of the onset of symptoms. Artificial kidney therapy, performed in 76 patients, was effective when continued for more than 7 days. These findings suggest that accurate and rapid diagnosis, and intensive care to maintain the cardiovascular system are crucial if these specific treatments for severe acute pancreatitis, are to succeed.