An enigmatic triad of acute pancreatitis, diabetic ketoacidosis and hypertriglyceridaemia: who is the culprit?

Abstract

Acute pancreatitis(AP) is one of the common causes of acute abdomen and known to be associated with high morbidity and mortality in severe cases. Though most common causes of AP are cholelithiasis and alcoholism, it has also been reported in association with diabetic ketoacidosis (DKA). Triad of AP, hypertriglyceridaemia (HTG) and DKA is rare co-association and here the causal factor of AP is still not fully established. We report a case of AP in a DKA patient with recent diagnosis of hyperlipidaemia and diabetes. Usually AP has been associated with severe HTG; interestingly, our patient showed only moderate raise in triglycerides but still suffered AP during DKA. Hence, it raises question about the real culprit in this enigmatic triad.

Background

Acute pancreatitis (AP) is a well-known and a common cause of emergency hospital admission. Worldwide, the incidence of AP varies between 4.9 and 73.4 cases per 100 000.^{1 2} In UK, the approximate incidence ranges from 15 to 42 cases per 100 000 population.^{3 4} In USA, in 2009, AP was the most common gastroenterology discharge diagnosis with a cost of 2.6 billion dollars.⁵ Though there was a slight reduction in the mortality over the period 1985–1994, the incidence clearly shows a steady increase.³

Hypertriglyceridaemia (HTG) is a well-recognised cause of AP.^{6 7} A triad of AP, diabetic ketoacidosis (DKA) in association with HTG is rare and only few cases have been reported.^{6 8 9} In this triad, co-association of all factors potentially leads to AP but HTG which appeared to be more vital.^{6 7 9} Pancreatitis secondary to HTG is typically seen in the presence of one or more secondary factors (uncontrolled diabetes, alcoholism, medications, pregnancy) in a patient with an underlying common genetic abnormality of lipoprotein metabolism (familial combined hyperlipidaemia or familial HTG).^{10 11}

Case presentation

A 40-year-old South Asian man presented with back pain, polyuria and polydipsia for 2 weeks. He has experienced intermittent abdominal discomfort, nausea with no change of bowel habits. Intermittent episodes of vomiting had started 2 days earlier with acute worsening of general condition in last 24 hours. On general examination, he was tachycardic (pulse rate 110 per min), hypotensive (90/60 mm Hg), febrile (temperature 38°C) and severely dehydrated. The abdomen was grossly distended; tenderness was elicited in the epigastrium, right hypochondrium and in both renal angles. External genitalia and digital rectal examination were essentially normal.

Six weeks ago, he was found to have an incidental HTG (serum level 290 mg/dL) but no action was taken other than an advise for dietary and lifestyle modification. Subsequently for two weeks, he was also diagnosed with type 2 diabetes and started on metformin. Unfortunately, patient had discontinued metformin after 2 days without knowledge of medical professionals. Patient had a strong family history of type 2 diabetes with mother and both maternal grandparents were diagnosed in their 50s.

He had been diagnosed with benign left adrenal adenoma 2 years back and underwent laparoscopic adrenalectomy; no metabolic abnormalities were noted in blood tests at that time. He was working as a support worker in a supermarket and lives with his family.

Investigations

Preliminary investigations including full blood count (FBC), renal function test (RFT), liver function test (LFT) and clotting profile were performed. Urgent serum glucose was found to be 39 mmol/L and arterial blood gas analysis showed a metabolic acidosis (pH 7.20, PaO₂ 14.1 kPa, PCO₂ 2.1 kPa, base excess (BE)  10 mEq/L, HCO₃ 14 mEq/L, lactate 3.6 mmol/L). Urine dipstick test was positive for ketones (3+), sugar (3+) and otherwise normal. Blood results showed high lipase (275 IU/L) and normal liver function.

Chest and abdominal X-rays were normal and an urgent abdominal CT scan was performed. CT scan showed the presence of oedematous pancreas (figure 1), surrounded by peri-pancreatic fluid with fat stranding confirming the diagnosis of AP.

