Clinical Gastroenterology and Hepatology
Volume 7, Issue 11, Supplement , Pages S15-S17, November 2009

Long-Term Prognosis of Acute Pancreatitis in Japan

  • Yoshifumi Takeyama

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Yoshifumi Takeyama, Department of Surgery, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-sayama 589-8511, Japan. fax: (81) 72-367-7771

Article Outline

This study was undertaken to evaluate the long-term prognosis of acute pancreatitis (AP) in Japan and to identify factors that predict major complications. In 1987, 2533 patients with moderate or severe acute pancreatitis were registered in a national survey in Japan. Follow-up studies were done in 2000 and in 2004 to evaluate recurrence of acute pancreatitis, transition to chronic pancreatitis, development of diabetes mellitus, and mortality. The relationship between incidence of complications and alcohol consumption during follow-up period was also analyzed. Valid replies were obtained from 714 cases in 2000 and 450 cases in 2004. Recurrence of acute pancreatitis occurred in 145 cases, and the recurrence rate was significantly higher in alcoholic pancreatitis compared with other etiologies. A transition to chronic pancreatitis occurred frequently in alcoholic pancreatitis and inversely correlated with existence of pancreatic necrosis in the initial disease. Complication with diabetes mellitus and the transition to chronic pancreatitis strongly correlated with persistent alcohol intake during follow-up period. During the follow-up period, 199 patients died, and 43 died of malignant disease. Recurrence of acute pancreatitis and a transition to chronic pancreatitis frequently occurred in alcoholic pancreatitis. Transition to chronic pancreatitis was inversely correlated with the existence of pancreatic necrosis at the initial presentation. Mortality as a result of malignant disease was not excessive in the patients with history of acute pancreatitis.

Abbreviations used in this paper: AP, acute pancreatitis, CE-CT, contrast-enhanced computed tomography, CP, chronic pancreatitis, DM, diabetes mellitus, JSS, Japanese Severity Score, SAP, severe acute pancreatitis

 

At the Second International Symposium on the Classification of Pancreatitis in Marseille, France, in 1984 it was proposed that acute pancreatitis (AP) rarely undergoes a transition to chronic pancreatitis (CP).1 However, Riaz et al2 proposed that recurrent AP might undergo the transition to CP in an appreciable number of patients. Moreover, it was also demonstrated that alcoholic AP frequently recurs.3, 4 Also, the long-term prognosis after severe acute pancreatitis (SAP) is often complicated, because severe inflammation and pancreatic necrosis can affect the function and morphology of pancreas. According to previous reports on SAP, the recurrence rate of AP was 21%–27%,5, 6 and the complication rate with diabetes mellitus (DM) was 43%–54%.5, 6, 7 It was also demonstrated that the development of DM is associated with the need to operate on the pancreas for complications of AP.8, 9 There is little information on the long-term prognosis of AP in Japan. In this context, a national database in Japan was used to examine the long-term follow-up of patients with SAP and to determine whether specific clinical features predict poor outcomes.

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Patients and Methods 

In Japan under the financial support of the government, nationwide survey of AP has been done periodically from 1987, and a database of 2533 cases registered in 1987 has been available. From this registry a follow-up study was performed in 2000, and valid replies were available from 714 cases. At the time of admission, all the patients were classified by severity into moderate and severe according to the criteria for clinical diagnosis and grading severity (1990) formulated by the Research Committee of Intractable Diseases of the Pancreas, Japanese Ministry of Health, Labor and Welfare (Japanese Severity Score [JSS]).10, 11 In the criteria, SAP is defined as JSS ≥2. Pancreatic necrosis was also evaluated by dynamic contrast-enhanced CT (CE-CT) on admission and was defined as uneven density in the parenchyma (areas of hypoperfusion).

Among these cases, 311 patients had severe disease, and 403 patients had moderate disease. For etiology, 281 cases were alcoholic, 121 cases were gallstone, 162 cases were idiopathic, and 150 cases were of other origins. In regard to pancreatic necrosis in the initial presentation of pancreatitis, significant necrosis was observed in 98 of 499 cases (19.6%). In the other 117 cases the existence of pancreatic necrosis was not determined because CE-CT was not performed. As for surgical operation during the initial episode of pancreatitis, no operation, pancreatic operation, and biliary operation were performed in 434 cases, 207 cases, and 64 cases, respectively. In the other 9 cases, the information concerning operation was not available.

