Acute pancreatitis (AP) is associated with significant mortality and requires emergency hospitalization.¹ Furthermore, the global incidence of AP is increasing.² In Korea, it has been documented that the annual incidence of admissions for AP reached 9,162 in 2000.³ Nevertheless, the precise count of newly diagnosed cases within this cohort remains undetermined. If organ failure persists for >48 hours during initial treatment in the acute phase, the mortality rate is about 20%.⁴ Therefore, appropriate treatment in the acute phase is very important. Treatment in the convalescent phase prevents relapse, exocrine and endocrine dysfunction, and progression to chronic pancreatitis (CP), and thus greatly impacts prognosis and quality of life.^5,6 To ensure appropriate early and convalescent treatment, it is essential to identify the cause of AP. By addressing the cause, future acute exacerbation, recurrence, and progression to CP can be prevented. However, 16% to 30% of patients have idiopathic AP (IAP); i.e., pancreatitis without an identifiable cause.^7,8 Recently, high-resolution imaging techniques including endoscopic ultrasound (EUS) and magnetic resonance imaging have been used to identify the etiology of AP and may affect the incidence of IAP and distribution of AP etiologies.^9,10 From a clinical perspective, determining both the cause and severity of AP is widely regarded as crucial for guiding future treatment decisions. Notably, however, the evidence supporting this viewpoint is insufficient.

Based on recent evidence, clinical guidelines have been developed in Korea and many other countries by various organizations but have not been validated through analysis of multicenter data.¹¹ In this study, the current status of the etiology and treatment of AP in Korea is investigated in patients diagnosed with AP for the first time, and ways to improve clinical care are discussed.

1. Patients

From 1 January 2018 to 31 December 2019, we retrospectively analyzed the medical records of adult patients (aged ≥18 years) diagnosed with AP of any cause for the first time and hospitalized at 12 tertiary medical institutions in Korea (Fig. 1). Patients with a history of AP or CP, as well as those currently receiving treatment for these conditions, were excluded. This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki as revised in 2013 and approved by the Institutional Review Board of each participating institution (IRB number: 2106-073-1226). The informed consent was waived.

Figure 1. Map showing the locations of the 12 Korean institutions participating in this retrospective multicenter study.

2. Data collection

We retrospectively collected the following data from 12 tertiary referral centers in Korea: patient characteristics at admission, including age, sex, body weight, height, comorbidities, smoking history, history of AP or CP, presence of organ failure, presence of systemic inflammatory response syndrome, presence of local complications, bedside index for severity in AP score, severity according to the revised Atlanta classification, and laboratory findings (including hemoglobin, hematocrit, white blood cell count, C-reactive protein, procalcitonin, amylase, lipase, liver function tests, serum blood urea nitrogen, serum creatinine, serum triglyceride, serum glucose, and serum calcium); etiology of AP during admission, including imaging used during the admission and etiology of AP at discharge; treatments received during admission, including the crystalloid fluid infusion volume during the initial 24 hours of admission, use of antibiotics, use of proton pump inhibitors, cholecystectomy during initial admission, reason for not performing cholecystectomy during initial admission, fasting duration, type of refeeding, and route of refeeding; and prognosis, including mortality at initial admission, development of recurrent AP during follow-up, and etiology of recurrence.

3. Definitions

The diagnosis of AP is based on abdominal pain, serum amylase and/or lipase levels >3-fold the upper normal limits, and radiographic findings consistent with AP. A diagnosis of AP is made when at least two of these three criteria are fulfilled. Acute biliary pancreatitis (ABP) was defined as gallstones or microliths in the common bile duct evident on transabdominal ultrasound, computed tomography, EUS, magnetic resonance cholangiopancreatography, or endoscopic retrograde cholangiography and fulfilment of the AP criteria. Hypertriglyceridemia-induced AP (HTG-AP) was defined as a serum triglyceride level ≥1,000 mg/dL at the time of admission. Acute alcoholic pancreatitis was diagnosed in cases of alcohol abuse or a chronic drinking history with no other identifiable cause of AP. Presumptive IAP was diagnosed when no cause was found at initial admission. The definition of severity was based on the revised Atlanta classification.¹² We defined mild AP as AP without organ failure or local or systemic complications, severe AP as organ failure lasting >48 hours, and moderately severe AP as AP with transient organ failure (<48 hours) or local complications.

