Severe hyperlipidemia-associated pregnancy: prevention in subsequent pregnancy by diet.

Abstract

Severe asymptomatic hyperlipidemia is a rare complication of pregnancy, usually occurring in the second and third trimester. Treatment modalities include a very low-fat diet, intravenous fluids, low-dose heparin, and plasma exchange. A 20-year-old asymptomatic primigravida was found to have a ‘milky blood sample’ at 33 weeks' gestation. At admission her triglyceride and total cholesterol levels were 156 and 40 mmol/l, respectively. To decrease her serum lipid levels, intravenous fluids and an isocaloric low-fat and low-carbohydrate diet were implemented. This action was associated with a significant decrease in her plasma lipid levels. A healthy infant was delivered vaginally at 36 weeks' gestation. In her second pregnancy this complication was avoided by strict restriction of dietary fat and close monitoring of plasma lipids. Fasting followed by a hypocaloric low-fat, low-carbohydrate diet can rapidly and safely resolve extreme hyperlipidemia in pregnancy, thereby diminishing the risk of pancreatitis. The institution of relatively simple management strategies can prevent this complication in future pregnancies. Plasma lipid levels normally rise in pregnancy as a result of estrogen-induced hepatic production of triglyceride (TG)-rich lipoproteins and a decrease in hepatic lipase (predominantly) and postheparin lipoprotein lipase (PHLPL) activity (1). In an analysis of lipoproteins during the course of pregnancy, a positive correlation between the lipids and gestational age was found, with a peak of low density lipoprotein cholesterol (LDL-C) at approximately 36 weeks' gestation (2). In normal pregnancies plasma triglyceride levels increase between two- and four-fold, while plasma cholesterol levels rise by approximately 50% (3). However, severe hyperlipidemia, defined as plasma triglyceride levels above 22.6 mmol/l, is a rare complication of pregnancy (4). In patients with pre-existing abnormalities in lipid metabolism in which hyperlipidemia has not been unrecognized, pregnancy can be complicated by pancreatitis 5-9), respiratory distress syndrome, and even by maternal death (10). We describe two pregnancies in a patient whose first pregnancy was complicated by severe hyperlipidemia but whose second pregnancy was avoided by implementing strict dietary measures, which included a low-fat, low-carbohydrate diet, nutritional support with medium-chain triglycerides (MCT), and close monitoring. To the best of our knowledge this is the first reported case of such extreme hyperlipidemia in a completely asymptomatic patient treated solely by diet and MCT. A 20-year-old primigravida was referred to our department because of a milky blood sample discovered incidentally at 33 weeks' gestation. The woman was asymptomatic and had no family history of hyperlipidemia. No previous lipid level studies had been carried out. Physical and obstetric examinations were unremarkable. Initial laboratory investigations showed a milky blood sample with 156 mmol/l serum TG (normal < 2.2 mmol/l) and 40 mmol/l cholesterol (normal < 5.2 mmol/l). Other liver function tests found 28 IU/l aspartate aminotransferase (normal < 30 IU/l), 19 IU/l alanine aminotransferase (normal 7–40 IU/l), and 32 IU/l γ-glutamyl transpeptidase (normal 7–40 IU/l). Electrolytes and renal function tests were within normal limits. Her fasting glucose level was 123 mg/dl. Glucose tolerance test with 50 g glucose at 26 weeks' gestation was 135 mg/dl. Serum amylase and lipase, as well as urine amylase levels, were within normal limits. White blood cell count was 11 600/mm (3), hemoglobin was 10.8 g/dl, and the platelet count was 106 000 mm (3). Overnight refrigeration of the serum showed a chylomicron cream layer. Abdominal ultrasound showed mild splenomegaly, with a normal pancreas. On obstetric ultrasound the fetus was appropriate for gestational age and had a reassuring biophysic profile. Daily intravenous hydration with 3000 ml of 5% dextrose in water solution was started, and the patient was placed on a hypocaloric low-carbohydrate, low-fat diet containing 10 g fat per day and MCT. Within 6 days her TG levels dropped to 63 mmol/l. The lipoprotein profile, using ultracentrifugation, exhibited type V hyperlipoproteinemia with massive accumulation of chylomicron and very low-density lipoprotein (VLDL) particles and a decreased cholesterol content of LDL and high density lipoproteins. The PHLPL was normal. A further evaluation of the patient's serum revealed apolipoprotein apoA 191 mg/dl (n < 200), apo B100 119 mg/dl (n < 200), apo CII 6.1 mg/dl (n=6–8), apo CIII 28.4 mg/dl (n=9–19), and lipoprotein < 10 mg/dl, (n<10). Restriction typing revealed that the patient was a compound heterozygote for E4 and E3 variants of apolipoprotein E. The lipid profiles of the patient's first-degree