A detailed surveillance of alcohol consumption during the follow-up period was performed in 2004, and valid replies were obtained from 450 cases. Among these cases, complete abstinence was achieved in 177 cases (39.3%). In 106 cases (23.6%), the amount of alcohol intake decreased, but patients periodically drank. In 30 cases (6.7%), the amount of alcohol intake decreased, but the patients drank every day. In the other 137 cases (30.4%), the patients continued drinking as before AP.

Data from this cohort were analyzed to clarify the long-term prognosis (shortest 13 years) of AP in Japan.

During the follow-up period, recurrence of AP, transition to CP, development of DM, and complication with malignant disease were evaluated. Recurrent AP was defined as upper abdominal pain with hyperamylasemia. Diagnosis of CP was made according to the diagnostic criteria for CP (1995) by the Japan Pancreas Society.12 DM was defined as fasting blood glucose higher than 120 mg/dL on repeated measurements. The relationship of poor long-term outcomes (recurrence of AP, transition to CP, development into DM, and development of malignancy) with the findings of initial AP (severity, etiology, pancreatic necrosis, and surgical operation) and drinking status in follow-up period after AP were analyzed.

Statistical analyses were performed by using SPSS II software (SPSS Inc, Chicago, IL). The results are expressed as mean ± standard error of the mean. The Mann–Whitney U test or Pearson χ2 test was used to evaluate differences between 2 groups. Multivariate testing was performed by logistic regression analysis (stepwise method). A P value less than .05 was considered statistically significant.

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Results 

Recurrence of Acute Pancreatitis 

During the follow-up period, recurrence of AP was observed in 145 cases (20.3%). The recurrence rate was 23.1% in moderate pancreatitis and 16.7% in SAP. The recurrence rates in alcoholic pancreatitis, biliary pancreatitis, idiopathic pancreatitis, and pancreatitis of other etiologies were 32.4%, 7.4%, 17.9%, and 10.7%, respectively. Recurrence rate was significantly higher in alcoholic pancreatitis compared with the other origins (P < .01). The recurrence rate was not influenced by either the presence of pancreatic necrosis or surgical operation.

Transition to Chronic Pancreatitis 

During the follow-up period, 106 cases (14.8%) underwent a transition to CP. With respect to initial disease severity, transition rate was 14.9% in moderate pancreatitis and 14.8% in the SAP, showing no difference as a result of severity. With respect to etiology, transition rates to CP from alcoholic pancreatitis, biliary pancreatitis, idiopathic pancreatitis, and pancreatitis of other etiologies were 26.0%, 1.7%, 13.0%, and 6.7%, respectively. Transition rate was significantly higher in alcoholic pancreatitis (P < .01 vs every other etiology). With respect to pancreatic necrosis in initial AP, the transition rate for the cases with necrosis was 5.1% and for those without necrosis 16.2% (Figure 1). In the present study, the existence of necrosis inversely correlated with the transition to CP, suggesting that the existence of pancreatic necrosis was not a contributing factor for transition of CP. As for the need for surgery during initial disease, the transition rates from the cases without surgery, for those who underwent pancreatic surgery, and for those who underwent biliary surgery were 14.5%, 16.4%, and 3.1%, respectively (Figure 1). Thus, pancreatic operations including necrosectomy did not have impact on the transition to CP.

Development of Diabetes Mellitus 

The overall complication rate with DM was 13.0% (93/714). With respect to the initial severity, diabetes developed in 10.7% with moderate pancreatitis and 16.1% with SAP. Thus, the initial severity does not appear to significantly affect the risk of developing DM. However, when rates were compared among etiologies, a significantly increased risk of diabetes (20.6%; P < .01) was observed in those with an alcoholic etiology when compared with biliary (9.1%), idiopathic (9.9%), or other etiologies (5.3%). Diabetes was observed in 7.1% of those with necrosis and in 14.4% without necrosis (P > .05), indicating that existence of pancreatic necrosis was not a contributing factor for transition of CP. Diabetes developed in 11.5% of those who underwent pancreatic surgery, 3.1% who had biliary surgery, and 17.4% of those who had no surgery.

Alcohol Consumption 

The relationship between alcohol intake during follow-up period and complications such as recurrent pancreatitis, transition to CP, and complication with DM is demonstrated in Table 1. The incidence of every complication was significantly higher in persistent drinkers.

Table 1. Alcohol Consumption During Follow-Up Period and Incidence of Complication
Alcohol consumptionRecurrent pancreatitisTransition to CPComplication with DM
Complete cessation19.8%13.6%14.1%
Decreased but occasional18.9%12.3%14.2%
Decreased but daily36.7%23.3%30.0%
Continue drinking as before57.7%a40.9%a37.2%a

aSignificant against upper 2 rows of data (P < .05).