4. Statistical analysis

Continuous variables are presented as means±standard deviations and categorical variables as percentages (%) or number of cases. When comparing two independent groups, the t-test was performed if the data were normally distributed; otherwise, the Mann-Whitney U test was used. One-way analysis of variance was used to compare three or more groups, and Welch test was employed when equal variance could not be assumed. Categorical variables were analyzed using the chi-square test and the Fisher exact test. All p-values <0.05 were considered statistically significant. All statistical analyses were performed using SPSS software (version 19.0; IBM Corp., Armonk, NY, USA).

1. Baseline characteristics

During the study period, 676 patients admitted to 12 tertiary hospitals were diagnosed with AP for the first time and received treatment (Table 1). There were 388 males (57.4%) and the mean age of all patients was 58.6 years (Fig. 2). According to the revised Atlanta classification, 355 cases (52.5%) were mild, 301 (44.5%) were moderate, and 20 (3.0%) were severe. Among all patients, the mortality rate during the first hospitalization was 3.3% (22/676). However, the mortality rate of patients with severe AP was 45.0% (9/20), which was significantly higher than that of patients with moderate (3.0%, 9/301) and mild AP (1.1%, 4/351) (p<0.001). The mean hospitalization period was 6.6±4.7, 10.4±11.7, and 13.7±13.6 days for those with mild, moderate, and severe AP, respectively (p<0.001). Serum levels of the pancreatic enzymes amylase and lipase did not differ significantly according to AP severity at the time of admission (p=0.697 and p=0.933, respectively). On admission, the mean white blood cell count was 10.8±4.6, 12.8±5.5, and 14.2±6.3 ×10³/µL in the mild, moderate, and severe AP patients, respectively (p<0.001). The mean blood urea nitrogen levels were 16.3±9.2, 17.7±13.5, and 40.1±23.8 mg/dL, respectively, and were significantly higher in severe than mild and moderate cases (p<0.001). There was no significant difference in body mass index (BMI) according to AP severity (p=0.716). However, after excluding 33 patients without BMI data, the rate of obesity (BMI >30 kg/m²) was significantly higher among patients with severe AP (27.8%, 5/18) compared to mild and moderate AP (9.4%, 59/625) (p=0.026) (Table 2).

Figure 2. Age distribution of the patients.

Table 1

Baseline Patient Characteristics.

Characteristic	Acute pancreatitis (n=676)
Male sex	388 (57.4)
Age, yr	58.6±17.7
Height, cm	164.0±9.8
Weight, kg	66.8±27.4
Body mass index, kg/m2	24.7±8.8
Current smoker	123 (18.2)
History
Diabetes mellitus	159 (23.5)
Dyslipidemia	101 (14.9)
Acute pancreatitis	0
Chronic pancreatitis	0
Systemic inflammatory response	197 (29.1)
Severity, Atlanta classification
Mild	355 (52.5)
Moderate	301 (44.5)
Severe	20 (3.0)
Initial laboratory findings
Hemoglobin, g/dL	13.7±2.2
Hematocrit, %	40.3±6.1
White blood cell, ×103/μL	11.8±5.2
Amylase, U/L	866.3±938.8
Lipase, U/L	2,024±2,489
Hospitalization, day	8.5±9.1
Death	22 (3.3)

Data are presented as number (%) or mean±SD..

Table 2

Characteristics of Non-Severe and Severe AP Patients.

