Management of hypertriglyceridaemic pancreatitis in the acute setting and review of literature

Abstract

Acute pancreatitis (AP) is a potentially life-threatening complication of severe hypertriglyceridaemia, which is the third most common cause of AP after gallstone disease and alcohol excess. Standard therapy involves the use of lipid-lowering agents, low-molecular-weight heparin and insulin infusion. In some cases, when standard medical therapies fail, non-pharmacological methods based on the removal of triglycerides with therapeutic plasma exchange can provide positive results in the acute phase. There are currently no guidelines covering management in the acute phase, however, these approaches should be considered in severe or very severe hypertriglyceridaemia. Here, we report the case of a 37-year-old man with recurrent AP due to hypertriglyceridaemia and review the literature.

Background

Severe hypertriglyceridaemia (HTG) can result in potentially fatal pancreatitis and is characterised by high plasma levels of triglycerides (TGs) >11.3 mmol/L.¹ Also known as ‘hypertriglyceridaemic pancreatitis (HP)’, this is characterised by the presence of severe HTG and acute pancreatitis (AP) in the absence of other causes.² Treatment options in the acute setting include insulin infusion and plasma exchange (PEX). Endocrine Society guidelines do not recommend these therapies as part of their HTG guidelines due to a lack of evidence base, and therefore, there is no clear guidance for general physicians in this specialist area.³ We present a case of recurrent HP and literature review to focus on the acute management of pancreatitis triggered by severe HTG.

Case presentation

A 37-year-old man attended the emergency department with a 3-day history of intermittent sharp left loin pain. He had no significant medical history and no family history of diabetes or any metabolic disorders, but there was a history of binge drinking. Clinical examination revealed reduced air entry at the left base with a normal chest radiograph. Urinalysis was positive for blood and glucose. Bloods tests revealed raised inflammatory markers C reactive protein (CRP 287.7 mg/L, white blood cells 29.6×10⁹/L) and hyperglycaemia (plasma glucose 20 mmol/L). The blood sample was noted to be lipaemic, however, TGs were not measured. The patient was started on oral antibiotics for a presumed lower respiratory tract infection and a fixed rate insulin infusion for the hyperglycaemia. He was allowed to eat and drink as normal. Unenhanced CT kidneys, ureter, bladder performed to rule out pyelonephritis demonstrated inflammation of the pancreas consistent with AP (figure 1A). Serum amylase was, however, normal. An elevated haemoglobin A1c at 112 mmol/mol (12.4%) signified chronic hyperglycaemia. The patient remained on the insulin infusion until review by the diabetic team who initiated a basal bolus insulin regimen. The patient was discharged after 48 hours with a plan for outpatient diabetes review. He had a negative islet cell and glutamate decarboxylase-65 antibody screen, random paired C peptide 1468 pmol/L and glucose 14.4 mmol/L, which excluded a diagnosis of type 1 diabetes.

Figure 1.

CT imaging of the abdomen during (A) admission July 2017 showing acute pancreatitis (B) admission September 2017 showing acute necrotising pancreatitis (C) admission January 2018 showing acute necrotising pancreatitis.

The patient had two further attendances to the emergency department with radiological evidence of acute necrotising pancreatitis (figure 1A,C) secondary to severe HTG. We summarise investigations at his second presentation.

Investigations

Initial blood samples were grossly lipaemic and haemolysed, raising the suggestion of a hypertriglyceridaemic crisis. Admissions bloods random glucose 16 mmol/L, cholesterol 9.04 mmol/L, TG 20.10 mmol/L, high density lipoprotein (HDL) cholesterol 0.71 mmol/L, total/HDL cholesterol 12.73 mmol/L, non-HDL cholesterol 8.3 mmol/L, CRP 178.9 mg/L, amylase unavailable due to lipaemia. CT imaging subsequently confirmed acute necrotising pancreatitis with no evidence of gallstones (also absent on abdominal ultrasound). The patient scored 2points (glucose >11.1 mmol/L; white cell count >16×10⁹/L) on Ranson’s criteria (on admission) and a Balthazar score (CT severity index) indicating severe AP (peripancreatic inflammation, necrosis <30%).⁴ This was despite an apparently normal amylase result—discussed further below.

