Impact of Stress hyperglycemia on Long-Term Prognosis in Acute Pancreatitis without diabetes

doi:10.21203/rs.3.rs-3239777/v1

Background

Stress hyperglycemia has been confirmed as a strong predictor of poor short-term prognosis in acute pancreatitis. However, whether stress hyperglycemia affects the long-term prognosis of patients with acute pancreatitis is unclear. We aimed to investigate the effect of stress hyperglycemia on the long-term prognosis of non-diabetic patients with acute pancreatitis.

Methods

This retrospective observational study was conducted on 4055 patients with acute pancreatitis from 1 January 2016 to 31 October 2020. The association between Stress hyperglycemia and the prognosis was evaluated using regression modeling.

Results

There were 935(71.5%) normoglycemic and 373(28.5%) Stress hyperglycemia patients. 46(12.3%) patients with Stress hyperglycemia had evidence of diabetes compared with 33(3.5%) patients without stress hyperglycemia (P < 0.001). After multivariate adjustment, patients with Stress hyperglycemia were more likely to have evidence of diabetes (OR 2.905, 95% CI 1.688–4.999) compared with normoglycemic. However, Stress hyperglycemia is not associated with the recurrence of pancreatitis and progression to chronic pancreatitis.

Conclusions

Stress hyperglycemia was independently associated with diabetes secondary to acute pancreatitis. Accordingly, a follow-up diabetes-screening program for AP with stress hyperglycemia is an important part of identifying the disease as soon as possible, delaying islet damage, and improving the prognosis of post-acute pancreatitis diabetes mellitus.

Stress hyperglycemia

acute pancreatitis

pancreatitis diabetes

Stress hyperglycemia (SH) often occurs in acute or critical illnesses, and in the past, transient hyperglycemia was frequently considered harmless or even advantageous¹. In recent years, much attention has been paid to the evidence that stress hyperglycemia increases the adverse prognosis, particularly in patients without known diabetes ^2–4. In myocardial infarction, stroke, severe infections, and perioperative patients, stress hyperglycemia is significantly correlated with increased aggravation, mortality, and poor recovery ^4–7.

Acute pancreatitis (AP) is the most common gastrointestinal disease, and the incidence of AP is increasing worldwide ^8–10. AP was originally considered a fully recoverable disease. However, in recent years, accumulating evidence shows that metabolic abnormalities are a frequent sequela of acute pancreatitis^11–13.Whether stress hyperglycemia increases the long-term adverse prognosis of AP has not been reported. Therefore, we performed this study to investigate the correlation between SH and adverse events in AP patients without pre-existing diabetes.

Study design and Ethics Statement

We conducted a cross-sectional follow-up study of patients with first-episode AP at Zhongda Hospital, Changji Branch, First Affiliated Hospital of Xinjiang Medical University, and Hunan Provincial People’s Hospital. Participants were followed up until they developed diabetes or the end of the observation period (1 February 2022 Participants were followed up until they developed diabetes or the end of the observation period (1 February 2022, median follow-up 2.97 years; range: 1.68–4.51).

All study protocols were approved by the ethics committee of Zhongda Hospital, affiliated to Southeast University. The protocol of this study was performed according to the Declaration of Helsinki and relevant regulations (approval no: 2022ZDKYSB141). Additionally, written/oral informed consent was obtained from all participants. To protect privacy, all patient information was anonymized and de-identified before analysis.

Study Population

From 1 January 2016 to 31 October 2020, all consecutive AP patients admitted were screened for eligibility. Inclusion criteria were as follows: (1) age ≥ 18 years with the diagnosis of AP¹⁴; (2) admitted with abdominal pain for < 48 h. Exclusion criteria were as follows: (1)Recurrent AP; (2) Chronic pancreatitis(CP); (3) History of diabetes, HbA1c ≥ 6.5% or hypoglycemic drugs diagnosed before AP attack; (4) History of malignant tumor; (5) Severe heart, liver, kidney, and other organ dysfunction; (6) History of immune system diseases or hormone use; (7) Mental illness, unable to cooperate with research; (8) Pregnancy and lactation; (9) Data missing > 10%; (10) death during admission.

