ORIGINAL RESEARCH published: 09 April 2020 doi: 10.3389/fmed.2020.00126 Dietary Fat Patterns and Outcomes in Acute Pancreatitis in Spain Guillermo García-Rayado 1 , Gregorio Varela-Moreiras 2 , Ángel Lanas 1 , Ángel Ferrández 1 , Nelly Balza-Lareu 3 , Juan I. Cervera 4 , María P. Bodenlle-Bello 5 , Ana M. Argüelles-Arias 6 , Patricia Latorre 7 , María A. Udaondo-Cascante 8 , María J. Soria-de-la-Cruz 9 , José Lariño-Noia 10 , Roberto García-Figueiras 11 , Cristina Gil-García-Ollauri 12 , Ricardo Ituarte-Uriarte 13 , Carmen L. Rosales-Alexander 14 , Jordi Soriano 14 , María Rodríguez-Peláez 15 , Alicia Mesa-Álvarez 16 , Elida Oblitas 17 , María M. Menso 18 , Federico Bertoletti 17 , José I. Rodríguez-Prada 19 , Silvia Guzmán-Suárez 20 , Daniel Closa 21 and Enrique de-Madaria 22* 1 Service of Digestive Diseases, University Clinic Hospital Lozano Blesa, Aragón Health Research Institute (IIS Aragón), Edited by: CIBERehd, Zaragoza, Spain, 2 Department of Pharmaceutical & Health Sciences, Universidad CEU San Pablo, Madrid, Ionut Negoi, Spain, 3 Department of Gastroenterology, Hospital Son LLatzer, Palma, Spain, 4 Department of Radiology, Hospital Clínico Carol Davila University of Medicine Universitario, Valencia, Spain, 5 Department of Radiology, Hospital Meixoeiro, Vigo, Spain, 6 Department of Radiology, and Pharmacy, Romania Hospital Universitario Vírgen Macarena, Seville, Spain, 7 Department of Gastroenterology, Hospital Universitario Doctor Peset, Valencia, Spain, 8 Department of Radiology, Hospital Clínico Universitario, Valladolid, Spain, 9 Department of Gastroenterology, Reviewed by: Hospital Puerta del Mar, Cádiz, Spain, 10 Department of Gastroenterology and Hepatology, University Hospital of Santiago de Carla Ferreri, Compostela, Santiago de Compostela, Spain, 11 Department of Radiology, University Hospital of Santiago de Compostela, Italian National Research Council, Italy Santiago de Compostela, Spain, 12 Department of Gastroenterology, Hospital Universitario Cruces, Barakaldo, Spain, Hanna Sternby, 13 Department of Radiology, Hospital Universitario Cruces, Barakaldo, Spain, 14 Department of Gastroenterology, Hospital Lund University, Sweden Universitari Doctor Josep Trueta, Girona, Spain, 15 Department of Gastroenterology, Hospital Universitario Central de *Correspondence: Asturias, Oviedo, Spain, 16 Department of Radiology, Hospital Universitario Central de Asturias, Oviedo, Spain, 17 Department Enrique de-Madaria of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 18 Department of Radiology, Hospital de la madaria@hotmail.com Santa Creu i Sant Pau, Barcelona, Spain, 19 Department of Gastroenterology, Hospital Xeral, Vigo, Spain, 20 Department of Surgery, Hospital Xeral, Vigo, Spain, 21 Department of Experimental Pathology, Institut d’Investigacions Biomèdiques de Specialty section: Barcelona (IIBB-CSIC-IDIBAPS), Barcelona, Spain, 22 Department of Gastroenterology, Alicante University General Hospital, This article was submitted to Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain Gastroenterology, a section of the journal Frontiers in Medicine Background/Objective: Evidence from basic and clinical studies suggests that Received: 08 November 2019 unsaturated fatty acids (UFAs) might be relevant mediators of the development of Accepted: 20 March 2020 complications in acute pancreatitis (AP). Objective: The aim of this study was to analyze Published: 09 April 2020 outcomes in patients with AP from regions in Spain with different patterns of dietary Citation: García-Rayado G, Varela-Moreiras G, fat intake. Lanas Á, Ferrández Á, Balza-Lareu N, Materials and Methods: A retrospective analysis was performed with data from Cervera JI, Bodenlle-Bello MP, Argüelles-Arias AM, Latorre P, 1,655 patients with AP from a Spanish prospective cohort study and regional nutritional Udaondo-Cascante MA, data from a Spanish cross-sectional study. Nutritional data considered in the study Soria-de-la-Cruz MJ, Lariño-Noia J, concern the total lipid consumption, detailing total saturated fatty acids, UFAs and García-Figueiras R, Gil-García-Ollauri C, Ituarte-Uriarte R, monounsaturated fatty acids (MUFAs) consumption derived from regional data and not Rosales-Alexander CL, Soriano J, from the patient prospective cohort. Two multivariable analysis models were used: (1) a Rodríguez-Peláez M, Mesa-Álvarez A, Oblitas E, Menso MM, Bertoletti F, model with the Charlson