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Concurrent Diabetic Ketoacidosis and Acute Pancreatitis in Mild Hypertriglyceridemia: An Enigmatic Triangle

Hypertriglyceridemia (HTG) is a well-established cause of acute pancreatitis (AP). Diabetic ketoacidosis (DKA) leads to lipolysis and HTG, and can result in AP. Triad of AP, DKA, and HTG is rare and not fully understood. Usually AP is associated with severe HTG with serum triglyceride (TG) level over 1,000 mg/dL. However, we experienced two cases of AP in DKA with mild HTG with TG level less than 200 mg/dL. Herein, we report these unusual cases and provide a review of the literature about the triad of DKA, HTG, and AP. Korean J Pancreas Biliary Tract 2021;26(2):111-115


INTRODUCTION
Acute pancreatitis (AP) is an inflammatory disease of the pancreas characterized by epigastric pain and elevated serum pancreatic enzymes more than 3 times the upper normal value.
While the mortality in mild pancreatitis is known to be less than 1%, it is up to 10% in necrotizing pancreatitis, and is about 25-30% in infectious necrotizing pancreatitis. 1 Assessment of severity and etiology, prediction of prognosis, and subsequent intensive care at the time of diagnosis is crucial for successful treatment of AP.
Hypertriglyceridemia (HTG) is a well-known cause of AP. In a recent systematic review, HTG was attributable to 9% of AP and incidence of AP in patients with HTG was about 14%. 2 However, little is known about the triad of diabetic ketoacidosis (DKA), HTG, and AP, hence it is referred to as "the enigmatic triangle". DKA is a condition of profound insulin deficiency, leading to hyperglycemia, ketogenesis and lipolysis, resulting in hypertriglyceridemia.
The risk of AP increases with serum triglyceride (TG) levels   was no sign of infection and therefore antibiotics were not used. Her condition improved and she was transferred to ward after 4 days. Her abdominal pain improved gradually and oral feeding was started from the 4th day of admission. She was discharged with subcutaneous insulin after 10 days. She has been followed upon discharge and remains well without further episodes of DKA and AP.

Case 2
A showed elevated AST of 50 U/L and ALP of 310 U/L, but normal ALT, r-GTP, and bilirubin levels.
Abdominal CT scan with contrast showed edematous change of the pancreas with a single fluid collection around the pancreatic tail (Fig. 2), which was consistent with mild acute pancreatitis in CT severity index. No gallstone or choledocholithiasis was identifiable in the CT. The patient was diagnosed with DKA, acute interstitial edematous pancreatitis, and concurrent mild HTG. Her modified Marshall score for organ  The patient was transferred to ICU for adequate management.
Vigorous hydration, continuous intravenous insulin infusion, and analgesics were started. Her systolic blood pressure raised to 100 mmHg within 6 hours after hydration. Her health status improved and she was transferred to ward after 3 days. In an attempt to rule out radiolucent stones in the biliary tree as a possible cause of acute pancreatitis because her AST and ALP were elevated, EUS was performed after 3 days. EUS revealed edematous pancreas with some fluid collections in the parenchyma, but no stones in the biliary tract and the gallbladder (Fig. 3). After 3 days, oral diet was started while her abdominal pain was controlled with analgesics. She was discharged with subcutaneous insulin after 8 days and remains well without further episodes of DKA and AP until now.

DISCUSSION
We report two cases of AP associated with DKA with only mild HTG. The patients had poor glycemic control and developed DKA. Both patients had TG level under 200 mg/dL, which is generally not considered as the level for the cause of AP. 5 Imaging studies showed no other causes for AP and both patients denied alcohol consumption. According to revised Atlanta classification, the severity of AP was mild in one patient and moderately severe AP in another patient. Both patients recovered well after aggressive hydration and insulin therapy.
The association between DKA, HTG, and AP has been reported infrequently in several case reports. 6,7 In DKA, insulin deficiency activates lipolysis in adipose tissue and results in release of free fatty acids (FFA). Increased delivery of FFA to the liver leads to excessive very low density lipotroteins (VLDL) formation. In addition, the activity of lipoprotein lipase in peripheral tissue is decreased and removal of VLDL from the plasma is reduced, resulting in HTG. 6 The exact mechanism of HTG induced AP has not been fully elucidated. The most widely accepted hypothesis proposes that excessive FFAs, which are hydrolyzed from TGs by pancreatic lipase, result in toxic injury to acinar cell and capillary endothelium, leading to pancreatic ischemia. Also, high chylomicron concentration results in pancreatic capillary hyperviscosity and leads to ischemia and acidosis. 5 HTG is defined by fasting serum TG level above 150 mg/dL. HTG is classified into different severity categories: mild (serum TG levels of 150 to 199 mg/dL), moderate (200 to 999 mg/dL), severe (1,000 to 1,999 mg/dL), and very severe (≥2,000 mg/ dL). 8 While more studies are needed to define the exact TG level causing AP, AP usually occurs when the TG level is more than 1,000 mg/dL. TG levels over 500 mg/dL raises high degree of suspicion that HTG is the cause of AP, especially when TG level estimation is delayed. 5 Little is known about the mechanism of AP in DKA. Nair and Pitchumoni 7 reported three cases of AP in DKA patients with HTG and suggested the hypothesis that DKA leads to HTG and AP occurs as a result. However, we experienced two cases of AP in DKA patients with mild HTG. In both cases, serum TG levels were checked on the day of presentation. In a prospective study evaluating the incidence and prognosis of AP in 100 DKA patients, AP occurred in 11 patients. 9 Among these patients, the cause of AP was classified as: HTG in four patients (36.4%) because TG levels were above 1,000 mg/dL, alcohol in two (18.2%), drug induced in one (9%), and idiopathic in four (36.4%). The TG levels in the patients who were classified as idiopathic were all below 500 mg/dL (range, 145-447 mg/dL). Therefore, it is questionable whether HTG in DKA causes AP or DKA per se is a rare cause of AP and HTG is an epiphenomenon. More studies are needed in focusing the exact mechanism of AP in DKA.
The triad of DKA, HTG, and AP has the potential of poor prognosis because it is considered to be associated with more severe hyperglycemia, acidosis, and intravascular volume depletion. Bouchaala et al. 10 recently reported 50% mortality in four cases of AP in DKA patients. Other studies also found higher Ranson criteria and APACHE II scores in AP with DKA patients compared to non-DKA patients. [9][10][11][12] However, the clinical course of AP including the length of stay and in-hospital mortality did not differ significantly among DKA patients and non-DKA patients. 11,12 The patients in our case Korean J Pancreas Biliary Tract 2021;26(2):111-115 report had mild AP according to CT severity index. Transient organ failure was found in one of our patients, but she recovered well after treatment. Nair et al. 9 also reported that AP in DKA appeared to be mild in their study. Prospective, largescale studies are warranted with regard to the severity of the concurrent DKA, HTG, and AP.
Diagnosis of AP in DKA is somewhat challenging. Our patients complained of abdominal pain and had elevated level of amylase more than 3 times the upper normal value.
However, it is common for patients with DKA to complain of abdominal pain. Serum amylase, lipase, or TG levels are elevated frequently in these patients. 9 Therefore, it is the clinician's suspicion and adequate evaluation that makes the correct diagnosis.

Conflicts of Interest
The authors have no conflicts to disclose.