Study Variables and Outcome Measures

Patients’ information on age, gender, time to hospital admission, family history of diabetes, smoking and drinking status, clinical comorbidities (non-alcoholic fatty liver disease (NAFLD) and hypertension), vital signs (systolic blood pressure, diastolic blood pressure, Body mass index (BMI)), laboratory studies (amylase, fasting or random blood glucose on the first day of admission, glycated hemoglobin (HbA1c), serum calcium, hepatic and renal functions, lipid profiles), etiology of AP, severity of disease¹⁵, infection condition, local complications and systemic complications of AP were extracted through hospital information system (HIS). Participants were followed up from hospital discharge until they developed diabetes or the end of the observation period (1 February 2022). Post-discharge telephone follow-up is a documented phone encounter using a standardized list of questions, conducted by a trained registered doctor. The list included data on recurrence of AP, blood glucose levels, HbA1c, pancreatic enzyme, clinical features (abdominal pain, diarrhea, nutrition status) and imaging data. If the physician has any concerns or the patient requests an in-person follow-up, they will be scheduled for an in-person follow-up visit to the hospital. The diagnosis of diabetes, chronic pancreatitis, and pancreatic cancer was confirmed by two experienced specialists.

Definitions and Classifications

BMI was calculated as weight (kg) divided by the square of height (m). Obesity was defined as BMI ≥ 28 kg/m² (according to the Guidelines for Prevention and Control of Overweight and Obesity in Chinese adult); Post-acute pancreatitis diabetes mellitus was defined as developing diabetes more than 90 days after hospitalization^{16 17}; Stress hyperglycemia was defined as admission fasting glucose ≥ 7.0 mmol/L or random glucose ≥ 11.1mmol/L without evidence of previous diabetes¹⁸. The diagnosis of CP was based on the M-ANNHEIM diagnostic criteria¹⁹.According to the revised Atlanta classification, the severity of the disease is categorized into mild, moderately severe, and severe¹⁴.

Statistical analysis

All analyses were performed using SPSS software (SPSS version 22, IBM, Armonk, NY, USA). Continuous data are presented as medians with interquartile ranges (IQR) and compared using Mann–Whitney U. Categorical data are displayded as number with percentages and compared using Chi-square test (or Fisher’s test). Binary logistic regression analysis was used to identify independent predictors of Long-term adverse outcomes. In all cases, two-tailed and P values < 0.05 was considered significant.

Characteristics at Baseline

As shown in the study flowchart (Fig. 1), 4055 admissions for AP were screened in the electronic medical record system, of which 1308 met the inclusion criteria. The baseline parameters and clinical characteristics of patients are shown in Table 1. In our final study cohort, the median age was 49 (38–63) years, 795 (60.8%) patients were men, obese patients accounted for 16.7%, hypertension was diagnosed in 36 (25.7%) patients, 607(46.4%) patients combined with NAFLD, 22.8% of patients were current smokers, and 302 (23.1%) patients were drinking. Among these patients, 373 patients (28.5%) had SH, and normoglycemia in 935 patients (71.5%). There were no significant differences between hyperglycemia and normoglycemia in terms of demographic characteristics (age, gender), smoking, drinking, combined hypertension, and family history of diabetes. However, patients with SH had higher levels of triglyceride and total cholesterol, and they were more likely to be obese and tended to have comorbid NAFLD (59.8% vs. 41.4%, P < 0.001).