comorbidity index, sex, alcoholic etiology, and recurrent AP; (2) Rodríguez-Prada JI, a model that included these variables plus obesity. Guzmán-Suárez S, Closa D and de-Madaria E (2020) Dietary Fat Results: In multivariable analysis, patients from regions with high UFA intake had Patterns and Outcomes in Acute a significantly increased frequency of local complications, persistent organ failure Pancreatitis in Spain. Front. Med. 7:126. (POF), mortality, and moderate-to-severe disease in the model without obesity and a doi: 10.3389/fmed.2020.00126 higher frequency of POF in the model with obesity. Patients from regions with high Frontiers in Medicine | www.frontiersin.org 1 April 2020 | Volume 7 | Article 126 García-Rayado et al. Dietary Fat Acute Pancreatitis Spain MUFA intake had significantly more local complications and moderate-to-severe disease; this significance remained for moderate-to-severe disease when obesity was added to the model. Conclusions: Differences in dietary fat patterns could be associated with different outcomes in AP, and dietary fat patterns may be a pre-morbid factor that determines the severity of AP. UFAs, and particulary MUFAs, may influence the pathogenesis of the severity of AP. Keywords: acute pancreatitis, diet, fat intake, obesity, unsaturated fatty acids INTRODUCTION study, the ANIBES (Anthropometric data, macronutrients and micronutrients intake, practice of physical activity, Acute pancreatitis (AP) is a common health issue (1). socioeconomic data, and lifestyles in Spain) study. While most patients have a mild disease course, one-third The Atlantis Project was endorsed by the Spanish Association experience local and/or systemic complications that produce an of Pancreatology (AESPANC) and by the Spanish Association of increase of morbidity (2). Furthermore, patients with systemic Gastroenterology (AEG). It aimed to validate and compare the complications have a higher mortality, which is as high as 50% determinants of AP severity and the severity classifications of AP among patients with persistent (>48 h) organ failure (POF) (2). (2) as well as to ascertain the role of comorbidity in the course The factors that determine the development of complications in of AP (4). Described in detail elsewhere (2), the Atlantis project AP are currently poorly understood. Obesity, particularly visceral was a 23-center nationwide prospective study which analyzed adiposity, is associated with local complications, with systemic 1,655 patients with AP recruited from June 2013 to February complications, and with increased risk of death (3–5). In vitro 2015. All centers were tertiary care hospitals with availability experiments using acinar cells of the pancreas have shown that of critical care. In Spain, there is a public healthcare system unsaturated fatty acids (UFAs) are associated with inflammation and citizens have similar access with similar quality of care in and necrosis, while saturated fatty acids (SFAs) are not harmful. the different regions of the country. The project was carried These experiments suggest that UFAs produce necrosis of acinar out following the rules of the Declaration of Helsinki of 1975. pancreatic cells and uncontrolled UFA release results in high UFA The study required written informed consent and was approved levels in the bloodstream and is associated with kidney failure by the Institutional Review Boards (IRBs) of the participating and with cell damage in lung alveoli (6, 7). UFAs have been centers. This new analysis was also approved by the central IRB detected in pancreatic necrosis collections (6–9). Furthermore, of the Atlantis study, namely the Comité Ético de Investigación oleic acid chlorohydrin, a halogenated product derived from con Medicamentos del Hospital General Universitario de Alicante monounsaturated oleic acid, was recently described as a blood (PI2018-102). For the diagnosis of AP, two or more criteria had to marker and mediator of complications in a rat model of AP (10) be fulfilled: (A) typical upper abdominal pain; (B) serum amylase and in patients with AP (11). Thus, UFA-mediated toxicity seems and/or lipase levels that were at least three times greater than the to be a key pathway in determining complications of AP (11, 12). upper limit of normal; and (C) imaging compatible with AP (15). Preceding studies have suggested that diet affects body fatty acid Patients with a diagnosis of chronic