Complication With Malignancy 

During the follow-up period, 199 patients out of 713 died. Among those who died, 43 (21.6%) succumbed to malignancy. Five patients from this cohort died of pancreatic cancer that developed after AP (4 men and 1 woman). For those with pancreatic cancer, the age at onset of initial pancreatitis ranged from 61–75 years old. Two patients had alcoholic AP, and 2 had idiopathic AP. In the other patient, pancreatoduodenectomy was performed because of ampullary cancer 5 years before pancreatitis. In this patient, acute obstructive pancreatitis developed as a result of an anastomotic stricture. Five years after pancreatitis, he died with cancer in the remnant pancreas. Histology in all cases was pancreatic ductal adenocarcinoma. Recurrent pancreatitis, transition to CP, and development of DM were not observed in these 5 patients.

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Discussion 

Previous reports on overall recurrence rates of AP range from 21%–27%.5, 6 The recurrence rate in the present analysis was 20.3%, which was similar to the previous reports. With respect to the etiology of AP, Pelli et al3 reported that the recurrence of AP was noted in 46% of 568 patients with alcoholic AP and that 80% of recurrent AP occurred within 4 years after the first episode. In the present study, the recurrence rate in alcoholic AP was significantly higher (32.4%) than other etiologies.

Seidensticker et al13 reported that the transition rate to CP was 16% in 34-month follow-up of 38 patients with AP. In the present study, the transition rate to CP after AP was 14.8%, indicating that the transition rate to CP is comparable among countries.

In the present study, the presence of pancreatic necrosis at the time of initial presentation reduced the risk of developing CP. Furthermore, the transition rates to CP were highest in patients with alcoholic pancreatitis (26%). Finally, continued drinking was a significant contributing factor for the transition to CP. These results suggest that Japanese subjects with alcoholic AP who persist in drinking after an initial episode of pancreatitis are at greater risk for transitioning to CP. With respect to the mechanism for the evolution from AP into CP, Kloppel and Maillet14 have suggested that recurrent AP can lead to CP (necrosis-fibrosis sequence hypothesis). The results from the present study also suggest that recurrent attacks of alcoholic pancreatitis in persistent drinkers lead to the development of pancreatic fibrosis. Recently, Lankisch et al15 reported the results of a long-term follow-up study of AP. They reported that transition rate to CP was 16% in 20 years, which is comparable to our results, and concluded that the progression from AP to CP occurred only in alcoholic AP.

In previous reports, the complication rate with DM after SAP was 43%–54%.5, 6, 7 In the present results, however, the complication rate with DM was 13% overall and only 16.1% in SAP. With respect to the etiology of AP, Doepel et al7 reported the high rate of DM in alcoholic SAP, which is in accordance with the present study. The present results indicate that alcoholic pancreatitis combined with persistent alcohol abuse is a major risk factor for developing DM.

In previous reports, the complication rate with DM was high in patients with pancreatic surgery,8, 9 especially after pancreatic resection.16, 17 In this study, the complication rate with DM was relatively high in the patients with pancreatic surgery, but the difference was not significant.

Although it was reported that the risk of pancreatic cancer is significantly elevated in patients with CP,18 there have been no reports concerning relationship between AP and malignant disease. As demonstrated, 21.6% of subjects in the present study died of malignancy. Because 30.7% of the deaths in the general Japanese population are from cancer, the present findings suggest that a history of AP does not increase the risk of dying from malignancy. However, pancreatic cancer developed in 11.6% (5 patients) of those with some type of malignancy in this study. Although this value is higher than the 6.4% observed in our general population, there are too few patients in this study to speculate on the importance of this finding.

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Summary 

This prospective longitudinal study has examined the natural history of AP in a Japanese population that has been followed for more than 20 years. The key findings of this study are that the extent of necrosis at the time of initial presentation affects the risk of subsequently developing CP. In patients with alcoholic pancreatitis, continued drinking had a significant impact on the risk for developing CP and DM. Finally, a history of AP did not appear to affect the risk for developing pancreatic cancer.

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References 

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 Conflicts of interest The author discloses no conflicts.

PII: S1542-3565(09)00810-6

doi:10.1016/j.cgh.2009.08.022

Clinical Gastroenterology and Hepatology
Volume 7, Issue 11, Supplement , Pages S15-S17, November 2009