Stefan Appelros

Trends in incidence of acute pancreatitis in a Swedish population: is there really an increase?

BACKGROUND AND AIMS Recent reports have suggested an increasing incidence of acute pancreatitis, and changing patterns of risk factors, over the past decades. The aim of this study was to investigate trends in the incidence of acute pancreatitis, and risk factors related to the disease, in a general population over a 15-year period. METHODS Clinical, autopsy, and forensic records for all patients with a first attack of acute pancreatitis in Malmö, Sweden, from 1985 to 1999, were validated retrospectively. Evidence for diagnosis was reconsidered and plausible cause was assessed. The incidence of gallstone disease, lung cancer, and alcohol-related conditions in the background population were retrieved from hospital diagnosis records and cancer and cause-of-death registries. RESULTS A total of 929 first attacks of acute pancreatitis were identified. The total incidence of acute pancreatitis increased by 3.9% per year (95% confidence interval [CI], 2.1-5.8). The incidence of gallstone-related pancreatitis increased by 7.6% per year (95% CI, 4.0-11.4), and this correlated with an increase in the incidence of other gallstone-related conditions ( r = 0.68; P = 0.005). Alcohol-related pancreatitis decreased by -5.1% per year (95% CI, -7.4 to -2.8), and this correlated with a decrease in the incidence of delirium tremens ( r = 0.75; P = 0.001), mortality from cirrhosis ( r = 0.81; P < 0.001), and incidence of lung cancer ( r = 0.57; P = 0.026). CONCLUSIONS There was a statistically significant increase in the incidence of acute pancreatitis. Gallstone-related pancreatitis increased, and alcohol-related pancreatitis decreased. Both of these trends were statistically significant and correlated with trends in the incidence of other conditions associated with either gallstone disease or alcohol abuse.

Activation peptide of carboxypeptidase B in serum and urine in acute pancreatitis

Background—The pathophysiology of acute pancreatitis involves activation of the pancreatic proenzymes. Levels of the trypsinogen activation peptide in urine in acute pancreatitis has been shown to correlate with the severity of disease. However, this peptide is unstable in urine and, because of its low molecular mass, difficult to measure. Procarboxypeptidase B has a larger activation peptide which could be more suitable for analysis in serum and urine. Aims—To study the presence of the activation peptide from procarboxypeptidase B (CAPAP) in serum and urine in acute pancreatitis. Patients—Urine and serum samples were obtained within 48 hours of admittance from 40 patients with acute pancreatitis. Severity was classified retrospectively according to levels of C-reactive protein and clinical course. Thirty four patients with abdominal pain from other causes were studied as controls. Methods—CAPAP was purified from human pancreatic juice. Specific antibodies were obtained and a radioimmunoassay was developed. Results—Levels of CAPAP in serum and urine in acute pancreatitis correlate with the severity of the attack. CAPAP is very stable, and urine contains only CAPAP whereas, in serum, cross reacting procarboxypeptidase B is found together with CAPAP. Conclusions—CAPAP could be a valuable tool in the diagnosis and early determination of severity in acute pancreatitis.

Short and long term outcome of severe acute pancreatitis.

OBJECTIVE Between 1985 and 1994, 883 cases of acute pancreatitis were treated in Malmö, Sweden (population 233,000). The purpose of this study was to report the short- and long-term outcome of the 79 cases that were severe, according to the Atlanta classification. DESIGN Retrospective and follow-up study a median time of 7 years since the attack. SETTING University hospital, Sweden. SUBJECTS 79 patients with severe acute pancreatitis. MAIN OUTCOME MEASURES Mortality, cause of death, organ failure, local complications, surgical procedures, mortality since the attack, and endocrine and exocrine dysfunction. RESULTS Twenty-one patients died from their attack. Organ failure was the predominant cause of death in the 13 patients who died during the first 10 days after admission, whereas infection was the most common cause of death in patients who died later. Mortality was low under the age of 60 and increased with age. Organ failure developed in 72 patients. Twenty-four patients developed pancreatic necrosis or abscesses and 18 patients were treated by necrosectomy and open or closed drainage. At follow-up, 13 patients had died, 2 from pancreatic carcinoma. 35 patients were included in the follow-up survey. 15 of these had diabetes and an additional 4 had impaired glucose tolerance. 9 patients had signs of severe exocrine dysfunction. CONCLUSIONS There was a high incidence of endocrine and exocrine dysfunction together with, in many patients, ongoing social problems related to chronic alcoholism several years after an attack of severe acute pancreatitis.