Characteristic	Severe AP	Non-severe AP	p-value
Male sex	13 (65.0)	375 (57.2)	0.505
Age, yr	64.6±17.4	58.4±17.7	0.123
Height, cm	164.1±10.5	164.0±9.8	0.972
Weight, kg	68.6±15.1	66.8±27.7	0.783
BMI, kg/m2	25.5±5.1	24.6±8.9	0.671
BMI >30 kg/m2	5 (27.8)	59 (9.4)	0.026
Current smoker	5 (26.3)	67 (11.1)	0.106
History
Diabetes mellitus	6 (30.0)	153 (23.3)	0.592
Dyslipidemia	2 (10.0)	99 (15.1)	0.753
Systemic inflammatory response	16 (80.0)	181 (27.6)	<0.001
Initial laboratory findings
Hemoglobin, g/dL	12.7±2.0	13.7±2.2	0.044
Hematocrit, %	37.7±6.7	40.3±6.1	0.059
White blood cell, ×103/μL	14.2±6.3	11.7±5.1	0.031
Amylase, U/L	984.7±908.6	862.7±940.1	0.284
Lipase, U/L	2,088±1,564	2,022±2,513	0.908
BUN, mg/dL	40.1±23.8	17.0±11.4	<0.001
Creatinine, mg/dL	3.3±2.8	1.0±1.1	0.002
Etiology
Alcohol	7 (35.0)	159 (24.2)	0.293
Biliary	8 (40.0)	273 (41.6)	>0.999
HTG	0	46 (7.0)	0.388
Death	9 (45.0)	13 (2.0)	<0.001

Data are presented as number (%) or mean±SD..

AP, acute pancreatitis; BMI, body mass index; BUN, blood urea nitrogen; HTG hypertriglyceridemia..

2. Etiology

Imaging was performed at the discretion of the clinicians. During initial admission, computed tomography, EUS, and magnetic resonance imaging were performed on 95.4% (645/676), 26.3% (178/676), and 17.5% (118/676) of all patients, respectively. The most common etiologies of AP identified during the first hospitalization were cholelithiasis (41.6%, 281/676), alcohol (24.6%, 166/676), and HTG (6.8%, 46/676). Other causes included malignant disease, mucinous cysts, and drug-induced AP in 2.7% (18/676), 2.1% (14/676), and 1.8% (12/676) of patients, respectively. During the first hospitalization, 16.4% (111/676) of patients were discharged with unexplained AP (presumptive IAP). ABP was more prevalent in older age groups, while HTG-AP was more prevalent in younger age groups (Fig. 3).

Figure 3. Age distribution of the patients according to the etiology of acute pancreatitis.

The etiology of AP varied between males and females. In males and females, alcohol and gallstones were the most frequent causes (37.6% [146/388] and 54.2% [156/288], respectively). The severity of AP also differed by sex. In males, the frequencies of mild, moderate, and severe AP were 46.6% (181/388), 50.0% (194/388), and 3.4% (13/388), respectively; the rates for females were 60.4% (174/288), 37.2% (107/288), and 2.4% (7/288), respectively; and the proportion of females with mild AP was higher than that of males (p=0.002). However, when analyzing severity according to etiology, the proportion of severe AP cases was higher among acute alcoholic pancreatitis patients compared to those with AP of other etiologies (4.2% vs 2.5%, p<0.001), and the proportion of mild AP was higher among ABP patients compared to those with AP of other etiologies (59.4% vs 47.6%, p=0.009). Considering that the identified disparity is exclusively derived from univariate analysis, and multivariate analysis has not been undertaken, the potential association between gender and severity remains ambiguous.

3. Initial treatments

After excluding 26 patients for whom the volume of crystalloid fluid administered during the first 24 hours was not recorded, 86.8% (564/650) of the remaining patients received 2 to 4 L of fluid during the first 24 hours of hospitalization and 13.2% (86/650) received ≥4 L. The mortality rate was significantly higher in patients who received ≥4 L of fluid (9.3% vs 2.1%, p=0.002), even when patients with severe AP were excluded (1.3% vs 5.0%, p=0.040). However, deriving a precise conclusion from this dataset poses a challenge because the incidence of severe AP was significantly higher among patients who received ≥4 L of fluid than among those who received <4 L (7.0% vs 2.5%, respectively; p=0.037). Interestingly, 70.0% (14/20) of patients with severe AP and 81.5% (154/189) of patients with systemic inflammatory response syndrome had received <4 L per day during the initial 24 hours of admission (Table 3).

Table 3

Characteristics of Patients: Initial Aggressive Hydration (>4 L/day) versus Non-Aggressive Hydration (<4 L/day).

