Background: Hypertriglyceridemia can develop during pancreatitis from other etiologies even in the absence of preexisting HTG (PMID: 31229460, 28655321, 30885545). For unclear reasons HTG-AP can be more severe than other AP etiologies. While rapid lipolysis of triglycerides from visceral fat necrosis can release NEFA (PMID:31917686) that can worsen AP, the mechanisms relevant to HTG AP are unknown. We thus studied whether lipolytic generation of non-esterified fatty acids (NEFA) from circulating triglycerides (TGs) could worsen clinical outcomes.
Methods: The serum TG, NEFA compositions and concentrations were analyzed prospectively in 263 patients admitted with AP between August 2019 and Nov 2021 using Gas chromatography. These and clinical outcomes were compared between HTG-AP and other AP etiologies. HTG was defined as serum TGs >500mg/dL based on the AHA 2018 guidelines (PMID: 30586774). Serum NEFAs were correlated with the serum triglyceride fatty acids (TGFAs) alone, and with the product of TGFA x serum lipase (NEFA-TGFAxlipase). Normality of data was compared using Anderson-Darling test. P values of <0.05 were regarded as significant. Pancreatitis was induced in HTG mice and in vitro were used to dissect the role of TG lipolysis on cell injury and organ failure and interpret the NEFA-TGFA correlations.
Results: The 26 AP patients with TGs >500 mg/dL had higher serum long chain unsaturated NEFA and more severe AP (19% vs. 7% p<0.03) compared to other etiologies. 5/26 patients had Biliary (1), alcoholic (3) or other etiologies of AP(1). Compared to patients with normal TGs (150mg/dl), correlations of long-chain unsaturated NEFA with corresponding TGFAs increased with TG concentrations up to 500mg/dL and declined thereafter. However, NEFA-TGFAxlipase correlations got stronger with TGs >500mg/dL and remained significantly elevated compared to controls. Unsaturation of TGFAs increased their lipolysis by pancreatic lipases in vitro, and AP-induced lipolysis of circulating TGs in HTG mice with a drop in mean triglyceride levels from 22000mg/dl to 17000 mg/dl and an increase in serum FFA from 2200µM to 3800 µM which led to multi-system organ failure. Reclassifying the 5 HTG-AP patients to the primary AP etiology negated the NEFA elevation, and AP severity for the new Pure-HTG AP group.
Conclusions: Increased strength of NEFA-TGFA correlation on factoring in lipase at TG > 500mg/dL shows that during HTG AP unsaturation of TGFA leads to NEFA generation as opposed physiologic synthesis of TGs from NEFA as previously shown via the Kennedy pathway (PMID:13843753). Greater severity during HTG-AP may be due to such lipolysis of circulating TGs irrespective of the cause of hypertriglyceridemia or AP etiology. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes of HTG-AP.

Megan Summers

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