Extreme Pregnancy-Induced Hypertriglyceridemia Resulting in Pancreatitis: A Case Report

Introduction

Pancreatitis in pregnancy is uncommon, with an estimated incidence of 1 in 1000 to 1 in 12 000 pregnancies [1], but is increasing in frequency [2]. In addition to maternal morbidity and mortality from pancreatitis, risks to the fetus include preterm delivery, fetal distress, and fetal death [3]. The most common cause is gallstones, followed by alcohol-induced pancreatitis [4,5].

Hypertriglyceridemia is an uncommon cause of pancreatitis in pregnancy, accounting for approximately 4–5% of cases [4,5]. Outside of pregnancy, hypertriglyceridemia is often seen in the setting of comorbidities such as obesity, diabetes, or a high-fat diet [6,7]. During pregnancy, an increase in maternal triglyceride levels is a normal physiological response [5]. However, levels generally remain below 300 mg/dL, while the risk of acute pancreatitis progressively increases as triglyceride levels exceed 500 mg/dL [8]. Uncommonly, severe pregnancy-induced hypertriglyceridemia, often in the setting of a genetic disorder such as familial chylomicronemia syndrome, familial hypertriglyceridemia, or familial combined hyperlipidemia [6,7], leads to pancreatitis. Treatments for hypertriglyceridemia-induced pancreatitis include intravenous hydration, analgesics, insulin, heparin, and plasmapheresis [2,7,9–11].

This case describes the unusual scenario of a patient with pancreatitis due to severe pregnancy-induced hypertriglyceridemia over multiple pregnancies in the setting of only mildly elevated nonpregnant triglyceride levels. This case highlights the potential severity of pregnancy-induced hypertriglyceridemia, which is important for providers to know in their evaluation of pregnancy-associated pancreatitis.

Case Report

A 33-year-old woman with gravida 7 para 5 at 37w1d with a history of gestational hypertriglyceridemic pancreatitis in previous pregnancies presented with epigastric abdominal pain, nausea, and emesis after eating deep-fried chicken and cheese. Due to the location of her pain as well as her history, an evaluation for pancreatitis was performed, which revealed a lipase was 153 U/L, amylase 160 U/L, and triglycerides 6280 mg/dL. She was diagnosed with recurrent pancreatitis secondary to hypertriglyceridemia and was admitted for inpatient treatment.

The patient’s history was significant for recurrent pancreatitis secondary to hypertriglyceridemia during 4 of her 6 previous pregnancies (Table 1). Her medical history was negative for diabetes or other secondary causes of hypertriglyceridemia, and there was no past or current history of gestational diabetes or gestational hypertension. Pancreatitis in prior pregnancies had been successfully managed with niacin and gemfibrozil as well as intravenous insulin. She had also undergone a cholecystectomy after her fourth pregnancy for cholelithiasis with suspected cholecystitis.

Given her prior pregnancy experiences and dietary education, she reported that she had self-managed the current pregnancy with a low-fat diet alone until the day of admission, when she had consumed a meal of fried chicken and cheese. Importantly, she denied any episodes of pancreatitis or severely elevated lipids outside of pregnancy, though she received minimal medical care while not pregnant. Between her third and fourth pregnancies, a fasting lipid profile showed triglycerides of 280 mg/dL, HDL 12 mg/dL, and LDL 94 mg/dL without lipid-lowering therapy. Similarly, before the current pregnancy, fasting triglycerides were 238 mg/dL, LDL 76 mg/dL, and HDL 17 mg/dL.

She denied any known family history of hypertriglyceridemia, pancreatitis, or early-onset cardiovascular disease. Genetic consultation was recommended but was never completed.

