Acute necrotizing pancreatitis is a severe condition with a high mortality rate [1]. In the Western world, alcohol and biliary stones are the main causes of acute pancreatitis [2,3]. As shown by the Ranson, J. H. C. [4] grading of acute non- alcoholic pancreatitis, severe pancreatitis is associated with a decrease in serum calcium levels. However, the relationship between increased serum calcium levels and acute pancreatitis may be a diagnostic clue to primary hyperparathyroidism (PHPT) [5]. Acute pancreatitis caused by hypercalcemia due to PHPT is a very rare condition [6]. We present a case report of a female patient with hypercalcemia-induced acute necrotizing pancreatitis due to  PHPT.

Case Report

A 69-year-old female presented at the emergency room with a sudden attack of severe epigastric pain and vomiting. Nine years ago she had undergone cholecystectomy for  lithiasis gallbladder. Her medical history also mentioned an episode of pulmonary embolism. She was a non-smoker and without alcohol consumption. She did not travel abroad.

Clinical examination revealed a severely ill patient, a silent abdomen which was distended with painful percussion and palpation of the epigastrium.

Blood analysis showed signs of inflammation with an elevated C-reactive protein (CRP) of 13 mg/L (< 3 mg/d) and leukocytosis of  14 × 10E9/L (4.3-10 × 10E9/L) with elevated neutrophils of 11.2 × 10E9/L (2.0-7.0 × 10E9/L). Pancreatic enzymes were elevated, serum lipase was 12062 U/L (73-393 U/L). Both liver transaminases and canalicular liver tests were normal. In contrast to what was expected in a case of severe pancreatitis, serum calcium was increased to 12.7 mg/dL (8.5-10.1 mg/dL), the albumin-modified serum calcium concentration  was  12.9 mg/dL.  IgG4  was normal  as were serum triglycerides was moderately increased to 0.23 g/dL (<0.14mg/dL).

Based on the clinical picture and blood analysis she was diagnosed with acute pancreatitis. Abdominal ultrasound was carried out and showed no evidence of cholelithiasis or dilated bile ducts. Abdominal computed tomography (CT) scan confirmed the diagnosis of exudative pancreatitis. The patient was admitted to the ward and was treated conservatively with intravenous fluids and analgesia. The patient improved gradually during the following days. At day 10 after admission, abdominal CT scan was repeated and showed the same findinf as the initial CT scan. Echoendoscopy (EUS) was carried and showed no evidence of cholelithiasis or dilated bile ducts.                

After exclusion of alcohol-induced and biliary pancreatitis as well as auto-immune pancreatitis, elevated serum  calcium levels remained another potential etiology of acute pancreatitis. On reviewing her medical records, persistent high serum calcium levels were  noted. Serum levels of para- thyroid hormone (PTH) were determined and showed an increase up to 480.3 pg/mL (11.5-79.5 pg/mL). This result confirmed hypercalcemia caused by hyperparathyroidism. Ultrasound of the parathyroid glands showed no abnormalities. A 99mTc-Sestamibi scintigraphy was carried out which was consistent with a lower left side parathyroid adenoma. The patient underwent surgical resection of this tumor, and histological examination confirmed the diagnosis of benign parathyroid adenoma.

Acute pancreatitis caused by PHPT-induced hypercalcemia is a rare condition. It was first described in 1957 by Cope, O [5]. Since then, the relationship between PHPT and pancreatitis has been questioned, but nowadays PHPT has been acknowledged as an accepted etiology of pancreatitis [1,7,8]. The prevalence of acute pancreatitis in patients with PHPT is estimated between 1.5% and 7% [6]. Some studies have associated hyperparathyroidism with pancreatitis, however, the prevalence of acute pancreatitis in patients with PHPT seems no different from that in the general population [9,10]. It has been shown that hypercalcemia of any cause can lead to acute pancreatitis [11]. When this combination occurs, pancreatitis is likely to be severe and the degree of hypercalcemia may play an important role in this association [12,13]. Three pathophysiological mechanisms are suggested. The deposition of  calcium in the pancreatic duct may cause pancreatic duct obstruction [14]. Hypercalcemia may also lead to activation of trypsinogen within the pancreatic parenchyma causing autodigestion of the pancreas [15]. Finally, genetic variants in SPINK 1 (serine protease inhibitor Kazal type 1) and CFTR (cystic fibrosis transmembrane conductance regulator) genes in combination with hypercalcemia increase the risk of developing acute pancreatitis in patients with PHPT [16].