A Prospective Cohort Study of Smoking in Acute Pancreatitis

Background/Aims: Little is known about risk factors for acute pancreatitis other than gallstones and alcohol consumption. The aim of this study was to investigate if smoking or body mass index (BMI) are associated with acute pancreatitis and to determine relative risks (RR) for acute pancreatitis related to smoking, BMI, and alcohol consumption. Methods: From 1974 to 1992, selected birth-year cohorts of residents in Malmö, Sweden (born 1921–1949) were invited to a health-screening investigation including physical examination, blood sampling and a questionnaire. In total, 33,346 individuals participated. Cases of acute pancreatitis were identified from diagnosis registries (n = 179). Incidence rates were calculated in different risk factor categories. A Cox’s analysis revealed RR. Results: Current versus never smoking at baseline was associated with acute pancreatitis (RR 2.14, 95% confidence interval (CI) 1.48–3.09) after adjustment for age, sex, BMI and alcohol consumption. This association was stronger in heavy smokers (20–30 cigarettes/day) (RR 3.19, 95% CI 2.03–5.00). Smoking was associated with a RR of 3.57 (95% CI 0.98–13.0) for acute pancreatitis in subjects who reported no alcohol consumption. An increased risk for acute pancreatitis was also found for high versus low risk, self-reported alcohol consumption (RR 2.55, 95% CI 1.59–4.08) and for γ-GT levels in the highest versus the lowest quartile (RR 2.14, 95% CI 1.32–3.49). There was also a weak correlation between BMI and acute pancreatitis. Conclusions: Smoking is associated with the incidence of acute pancreatitis in a dose-response manner.

Serum levels of procarboxypeptidase B and its activation peptide in patients with acute pancreatitis and non-pancreatic diseases

Background: Carboxypeptidase B from the pancreatic gland may exist in three different molecular and immunoreactive forms: the proenzyme, the active enzyme, and the activation peptide. Aims: To investigate levels of procarboxypeptidase B (proCAPB) and its activation peptide in serum in acute pancreatitis to test the accuracy of these two variables as markers for the diagnosis of acute pancreatitis and for prediction of pancreatic necrosis. To elucidate whether leakage of proenzymes and activation of proenzymes reflect two different pathophysiological events in acute pancreatitis. Methods: Sera from patients with acute pancreatitis (n=85) and acute abdominal pain of non-pancreatic origin (n=53) were analysed for proCAPB and its activation peptide. Patients with pancreatitis were divided into necrotising (n=33) and oedematous attacks (n=52) using contrast enhanced computed tomography. Accuracy was determined using receiver operating characteristic curve analysis. Results: Immunoreactive carboxypeptidase B activation peptide (ir-CAPAP) concentration in serum on admission was 0.7 nmol/l (0–18.1) in patients with oedematous pancreatitis compared with 5.8 nmol/l (1.9–34) in patients with later development of pancreatic necrosis. Elevated levels of the activation peptide on admission correlated with an accuracy of 92% to later development of pancreatic necrosis. Ir-proCAPB concentration in serum on admission was 16.0 nmol/l (1.4–50.5) in all patients with acute pancreatitis versus 0.3 nmol/l (0–3.6) in patients with non-pancreatic acute abdominal disorders. Cases with oedematous pancreatitis had ir-proCAPB levels of 15.4 nmol/l (1.4–50.5) versus 19.1 nmol/l (2.7–36.1) in cases with later development of pancreatic necrosis. Measurement of the proenzyme can thus be useful for the diagnosis of acute pancreatitis (accuracy 99%) but levels did not correlate with later development of pancreatic necrosis (accuracy 56%). Conclusion: Leakage of proenzymes occurs in acute pancreatitis, irrespective of severity, while development of pancreatic necrosis occurs only when there is activation of the proenzymes.