The initial vital signs were temperature 36.9°C, heart rate 78 bpm, respiratory rate 18 breaths/min, blood pressure 110/73 mmHg, oxygen saturation 96% on room air, and body mass index 29.6 kg/m. She appeared uncomfortable, with epigastric tenderness. Fetal heart tones were category 1. In addition to elevated pancreatic enzymes and triglycerides, as previously noted, laboratory evaluation showed a white blood cell count of 12.5×109/L, hemoglobin 14.0 g/dL, glucose 112 mg/dL, calcium 9.1 mg/dL, AST 41 U/L, ALT 53 U/L, and lactic acid of 1.2 mmol/L. Thus, the Ranson score for pancreatitis on admission was less than 2.

Despite the severity of her initial hypertriglyceridemia, due to the success of medical management in prior pregnancies, she was immediately started on intravenous hydration and insulin with bowel rest (nothing by mouth). Imaging was deferred due to the consistency of her presentation with hyper-triglyceridemic pancreatitis, and her history of this in multiple prior pregnancies. In addition, abdominal ultrasounds in multiple prior pregnancies during pancreatitis attacks demonstrated a normal-appearing pancreas. Oral niacin 250 mg daily and oral gemfibrozil 600 mg twice daily were started the next day. Figure 1 demonstrates the course of her triglycerides and pancreatic enzymes through her hospital course. Twenty-four hours after admission, her pain improved and her triglycerides decreased to 3413 mg/dL. Amylase rose at that time to 300 U/L and lipase to 359 U/L. Over the following several days, her clinical status and triglycerides continued to gradually improve. By day 5 of hospitalization, her pain resolved, and she could tolerate a low-fat diet. At this time, she underwent cervical ripening and induction of labor followed by an uncomplicated vaginal delivery of a viable, healthy infant. On postpartum day 1 she remained asymptomatic and her triglycerides had dropped to 561 mg/dL, amylase 40 U/L, and lipase 67 U/L. She continued to remain clinically stable and was discharged on postpartum day 2 with oral niacin 250 mg daily and oral gemfibrozil 600 mg twice daily. She self-discontinued these medications shortly after discharge but was doing well at her 2- and 6-week postpartum follow-ups.

Discussion

To our knowledge, this is the first case of recurrent gestational hypertriglyceridemic pancreatitis described in the context of only mildly elevated triglyceride levels outside of pregnancy. Although our patient met the criteria for hypertriglyceridemia prior to pregnancy, her levels remained less than 300 mg/dL, and just above the upper limit [12]. This was in stark contrast to triglyceride levels that exceeded 6000 mg/dL during her third trimester of pregnancy. Although several described cases of pancreatitis in pregnancy have been attributed to gestational hypertriglyceridemia [11,13–16], previous reports generally describe gestational hypertriglyceridemia without knowing nonpregnant lipid levels. However, this case illustrates the extreme degree to which the physiologic changes in pregnancy can increase triglycerides.

During a normal pregnancy, total cholesterol can increase by 25% to 50%, LDL cholesterol by 66%, and triglycerides by 200% to 400%. The normal physiological increase in triglycerides is largely due to the hyperestrogenic state, as estrogen can increase lipogenesis and decrease lipase activity. Progesterone, human placental lactogen, and pregnancy-induced insulin resistance also contribute, and gestational diabetes can further exacerbate these changes [4,17–19]. Starting around the 7th week of pregnancy, lipid levels rise to support the proper growth and development of the fetus. Levels increase more significantly towards the end of the second trimester and peak during the third trimester [4,18,20], followed by a return to baseline by 6 weeks after delivery [18].

Under normal circumstances, triglycerides rarely exceed 300 mg/dL, well below the levels commonly associated with pancreatitis [5]. However, the physiological increase in triglycerides during pregnancy can be further exacerbated in women with familial hypertriglyceridemia [20], or similarly, a genetic abnormality in triglyceride metabolism [17]. Several specific mutations have been identified involving genes related to TRL overproduction, reduced lipolysis, or decreased hepatic lipid clearance [17]. Other cases of severe hypertriglyceridemia may not have a recognizable underlying genetic mutation, with the likelihood that multiple genetic variants provide a cumulative effect [7]. Therefore, hypertriglyceridemia-induced pancreatitis during pregnancy is usually seen in the setting of preexisting or familial hypertriglyceridemia [3,5,17].