Treatment

Following specialist advice, the patient was initiated on a fixed rate insulin infusion (2 units/hour) to treat the HTG (note there was no evidence of diabetic ketoacidosis). Repeat bloods 2 days later cholesterol 5.09 mmol/L, TG 5.28 mmol/L, HDL cholesterol 0.79 mmol/L, total/HDL cholesterol 6.44 mmol/L, non-HDL cholesterol 4.3 mmol/L, amylase 56 IU/L, CRP 309.4 mg/L.

Outcome and follow-up

The patient was kept nil by mouth for 48 hours until his symptoms settled at which point the insulin infusion was stopped. He was discharged home on his preadmission insulin regimen and atorvastatin 80 mg every night with referral to the lipid clinic. He failed to attend his outpatient clinic appointment and was readmitted 3 months later with similar symptoms consistent with AP (figure 1C). He admitted to non-compliance with his medications. He was successfully treated with an insulin infusion, intravenous antibiotics and kept nil by mouth. During his third admission, the atorvastatin was changed to bezafibrate 200 mg three times a day. He was thereafter lost to follow-up, after failing to attend his outpatient clinics.

Discussion

The association between HTG and AP was first described by Speck in 1865.⁵ Severe HTG can result in potentially fatal AP and is an important differential diagnosis. The exact mechanisms involved in AP secondary to HTG are poorly understood but the most accepted mechanism proposed by Havel⁶ suggests that hydrolysis of TGs by pancreatic lipase which occurs in and around the pancreas, promotes accumulation of free fatty acids within the capillary beds. This in turn leads to capillary plugging and subsequent ischaemia and acidosis. Patients with TG levels above 11.3 mmol/L require urgent treatment to reduce the risk of pancreatitis.^{7 8} In patients who develop AP secondary to HTG, the goal is to bring the TG levels down to <5.7 mmol/L (500 mg/dL) as studies achieving these levels show improved clinical outcomes.⁹

This case presents a diagnostic challenge due to the initial delay in diagnosis of AP as a result of lipaemic serum samples. TG levels >5 mmol/L may cause falsely normal amylase levels. Traditionally, this has been thought to be due to interference of the colorimetric reading.¹⁰ The potential role of circulating amylase inhibitors has also been investigated but has not been well substantiated.^{11 12} Alternatively, patients with HTG may have a more insidious course of disease progression than other patients with AP, leading to normalisation of amylase levels by the time they seek medical help.^{11 12} Acute recurrent pancreatitis can lead to an ongoing loss of pancreatic exocrine and endocrine function resulting in fat malabsorption and glucose intolerance/diabetes and chronic pancreatitis.¹³ The aetiology of HTG in this man’s case is likely to be multifactorial, secondary to alcohol excess, hyperglycaemia and possibly a genetic component.

HTG is a well-established cause of acute recurrent pancreatitis. There is no uniform classification system for HTG, but it may be classified according to the degree of TG elevation: TG <1.7 mmol/L is regarded as normal, mild HTG 1.7–2.3 mmol/L, moderate HTG 2.3–11.2 mmol/L, severe HTG 11.3–22.4 mmol/L and very severe HTG more than 22.4 mmol/L.³ Another classification system used is: primary HTG (ie, a molecular aberration of lipoprotein metabolism, no other metabolic abnormalities) or secondary HTG (due to environmental contributors such as diabetes, diet or alcohol).