A prospective cohort study on risk of acute pancreatitis related to serum triglycerides, cholesterol and fasting glucose

BACKGROUND/OBJECTIVES To investigate risk for acute pancreatitis related to moderately elevated triglycerides, cholesterol and fasting glucose. METHODS This was a prospective cohort study in Malmö, Sweden of 33,346 subjects investigated 1974-1992 and followed until December 31, 2006. Baseline investigation included a self-administered questionnaire and analysis of serum triglycerides, cholesterol and fasting glucose. Cases of acute pancreatitis (n = 277, median time since baseline investigation 15.6 years) were identified in diagnosis registries and validated retrospectively. Attacks were classified as obstructive or non obstructive (alcohol or non alcohol related). Cox proportional hazards analysis was used to calculate hazard ratios (HR) for acute pancreatitis related to relevant risk factors, adjusting for age, sex, smoking habits and alcohol consumption. RESULTS Triglycerides were associated with overall, non obstructive and non obstructive non alcohol related acute pancreatitis with adjusted HRs of 1.21 (95% confidence interval (CI), 1.07-1.36), 1.23 (95% CI, 1.06-2.43) and 1.34 (95% CI, 1.11-1.62) per 1 mmol/l increment, respectively. Corresponding HRs for forth versus first quartile of triglycerides were 1.55 (95% CI, 1.09-2.21), 1.60 (95% CI, 1.60-1.01-1.35) and 2.07 (95% CI, 1.13-3.79). Triglycerides were not associated with obstructive acute pancreatitis and there were no associations between glucose or cholesterol and the risk of acute pancreatitis. CONCLUSIONS We found an association between prediagnostic levels of triglycerides and risk for acute pancreatitis. This association was most pronounced in the non obstructive non alcohol related group. Our findings suggest that triglycerides may be a more important risk factor for acute pancreatitis than what has previously been estimated.

Protease Activation, Pancreatic Leakage, and Inflammation in Acute Pancreatitis: Differences between Mild and Severe Cases and Changes over the First Three Days

Background/Aims: The pathophysiology of acute pancreatitis (AP) may be studied using markers of protease activation (active carboxypeptidase B (aCAP), the activation peptide of carboxypeptidase B (CAPAP)), leakage of pancreatic enzymes (trypsinogen-2, procarboxypeptidase B (proCAP), amylase), and inflammation (monocyte chemoattractant protein-1 (MCP-1), CRP). Methods: This prospective study included 140 cases of AP. Mild (n = 124) and severe (n = 16) cases were compared with respect to serum levels of trypsinogen-2, proCAP, amylase, aCAP, CAPAP (serum/urine), MCP-1 (serum/urine) and CRP on days 1, 2 and 3 from onset of symptoms. All patients with information on all 3 days were included in a time-course analysis (n = 44–55, except amylase: n = 27). Results: High levels in severe versus mild cases were seen for trypsinogen-2, CAPAP in serum and urine, and MCP-1 in serum on days 1–3. No differences were seen for proCAP, amylase and aCAP. MCP-1 in urine was significantly elevated on day 1–2, and CRP on day 2–3. CAPAP and MCP-1 levels peaked early and stayed elevated for 48 h in serum. Conclusion: Protease activation and inflammation are early events in AP, with high levels of these markers within 24 h. Protease activation declines after 48 h, whereas inflammation is present for a longer time.