Figure 1.

Oedematous pancreas surrounded by peri-pancreatic fluid.

Treatment

The patient was immediately transferred to intensive care unit for aggressive fluid correction and intravenous insulin. His condition was stabilised and followed by a dramatic improvement in his blood sugar which returned to normal within 12 hours. Later he was transferred to the surgical ward with regular insulin and metformin. Arterial blood gas analysis, renal function, lipase level were back to baseline after treatment.

Outcome and follow-up

Further ultrasonography of abdomen did not show any gallstones. Lipid profile was performed at 12 hours after admission and borderline increase of triglycerides (TG) (170 mg/dL) but other parameters were within normal limits. Daily blood tests including FBC, LFTand RFT did not show abnormality. Patient was started on statins after his condition improved. During the follow-up, patient underwent autoimmune profile including immunoglobulin G4 which was found to be within normal range and fasting plasma C peptide was 0.25 nmol/L. Unfortunately, the patient do not wish to undergo investigation for genetic screening for AP.

Discussion

In DKA, the deficiency of insulin activates lipolysis in adipose tissue releasing increased free fatty acids (FFA), which accelerates the formation of very low-density lipoproteins (VLDL) in the liver.¹² Further, reduced activity of lipoprotein lipase in peripheral tissues decreases removal of VLDL from the plasma, resulting in HTG.¹³ It is common finding to see elevated plasma TG during DKA.¹⁴ Overall, HTG accounts for a minority of AP (2%–7%) cases. However, the risk increases significantly when HTG levels raise above 1000 mg/dL.⁶

The chylomicrons are large particles which consist of TG, phospholipids, cholesterol and proteins. Due to their sheer size, they could occlude fine capillaries in the pancreas, thereby initiating ischaemia. This causes alterations at acinar cells of pancreas and also releases pancreatic lipase.¹⁵ Further lipolysis in the above scenario increases the levels of cytotoxic free fatty acids in the blood which leads to damage at vascular endothelium, sludging of red cells, and worsens the pancreatic ischaemia.¹⁶ Nair et al have postulated that HTG during DKA might be the cause of AP.⁹ There is a recent report of HTG-associated drug-induced AP, but our patient was on any of these notorious medications.¹⁷ Prognosis of AP in this triad is extremely good. A recent article showed that length of hospital stay, mortality and re-admission were not increased.¹⁸

A clinical suspicion of latent autoimmune diabetes in adults with the combination of near normal weight, low C peptide was raised but unfortunately patient do not wish to proceed with further investigations. Hence this possibility could not be excluded in our patient. Second as our patient had adrenalectomy, we had also reviewed the literature about the possibility of coexistence of pancreatitis/HTG with adrenal adenoma and found that no correlations were reported. The PRSS1 gene mutation is the the most common cause in hereditary pancreatitis but in our case this could not be ruled out as patient did not agree for genetic screening.

A retrospective analysis showed that AP usually happens when the TG level is more than 500 mg/dL. But this view was questioned by another report where a DKA patient developed AP with a moderately elevated TG.⁸

In the case presented here, we have noted a similar finding where the TG level is not raised markedly but induced AP. Hence it might be sensible to conclude that mild to moderate HTG may be an epiphenomenon for AP in diabetic patients. These patients clearly require early management for HTG before it causes AP.

To date, it is unclear what causes AP in this enigmatic triad. The culprit in this triad is still appeared to be elusive. Though the treatment for AP in association with HTG is not different, it is essential that the high-risk patients, particularly those who have strong family history of metabolic disease, are managed early to prevent AP.

Learning points.

• Although triad of acute pancreatitis (AP), hypertriglyceridaemia (HTG) and diabetes is known, real causative factor is still elusive.

• AP can evolve in patients with mild to moderate HTG in association with diabetes.

• These patients should be given early treatment for HTG and diabetes to prevent AP.

• This message should reach teams who manage these patients with metabolic disorders.