Children with primary LPL deficiency can be effectively managed on fat-restricted diets and grow normally into adulthood. However, they can present with extreme elevation of TG levels with serious acute pancreatitis. This LPL-deficient subject developed severe hypertriglyceridemia in early pregnancy, with eruptive xanthomas and pancreatitis. With the diligent efforts from the patient, her family, and a team of specialists in lipid metabolism, dietetics, high-risk obstetrics and gastroenterology, a successful outcome was achieved. Outcome goals were clearly set at the onset of her pregnancy care, including nutritional management of the expected rise in triglyceride levels associated with the estrogen surge of pregnancy to prevent acute pancreatitis, and avoidance of clinical EFA deficiency in both the mother and the fetus.
Pregnancy and hypertriglyceridemia
Pregnancy-induced hypertriglyceridemia is estimated to be the cause in 4–6% of all pancreatitis cases during pregnancy, while most cases result from cholelithiasis . Hypertriglyceridemia-related pancreatitis in pregnancy also has been reported due to other causes of severe hypertriglyceridemia . Successful management requires early detection of signs and symptoms of acute pancreatitis often accompanied by increases in serum lipase and amylase levels and characteristic findings in imaging studies. Once the pancreatitis is suspected, these individuals should be admitted for aggressive medical management including intravenous hydration concurrent with no oral intake of solids or liquids. Obstructive processes in the biliary system need to be ruled out specifically since treatment modalities are quite different.
Pregnancy and LPL deficiency
Pregnancy is a well known situation in which the physiologic estrogen surge profoundly alters the TG-rich lipoprotein metabolism, resulting in a gradual rise in TG levels over the course of non-complicated pregnancy, peaking at the level of 200–300 mg/dl (2.26 – 3.39 mmol/L) at term . During the first two trimesters of pregnancy, adipose fat storage, as maternal fuels, occurs in preparation for an active transfer of maternal glucose, amino acids, and free fatty acids (FFA) across the placenta for accelerate fetal growth in late phase of gestation . In late gestation, adipose tissue lipolysis is greatly augmented generating FFA and glycerol, for further hepatic VLDL production, contributing to the flux of circulating TG-fatty acids in pregnancy [18, 19]. Greater concentration of chylomicrons from dietary fat as a result of maternal hyperphagia in late pregnancy also contributes to the circulating TG-rich lipoprotein pool [18, 19], and provides alimentary substrates for VLDL production [20, 21]. LPL activities in the liver, heart, and particularly adipose tissue are, however, reduced by an estimated total of 85% [19, 22] in late gestation. Concomitantly, clearance of circulating TG-rich lipoproteins is reduced in late pregnancy. Hepatic lipase activity is decreased as well and could explain the observation of parallel TG-enrichment of LDL and high-density lipoproteins (HDL) particles during normal gestation. All these changes take place to ensure a stable supply of fuel substrates across the placenta for normal fetal development while preserving maternal metabolic homeostasis [18, 19].
Very low fat diet and EFA deficiency
Arachidonic acid [AA, 20:4(n-6)], an important precursor of the prostaglandin compounds, cannot be synthesized de novo from FFA in mammals and must be derived from another EFA in the diet, namely linoleic acid [LA, 18:2(n-6)]. In the case of life long low oral fat intake, as in our patient, clinical EFA deficiency might occur with depletion of n-3 and n-6 FA stored in adipose tissue. Therefore, her source of EFA would be entirely from recent dietary intake and deficiency might occur sooner than in individuals with normal LPL and abundant EFA storage . Eicosatrienoic acid [ETA, 20:3(n-9)], on the other hand, is not an EFA because it can be synthesized in mammals from palmitic acid [16:1(n-9)]. In the event of diminishing pool of both n-3 and n-6 fatty acids due to absence or deficiency in the diet, more ETA are produced and the amount parallels the degree of deficiency [24–26]. EFA deficiency syndrome commonly results from a combined deficiency in both n-3 and n-6 fatty acids. A ratio of ETA to AA > 0.2, is suggestive of EFA deficiency [24–26]. Clinical manifestations in EFA deficiency are unusual on a diet containing > 2% of the calories as linoleic acid . While the clinical symptoms of dryness and desquamation of the skin are annoying at best, a more serious consequence could be impaired fetal brain and visual development. The proband did not develop signs of clinical EFA deficiency, nor did the ratio of 20:3(n-9) to 20:4(n-6) exceed 0.2 at any stage of her pregnancy, although an upward trend did occur. Additionally, the report that infants fed a formula low in EFA grew poorly and developed multiple medical complications was a concern . Several reports have documented a reversal of biochemical and clinical manifestations of EFA deficiency in infants and adults by cutaneous administration of EFA-rich oil, such as sunflower oil [29–35]. Therefore, application of sunflower oil to the proband's skin was initiated at week 25 and may have had prevented progression of EFA deficiency in mother, as suggested by the stabilization of the 20:3(n-9) to 20:4(n-6) ratio. Surprisingly, we found low levels of n-3, n-6, and PUFA precursor levels in the cord blood taken during the delivery, and yet there was abundant long chain PUFA in the infant circulation. This would suggest that other adaptive mechanisms were involved in maintaining the critical levels of long chain EFA in fetal circulation in the face of inadequate maternal supply.
Use of gemfibrozil in LPL deficiency
Use of TG lowering drugs, such as gemfibrozil (a fibrate), can be used to directly lower the triglyceride level in the prevention of acute pancreatitis. Pregnancy induces hepatic production of TG-rich VLDL and may respond to fibrates through inhibition of hepatic production of VLDL. Gemfibrozil, which is an FDA category C drug, has not been observed to be associated with adverse drug effects in reports of pregnancy-related severe hypertriglyceridemia [6, 10, 36, 37]. During the last few weeks of her gestation low dose gemfibrozil in our subject seemed to have stabilized her TG level (Fig 1), which might otherwise have continued to rise due to the estrogen effect on hepatic VLDL production in the third trimester. A lower than usual dose of gemfibrozil was used due to the concern for excess placental transfer of its metabolites that has been reported in pregnant cats . Analysis of the parent compound and metabolites did not detect excessive accumulation in the fetal cord circulation in contrast to the reports in animal models. While this observation needs to be independently confirmed, adverse drug effects in the infants born to mothers on gemfibrozil or other fibrates have not been reported. Moreover, gemfibrozil has been used and appears to be free of short-term side effects in pediatric populations [39–42]. Therefore, low dose gemfibrozil may be safe for use during the last trimester in hyperlipidemic patients at high risks for acute pancreatitis.
In conclusion, a successful pregnancy outcome was achieved in our LPL deficient patient, confirming previous reports [6, 43] that aggressive lipid lowering strategies under the supervision of experienced health care providers works in this high risk setting. Although the patient developed pancreatitis during her pregnancy, the use of an extremely low fat diet together with a fibrate helped limit the increase in the triglycerides, and her pancreatitis was neither life threatening nor adversely affected fetal survival. Sunflower oil applied topically may have helped prevent EFA deficiency in both the mother and fetus. Use of gemfibrozil did not appear to have any adverse effect on the child. Thus, the use of these two therapeutic approaches appears safe and appropriate in the medical management of pregnancy-associated severe hypertriglyceridemia, where EFA deficiency and recurrent pancreatitis are major concerns.