Monocyte Chemoattractant Protein 1, Active Carboxypeptidase B and CAPAP at Hospital Admission Are Predictive Markers for Severe Acute Pancreatitis

Background: CAPAP, the activation peptide of procarboxypeptidase B, is a predictor of severe acute pancreatitis (AP). Active carboxypeptidase (aCAP) may be a better predictor, as its turnover is slower. Monocyte chemotactic protein-1 (MCP-1) is an early inflammatory marker and increases before complications in severe AP. We conducted a cohort study to evaluate these markers as predictors for severe AP. Method: 140 patients with AP were included, retrospectively grouped as severe or mild by the Atlanta classification. CAPAP, MCP-1 and aCAP were analyzed in admission samples. Receiver operating characteristic curves determined high vs. low levels. Results: The levels of all markers were significantly higher in patients with severe disease. High levels of serum MCP-1 was associated with a high risk of developing severe AP (OR 40.8; 95% CI 8.5–195). High ORs were also seen for urine MCP-1 (OR 7.3; 95% CI 2.2–24.3), serum CAPAP (OR 5.4; 95% CI 1.6–17.7), urine CAPAP (OR 4.8; 95% CI 1.6–14.2), and serum aCAP (OR 3.7; 95% CI 1.2–11.3). Conclusion: Serum MCP-1 at admission was strongly associated with development of severe AP. MCP-1 in urine, CAPAP in serum and urine and aCAP may also be useful for predicting severe AP.

Studies on the Turnover of Procarboxypeptidase B, Its Active Enzyme and the Activation Peptide in the Pig

Recent developments in the treatment of acute pancreatitis have focused on the importance of early determination of the severity of an attack. Measuring levels of activation peptides from pancreatic proenzymes seems to be one way to predict severity. Levels of the activation peptide from procarboxypeptidase B, in both serum and urine on admission, have been shown to correlate to the outcome. To be able to interpret levels of this peptide in serum and urine under normal and in various acute abdominal conditions, we need knowledge about its turnover in the circulation. Procarboxypeptidase B, active carboxypeptidase and the activation peptide were therefore purified from porcine pancreatic juice. These proteins were labelled with 125I or 131I and their turnovers were studied in vivo in the pig. The proenzyme and the activation peptide were eliminated without interaction with any substance in the circulation. The active enzyme was to some degree bound to a substance with a molecular mass of 10-20 kDa. Active CPB was eliminated more slowly than proCPB and the activation peptide. Five percent of the activation peptide was detected nondegraded in the urine. After intraduodenal administration of the activation peptide there was no sign of the peptide in the urine.

Different patterns in immunoreactive anionic and cationic trypsinogen in urine and serum in human acute pancreatitis

SummaryBackgroundAcute pancreatitis (AP) results in elevated concentrations of trypsinogen (T) isoenzymes in serum. Immunoreactive anionic trypsinogen in urin (irAT/u) is elevated in AP, and has recently been proposed as a rapid diagnostic instrument and severity predictor. These results have not been confirmed by other groups, and irAT/u has not been further characterized. The concentration of immunoreactive cationic trypsinogen in urine (irCT/u) and the serum irAT/irCT ratio in AP have not been extensively examined.MethodsLevels of irAT and irCT were studied in urine and serum from 50 AP patients and in urine from 41 non-AP patients. Severity was assessed according to the Atlanta classification. irAT/u was characterized by gel filtration.ResultsGel filtration revealed only AT in the urine. Highly significant differences in irAT/u were seen between AP/non-AP (p < 0.0001) and mild/severe disease (p = 0.0012). The irAT/irCT ratio in serum changed from normal 0.8 to 1.3 in AP.ConclusionsIrAT and only traces of irCT were found in the urine in AP. IrAT/u was higher in AP than in other acute abdominal disorders (non-AP) and also higher in severe than in mild AP. IrAT in serum (irAT/s) increased proportionally more than irCT/s in AP, but did not discriminate mild from severe forms. High levels of irAT/u in some non-AP cases and a wide range in AP cases make the clinical value of the test questionable.