relatives were studied. Her father, an alcohol consumer, was found to have a TG level of 10.85 mmol/l and a cholesterol level of 8.8 mmol/l. Her mother's TG and her cholesterol levels were 2.5 and 6.2 mmol/l, respectively. Her sister was found to have TG and cholesterol levels of 1.44 and 4.2 mmol/l, respectively. On day 21 of hospitalization, the patient's TG value was 11.7 mmol/l. The lipid levels did not decrease further and the clinical course during pregnancy was uneventful. At 36 weeks, labor was induced with intracervical prostaglandins, and the patient had normal labor and delivered a healthy female infant weighing 2780 g. On day 5 postpartum the patient's serum TG and cholesterol levels fell to 9.72 and 8.93 mmol/l, respectively, without lipid lowering drugs. The patient's second pregnancy was electively terminated at 8 weeks' gestation because of a maternal request. The patient become pregnant for the third time at age 24 years. She was instructed to reduce her daily fat intake to 10 g/day and was placed on MCT to avoid exacerbating hyperlipoproteinemia. Throughout her pregnancy TG and cholesterol levels ranged between 9 and 11.3 mmol/l and between 7.77 and 10.36 mmol/l, respectively. At 39 weeks, the patient gave birth to a male infant weighing 2945 g. Six weeks' postpartum on a 30-g fat diet her TG and cholesterol levels were 5.17 and 7 mmol/l, respectively. Severe hyperlipoproteinemia complicating pregnancy is rare, but can have severe consequences. Maternal and fetal mortality is estimated to be 21 and 20%, respectively (11), and early intervention is mandatory to stabilize this acute illness. There may be several possible explanations for severe hyperlipoproteinemia in our patient. Although she was a compound heterozygote for the apo E isoforms E4 and E3, the E4 isoform has been associated with high LDL levels, but not with type V dyslipidemia. The primary disorders in familial hyperlipidemia type V is LPL deficiency, defective LPL or, rarely, apo CII deficiency (12). A homozygote carrier of a partial defect in LPL can become severely hypertriglyceridemic during pregnancy (13). In our patient, LPL activity was normal. Apo CII was in normal limits despite very high levels of VLDL. Defective apo CII can be excluded because in this type of situation there is a compensatory increase in apo CII production. Although the patient had normal levels of apo CII she had a relative apo CII deficiency. The patient and her father definitely have type IV/V dyslipidemia, which has been aggravated by alcoholism in the father and by pregnancy in the daughter. There are several treatment modalities for when hypertrigiyceridemia complicates pregnancy. The prompt institution of a low-fat diet usually decreases the intestinal production of chylomicrons, lowering the plasma TG levels (8, 16). Essential fatty and amino acids must also be ensured through the use of supplements if severe fat restriction is implemented. Total parenteral nutrition is another therapeutic option, as enteral compared with intravenous administration of carbohydrate produces a greater rise in plasma TG levels (14). A combination of diet therapy and nutritional support with MCT has been used for the prevention of hyperlipidemia in susceptible patients (15). The MCT channels directly into the portal circulation avoiding the hyperlipoproteinemia induced by the accumulation of chylomicron particles. Some authors have also treated hyperlipoproteinemic patients by intravenous heparin administration (9, 17). Heparin releases hepatic lipase and LPL from the capillary wall into the circulation, resulting in immediate clearance of alimentary lipids from the circulation. Prolonged intravenous heparin administration may cause LPL depletion with a decrease in LPL activity and a paradoxical hypertriglyceridemia as a result of chylomicron accumulation (18). Heparin does not cross the feto-placental barrier, but complications associated with chronic use are well known (19). When dietary fat restriction is insufficient to control plasma lipid levels or when treating severely ill patients, plasmapheresis for immediate lowering of plasma TG levels has been used (10, 20, 21). However, long-term plasma exchange may be accompanied by severe adverse effects such as local vascular thrombosis and even hemodynamic deterioration (20). Therefore, cardiovascular evaluation and careful hemodynamic monitoring throughout pregnancy are advised. Our report is of interest because our patient, unlike many other patients with extremely severe hypertriglyceridemia, was completely asymptomatic, and we considered conservative management with intravenous fluids, low-fat diet and MCT to be a reasonable option. Successful prevention of hyperlipidemia by diet in the second full-term pregnancy only, demonstrates the importance of dietary means in patients with familial hypertriglyceridemia, even when pregnant.