Table 1

Baseline and biochemical characteristics of the study cohort stratified by admission glycemic status
Characteristics	Total	Stress hyperglycemia	Normoglycemia	P value
	(n = 1308)	(n = 373, 28.5%)	(n = 935, 71.5%)
Age, years	49 (38–63)	49 (37–61)	50 (38–63)	0.259
Sex, male, n (%)	795 (60.8)	240 (64.3)	555 (59.4)	0.095
Length of stay, d	9 (7–14)	10.5 (7–16)	9 (6–13)	< 0.001
BMI (kg/m2)	24.9 (22.8–27.6)	25.6 (23.4–28.3)	24.8 (22.5–27.3)	< 0.001
BMI ≥ 28 kg/m2, n (%)	219 (16.7)	82 (27)	137 (13.7)	< 0.001
Family history of diabetes, n (%)	69 (5.3)	20 (5.4)	49 (5.2)	0.921
Smoking, n (%)	298 (22.8)	98 (26.3)	200 (21.4)	0.403
Drinking, n (%)	302 (23.1)	93 (24.9)	209 (25.6)	0.165
Hypertension, n (%)	336 (25.7)	107 (28.7)	229 (24.5)	0.117
NAFLD, n (%)	607 (46.4)	223 (59.8)	384 (41.4)	< 0.001
Etiology, n (%)				< 0.001
Biliary	699 (53.4)	173 (47.5)	526 (57)
HTG-associated	185 (14.1)	95 (26.1)	90 (9.8)
Alcohol excess	39 (3)	9 (2.5)	30 (3.3)
Others or unknown	363 (27.8)	87 (23.9)	276 (29.9)
Severity, n (%)				< 0.001
Mild	813 (62.2)	211 (56.7)	602 (64.5)
Moderate	414 (31.7)	124 (33.3)	290 (31.3)
Severe	72 (5.5)	31 (9.9)	41 (4.4)
ALT (U/L)	43 (21.2-140.2)	40.1 (21–125)	44.9 (21.4–147)	0.409
AST (U/L)	35 (19.6–95.7)	39 (20.3-104.1)	33 (19-86.5)	0.114
BUN (mmol/L)	4.4 (3.4–5.9)	4.3 (3.6–6.4)	4.7 (3.3–5.6)	0.001
Cr (umol/L)	65 (52–77)	64.2 (51.5–78)	65 (53–77)	0.867
UA (umol/L)	296 (226–373)	309.5 (222.3-398.8)	292 (226–362)	0.134
TG (mmol/L)	1.3 (0.83–3.1)	1.94 (0.89–6.72)	1.21 (0.81–2.33)	< 0.001
TC (mmol/L)	4.4 (3.65–5.54)	4.72 (3.78–6.77)	4.33 (3.63–5.3)	< 0.001
LDL (mmol/L)	2.42 (1.88–3.06)	2.41 (1.83–3.03)	2.43 (1.89–3.09)	0.544
HDL (mmol/L)	1.02 (0.78–1.3)	1.07 (0.76–1.33)	1.02 (0.78–1.26)	0.316
Ca (mmol/L)	2.2(2.09–2.32)	2.18(2.06–2.33)	2.21 (2.1–2.32)	0.053
Amylase (U/L)	554 (167–1309)	488.3 (184.3–1388)	574 (161–1300)	0.503
Lipase (U/L)	308 (80.5-1126.8)	426.1 (94-1516)	275.6 (78-1048.8)	0.063
BMI: body mass index, ALT: alanine transaminase, AST: aspartate aminotransferase, NAFLD: non-alcoholic fatty liver disease, Cr: creatinine, BUN: blood urea nitrogen, UA: uric acid, Ca: calcium, TG: triglyceride, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol. Values are given as median (IQR) or frequencies (percentages).

Post-acute pancreatitis diabetes mellitus

New evidence of diabetes was present in 79 patients (6%) of the study cohort. 46 patients (12.3%) with SH had evidence of diabetes compared with 33 patients (3.5%) without SH (P < 0.001). Univariable logistic regression analysis indicated that BMI, smoking, Family history of diabetes, NAFLD, uric acid, triglyceride, total cholesterol, recurrence and SH were statistically associated with post-acute pancreatitis diabetes mellitus (Table 2). After multivariate adjustment, SH was significantly associated with subsequent diabetes odds ratio 2.905 (95% CI 1.688–4.999). Additional factors associated with evidence of diabetes were NAFLD (OR 2.228 ,95% CI 1.175–4.226), and recurrent pancreatitis (OR 2.351, 95% CI 1.363–4.054) associated with a greater likelihood of diabetes. None of the other covariates included in this analysis were significantly associated with new evidence of diabetes.

Table 2 Risk factors associated with post-acute pancreatitis diabetes mellitus

Variables	Univariate analysis		Multivariate analysis
Variables	P-value	OR (95% CI)	p-value		OR (95% CI)
Age, years	0.106	0.988 (0.974-1.003)
Sex	0.157	1.423 (0.873-2.317)
BMI	<0.001	1.108 (1.049-1.172)	0.405	1.028 (0.963-1.099）
Family history of diabetes	0.001	3.263 (1.638-6.502)	0.052	2.196 (0.993-4.853)
Hypertension	0.078	1.543 (0.952-2.499)
NAFLD	<0.001	3.628 (2.158-6.100)	0.014	2.228(1.175-4.226）
Smoking	0.024	1.738(1.076-2.807)	0.475	1.227(0.701-2.147）
Drinking	0.637	0.873 (0.469-1.535)
Severity	0.104	1.337 (0.942-0.897)
Etiology	0.684	1.054 (0.819-1.355)
SH	<0.001	4.004 (2.361-6.790)	<0.001	2.905 (1.688-4.999）
TG	0.026	1.030 (1.004-1.057)	0.955	1.002 (0.951-1.055)
TC	<0.001	1.194 (1.110-1.284)	0.180	1.090 (0.961-1.237)
Ca	0.521	0.720 (0.264-1.961)
BUN	0.253	1.030 (0.979-1.083)
Cr	0.192	1.004 (0.998-1.010)
UA	0.007	1.003 (1.000-1.004)	0.260	1.001(0.999-1.004）
ALT	0.080	0.998 (0.996-1.000)
AST	0.251	0.999 (0.997-1.001)
Recurrence	<0.001	2.761 (1.719-4.433)	0.002	2.351 (1.363-4.054)
SH: Stress hyperglycemia, BMI: body mass index, ALT: alanine transaminase, AST: aspartate aminotransferase, NAFLD: non-alcoholic fatty liver disease, Cr: creatinine, BUN: blood urea nitrogen, UA: uric acid, Ca: calcium, TG: triglyceride, TC: total cholesterol, HDL-C: high-density lipoprotein cholesterol, LDL-C: low-density lipoprotein cholesterol. CI: confidence interval, OR: odds ratio.

