Postoperative hyperamylasemia—an early warning signal after distal pancreatectomy

In Annals of Surgery, Perri and colleagues present a comprehensive multicentric analysis on the clinical significance of postoperative hyperamylasemia (POH) following distal pancreatectomy (DP) (1). Analyzing data from more than 1,100 patients across three high-volume European centers, authors identify POH as an independent early predictor of postoperative pancreatic fistula (POPF) occurrence and severity. Their study provides an important bridge between biochemical markers and clinical outcomes, illuminating an early “red flag” that may refine postoperative management after DP.

A common operation with persistent morbidity

DP is the standard resection for left-sided pancreatic lesions, now most frequently performed with minimally invasive techniques (2-4). Despite remarkable progress in perioperative care, POPF remains the most frequent source of morbidity after pancreatic resection (5,6). While POPF after DP is often less catastrophic than after pancreato-duodenectomy (PD), it nonetheless prolongs hospitalization, delays recovery, might delay adjuvant therapy and can lead to severe sequelae such as post-pancreatectomy hemorrhage (PPH), sepsis, and death (7).

Enhanced recovery after surgery (ERAS) protocols and selective drain removal have accelerated postoperative pathways in DP (8,9). Yet this progress requires reliable early risk predictors. Identification of patients who will develop major morbidity remains a critical unmet clinical need.

Biochemical signature

POH, defined by the International Study Group for Pancreatic Surgery (ISGPS) as an elevation in serum amylase persisting for ≥48 hours postoperatively, was initially conceptualized as a prerequisite for post-pancreatectomy acute pancreatitis (PPAP) (10). However, emerging evidence suggests that POH reflects early pancreatic injury rather than a mere biochemical abnormality, anticipating pancreas-specific complications even when PPAP or POPF are not clinically evident (11-13). Previous reports, particularly from the Verona group, established that POH after PD substantially increases the likelihood of POPF, regardless of intraoperative fistula risk (5,14).

Importantly, this concept has recently been reinforced by data from our group. In a mixed PD and DP cohort, we demonstrated that early postoperative elevations in pancreatic enzymes, including both hyperamylasemia and hyperlipasemia on postoperative day (POD) 0, show a strong correlation with clinically relevant POPF. In this analysis, postoperative hyperlipasemia proved to be an independent predictor in the multivariable model (15). Perri et al. now extend this paradigm specifically to DP. Here, the pancreatic remnant, rather than an anastomosis, is the critical site of vulnerability. Their findings demonstrate that POH occurs in roughly one in five patients (18%), and that it nearly doubles the risk of POPF (43% vs. 26%), with a strong correlation between POH intensity and POPF severity.

These findings further support the notion that early postoperative pancreatic enzyme leakage into the systemic circulation reflects biologically distress of the pancreatic remnant.

In multivariable analysis, three early postoperative variables independently predicted POPF:

• POH [odds ratio (OR) 1.58];
• Drain fluid amylase (DFA) ≥2,000 U/L on POD 1 (OR 2.11);
• C-reactive protein ≥200 mg/L on POD 3 (OR 2.19).

Importantly, these predictors are available within the first 72 hours. During and after this period key management decisions are made: drain removal, imaging, or early discharge. POH thus emerges as an early, easily accessible biomarker that complements DFA and C-reactive protein (CRP). While DFA reflects direct leakage from the pancreatic stump and CRP mirrors the systemic inflammatory response, POH occupies an intermediate position. It indicates early pancreatic parenchymal injury and enzymatic activation at a stage when complications have not yet become clinically visible.

A marker of systemic impact

Perri et al. provide robust evidence that POH is not merely associated with biochemical leak but correlates with more severe outcomes: higher rates of sepsis, PPH, unplanned ICU admission, reoperation, and mortality. Among patients who developed both POH and POPF, the mortality rate reached 3%, compared to 0.3% in those without POH. These findings underscore the concept that POH recapitulates a spectrum of pancreatic inflammation, extending beyond the fistula itself.

Interestingly, patients with “POH only”, meaning elevated serum amylase in the absence of POPF, still had higher rates of abscess formation and longer hospital stays compared with uncomplicated cases. This finding supports the view that POH is a clinically relevant postoperative phenomenon and not simply a biochemical marker of leakage.