pancreatitis were excluded. composition. In animal models, mice with diets with different Patient outcomes were recorded during their hospital stay, and content in oleic acid and linoleic acid show these differences on the following data were retrieved from the study database for the composition of fatty acids of their tissues. Studies in humans this analysis: local complications (acute peripancreatic fluid also show this association (13, 14). Consequently, it is possible collections or pancreatic and/or peripancreatic necrosis), POF, that the changes induced by dietary UFAs can modulate the mortality (in-hospital mortality), and disease severity (moderate- severity of AP. To our knowledge, there are no clinical studies to-severe disease). These were defined according to the revised studying this relationship. This study aimed to compare clinical Atlanta classification (15). Obesity was defined as body mass course of disease of AP in regions of Spain that have different index ≥30 kg/m2 . dietary fat intake patterns. The aim of the ANIBES study was to update the food and beverage intake, behavior, and anthropometric measurements MATERIALS AND METHODS of the Spanish citizens, as well as to determine their energy expenditure and physical exercise habits (sample: 2009 citizens) This was a retrospective analysis of data from a prospective (16). Diet was studied using a dietary diary (during 3 days) cohort study, the Atlantis Project, plus data from a cross-sectional recorded on a tablet device plus a 24-h dietary recall. The participants were explained that the diet during those 4 days had Abbreviations: AP, acute pancreatitis; APFC, acute peripancreatic fluid collection; to be representative of their diet of the past years. The ANIBES BMI, body mass index; CCI, Charlson comorbidity index; H, High consume; IQR, interquartile range; IRB, Institutional Review Board; L, Low consume; MUFA, study divided Spain into nine regions: Barcelona, Canary monounsaturated fatty acid; OR, odds ratio; POF, persistent organ failure; PUFA, Islands, Central, Levant, Madrid, North-East, North-West, polyunsaturated fatty acid; SFA, saturated fatty acid; UFA, unsaturated fatty acid. North-Central, and South (16). Data regarding the consumption Frontiers in Medicine | www.frontiersin.org 2 April 2020 | Volume 7 | Article 126 García-Rayado et al. Dietary Fat Acute Pancreatitis Spain of lipids, SFAs, monounsaturated fatty acids (MUFAs), and TABLE 1 | Baseline characteristics and outcomes of patients with acute polyunsaturated fatty acids (PUFAs) were retrieved from the pancreatitis. original ANIBES database. According to ANIBES, the Spanish Characteristics and outcomes Overall mean daily caloric intake is 1,810 kcal/day, including 38.5% from lipids (overall), 11.7% from SFAs, and 23.43% from UFAs (16.8% N 1,655 from MUFA and 6.63% from PUFAs) (17). Patients in the Atlantis Age, years; median (IQR) 66 (51–79) Project from regions that had intake levels that were higher than Male sex, n (%) 891 (53.8%) the national mean values were considered to be high consumers BMI, kg/m2 regarding that specific type of fatty acid, while patients from Median (IQR) 26.8 (24.3–29.7) regions that had intake levels that were lower than the Spanish BMI < 25 509 (31.5%) mean values were classified as low consumers. For example, the BMI 25–<30 (Pre-Obesity) 722 (44.7%) national mean intake of UFAs is 23.6% (mean percentages of total BMI ≥ 30 (Obesity) 383 (23.7%) caloric intake) and the mean intake of UFAs in North-Central CCI, points; median (IQR) 3 (1–5) region of Spain is 24.2%. Therefore, patients in the Atlantis Liver disease, n (%) 120 (7.2%) Project from North-Central region were considered to be high Etiology, n (%) consumers of UFAs. The differences in consumption of PUFAs Gallstones 984 (59.5%) in the different regions of Spain are minimal, so we have not Alcohol 251 (15.2%) included this type of fatty acid in the analysis. Idiopathic 235 (14.2%) Other 185 (11.2%) Statistics Recurrent AP, n (%) 422 (25.5%) Continuous data were analyzed for normality by the Shapiro- Local complications, n (%) Wilk test and were summed-up using means and standard Any local complication 444 (26.8%) deviations or medians and interquartile ranges (IQRs) depending APFC 163 (9.8%) on the variable distribution. Qualitative variables were expressed Peri(pancreatic) necrosis 281 (17%) as number (n) and percentage (%). The association