A retrospective study investigating the clinical significance of body mass index in acute pancreatitis

Background

A survey of 19.2 million participants in 200 countries has revealed a major shift over the past four decades: the prevalence of underweight individuals was once more than double that of obesity, but now there are more obese than underweight people (NCD Risk Factor Collaboration (NCD-RisC), 2016). This transition highlights the critical health crisis of obesity that needs global attention. Unfortunately, current interventions and policies have not successfully halted the rise in body mass index (BMI) in most countries (Ezzati & Riboli, 2012; Kleinert & Horton, 2015; Roberto et al., 2015). BMI, a standard measure of health based on weight and height, indicates whether a person is under or overweight. High BMI, a known risk factor for hypertension, diabetes mellitus, digestive system cancers, and musculoskeletal disorders, has been confirmed in various studies (Drøyvold et al., 2005; Wei et al., 2019; Larsson, Spyrou & Mantzoros, 2022; Zhao et al., 2022).

Pancreatitis is one of the leading causes for GI-disease related hospital admissions and it is associated with considerable morbidity, mortality and socioeconomic burden (Peery et al., 2019). Acute pancreatitis (AP) can be characterised as acute episodes of persistent severe epigastric pain, accompanied by abdominal distension, nausea and vomiting. Most (~80%) AP cases are mild, resulting in minimal damage to the pancreas and with a relatively short recovery period (Banks et al., 2013). However, around 10–20% of acute pancreatitis patients progress to severe acute pancreatitis (Zhao et al., 2022). This severe form is marked by an intense inflammatory response in its early phase and the development of infected pancreatic necrosis in the later phase (Al Mofleh, 2008). This raises an important question: why do some patients with acute pancreatitis (AP) develop complications like multiple organ dysfunction syndrome, sepsis, or even face mortality, whereas others do not? Identified risk factors, such as age, triglyceride levels, the degree of localized pancreatic damage, and genetic factors, have been shown to predict the onset of organ failure in AP patients (Garg & Singh, 2019). However, the role of obesity as a risk factor for adverse outcomes in AP remains under-analyzed. Evidence from population-based cohort studies has demonstrated a clear association between being overweight or obese and the development of severe acute pancreatitis (SAP) (Dobszai et al., 2019). Conversely, other studies have arrived at contrary conclusions (Párniczky et al., 2016). Choi et al. (2022) posited that a low BMI might also elevate AP risk in individuals with type two diabetes.

The aim of this research is to clarify the causal link between the incidence and progression of acute pancreatitis and BMI, explore the correlation between BMI categories and the severity of acute pancreatitis, and thereby offer additional insights into focused prevention and treatment approaches for this condition.

Materials and Methods

Results

Analysis for inducement and etiology

In a cohort of 117 cases with various inducements, the etiology was diverse: improper diet in 45 patients (38.46%), undetermined causes in 35 cases (29.91%), alcohol abuse in 13 (11.11%), fatigue in eight (6.84%), poorly controlled diabetes in seven (5.98%), exposure to cold in five (4.27%), and iatrogenic factors in four (3.42%). The BMI comparison revealed a statistically significant variance between the healthy control group and those with AP (p = 0.042). Among AP cases with different etiologies, the hyperlipidemia subgroup showed a significant BMI disparity compared to the control group (p = 0.003). However, no significant BMI differences were noted among other etiological subgroups of AP, as illustrated in Fig. 1.

Predictors of severity

As shown in Fig. 2, the association between a BMI below 25.4 kg/m² and the severity of MSAP and SAP was more pronounced when stratified by factors such as age, gender, BMI, diabetes mellitus/hypertension/steatohepatitis, smoking and drinking habits, menopausal status, history of abdominal surgery, and palindromia. The odds ratio (95% CI) for BMI < 25.4 kg/m² was 3.44 (1.82–6.48) and for BMI ≥ 25.4 kg/m², it was 0.37 (0.25–0.54), both statistically significant (p < 0.05). This indicates that a BMI ≥ 25.4 kg/m² may act as a protective factor against exacerbations, which contrasts with our initial hypothesis. To delve deeper, given the potential limitations in BMI categorization, we compared severity across different BMI categories: Overweight (OW, 23–24.9 kg/m²), Obesity Class I (OB I, 25–29.9 kg/m²), and Obesity Class II (OB II, ≥30 kg/m²). The severity in the OB II group was markedly distinct from OW and OB I groups (Chi-square, df = 15.25, 2, p < 0.001). Further analysis of OB I and OB II suggests that a BMI between 25 and 29.9 kg/m² remains a risk factor for SAP progression. While the impact of a BMI ≥ 30 kg/m² on disease worsening may not be as pronounced as in OW and OB I groups, its potential protective effect warrants further investigation. No cases of moderate to severe pancreatitis were observed in the underweight (UW) or normal weight (NW) groups, potentially due to sample size limitations; hence, no further subgroup analysis was conducted. However, the possibility that a low BMI increases the risk of adverse disease progression cannot be dismissed, aligning with findings from several other studies.

Predict the incidence and assist in the diagnosis of acute pancreatitis type

As depicted in Fig. 3, the AUCs for BMI in estimating the risk and aiding the diagnosis of AP types were 0.6086 ± 0.04 and 0.7893 ± 0.04, respectively. The lower AUC for predicting AP (less than 0.7) suggests limited accuracy, with a cut-off value at 23.56 kg/m² (p < 0.05). However, BMI (AUC = 0.7893) enhances the diagnostic accuracy when combined with CECT in differentiating AEP from ANP, especially at a BMI of ≥25.88 kg/m² (p < 0.0001). Additionally, while BMI is not a significant predictor for AP recurrence (AUC = 0.5591), a positive correlation exists between BMI and the likelihood of recurrence within 6 months (r = 0.7532, p < 0.01), indicating that higher BMI may be associated with increased recurrence risk.

