Insulin can be used to treat severe hypertriglyceridaemia in pregnant women without diabetes

Abstract

Severe hypertriglyceridaemia can lead to acute pancreatitis, which is associated with maternal and perinatal mortality when it occurs in pregnancy. Rapid reduction of triglyceride levels is a primary goal in the management of severe hypertriglyceridaemia, however, there are limited safe option for treatment in pregnancy. We present a case of a woman without diabetes presenting with severe hypertriglyceridaemia in late gestation who was safely and successfully treated with insulin and review the literature surrounding the management of this important condition.

Background

Insulin can be used to treat severe hypertriglyceridaemia in people with diabetes. In people without diabetes, plasma exchange is often used, which may be intensive, expensive and complicated in pregnancy. Pregnant women without diabetes who have severe hypertriglyceridaemia may benefit from insulin administration to prevent the onset of pancreatitis, which is associated with both maternal and perinatal mortality in pregnancy.

Case presentation

A 31-year-old woman at 38 weeks’ gestation presented with headache and was incidentally found to have a triglyceride level of 107.5 mmol/L. She had no significant previous medical history. Her mother had been diagnosed with hypercholesterolaemia late in life and she did not have a history of familial lipid disorders.

Her BMI was 25.9 kg/m². She did not have xanthelasma or eruptive xanthomas. She did not have abdominal pain or tenderness to suggest acute pancreatitis, and her lipase level was only mildly elevated at 97 U/L.

Investigations

Figure 1.

Figure 1.

Triglyceride levels reduced rapidly when insulin infusion was commenced and continued to reduce after parturition.

Differential diagnosis

Altered maternal lipid metabolism can be adaptive in pregnancy. Modest elevations in lipids occur in early pregnancy and significant elevations occur in late pregnancy, in particular of triglycerides.¹ Triglyceride levels, however, rarely rise above 3.42 mmol/L.² These changes are considered beneficial because cholesterol is necessary for embryonic and fetal nervous system development.²

Severe hypertriglyceridaemia is associated with type I hyperlipoproteinaemia (or chylomicronaemia) and type V hyperlipoproteinaemia (or hyperbetalipoproetinaemia).³ Patients with type I hyperlipoproteinaemia generally present in childhood or adolescence with marked hypertriglyceridaemia, very high levels of plasma chylomicrons and often pancreatitis.⁴ Patients with type V hyperlipoproteinaemia generally have elevated levels of both plasma chylomicrons and very low density lipoproteins (VLDL).³ This form of hypertriglyceridaemia is approximately 10 times more common than type I hyperlipoproteinaemia. It is usually caused by an accumulation of several genetic variants, along with secondary factors such as uncontrolled diabetes, obesity, poor diet, excess alcohol intake and excess oestrogen.⁵ Oestrogen increases the production of triglyceride-rich lipoproteins, which can exacerbate hypertriglyceridaemia in pregnancy,⁶ and this is the likely aetiology of hypertriglyceridaemia in our case patient.

Genetic causes of hypertriglyceridaemia include lipoprotein lipase (LPL) deficiency, which is an uncommon autosomal recessive disorder and apolipoprotein C-II deficiency.⁷

Treatment

The patient was admitted to a high dependency unit and treated with an insulin infusion and a strict low-fat diet for 4 days before undergoing induction of labour at 39 weeks gestation. At this point, her triglyceride level was 30.4 mmol/L and insulin infusion was ceased (figure 1). She delivered a healthy baby and her triglyceride level improved to 29.5 mmol/L at discharge.

Outcome and follow-up

The patient was reviewed as an outpatient at 4 weeks postpartum at which point her triglyceride level was 10.4 mmol/L and she commenced omega-3 fish oil tablets equivalent to 2 g/day. She was advised to avoid the use of hormonal contraception due to the risk of recurrence of severe hypertriglyceridaemia with excess oestrogen and to engage in early and specialised antenatal care in the event of a subsequent pregnancy. Advice about restricting dietary fat intake was reiterated. The patient was referred to a lipidologist for ongoing management, consideration of genetic testing and investigation of an underlying lipid disorder.

Discussion

Severe hypertriglyceridaemia is a potent risk factor for acute pancreatitis. This is rare in pregnancy but is associated with maternal and perinatal mortality.² Rapid lowering of excessively elevated serum triglyceride levels is a primary goal in preventing complications of severe hypertriglyceridaemia, but options for treatment are limited in pregnancy. Fibrates, statins and nicotinic acid are contraindicated in pregnancy. The only safe oral medication during pregnancy is omega-3 fatty acids, which have a moderate effect on lowering triglyceride levels. Patients should also be instructed to adhere to a fat-restricted diet.^7–9

In patients with diabetes-associated hypertriglyceridaemia, insulin can be used.⁸ Insulin activates LPL in the muscle and adipose tissues, which leads to an acceleration of chylomicron degradation (figure 2).^{7 10 11} In a hospital setting that allows close monitoring of blood glucose levels, this is a safe and effective treatment method for severe hypertriglyceridaemia. Its use, however, may not be limited to individuals with diabetes^{10 11} as seen in our case patient, although there are no randomised controlled trials comparing its efficacy to standard treatment (diet restriction and omega-3 fatty acids) in pregnant women with hypertriglyceridaemia.

Figure 2.

Insulin activates lipoprotein lipase, which leads to the breakdown of triglycerides into free fatty acids. LPL, lipoprotein lipase.

Similar to insulin, heparin also stimulates LPL and accelerates chylomicron degradation¹² and can be used to rapidly reduce serum triglyceride levels. Although heparin use in pregnancy is not associated with fetal malformations, an increased incidence of human fetal loss and prematurity associated with haemorrhage have been reported.¹³

In the nonpregnant population, plasma exchange is a safe and effective method to manage severe hypertriglyceridaemia where conventional therapy has failed.⁷ There have also been case reports of this being used in pregnant women with effective outcomes and no harm caused.^{4 14} The effects of plasma exchange, however, are transient and, in some cases, its cost may preclude its use.

Novel therapies to target hypertriglyceridaemia are in various stages of development. Lomitapide, which is a microsomal triglyceride transfer protein inhibitor,¹⁵ is available for the treatment of familial homozygous hypercholesterolaemia, but its use in hypertriglyceridaemia is ‘off label’ and its safety in pregnancy has not been demonstrated. It has, however, been successfully used to treat severe intractable hypertriglyceridaemia. The primary safety concern with this therapy is hepatic steatosis.

Apo C-III is a protein that modulates plasma triglycerides by inhibiting LPL activity and enhancing intrahepatic production of VLDL.¹⁶ Volanesorsan is an antisense inhibitor of Apo-C III synthesis and has been found to significantly lower triglyceride levels among patients with a broad range of baseline levels.¹⁷ Again, this therapy has not been evaluated in pregnant women.

Termination of pregnancy or delivery leads to a 10%–20% reduction in triglyceride levels within 24 hours^{8 18} and this should be considered on a case by case basis depending on other maternal and fetal factors.

Learning points.

• Severe hypertriglyceridaemia is an uncommon but serious complication of pregnancy and early recognition and treatment is important to prevent acute pancreatitis.

• There are limited treatment option for management of severe hypertriglyceridaemia in pregancy.

• Insulin is a safe and effective method to treat severe hypertriglyceridaemia in pregnant women both with and without diabetes.

Ethics statements

Patient consent for publication

Obtained.