Characteristic	Aggressive (>4 L/day)	Non-aggressive (<4 L/day)	p-value
Male sex	57 (66.3)	315 (55.9)	0.079
Age, yr	57.7±16.8	58.7±17.9	0.644
Height, cm	165.1±9.8	163.9±9.9	0.275
Weight, kg	67.3±14.6	66.8±28.9	0.864
BMI, kg/m2	24.6±4.5	24.6±9.3	0.968
BMI >30 kg/m2	9 (11.3)	53 (9.9)	0.842
Current smoker	12 (15.6)	58 (11.2)	0.195
History
Diabetes mellitus	28 (32.6)	125 (22.2)	0.041
Dyslipidemia	12 (14.0)	87 (15.4)	0.752
Systemic inflammatory response	35 (40.7)	154 (27.3)	0.015
Severe AP	6 (7.0)	14 (2.5)	0.037
Initial laboratory findings
Hemoglobin, g/dL	13.7±2.2	13.7±2.2	0.934
Hematocrit, %	40.2±5.8	40.3±6.1	0.820
White blood cell, ×103/μL	12.8±5.8	11.6±5.1	0.056
Amylase, U/L	910.4±888.7	859.1±947.1	0.637
Lipase, U/L	2,343±2,695	1,977±2,457	0.208
BUN, mg/dL	20.8±14.9	17.2±12.1	0.012
Creatinine, mg/dL	1.1±0.6	1.1±1.3	0.899
Etiology
Alcohol	27 (31.4)	134 (23.8)	0.140
Biliary	28 (32.6)	243 (43.1)	0.078
HTG	8 (9.3)	36 (6.4)	0.353
Death	8 (9.3)	12 (2.1)	0.002

Data are presented as number (%) or mean±SD..

BMI, body mass index; AP, acute pancreatitis; BUN, blood urea nitrogen; HTG hypertriglyceridemia..

Empirical antibiotics were started within 48 hours of hospitalization in 72.9% (493/676) of all patients. Among the patients who did not receive antibiotics within the first 48 hours, 59.8% (110/184), 39.7% (73/184), and 0.5% (1/184) had mild, moderate, and severe AP, respectively. Among patients on antibiotics, 49.8% (245/492), 46.3% (228/492), and 3.9% (19/492) had mild, moderate, and severe AP, respectively. Antibiotics were prescribed mainly to treat cholecystitis and cholangitis (33.3%, 164/493). However, they were also prescribed for shock (4.3%, 21/493), fever (39.6%, 195/493), infected necrosis (0.2%, 1/493), other types of infection (1.6%, 8/493), and other reasons including prophylaxis (21.0%, 104/493).

4. Convalescent treatment

Nutrition was resumed after a mean fasting duration of 2.9±2.7 days, and 94.2% of patients (637/676) were started on an oral diet. Nutrients were delivered via a nasogastric tube in 0.7% of patients (5/676); no nasojejunal tube was employed. In 48.1% of patients (325/676), nutrition was gradually increased starting with sips of water, while in 3.1% the initial dietary recommencement (21/676) was solid food.

During hospitalization, proton pump inhibitors were prescribed for 57.1% of the patients (386/676), including 5.6% (23/386) because of bleeding after endoscopy, 4.9% (19/386) because of gastrointestinal ulcers, 2.6% (10/386) because of gastroesophageal reflux disease, and 84.7% (327/386) for no recorded reason.

Of the 281 patients diagnosed with ABP, 23.8% (67/281) underwent cholecystectomy during their initial hospitalization. Among patients with ABP, 59.4% (167/281) had mild AP, 37.7% (106/281) had moderately severe AP, and 2.8% (8/281) had severe AP. Specifically, only 21.6% (36/167) of those with mild ABP underwent cholecystectomy during their initial hospitalization. Among the 214 patients diagnosed with ABP who did not undergo surgery, 61.2% (131/214) presented with mild AP. Reasons for not undergoing surgery included patient refusal in 37.4% (80/214), severe AP or local complications in 10.3% (22/214), advanced age and/or high-risk comorbidities in 17.8% (38/214), and non-medical reasons such as the surgeon’s opinion or a delay in surgical scheduling in 19.6% (42/214). In total, 21.0% of all patients (142/676) were lost to outpatient follow-up. During follow-up, AP recurrence was confirmed in 17.8% of patients (95/534). Of the patients who developed relapse, 44.2% (42/95) had acute alcoholic pancreatitis and 17.9% (17/95) had ABP. Of the initial 131 patients with mild ABP who did not undergo cholecystectomy, 30 patients were lost to follow-up and 9.9% of the remaining patients (10/101) developed recurrent ABP. None of the patients with recurrent ABP had undergone cholecystectomy at the time of the initial admission, and they subsequently developed recurrent AP within a mean duration of 686 days (range, 55 to 1,235 days).