Pathophysiologic considerations

The mechanisms linking POH to subsequent morbidity likely involve early acinar cell injury and local ischemia of the pancreatic stump. Surgical manipulation, devascularization, or transection technique can trigger enzyme activation and peripancreatic inflammation (16). In the present analysis, transection left to the isthmus and use of ultrasonic devices were independent predictors of POH, supporting this hypothesis.

Such inflammation may impair healing of the pancreatic remnant, predisposing to delayed leakage and abscess formation. Whether POH and PPAP represent distinct entities or points along a continuum of postoperative pancreatic inflammation remains an open question. Future prospective work with standardized imaging and biochemical surveillance could clarify this relationship.

Clinical translation

The clinical message from this study is clear: POH identifies patients at risk for a complicated course after DP, already within 48 hours of surgery. For surgeons implementing ERAS pathways or early drain removal protocols, POH can serve as a “stop signal”. When POH is present, drains should be retained, imaging considered, and discharge delayed. Conversely, in the absence of POH and other red flags (low DFA and CRP), early discharge appears safe.

This stratified approach aligns with the findings of Smits et al., whose nationwide algorithm-based care trial in the Netherlands demonstrated a substantial reduction in severe morbidity by standardizing early postoperative responses to warning signs (8). POH now adds a pancreas-specific dimension to such algorithms, particularly valuable in the context of drainless DP, where drain-based biomarkers are unavailable.

Balancing minimalism and vigilance

The evolution of DP toward minimal invasiveness and reduced drainage has delivered tangible benefits in recovery and patient comfort (17,18). Yet, as drains disappear, so do some of our early warning tools. Serum-based markers like POH thus gain strategic importance. Measuring serum amylase is inexpensive, universally available, and reproducible, which makes it well suited for integration into fast-track protocols.

Some may argue that routine serum amylase testing offers limited benefit given that CRP measurements are performed daily. Perri et al. address this directly: nearly one-fifth of patients with POPF and CRP <200 mg/L still had POH, highlighting incomplete overlap. Unlike CRP, POH is pancreas-specific and may precede systemic inflammation. Incorporating both markers offers complementary sensitivity.

Strengths and limitations

The strengths of this study are in its large sample size, multicentric design, and uniform application of ISGPS definitions. With over 1,100 DPs analyzed, this is among the most comprehensive datasets exploring early postoperative biochemistry and outcome correlation.

Nevertheless, certain caveats deserve being mentioned. The retrospective nature introduces potential selection bias, and serum amylase thresholds varied slightly between centers. The absence of standardized imaging to confirm or exclude PPAP limits the ability to distinguish inflammatory from ischemic mechanisms. Furthermore, intraoperative factors such as gland texture, duct size, and surgeon-specific technique were not fully reported, and these remain important determinants of POPF risk.

Despite these limitations, the study’s internal consistency and biological plausibility make its conclusions compelling.

Future directions

Several avenues merit exploration:

• Prospective validation: incorporate POH into predictive algorithms alongside DFA, CRP, and intraoperative risk scores such as the Distal Fistula Risk Score (D-FRS) (5).
• Mechanistic studies: utilize imaging, perfusion metrics, and inflammatory biomarkers to clarify the link between POH, PPAP, and POPF.
• Drain-free surgery: evaluate the role of POH in guiding postoperative care after drainless minimally invasive DP.
• Therapeutic response: test whether early interventions triggered by POH (e.g., prophylactic antibiotics, imaging or sandostatin analogues) improve outcomes.

If validated prospectively, POH could become part of a composite early-warning algorithm—objective, pancreas-specific, and readily implementable in any surgical unit.

Conclusions

The study by Perri et al. redefines POH as more than a laboratory anomaly. It is an early biochemical manifestation of pancreatic distress that forecasts the trajectory of postoperative recovery. Recognizing POH within 48 hours of DP enables timely intervention, safer implementation of ERAS protocols, and potentially lower morbidity and mortality.