Usually, acute pancreatitis is associated with a decrease in serum calcium levels. Based on the Ranson, J. H. C. [4] grading, low serum calcium levels have prognostic importance. Therefore, it is uncommon to detect hypercalcemia in a patient presenting with severe acute pancreatitis. This unusual condition should always alert physicians to the presence of hyperparathyroidism or malignancy [17,18]. In order to complete the diagnosis, parathyroid hormone levels should be determined and imaging of the parathyroid glands is important. Good cooperation between gastroenterologists, endocrinologists and surgeons is important in treating this rare phenomenon of acute necrotizing pancreatitis caused by PHPTinduced hypercalcemia.

1. Banks, P.A. et al. “Practice Guidelines in Acute Pancreatitis.” American Journal of Gastroenterology, vol. 101, no. 10, 2006, pp. 2379–2400.

2. Yang, A.L. et al. “Epidemiology of Alcohol-Related Liver and Pancreatic Disease in the United States.” Archives of Internal Medicine, vol. 168, no. 6, 2008, pp. 649–656.

3. Forsmark, C.E., and J. Baillie. “AGA Institute Technical Review on Acute Pancreatitis.” Revista de Gastroenterología de México, vol. 72, no. 3, 2007, pp. 257–281.

4. Ranson, J.H.C. “Etiological and Prognostic Factors in Human Acute Pancreatitis.” American Journal of Gastroenterology, vol. 77, 1982, pp. 633–638.

5. Cope, O. et al. “Pancreatitis, a Diagnostic Clue to Hyperparathyroidism.” Annals of Surgery, vol. 145, no. 6, 1957, p. 857.

6. Valenzuela, J.E. et al. “Acute Pancreatitis Associated with Hypercalcemia: A Report of Two Cases.” Revista Española de Enfermedades Digestivas, vol. 101, 2009, pp. 65–69.

7. Carnaille, B. et al. “Pancreatitis and Primary Hyperparathyroidism: Forty Cases.” Australian and New Zealand Journal of Surgery, vol. 68, no. 2, 1998, pp. 117–119.

8. Koppelberg, T. et al. “Pancreatitis in Primary Hyperparathyroidism (pHPT) Is a Complication of Advanced pHPT.” Deutsche Medizinische Wochenschrift, vol. 119, 1994, pp. 719–724.

9. Khoo, T.K. et al. “Acute Pancreatitis in Primary Hyperparathyroidism: A Population-Based Study.” Journal of Clinical Endocrinology & Metabolism, vol. 94, no. 6, 2009, pp. 2115–2118.

10. Bess, M.A. et al. “Hyperparathyroidism and Pancreatitis: Chance or a Causal Association?” JAMA, vol. 243, no. 3, 1980, pp. 246–247.

11. Brandwein, S.L., and K.M. Sigman. “Milk-Alkali Syndrome and Pancreatitis.” American Journal of the Medical Sciences, vol. 308, 1994, pp. 173–176.

12. Prinz, R.A., and G.V. Aranha. “The Association of Primary Hyperparathyroidism and Pancreatitis.” American Surgeon, vol. 51, no. 6, 1985, pp. 325–329.

13. Curto, C. et al. “Acute Pancreatitis and Primary Hyperparathyroidism: A Multicentric Study by the Francophone Association of Endocrine Surgeons.” Journal de Chirurgie, vol. 146, no. 3, 2009, pp. 270–274.

14. Ward, J.B. et al. “Is an Elevated Concentration of Acinar Cytosolic Free Ionised Calcium the Trigger for Acute Pancreatitis?” The Lancet, vol. 346, no. 8981, 1995, pp. 1016–1019.

15. Sumrein, F., and M. Raghuwanshi. “Necrotizing Pancreatitis, an Unusual Presentation of Longstanding Primary Hyperparathyroidism.” Archives of Clinical Case Studies, vol. 1, no. 3, 2019.

16. Felderbauer, P. et al. “Pancreatitis Risk in Primary Hyperparathyroidism: Relation to Mutations in the SPINK1 Trypsin Inhibitor (N34S) and the Cystic Fibrosis Gene.” American Journal of Gastroenterology, vol. 103, no. 2, 2008, pp. 368–374.

17. Braun, C. et al. “Acute Pancreatitis Due to Hypercalcemia Revealing Adult T-Cell Leukemia.” La Revue de Médecine Interne, vol. 28, no. 2, 2007, pp. 116–119.

18. Kanno, K. et al. “Esophageal Small Cell Carcinoma Associated with Hypercalcemia Causing Severe Acute Pancreatitis.” Fukushima Journal of Medical Science, vol. 53, no. 1, 2007, pp. 51–60.