We investigated the current AP diagnosis and treatment status in Korea by analyzing the largest multicenter dataset available. We have reported the distribution of AP etiologies in the era of high-resolution medical imaging techniques, such as EUS and magnetic resonance cholangiopancreatography. The incidence and mortality rates were reported according to AP severity, and the data suggested a possible relationship between obesity and AP severity. In addition, we tried to bridge the gap between clinical guidelines and real-world practice by identifying real-world treatment trends and reasons for not following guidelines.

The incidence of severe AP in this study (3.0%) is lower than that reported in prior studies. However, in a study based on Korean multicenter data, Lee et al.¹³ reported the distribution of severity based on the revised Atlanta classification. They found a 3.7% incidence of severe AP, which aligns closely with our own findings. The etiological factors contributing to AP exhibit variations based on global geographical regions. The most frequent causes of AP are gallstones and alcohol abuse in developed countries, and our data are in accordance with this. Retrospective studies conducted in Western countries revealed an equivalent prevalence of alcohol-induced and gallstone-related pancreatitis, with each causative factor contributing to a range of 23% to 36% of cases.¹⁴ In another study, dominance of gallstone-related pancreatitis was noted in southern European countries.¹⁵ Baig et al.¹⁶ identified alcoholism as the predominant cause of AP, followed by biliary stones, and Wang et al.¹⁷ similarly found that biliary stones (38%) and alcohol abuse (36%) were the foremost etiological factors in AP. Conversely, Alkareemy et al.¹⁸ reported gallstones and idiopathic causes as the most prevalent etiologies. These discrepancies seem to be attributed to regional disparities in alcohol consumption.

In our study, HTG was the third most common cause of AP. Generally, serum triglyceride levels of 500 mg/dL (5.6 mmol/L) are suspected to cause AP, and patients with levels ≥1,000 mg/dL (11.3 mmol/L) are diagnosed with AP.¹⁹ However, a major practical difficulty when aiming to identify the etiology of AP is that it is not easy to determine whether HTG simply reflects excessive alcohol consumption or is the cause of AP. Given the retrospective nature of this study, it is possible that the reported HTG frequency was lower than the actual frequency because alcohol may be identified as the cause of AP when clinicians encounter patients who consume it to excess; clinicians may not test for HTG. Some experimental and clinical studies found that HTG-AP was more severe than AP of other etiologies.^20,21 However, in the present study, among 46 HTG-AP patients, none had severe AP (mild, n=23; moderate, n=23). Thus, we did not identify a relationship between HTG-AP and AP severity.

Together with HTG, obesity has been suggested to increase AP severity. Obesity is known to exacerbate the systemic inflammatory response and increase mortality.^22-25 We found that the proportion of obese patients (BMI >30 kg/m²) was significantly higher among the severe than the mild and moderate AP groups. As the number of obese subjects in Korea is increasing, it is possible that obesity will emerge as a clinically important predictor of AP severity.²⁶ However, according to the 2012 revised Atlanta classification, 20 patients included in this study were classified as having severe AP, and multivariate analysis of risk factors for predicting severe AP was not possible.

Previous studies found that IAP accounted for 16% to 30% of all AP cases.^7,8 In this study, the cause of AP during initial admission could not be found in 16.4% of patients. This is lower than the proportions in previous reports, possibly reflecting the use of more recent imaging techniques. EUS sensitively detects ABP, including microlithiasis, and magnetic resonance cholangiopancreatography is comparable to EUS.^9,27,28 However, there is no definitive evidence or guidelines supporting the use of any particular imaging modality during the acute phase of AP. Efforts to reduce the frequency of IAP and identify all of the etiologies are still needed because AP can recur and is a risk factor for the development of CP.²⁹

Traditionally, fluid therapy is used to maintain an effective circulating blood volume in patients with AP; rapid fluid therapy has been recommended. It is crucial to achieve an appropriate intravascular blood volume while also avoiding overloading the patient with crystalloid fluid. In this study, 70.0% (14/20) of patients with severe AP and 81.5% (154/189) of patients with systemic inflammatory response syndrome received <4 L per day during the initial 24 hours of admission. Considering that severity assessment can only be reliably conducted after 48 hours of admission, these findings underscore the challenges of estimating severity within the first 24 hours in current clinical practice. However, recent evidence suggests that excessive fluid administration should be avoided. Several randomized controlled trials have revealed an association between excessive fluid administration and multiple organ failure as well as an increased severity of AP.^30-33 Practical severity estimation protocols that can be implemented early in the admission process, ideally at the initial presentation, are required to identify patients who require aggressive fluid therapy as a tailored approach.

