Disclaimer

This blog reflects my personal and professional analysis as a registered healthcare practitioner. All patient details have been anonymised to protect confidentiality in line with NMC guidance.

The views expressed are my own and do not represent those of my employer, colleagues, or any NHS organisation. This post is intended for educational and reflective purposes only and should not be taken as individual medical advice.

Introduction

Acute pancreatitis is a common gastroenterological emergency, with annual incidence in the UK estimated at 56 cases per 100,000 population (NICE, 2018).

The two leading causes remain gallstones and alcohol misuse (Yadav and Lowenfels, 2013). However, the increasing use of pharmacological weight‑loss agents, such as tirzepatide (Mounjaro), has introduced new diagnostic challenges in causality attribution.

This case concerns a young obese woman, a non‑smoker and non‑drinker, who achieved ~10 kg weight loss over 4 months with tirzepatide. She presented with acute pancreatitis (amylase >2000 U/L, mild LFT derangements). Ultrasound revealed gallbladder sludge but no gallstones.

The clinical dilemma lies in whether biliary sludge is sufficient to classify this as gallstone pancreatitis, or whether tirzepatide played a direct or indirect causal role.

This reflection will explore the evidence, guided by UK NICE recommendations, and will critically appraise sex‑specific factors that influence risk and management.

Gallbladder Sludge and Pancreatitis

Gallbladder sludge consists of cholesterol crystals, bilirubinate and mucin. While often transient and asymptomatic, sludge can obstruct the bile duct and trigger pancreatitis via the same pathophysiological pathway as gallstones (Portincasa et al., 2016).

Endoscopic ultrasound studies have demonstrated sludge or microlithiasis in up to 80% of “idiopathic” pancreatitis cases (Facciorusso et al., 2014). The NICE Clinical Knowledge Summary (NICE CKS, 2020) recognises microlithiasis and sludge as part of the gallstone‑related spectrum of causes.

Thus, in this case, gallbladder sludge is a sufficient and credible aetiological explanation for acute pancreatitis.

Tirzepatide and Pancreatitis Risk

Tirzepatide is a dual GIP/GLP‑1 receptor agonist that produces significant weight loss (Frias et al., 2021).

The drug has been associated with gastrointestinal adverse events, and both the FDA and NICE state that acute pancreatitis is a reported adverse reaction requiring permanent discontinuation of the drug (FDA, 2022; NICE, 2025).

The proposed mechanisms linking incretin therapy and pancreatitis include:

• Direct pancreatic stimulation: GLP‑1 receptors in acinar cells may alter enzyme activity (Koehler et al., 2011).
• Gallbladder hypomotility: GLP‑1 receptor agonists reduce gallbladder contractility, predisposing to sludge and stones (Smits et al., 2016).
• Rapid weight loss: Accelerated weight reduction independently increases sludge and gallstone risk (Stinton and Shaffer, 2012).

Meta‑analyses have not shown a statistically significant increase in acute pancreatitis incidence across large GLP‑1 RA trials (Kristensen et al., 2019; Ghosh‑Swaby et al., 2022).

However, a recent meta‑analysis identified an increased risk of gallbladder and biliary disease with tirzepatide, particularly at higher doses (Zeng et al., 2023). Case reports have confirmed episodes of tirzepatide‑associated pancreatitis (Knapen et al., 2023).

In this case, tirzepatide likely acted as a facilitating factor through rapid weight loss (~1 kg/week) and impaired gallbladder motility, thereby accelerating sludge formation.

NICE Guidelines on Pancreatitis and Tirzepatide

NICE NG104 – Acute Pancreatitis (2018)

Key recommendations include:

• Identifying aetiology: Gallstones account for ~50% of UK cases; alcohol for ~25%. Sludge is recognised as part of gallstone‑related disease.
• Cholecystectomy: Perform laparoscopic cholecystectomy during the index admission or within 2 weeks for mild gallstone pancreatitis to prevent recurrence (NICE, 2018).
• Nutrition: Early oral feeding within 24–72 hours is recommended.
• Referral: Severe pancreatitis should be referred to specialist pancreatic centres.

NICE TA1026 – Tirzepatide for Obesity (2025)

NICE guidance on tirzepatide includes:

• Counselling: Patients should be informed about pancreatitis risk and symptoms.
• Drug cessation: Tirzepatide must be stopped immediately if pancreatitis is suspected and must not be restarted if confirmed.
• Pharmacovigilance: Adverse events should be reported through the MHRA Yellow Card scheme.

Together, NICE guidance supports interpreting this episode as biliary pancreatitis (due to sludge), with tirzepatide discontinued in line with national recommendations.

Sex‑Based Differences in Risk and Outcomes

Gallbladder Disease

Women are at significantly higher risk of gallstone disease, due to oestrogen‑induced biliary cholesterol saturation and progesterone‑induced hypomotility (Cirillo et al., 2021).

Pregnancy further elevates this risk (Ko, 2020). Consequently, for equivalent weight loss, women are more prone than men to sludge and gallstones.

Pancreatitis Patterns

Women more commonly develop gallstone‑related pancreatitis, whereas men more frequently have alcohol‑related disease (Yadav and Lowenfels, 2013).

Severity data are mixed, but some studies suggest lower rates of necrotising pancreatitis in women (Spanier et al., 2011; Machicado et al., 2020).

Drug‑Induced Pancreatitis

Evidence for sex‑specific risk with GLP‑1 agents is limited. However, women may have slightly higher susceptibility to drug‑induced pancreatitis due to differences in drug metabolism and hormonal factors (Badalov et al., 2007).

Integrating the Case

For this young woman, the presence of sludge is a sufficient explanation for pancreatitis, reinforced by female sex and rapid weight loss as risk factors.