Preventive management of pancreatitis secondary to hypertriglyceridemia during pregnancy centers on a low-fat diet, omega-3 ethyl esters, and glycemic control [2,4,9,10,12,17]. The patient described here reported that she followed a low-fat diet for the duration of her pregnancy and remained asymptomatic without the use of lipid-lowering agents, until a single high-fat meal led to her acute presentation. Thus, for some women, while dietary modification alone can prevent hypertriglyceridemic pancreatitis, they should be aware of the possibility of severe pancreatitis with even a single deviation from a lowfat diet. Careful triglyceride surveillance during pregnancy in those predisposed to severe hypertriglyceridemia is advised and might have avoided the pancreatitis complication that occurred in this case report.

Although acute pancreatitis in pregnancy was historically associated with high maternal and fetal mortality, modern medical treatment has reduced these risks [4,5]. Perinatal mortality has also decreased, although reported rates remain as high as 18% [5]. These trends speak to the importance of timely diagnosis and treatment. Treatment of acute hypertriglyceridemic pancreatitis in pregnancy is generally similar to that in the nonpregnant population. Several treatment regimens have been suggested in pregnancy, including insulin infusion, plasmapheresis, and heparin [2,7,9–11]. Insulin infusion and heparin therapy both work to modulate lipoprotein lipase activity. Insulin enhances lipoprotein lipase activity, leading to increased chylomicron degradation and lower triglyceride levels, while heparin stimulates the release of lipoprotein lipase. Plasmapheresis decreases circulating triglyceride levels, increases levels of depleted or deficient lipoprotein lipase, and reduces inflammatory cytokines [22]. While plasmapheresis was shown to have a significantly higher percentage decrease of triglyceride levels within 48 hours compared to supportive therapy and insulin, the rapid decrease in triglycerides were not found to significantly improve clinical outcomes for patients [23]. Experience with plasma exchange in pregnancy is limited, but its successful use has been reported in case reports and case series [3,5,14]. However, plasmapheresis is often costly, not readily available at most institutions, and has not consistently been shown to significantly improve clinical outcomes over conventional medical therapies [23]. Thus, conventional and supportive therapies remain viable options in this scenario.

Lipid-lowering agents, such as gemfibrozil and niacin, are widely used outside of pregnancy, although their use in pregnancy is more controversial and can take weeks to take effect [14,17]. Fenofibrates have been shown to cause various pregnancy complications in animal studies, such as delayed delivery, reduced birth weight, skeletal and visceral abnormalities, and fetal death. Thus, it is only recommended to use fibrates to treat hypertriglyceridemia in pregnancy when the benefits outweigh the risks [20]. While data on fibrate use during pregnancy are limited, case studies do report successful treatment of hypertriglyceridemia-induced pancreatitis with fibrates without obstetric complications [8,11,16].

This case demonstrates a successful treatment of acute pancreatitis induced by hypertriglyceridemia in pregnancy using a combination of intravenous insulin, fasting, niacin, and gemfibrozil. Although previous case reports more frequently describe pancreatitis successfully treated with plasmapheresis, this was not readily available at our institution. Thus, given the patient’s previous success in intravenous insulin treatment, a trial of this medical management was chosen again. It is unlikely that randomized data will become available comparing medical treatment with plasmapheresis in severe cases of gestational hypertriglyceridemic pancreatitis, so treatment must be individualized in this uncommon clinical scenario.

Conclusions

This case report describes severe pregnancy-induced hypertriglyceridemia and pancreatitis recurring over multiple pregnancies in a woman with minimally increased nonpregnant triglyceride levels. We also add to the limited data on treatment by describing successful management with a combination of intravenous insulin, fasting, niacin, and gemfibrozil. Gestational hypertriglyceridemic pancreatitis, although rare, may still be considered in women with normal baseline triglycerides due to the potential for severe pregnancy-induced changes. This information is crucial, as timely diagnosis and treatment of pancreatitis is important to optimize maternal and fetal outcomes.