Because infection is the leading cause of death 1 month after an initial AP attack, empirical prophylactic antibiotics are widely prescribed. In this study, the prescription rate within the first 48 hours was high (72.8%) considering the frequency of ABP and AP infectious complications requiring antibiotics.³⁴ Antibiotics were prescribed within 48 hours of admission mainly to treat cholecystitis and cholangitis, but they were also administered for shock (4.3%), fever (39.6%), infected necrosis (0.2%), other types of infection (1.6%), and other reasons including prophylaxis (21.0%). However, because this study was multicenter in nature, the observed trend is not indicative of an issue attributed to a single medical center; instead, it underscores the necessity for consensus among experts.

Cholecystectomy at the time of initial admission for ABP is recommended by clinical guidelines because it reduces the frequency of recurrent attacks and is economically advantageous.^33,35 However, we found that only 23.8% of ABP patients underwent cholecystectomy during the initial admission. This rate is low given the incidence of mild ABP. Notably, 57.0% of ABP patients did not undergo cholecystectomy because of refusal or non-medical reasons. Because 17.9% of patients who experienced AP recurrence during follow-up were ABP patients who did not undergo cholecystectomy at the time of the first attack, practical efforts such as proper patient education are needed to emphasize that cholecystectomy reduces the incidence of recurrent AP. Additionally, this study involved patients who had visited tertiary hospitals in Korea. The burden of major surgeries for malignancies other than cholecystectomy tends to be higher in tertiary hospitals. Consequently, the rate of patients who were unable to undergo surgery at the time of admission because of surgical scheduling reached 19.6% in this study. To reduce this rate, changes in the domestic healthcare system are warranted.

This study was performed to evaluate the current clinical status of AP in Korea and thus support development of Korean AP guidelines. However, despite utilizing the largest multicenter dataset in Korea to date, the retrospective nature of the study introduced the possibility of selection bias. A multivariate analysis of risk factors for severe AP or mortality was not performed because of the risk of overfitting in the multivariate calibration process. The study collected limited data, thereby impeding assessment of causality in the relationship between treatment interventions and clinical outcomes.

In conclusion, our study constitutes a comprehensive report on the current status of AP in Korea, including the distribution of the etiologies and the severity, mortality, and management, based on detailed clinical information obtained via a retrospective multicenter survey. Our study revealed notable differences in AP severity depending on the etiology, with obesity (BMI >30 kg/m²) serving as a potential risk and predictive factor for severe AP. Nevertheless, the cause of AP was unknown in 16.4% of patients, highlighting the need for long-term prospective studies and practical measures to reduce the incidence of IAP. Moreover, it is critical to address the discrepancies between clinical guidelines and actual clinical practices employed for managing AP.

This research was supported by a 2020 grant from the Korean Pancreatobiliary Association (KPBA).

No potential conflict of interest relevant to this article was reported.

Study concept and design: E.J.K., S.H.L., M.K.J. Data acquisition: D.K.J., J.H.J., J.M.L., J.W.C., S.Y.H., Y.H.C., S.H.K., J.M.P., K.H.P. Data analysis and interpretation: D.K.J., J.H.J., J.M.L., J.W.C., S.Y.H., Y.H.C., S.H.K., J.M.P., K.H.P. Drafting of the manuscript: E.J.K. Critical revision of the manuscript for important intellectual content: D.K.J., J.H.J., J.M.L., J.W.C., S.Y.H., Y.H.C., S.H.K., J.M.P., K.H.P. Statistical analysis: E.J.K. Obtained funding: E.J.K. Study supervision: S.H.L., M.K.J. Approval of final manuscript: all authors.