As minimally invasive and drainless pancreatic surgery continues to evolve, serum amylase may gain prominence as a simple yet powerful indicator of whether the pancreas is healing or suffering.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-915/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-915/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Perri G, Romandini E, Marchegiani G, et al. Postoperative Hyperamylasemia (POH) Is an Early Predictor of Pancreatic Fistula Occurrence and Severity After Distal Pancreatectomy: Results from a European Multicentric Study. Ann Surg 2025;282:291-8. [Crossref] [PubMed]
2. Asbun HJ, Moekotte AL, Vissers FL, et al. The Miami International Evidence-based Guidelines on Minimally Invasive Pancreas Resection. Ann Surg 2020;271:1-14. [Crossref] [PubMed]
3. Müller PC, Breuer E, Nickel F, et al. Robotic Distal Pancreatectomy: A Novel Standard of Care? Benchmark Values for Surgical Outcomes From 16 International Expert Centers. Ann Surg 2023;278:253-9. [Crossref] [PubMed]
4. van Hilst J, de Rooij T, Klompmaker S, et al. Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA): A Pan-European Propensity Score Matched Study. Ann Surg 2019;269:10-7. [Crossref] [PubMed]
5. De Pastena M, van Bodegraven EA, Mungroop TH, et al. Distal Pancreatectomy Fistula Risk Score (D-FRS): Development and International Validation. Ann Surg 2023;277:e1099-105. [Crossref] [PubMed]
6. Ecker BL, McMillan MT, Allegrini V, et al. Risk Factors and Mitigation Strategies for Pancreatic Fistula After Distal Pancreatectomy: Analysis of 2026 Resections From the International, Multi-institutional Distal Pancreatectomy Study Group. Ann Surg 2019;269:143-9. [Crossref] [PubMed]
7. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After. Surgery 2017;161:584-91. [Crossref] [PubMed]
8. Smits FJ, Henry AC, Besselink MG, et al. Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial. Lancet 2022;399:1867-75. [Crossref] [PubMed]
9. van Bodegraven EA, Balduzzi A, van Ramshorst TME, et al. Prophylactic abdominal drainage after distal pancreatectomy (PANDORINA): an international, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet Gastroenterol Hepatol 2024;9:438-47. [Crossref] [PubMed]
10. Marchegiani G, Barreto SG, Bannone E, et al. Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS). Ann Surg 2022;275:663-72. [Crossref] [PubMed]
11. Andrianello S, Bannone E, Marchegiani G, et al. Characterization of postoperative acute pancreatitis (POAP) after distal pancreatectomy. Surgery 2021;169:724-31. [Crossref] [PubMed]
12. Bannone E, Marchegiani G, Perri G, et al. Postoperative serum hyperamylasemia (POH) predicts additional morbidity after pancreatoduodenectomy: It is not all about pancreatic fistula. Surgery 2022;172:715-22. [Crossref] [PubMed]
13. Connor S. Defining post-operative pancreatitis as a new pancreatic specific complication following pancreatic resection. HPB (Oxford) 2016;18:642-51. [Crossref] [PubMed]
14. Giuliani T, Perri G, Kang R, et al. Current Perioperative Care in Pancreatoduodenectomy: A Step-by-Step Surgical Roadmap from First Visit to Discharge. Cancers (Basel) 2023;15:2499. [Crossref] [PubMed]
15. Aghamaliyev U, Cepele G, Hofmann FO, et al. Hyperlipasemia in the immediate postoperative period predicts postoperative pancreatic fistula after pancreatic resections. Surgery 2024;176:1732-8. [Crossref] [PubMed]
16. Kjeseth T, Yaqub S, Edwin B, et al. Peri-firing compression in prevention of pancreatic fistula after distal pancreatectomy: A systematic review and a cohort study. Scand J Surg 2024;113:73-9. [Crossref] [PubMed]
17. Emmen AMLH, Görgec B, Zwart MJW, et al. Impact of shifting from laparoscopic to robotic surgery during 600 minimally invasive pancreatic and liver resections. Surg Endosc 2023;37:2659-72. [Crossref] [PubMed]
18. Korrel M, Jones LR, van Hilst J, et al. Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial. Lancet Reg Health Eur 2023;31:100673. [Crossref] [PubMed]