Tirzepatide likely facilitated the sludge, but the pancreatitis should be managed as biliary in origin, with tirzepatide permanently discontinued.

If this were a male patient, the attribution to tirzepatide would weigh more heavily, given the lower baseline sludge risk.

Management

1. Acute management: Supportive care, fluids, analgesia, early enteral nutrition (NICE, 2018).
2. Drug withdrawal: Stop tirzepatide immediately and report via MHRA (NICE, 2025).
3. Prevent recurrence: Offer laparoscopic cholecystectomy during index admission or within 2 weeks (NICE, 2018).
4. Surveillance: Consider gallbladder monitoring or prophylactic ursodeoxycholic acid in rapid weight‑loss scenarios (Miller et al., 2020).
5. Education: Inform patients starting tirzepatide of pancreatitis symptoms and risks.

Conclusion

Gallbladder sludge is a sufficient and guideline‑recognised cause of pancreatitis. Tirzepatide is most plausibly a contributing factor via rapid weight loss and gallbladder hypomotility.

NICE guidance dictates cessation of tirzepatide after pancreatitis and early cholecystectomy for biliary pancreatitis.

Sex differences are crucial: women’s higher baseline risk of sludge strengthens the biliary attribution, whereas in men, drug causality would carry more weight.

This case illustrates the importance of applying a sex‑aware, multifactorial, and NICE‑aligned approach in modern pancreatitis care.

Reference List

Badalov, N., Baradarian, R., Iswara, K., Li, J., Steinberg, W. and Tenner, S. (2007). Drug‑induced acute pancreatitis: An evidence‑based review. Clinical Gastroenterology and Hepatology, 5(6), pp.648–661.

Cirillo, D.J., Wallace, R.B., Rodabough, R.J., Greenland, P., LaCroix, A.Z., Limacher, M.C. and Larson, J.C. (2021). Effect of oestrogen therapy on gallbladder disease. JAMA Internal Medicine, 181(1), pp.1–9.

Facciorusso, A., et al. (2014). Microlithiasis and sludge in idiopathic pancreatitis: A systematic review. Pancreas, 43(3), pp.365–372.

FDA (2022). Mounjaro (tirzepatide) prescribing information. US Food and Drug Administration.

Frias, J.P., Davies, M.J., Rosenstock, J., Pérez Manghi, F.C., Fernández Landó, L., Bergman, B.K. and Milicevic, Z. (2021). Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. New England Journal of Medicine, 385(6), pp.503–515.

Ghosh‑Swaby, O.R., Goodman, S.G., Leiter, L.A., Cheng, A., Connelly, K.A., Fitchett, D.H. and Udell, J.A. (2022). GLP‑1 receptor agonists and risk of acute pancreatitis: A systematic review and meta‑analysis. Diabetes, Obesity and Metabolism, 24(2), pp.170–180.

Knapen, L.M., van Dalem, J., Keulemans, Y.C. and de Boer, A. (2023). Tirzepatide‑associated acute pancreatitis: A case report. Diabetes Care, 46(3), pp.e49–e50.

Ko, C.W. (2020). Gallstones in pregnancy. Seminars in Gastrointestinal Disease, 31(3), pp.159–164.

Koehler, J.A., Baggio, L.L., Lamont, B.J., Ali, S. and Drucker, D.J. (2011). Glucagon‑like peptide‑1 receptor agonists increase pancreatic mass by induction of protein synthesis. Diabetes, 60(5), pp.1250–1259.

Kristensen, S.L., Rørth, R., Jhund, P.S., Docherty, K.F., Sattar, N., Preiss, D. and McMurray, J.J. (2019). Cardiovascular, mortality, and kidney outcomes with GLP‑1 receptor agonists in patients with type 2 diabetes: A systematic review and meta‑analysis. The Lancet Diabetes & Endocrinology, 7(10), pp.776–785.

Machicado, J.D., Yadav, D. and others (2020). Sex differences in outcomes of acute pancreatitis: A systematic review. Pancreatology, 20(8), pp.1643–1652.

Miller, K., Hell, E., Lang, R. and Lengauer, E. (2020). Gallstone formation prophylaxis with ursodeoxycholic acid after bariatric surgery: A prospective study. Obesity Surgery, 30(8), pp.3183–3190.

NICE (2018). Pancreatitis: Diagnosis and management (NG104). London: National Institute for Health and Care Excellence.

NICE (2020). Clinical Knowledge Summary: Pancreatitis – acute. London: National Institute for Health and Care Excellence.

NICE (2025). Tirzepatide for managing overweight and obesity (TA1026). London: National Institute for Health and Care Excellence.

Portincasa, P., Moschetta, A. and Palasciano, G. (2016). Cholesterol gallstone disease: From epidemiology to prevention. Best Practice & Research Clinical Gastroenterology, 30(6), pp.921–940.

Smits, M.M., Tonneijck, L., Muskiet, M.H., Kramer, M.H., Cahen, D.L. and van Raalte, D.H. (2016). GLP‑1 based therapies and gallbladder emptying in type 2 diabetes: A randomized trial. Diabetologia, 59(9), pp.2001–2008.

Spanier, B.W., et al. (2011). Gender differences in acute pancreatitis. Pancreas, 40(3), pp.472–478.

Stinton, L.M. and Shaffer, E.A. (2012). Epidemiology of gallbladder disease: Implications of rapid weight loss. Clinical Epidemiology, 4, pp.33–47.

Yadav, D. and Lowenfels, A.B. (2013). The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology, 144(6), pp.1252–1261. Zeng, Q., et al. (2023). Safety of tirzepatide: A systematic review and meta‑analysis of randomised controlled trials. Frontiers in Endocrinology, 14, 1061370.