of low Persistent organ failure, n (%) 113 (6.8%) or high fat consumption according to region and outcome Mortality, n (%) 70 (4.2%) was investigated using a chi-square test or Fisher’s exact test if necessary and using binary logistic regression analysis for IQR, interquartile range (Q1–Q3); BMI, body mass index; CCI, Charlson comorbidity multivariable analysis. Two multivariable analysis models were index; AP, acute pancreatitis; APFC, acute peripancreatic fluid collection; Peri(pancreatic) necrosis, pancreatic and/or peripancreatic necrosis. used: (1) a model without obesity that included age, comorbidity (according to the Charlson comorbidity index, cutoff ≥3) (18), sex, alcoholic etiology, and recurrent AP (≥1 previous episode); (2) a model with obesity that included all of these variables vs. 24.6%, p = 0.08]. Patients from regions with high intake plus obesity. The adjusted odds ratios (ORs) were calculated. of UFAs had significantly more local complications [28.6 vs. Statistical calculations were done using SPSS 21.0 (IBM, Armonk, 20.5%, p = 0.002], POF [7.7 vs. 3.8%, p = 0.01], mortality NY, USA). [4.8 vs. 2.2%, p = 0.03], and moderate-to-severe disease [36.7 vs. 29%, p = 0.007]. Being from a region with high MUFA RESULTS intake was significantly associated with more local complications [29.6 vs. 23.9%, p = 0.009] and moderate-to-severe disease [38.1 Table 1 shows the detailed baseline characteristics and outcomes vs. 31.7%, p = 0.007]. SFA intake had no effect on outcomes of the 1,655 patients with AP. The patients had a median age (Table 2). of 66 years; 54% were male, 24% were obese, 60% had gallstone etiology, 27% had local complications, 7% had POF, and 4% died. Multivariable Analysis Regarding these baseline characteristics, there were no significant In multivariable analysis (Table 3), patients from regions with differences between the different regions of Spain (p > 0.05). high overall lipid intake had significantly more frequent Supplementary Table 1 shows the caloric profile of lipid intake moderate-to-severe disease in the model without obesity [OR of the Spanish population as stratified by region according to = 1.26; 95% CI: 1.02–1.55; p = 0.034], but high overall lipid the ANIBES study. Supplementary Table 2 lists the number of intake was not significant after obesity was included in the medical centers and patients of the Atlantis database in the model [OR = 1.19; 95% CI: 0.96–1.48; p = 0.1]. Patients regions defined in the ANIBES study. with AP from regions with high UFA intake had significantly higher rates of local complications [OR = 1.53; 95% CI: 1.15– Univariate Analysis 2.05; p = 0.004], POF [OR = 2.1; 95% CI: 1.18–3.74; p = Table 2 shows outcomes according to lipid intake (univariate 0.01], mortality [OR = 2.37; 95% CI: 1.12–5.03; p = 0.02], and analysis). Moderate-to-severe disease was more frequently moderate-to-severe disease [OR = 1.42; 95% CI: 1.1–1.85; p present in patients from regions with a high overall lipid intake = 0.007] in the model without obesity compared to patients [37 vs. 32.1%, p = 0.04], who also showed a non-significant from areas with low UFA intake; after entering the variable trend toward a higher frequency of local complications [28.4 obesity into the model, high UFA intake remained a risk factor Frontiers in Medicine | www.frontiersin.org 3 April 2020 | Volume 7 | Article 126 García-Rayado et al. Dietary Fat Acute Pancreatitis Spain TABLE 2 | Outcomes of acute pancreatitis according to regional lipid intake. Lipid Intake Outcomes: n (%) Local complications Persistent organ failure Mortality Moderate-to-severe AP Lipids (overall) High 278 (28.4%) 71 (7.3%) 43 (4.4%) 362 (37%) Low 166 (24.6%) 42 (6.2%) 27 (4%) 217 (32.1%) P 0.08 0.4 0.7 0.04 SFAs High 327 (26.9%) 79 (6.5%) 47 (3.9%) 430 (35.4%) Low 117 (26.7%) 34 (7.7%) 23 (5.2%) 149 (33.9%) P 0.9 0.4 0.2 0.6 UFAs High 369 (28.6%) 99 (7.7%) 62 (4.8%) 473 (36.7%) Low 75 (20.5%) 14 (3.8%) 8 (2.2%) 106 (29%) P 0.002 0.01 0.03 0.007 MUFAs High 252 (29.6%) 65 (7.6%) 39 (4.6%) 324 (38.1%) Low 192 (23.9%) 48 (6%) 31 (3.9%) 255 (31.7%) P 0.009 0.2 0.5 0.007 Percentages are the proportions of the patients of the whole cohort (high or low consumers) that show each outcome of AP. SFAs, saturated fatty acids; UFAs, unsaturated fatty acids; MUFAs, monounsaturated fatty acids; High, patients from a region of Spain with a proportion of caloric intake from all lipids or