General strategies for treatment include lifestyle modification with restriction of dietary fat, cessation of alcohol intake and increased exercise. Standard therapeutic measures (alone or in combination) include high dose omega-3 fatty acids (4 g/day), fibrates (gemfibrozil or fenofibrate) or niacin, although the latter is no longer licensed in the UK. The Endocrine Society recommends the use of a fibrate as first-line agent for reduction of TGs in patients at risk of TG-induced pancreatitis.³ In the acute setting, treatment includes insulin infusion and fasting. Apheresis can also be used. There are no randomised clinical trials that compare the effect of insulin infusion versus apheresis on clinical outcome. Therapeutic PEX is the modality of choice if apheresis is considered.

Treatment modalities in the acute setting

Insulin infusion: Insulin can be used to treat severe HTG in an emergency setting as it is simple to initiate and usually well tolerated by patients. Insulin decreases TG levels by enhancing lipoprotein lipase (LPL) activity, which in turn hydrolyses TG into fatty acids and glycerol and facilitates storage of the fatty acids in adipocytes.^{14 15} Insulin also inhibits hormone-sensitive lipase in adipocytes, which is the key enzyme for breaking down adipocyte TG and releasing free fatty acids in to the circulation.

Intravenous insulin is more effective than subcutaneous insulin. Standard approach is 0.1–0.3 units/kg/hour intravenous regular insulin along with dextrose saline to maintain blood glucose between 8.3 and 11.1 mmol/L^{16 17} TG levels should be monitored every 12–24 hours with insulin dosage adjusted as required. Concomitant administration of either 5% or 10% dextrose prevents hypoglycaemia. Additionally, glucose may be required for insulin to increase the synthesis and secretion of LPL.¹⁷ Heparin is another potent activator of LPL and can be used alone^{18 19} or in conjunction with insulin.^{20 21}

PEX: this is an extracorporeal process shown to lower TG levels in HP, by the removal of plasma and replacement with a colloid solution (eg, albumin or plasma). Evidence to support the use of PEX is predominantly from observational studies, case reports and anecdotal reports, with randomised control trials lacking. In a case series of seven patients with severe HTG (with TG level >11.3 mmol/L), a 46% decrease in TG levels was reported with single PEX.²² In a study by Ramirez-Bueno et al,²³ the majority of patients (72.7%) required only one plasmapheresis session to achieve a serum TG <11.3 mmol/L. They found that treatment success depended on the intensity of the HTG rather than the time to treatment from onset of symptoms. However, Chen et al ²⁴ reported no statistical difference in the mortality, systemic and local complications between patients before and after PEX became available at their institution. In addition, they also found the mortality in severe hyperlipidaemic pancreatitis was not decreased by PEX.

Anticoagulation in PEX may include intravenous heparin or citrate. Heparin stimulates LPL activity thus aiding the clearance of very low density lipoprotein (VLDL). In an observational cohort study of 103 patients, citrate anticoagulation during plasmapheresis was associated with significantly lower mortality compared with heparin (1% vs 11%).²⁵

Despite the growing number of case studies and anecdotal reports, the efficacy of PEX in reducing important clinical endpoints such as severity of HTG-induced AP or mortality, has not been established. No randomised controlled trials comparing the efficacy of insulin to PEX in the treatment of severe HTG have been performed to date, and therefore, treatment is based on availability and local experience.²⁶

Although not included in clinical guidelines per se, we suggest the use of PEX should only be considered after trial with an insulin infusion has failed or in severe to very severe HTG with AP, lactic acidosis or worsening organ dysfunction.

The long-term goal for patients with recurrent episodes of AP secondary to severe HTG is prevention of further episodes through optimisation of lipid-lowering therapy and lifestyle modification.

Learning points.

• Severe hypertriglyceridaemia (HTG) can trigger potentially fatal acute pancreatitis with recurrence.

• Intravenous fixed rate insulin infusion should be initiated with a target blood glucose 4–8 mmol/L.

• Plasma exchange is able to rapidly reduce high serum triglyceride concentrations and should be considered in patients with severe hypertriglyceridaemic pancreatitis if there is no response to insulin.

• Further randomised controlled trials comparing the efficacy of intravenous insulin infusion with plasma exchange in the treatment of severe HTG are needed.