Recurrence of acute pancreatitis

A total of 264 patients in our study cohort experienced a recurrence of the disease after the first episode of pancreatitis. After multivariate adjustment, SH did not increase the risk of recurrence of pancreatitis (P = 0.679) (Supplementary Table 1).

Progression to chronic pancreatitis

A total of 30 people in our study cohort developed CP. After multivariable adjustment including age, sex, smoking status, drinking status, BMI, disease severity, etiology, and recurrence, SH was not associated with the development of chronic pancreatitis(P = 0.170) (Supplementary Table 2). However, recurrence of pancreatitis is an important factor in the progression to CP (OR 16.606, 95% CI 9.249-571.064).

Progression to pancreatic cancer

In our follow-up cohort, there was only one patient with a definite diagnosis of pancreatic cancer.

Prior studies have explored that patients with SH tend to have a poor prognosis. However, the evidence in acute pancreatitis is still insufficient. Only Yang et al. reported that SH was independ-ently associated with persistent organ failure, acute necrotic collection, infections, and mortality in patients with acute pancreatitis²⁰. However, whether SH affects long-term prognosis remains unclear.

In this study, we demonstrate for the first time that SH is an independent risk factor for diabetes after acute pancreatitis. Several studies have linked SH and subsequent diabetes in pneumonia, acute myocardial infarction, and critical illness ^21–23. A large cohort study from the United States found that SH was significantly associated with a subsequent diabetes advantage ratio of 2.56 (95% CI 2.15–3.06) in 10,499 acute myocardial infarction patients without known diabetes²¹. Recently, Xiansong Wang and colleagues found that bacteremic patients with SH had a higher risk of subsequent diabetes development (HR 1.7, 95% CI 1.2–2.4) compared with their normoglycemic counterparts. In nonbacteremic, stress hyperglycemia was similarly associated with a risk of subsequent diabetes (HR 1.4, 95% CI 1.2–1.7). Stress hyperglycemia was confirmed to be a diabetes predictor²⁴.

Post-acute pancreatitis diabetes is a specific type of diabetes and is the main component of exocrine pancreatic diabetes ²⁵. Compared with type 2 diabetes, post-pancreatic diabetes is associated with poorer glycaemic control and a higher risk of mortality^{26, 27}, which carries a heavy burden on human health and the economy. However, until recently, the pathogenesis of diabetes after acute pancreatitis was still unclear. Previous studies have suggested that diabetes secondary to acute pancreatitis stems from the destruction of β-cells and that severe acute pancreatitis and acute necrotizing pancreatitis increase the risk of diabetes²⁸. Growing evidence compels us to reconsider the destruction of β-cells as the sole mechanism of secondary diabetes. Several studies revealed that the disease severity of AP had no relationship with new-onset diabetes^{11, 12, 29}, which is similar to our study. In this observational study of nearly 1500 patients hospitalized with the first episode of AP, we found that SH was confirmed to be a predictor of diabetes mellitus independent of age, gender, comorbidity, severity of disease, serological markers, and recurrence of pancreatitis. In addition, our study found that several characteristics, including NAFLD and recurrent pancreatitis all increased the risk of diabetes in AP.