from the indicated types of lipids that was greater than the Spanish national mean; Low, patients from a region of Spain with a proportion of caloric intake from all lipids or from the indicated types of lipids that was lower than the Spanish national mean; AP, acute pancreatitis; P, P-value in the chi-square test (Fisher’s exact test was not required). Bold value indicates P-value statistically significant. TABLE 3 | Multivariate analysis of high overall lipid intake and lipid subtype intake and outcomes in acute pancreatitis. Lipid Model Adjusted odds ratio Local complications Persistent organ failure Mortality Moderate-to-severe AP Lipids (overall) Without obesity 1.21 (0.96–1.53) 1.21 (0.82–1.8) 1.15 (0.7–1.88) 1.26 (1.02–1.55) P = 0.1 P = 0.3 P = 0.6 P = 0.034 With obesity 1.11 (0.88–1.41) 1.23 (0.81–1.87) 1.11 (0.66–1.87) 1.19 (0.96–1.48) P = 0.4 P = 0.3 P = 0.7 P = 0.1 SFAs Without obesity 0.98 (0.76–1.26) 0.87 (0.57–1.32) 0.76 (0.45–1.28) 1.06 (0.84–1.3) P = 0.9 P = 0.5 P = 0.3 P = 0.63 With obesity 1.01 (0.78–1.3) 0.87 (0.57–1.34) 0.83 (0.48–1.42) 1.11 (0.88–1.4) P = 0.9 P = 0.5 P = 0.49 P = 0.4 UFAs Without obesity 1.53 (1.15–2.05) 2.1 (1.18–3.74) 2.37 (1.12–5.03) 1.42 (1.1–1.85) P = 0.004 P = 0.01 P = 0.02 P = 0.007 With obesity 1.34 (0.99–1.83) 2.4 (1.24–4.71) 2.09 (0.94–4.66) 1.27 (0.96–1.67) P = 0.06 P = 0.01 P = 0.07 P = 0.09 MUFAs Without obesity 1.3 (1.03–1.62) 1.36 (0.92–2) 1.29 (0.79–2.09) 1.33 (1.08–1.63) P = 0.025 P = 0.1 P = 0.3 P = 0.008 With obesity 1.2 (0.95–1.5) 1.37 (0.91–2.06) 1.24 (0.75–2.07) 1.26 (1.02–1.56) P = 0.1 P = 0.1 P = 0.4 P = 0.035 In the binary logistic regression analysis, the data are reported as adjusted odds ratios (95% confidence intervals) and P-values (reference group: low intake of lipids). Model, the model used for multivariable analysis; Without obesity, the model that included Charlson comorbidity index (cutoff ≥3), sex, alcoholic etiology, and recurrent AP; With obesity, the model that included these same variables plus obesity (body mass index ≥ 30 kg/m2 ); SFAs, saturated fatty acids; UFAs, unsaturated fatty acids; MUFAs, monounsaturated fatty acids; AP, acute pancreatitis. Bold value indicates P-value statistically significant. for POF [OR = 2.4; 95% CI: 1.24–4.71; p = 0.01], showing DISCUSSION a non-significant trend for the other outcomes. Patients from regions with high MUFA intake had significantly increased Obesity is an important factor in AP severity and is associated rates of local complications [OR = 1.3; 95% CI: 1.03–1.62; with worse outcomes (3, 4, 19). The Atlantis prospective cohort p = 0.025] and moderate-to-severe disease [OR = 1.33; 95% study confirmed that obesity is associated with a higher mortality CI: 1.08–1.63; p = 0.008], and the significance remained for and with a higher incidence of POF (4), and fatty acids could moderate-to-severe disease after entering the variable obesity be relevant mediators in the physiopathogenesis of moderate-to- into the model [OR = 1.26; 95% CI: 1.02–1.56; p = 0.035]. severe AP in obese patients. There is robust evidence from basic SFA intake was not associated with any effect on outcomes research that UFAs are more toxic than SFAs (6, 7, 9, 12, 20–22). (Table 3). Analysis of postmortem tissue from obese patients has shown Frontiers in Medicine | www.frontiersin.org 4 April 2020 | Volume 7 | Article 126 García-Rayado et al. Dietary Fat Acute Pancreatitis Spain that UFAs are the predominant fatty acids in the pancreas, that oleic acid is associated with local and systemic toxicity whereas the proportion of SFAs is lower (23, 24). Furthermore, (7, 10, 11, 33–35). In addition, in a study by Pironi et al. UFAs are the most common (70–75%) non-esterified fatty acids in patients with parenteral nutrition, the administration of a in necrotic pancreatic collections (6–9). The Singh group has lipid emulsion based on MUFA produces a higher inflammatory performed in vitro studies using pancreatic acinar cells and has status than in patients using a fish-oil based lipid emulsion (36). studied animal models of AP and reports that UFAs are associated In the present study, residing in a region with high MUFA with increased inflammation and necrosis, while SFAs are not intake was independently associated with local complications harmful (6, 7, 21, 22). These experiments suggest that (A) UFAs and with moderate-to-severe AP in the model without obesity are the consequence