Discussion

This study, involving 117 patients from the Jiangsu Provincial Hospital of Chinese Medicine, reveals several key insights regarding BMI and AP. First, there is a distinct difference in the BMI of AP patients compared to healthy controls, suggesting a potential AP risk at a BMI exceeding 23.56 kg/m². Second, a significant association was observed between BMI and AP severity. Specifically, OB I or a BMI under 25.4 kg/m² was identified as a risk factor for developing Mildly Severe/Severe AP (MSAP/SAP). Third, according to ROC analysis, while BMI does not effectively predict AP onset, it is a robust indicator for distinguishing between AEP and ANP, as evidenced by an AUC over 0.7. Finally, our findings indicate a novel observation: the higher the BMI, the greater the likelihood of AP recurrence within a short timeframe (≤6 months).

AP is an inflammatory condition triggered by trypsin activation in the pancreas due to various factors, leading to the digestion, edema, hemorrhage, and potentially necrosis of pancreatic tissue. Studies have shown that triglyceride (TG) levels in hepatocytes of patients with obesity, diabetes, and metabolic syndrome are significantly elevated (Raz et al., 2005). This excessive TG storage, when hydrolyzed by trypsin, releases a large amount of free fatty acids (FFA), directly damaging pancreatic acinar cells and vascular endothelial cells (Stimac et al., 2013). Moreover, the abundance of nutrients and obesity contribute to extensive white adipose tissue remodeling, leading to changes in adipokine production and a low-grade inflammatory response (Balistreri, Caruso & Candore, 2010). Calcium ion overload is another mechanism involved in AP. It promotes the release of lactate dehydrogenase or induces acinar cell apoptosis by activating various cellular zymogens (Gerasimenko, Gerasimenko & Petersen, 2014). The abnormal increase in calcium ions is often due to the excessive unsaturated fatty acids (UFA) produced during TG decomposition, causing the release of calcium ions from the endoplasmic reticulum into the cytoplasm (Petersen et al., 2009). Furthermore, elevated TG can increase blood viscosity and potentially lead to thrombosis, resulting in pancreatic microcirculation disorders and ischemic necrosis. Additionally, dyslipidemia deposits on the inner walls of blood vessels promote the infiltration of inflammatory cells and the release of various inflammatory cytokines (Pooran et al., 2003), playing a pivotal role in the pathogenesis of AP and its systemic complications. This background supports our findings that patients with Obesity Class I (BMI 25–29.9 kg/m²) had more organ failures and local complications than their NW counterparts, confirming the credibility of our results.

The various etiologies of AP are closely associated with obesity. Biliary diseases, such as stones, sludge, or micro-lithiasis in the biliopancreatic passages, can lead to AP by either causing bile reflux or increasing pancreatic duct pressure (Lerch & Gorelick, 2013). Overweight and obese individuals are at a higher risk of developing biliary diseases (Radmard et al., 2015), possibly due to a high-fat diet predisposing them to cholesterol-rich crystals or stones in the bile (Lee, Keane & Pereira, 2015). Additionally, recent epidemiological studies have highlighted an elevated risk of AP in obesity-related metabolic conditions, like type two diabetes, especially when combined with excessive alcohol consumption (Lai et al., 2011). Prior research has shown that acute alcohol administration in obese mice leads to pancreatic necrosis, systemic inflammation, and multi-organ dysfunction, in contrast to lean mice, where ethanol alone did not induce significant pancreatic changes (Yang et al., 2023). This model suggests that obese patients are particularly susceptible to progressing to severe AP and experiencing poor clinical outcomes. Our study corroborates this observation, underscoring the link between obesity and the severity of AP.

High BMI is intricately linked to the pathogenesis and etiology of AP, affecting its progression and prognosis, and it also correlates with genetic factors influencing AP occurrence. Recent discoveries highlight FGF21 as a key regulator of metabolic homeostasis with a potent anti-obesity effect (Lu, Li & Luo, 2021). Additionally, the loss of the FGF21 gene has been linked to increased intra-acinar triglyceride vacuole accumulation, and more severe edema and necrosis in chronic pancreatitis (Johnson et al., 2009). These findings emphasize the significance of genetic factors in the severity and evolution of pancreatitis, especially in relation to obesity. Moreover, while an association between BMI and AP recurrence is observed, not all high BMI individuals will experience relapses. Genetic factors might influence those with high BMI who have multiple AP recurrences in a short period.

Most studies indicate that a high BMI escalates the risk of acute pancreatitis, with no significant impact noted in cases of low BMI (Hansen et al., 2020). Contrary to these findings, our study reveals that not only obesity but also underweight status contributes to poor AP progression, suggesting that lower weight is not necessarily advantageous for AP patients. The underlying mechanisms and pathological changes warrant further investigation. While the course and severity of the disease are primarily influenced by inflammatory cells driving local and systemic immune responses, macro-level control can improve outcomes. In this context, BMI emerges as a valuable predictive and monitoring tool.

Conclusions

Our study indicates that a BMI exceeding 23.56 kg/m² raises the risk of developing acute pancreatitis. Notably, a BMI above 25 kg/m² but below 30 kg/m² most significantly increases the risk of adverse disease progression, suggesting that severity does not necessarily escalate with higher BMI levels. BMI effectively predicts AP type; specifically, a BMI of 25.88 kg/m² or higher suggests a potential progression to necrotizing pancreatitis. Furthermore, our findings link short-term (6 months) recurrence of AP with BMI, though this requires further validation due to the small sample size. Overall, BMI plays a crucial role in risk prediction and stratification for AP, underscoring the importance of monitoring patient BMI.

Supplemental Information