SH is a fundamental adaptive response of the body to a threat, which develops as a result of a highly complex interaction of endogenous glucocorticoids and inflammation ^30–32. This disturbance in the internal environment eventually leads to hepatic glucose overproduction and insulin resistance. In addition, hyperglycemia exacerbates cytokine, inflammatory, and oxidative stress responses, creating a vicious cycle³³. Furthermore, the cytokine storm may further exacerbate islet cell damage. Previous studies have discovered that IL6 is not only the predominant cytokine-inducible upon acute stress, but also a pro-inflammatory cytokine increased in obesity³⁴. Increased concentrations of circulating interleukin 6 are associated with hyperglycemia and insulin resistance following acute pancreatitis^{35, 36}. Moreover, abnormal lipid metabolism is another key feature of insulin resistance, especially in patients with fatty liver disease³⁷. Patients with fatty liver are characterized by chronic, low-grade systemic inflammation and abnormal liver fat deposition, which is causally related to IR^38–40.This result is consistent with our finding that NAFLD is a risk factor for acute pancreatitis secondary to diabetes mellitus.

In addition, acute pancreatitis generates a robust local and systemic inflammatory response (even in clinically mild episodes), which can produce a continuous irritation of the pancreas. This chronic inflammation can lead to insulin resistance on the one hand and damage to pancreatic tissue on the other hand⁴¹.

Overall, the development of diabetes secondary to acute pancreatitis may be a combination of factors (including loss of islet cell mass; abnormalities in lipid metabolism; local and systemic inflammatory responses; and alterations in the insulin-enteric proinsulin axis) ^{35, 36, 42–44}, which involves a cross-talk between fat, pancreas, liver, and peripheral target tissues.

Recurrence of acute pancreatitis is another vital factor in determining the consequences of late acute pancreatitis. Prevention of recurrent episodes of acute pancreatitis is usually considered to depend on the etiologic treatment of the disease, early therapeutic intervention can prevent the development of the disease⁴⁵. Our study demonstrated that SH is not associated with the recurrence of pancreatitis. However, recurrent episodes of pancreatitis increase the risk of post-pancreatitis diabetes.

The sequence of events in which acute pancreatitis progresses to chronic pancreatitis is not fully understood. Based on the analysis of our study, chronicity of pancreatitis was also not associated with SH. Nevertheless, in our study, the incidence of CP was much higher in patients who survived AP recurrence than in those with only one AP episode, which is consistent with previous studies^{46, 47}.

Some limitations are present in the study. Firstly, based on a retrospective study, clinical outcomes were obtained by telephone follow-up, with the potential for recall bias. Secondly, blood glucose on the first day of admission was utilized as the sole criterion for classifying stress hyperglycemia, missing those patients with delayed hyperglycemia. Thirdly, loss to follow-up bias may cause a potential bias. We compared the baseline data of patients lost to follow-up and those included and found the distribution of age, gender, BMI, smoking status, drinking status, and combined hypertension was similar among the patients lost to follow-up and those visited. In addition, the total number of AP cases in the studied cohort is limited, reducing the power of our analysis. These weaknesses may have limited the generalizability of the results. Our findings are exploratory, and further large-scale prospective population-based studies are needed to confirm the long-term prognostic impact of stress hyperglycemia on patients with AP in the future.

In conclusion, Stress hyperglycemia was independently associated with diabetes secondary to acute pancreatitis. Accordingly, a follow-up diabetes-screening programs for AP with stress hyperglycemia is an important part of identifying the disease as soon as possible, delaying islet damage, avoiding adverse outcomes and improving the prognosis of post-acute pancreatitis diabetes mellitus.

Authors’ contributions

Jun Zhang: Conceptualization, Data curation, and writing-original draft preparation. Xiaoyuan Wang: Formal analysis and investigation; Jiaying Hou, Yingqi Lv , Chi Zhang, and Xianghui Su: data collection and writing - review; Ling Li: contributed to the design of the study, discussion, reviewed and edited the manuscript. All authors read and approved the final manuscript.

Acknowledgements

The authors thank all staffs for their support.

Data availability

All the data are available upon request to the corresponding author.

Funding

This work was supported by National Natural Science Foundation of China (81970717 and 82170845).

Competing interests

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.

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SupplementaryTable.docx

Impact of Stress hyperglycemia on Long-Term Prognosis in Acute Pancreatitis without diabetes

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Study design and Ethics Statement

Study Population

Study Variables and Outcome Measures

Definitions and Classifications

Statistical analysis

Results

Characteristics at Baseline

Post-acute pancreatitis diabetes mellitus

Recurrence of acute pancreatitis

Progression to chronic pancreatitis

Progression to pancreatic cancer

Discussion

Declarations

References

Supplementary Files

Status:

Journal Publication

Version 1