of lipolysis of visceral fat by pancreatic and with moderate-to-severe AP in the model that included lipases; (B) local UFAs produce necrosis of acinar pancreatic cells; obesity. In addition, two studies investigated halogenated fatty and (C) uncontrolled UFA release results in high UFA levels in acids, a type of specific lipids produced from the oxidation the bloodstream and is associated with renal tubular apoptosis of fatty acids by hypochlorous acid, in humans and in an (and subsequently with kidney failure) as well as with cell damage animal model of AP. The animal model showed that the in lung alveoli that is similar to that seen in acute respiratory induction of AP produces an important release of free fatty distress syndrome (6, 7, 9, 12, 22). UFAs seem to induce cell death acids from adipose tissue and also in the release of the by inhibiting mitochondrial complexes I and V and by increasing chlorohydrins of oleic acid. Only the chlorohydrin of oleic acid intracellular calcium release (6, 25). In addition, in severe AP a was present in plasma (10). In humans, we found that oleic vicious cycle of inflammation and increasing oxidative stress is acid chlorohydrin was an excellent early marker of moderate-to- created. UFAs, but not SFAs, are sensitive to oxidative metabolic severe disease (11). conditions and can worse this deleterious cycle in AP (26). This This study has several strengths, including the use of role of UFA-mediated lipotoxicity in worsening AP is consistent multicenter data and nationwide prospective data from patients with the worse outcomes found in hypertriglyceridemic AP and with AP and the robust design and development of the in obese patients with AP (4, 27). On the other hand, studies show ANIBES study. There are also some limitations: we used indirect that dietary fatty acid patterns may affect body fat composition. data regarding dietary fat intake (regional consumption of fat Mice fed diets that have higher oleic acid and lower linoleic acid according to the ANIBES study) instead of obtaining individual show differences in adipose tissue and fat composition of the dietary data from every patient. It is difficult to conduct a pancreas (23). Studies in humans show that the proportion of prospective study that involves a similar sample of patients different fatty acids of adipose tissue and plasma reflects, at least with detailed individual dietary information, and the lack of in part, different dietary intake patterns (28–30). validated food questionnaires for the analysis of dietary fat UFAs are more toxic than SFAs, and body fat composition is and the different sources that are used in different countries affected by dietary fatty acid intake. Thus, we hypothesized that make it difficult to perform an international study. Furthermore, regional fat intake patterns could be associated with different dietary patterns are difficult to address in acutely ill patients, outcomes of AP. We also wanted to investigate whether dietary as this usually involves self-registry of food intake. Finally, a fat patterns had an independent effect on outcomes when we diet questionnaire is time-consuming, decreasing the feasibility controlled for the presence of obesity. Accordingly, we compared of such a study due to the high number of patients required to outcomes in patients from regions of Spain with different fat reproduce our findings. However, we encourage the development intake levels. To our knowledge, this is the first study of its of a multicenter prospective cohort study, which would provide kind, there are no clinical studies studying this association in more insights into the influence of lipids on AP. Besides, more Spain or in other countries. Our study found that patients with nutritional data should be analyzed in further studies as PUFA, AP from areas with a high UFA consumption had significantly including the omega-6/omega-3 ratio that can be crucial in higher rates of local complications, POF, mortality and frequency inflammatory processes. This is a limitation of the study although of moderate-to-severe AP in univariate analysis; this effect was future studies by our group will include the omega-6/omega- also observed in multivariable analysis (for all four variables 3 ratio in order to have a more complete and global vision of in the model not including obesity and for POF in the model the process. On the other hand, the de novo lipogenesis index including obesity). Patients from regions with high SFA intake (the synthesis of new fatty acids from non-lipid sources) will be did not have a worse prognosis. It is well-known that POF evaluated in further studies by our research team. This index has is the main determinant of severity in AP as reflected by the a known correlation with metabolic disorders such obesity and severe disease category of the revised Atlanta classification, type 2 diabetes and with inflammatory processes like moderate- which is defined exclusively by the presence of POF (15). Severe to-severe AP. Finally, the influence of dietary fat patterns with AP entails the greatest morbidity and mortality (2). Taken possible similar pathophysiology could be studied in other severe together, our results suggest that high UFA intake could be diseases like a sepsis. an important pre-morbid factor in determining the severity of In conclusion, differences in regional dietary fat patterns AP (31). seem to be associated with different outcomes of AP. Dietary Concerning the different types of UFAs, oleic acid is the fat patterns could represent a significant pre-morbid factor that more important MUFA, is the predominant fatty acid in human determines the severity of AP. Moreover, UFAs, and particularly pancreatic extracts (23, 32) and in human pancreatic necrotic MUFAs, seem to be important mediators of the pathogenesis of collections (6, 7). In vitro and laboratory animal studies suggest the severity of AP. Frontiers in Medicine | www.frontiersin.org 5 April 2020 | Volume 7 | Article 126 García-Rayado et al. Dietary Fat Acute Pancreatitis Spain DATA AVAILABILITY STATEMENT intellectual content. ÁF, NB-L, JC, MB-B, AA-A, PL, MU-C, MS-C, JL-N, RG-F, CG-O, RI-U, CR-A, JS, MR-P, AM-Á, EO, The datasets generated for this study are available on request to MM, FB, JR-P, and SG-S: acquisition of data and critical review the corresponding author. for important intellectual content. All authors gave final approval of the version to be published. ETHICS STATEMENT FUNDING The studies involving human participants were reviewed and approved by Comité Ético de Investigación con Medicamentos GG-R was supported by grant from the Instituto de Salud Carlos del Hospital General Universitario de Alicante (PI2018-102). The III and Instituto de Investigación Sanitaria (IIS) Aragón [Río patients/participants provided their written informed consent to Hortega grant CM17/00145]. participate in this study. ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS The results of this study were partially presented as a poster presentation at the 50th meeting of the European Pancreatic Club EM: conception, design, acquisition of data, analysis and celebrated in Berlin from June 13 to 16, 2018. interpretation of data, article drafting. GG-R: article drafting, acquisition of data, analysis and interpretation of data, and SUPPLEMENTARY MATERIAL critical review for important intellectual content. GV-M: acquisition of data, analysis and interpretation of data, article The Supplementary Material for this article can be found drafting, and critical review for important intellectual content. online at: https://www.frontiersin.org/articles/10.3389/fmed. ÁL and DC: article drafting and critical review for important 2020.00126/full#supplementary-material REFERENCES halogenated lipids during acute pancreatitis. Ann Surg. (2013) 257:943–51. doi: 10.1097/SLA.0b013e318269d536 1. 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Site-specific differences in the fatty acid composition of abdominal article distributed under the terms of the Creative Commons Attribution License (CC adipose tissue in an obese population from a Mediterranean area: relation with BY). The use, distribution or reproduction in other forums is permitted, provided dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am the original author(s) and the copyright owner(s) are credited and that the original J Clin Nutr. (2001) 74:585–91. doi: 10.1093/ajcn/74.5.585 publication in this journal is cited, in accordance with accepted academic practice. 31. García-Rayado G, Varela Moreiras G, Cárdenas Jaén K, Bozhychko M, No use, distribution or reproduction is permitted which does not comply with these Bolado F, Marra López C, et al. Dietary fat patterns and outcomes in acute terms. Frontiers in Medicine | www.frontiersin.org 7 April 2020 | Volume 7 | Article 126