Mary is a 40-year-old school teacher who was referred for severe elevation of triglycerides (TGs). She has a past medical history of hypertension, gestational diabetes, pregnancy-induced hypertension, former tobacco use and idiopathic gastroparesis. She was not pregnant at the initial consultation, and reported regular menses. She denied knowledge of hypertriglyceridemia during pregnancy. Family history was notable for premature coronary heart disease (CHD) in her father at age 45. Habits included walking up to 120 minutes daily in her school and classroom, the equivalent of 12,000 steps a day.
She reported multiple food and medication intolerances because of gastroparesis. Initial medications were omeprazole- bicarbonate, dicyclomine, domperidone, amitriptyline, losartan-hydrochlorothiazide, flush-free niacin (inositol hexanicotinate) 500mg twice daily, and a non-prescription fish oil supplement with an unknown content of eicoapentaenoic (EPA) and docosahexaenoic acid (DHA) taken twice daily. She denied using exogenous hormones.
Diet recorded at the initial visit included breakfasts of coffee with 2% milk and 2 teaspoons of sugar, lunches of a sandwich with white bread and deli meat, and dinners of chicken, fish or beef with potato or white rice and a vegetable. She reported eating sweets occasionally and had been drinking sugar-sweetened beverages up until 3 months prior to the visit. She reported drinking 12-24 ounces of beer most days.
She had body mass index (BMI) of 25.2 without signs of lipodystrophy. She had normal vital signs, including blood pressure. She had normal cardiovascular examination, no organomegaly, and no xanthomata. Serum creatinine, glucose and hemoglobin A1C (Hb A1c), thyroid and liver function tests were normal. Lipid results from 3 months prior to the first visit showed serum TGs of 969 mg/dl, total cholesterol of 304 mg/dl, high-density lipoprotein cholesterol (HDL-C) of 34 mg/ dl and non-HDL-C of 270 mg/dl (table 1).
Given Mary’s TGs in the 900 mg/dl range, we counseled her about the risks of acute pancreatitis and prescribed complete alcohol cessation as a first step. We considered a very low-fat diet, but given her GI symptoms and reluctance to increase her intake of fiber-rich carbohydrates, we prescribed a Mediterranean diet with restriction of added sugars and substitution of whole grains for refined grains. We also prescribed moderate-intensity exercise twice weekly in addition to her daily low-intensity walking. We discontinued the niacin and fish oil. We prescribed fenofibric acid 134 milligrams daily and a different non-prescription fish oil with a reported higher concentration of EPA (selected because of its higher EPA content and because it was available at lower cost and as liquid suspension since she had difficulties swallowing the large capsules). On the second visit 3 months later, she had lost 10 pounds and her TGs had normalized; we made no changes to her regimen. However, at her third visit, her lipid control worsened (see table). Total cholesterol had risen, calculated low-density lipoprotein cholesterol (LDL-C) was in the 150 mg/dl range, and her weight had increased 5 pounds. She admitted to eating out more often during the summer vacation, and to becoming more sedentary, though she denied regular alcohol intake.
Analysis and Diagnosis
Mary had been referred for severely elevated TGs in the 900-mg/dl range, putting her at risk for pancreatitis. Review of past records showed that previous TG levels were only moderately elevated, in the 200-499 mg/dL range. Given her combined lipid pattern, varying TG levels and family history of early CAD, this pattern is consistent with familial combined hyperlipidemia (FCH), a common polygenic lipoprotein disorder categorized by (a) an increase in cholesterol and/or TGs in at least two members of the same family, (b) intra-individual and intra-familial variability of the lipid phenotype over time, including intermittent chylomicronemia, and (c) an increased risk of premature coronary heart disease (CHD). Mary’s family history supported the diagnosis, although we were unable to confirm lipid levels in at least one parent or sibling. She was also noted to have a relatively high non-fasting ApoB at the third visit (148 mg/dL) consistent with the diagnosis of FCH or, at least, Friedrickson-Levy type IIb lipoprotein phenotype (elevated VLDL and LDL). This clinical diagnosis is consistent with the findings from application of the de Graff/Sniderman ApoB algorithm (now available for Android and iPhones as the ApoB app).
The published algorithm is based on data that recognizes FCH as a hypertriglyceridemic hyper-ApoB state resulting from excess low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) (aka type IIb in the Friedrickson-Levy classification). The algorithm enables classification based on more readily available parameters, rather than use of ultracentrifugation lipid profiling (UltraLP), which is not clinically available at most medical centers. It utilizes ApoB, serum triglycerides (TG), the TG:ApoB ratio, and other lipoprotein levels to differentiate the diagnosis. In this case, the application suggests FCH versus sitosterolemia (Figures 1-4). Apo B and non-HDL-C do not require fasting for accurate assessment. Endorsed by NLA Dyslipidemia Recommendations – Part 1, Apo B can be considered a secondary target for treatment, as it is a potential contributor to residual ASCVD risk. It may remain elevated in some whose non-HDL-C and LDL-C treatment goals are met, who have high triglycerides and low HDC levels.
Potential secondary causes of hypertriglyceridemia, (which are helpfully suggested by the algorithm) include type II diabetes, metabolic syndrome, abdominal obesity, alcohol excess, nephrotic syndrome, cholestasis, anti-retroviral therapies, glucocorticoids, anti-psychotic drugs, polycystic ovary syndrome, exogenous estrogen use, and the third trimester of pregnancy.4,5 The latter three are particularly important to consider in women, though they did not apply to Mary, in whom we suspected alcohol and dietary factors as the principal causes of her TG excursions.
Final Management and ASCVD Risk Assessment
At the third visit, Mary’s TGs were no longer severely elevated, but she had high levels of LDL-C, non-HDL-C and ApoB. In addition to the lipid disorder, she also has hypertension, and prior diagnoses of gestational diabetes and pregnancy-induced hypertension, the latter two also associated with significantly increased future atherosclerotic cardiovascular disease (ASCVD) risk and/or diabetes in women.6,7
Although Mary’s 10-year ASCVD risk via the 2013 pooled-risk equation was only 1.1%, her lifetime risk was above average, at 50%. Moreover, risk stratification via the National Lipid Association (NLA) framework indicated that, based on her two traditional risk factors, statin therapy should be considered to lower her non- HDL-C of 160 mg/dl.
Given this, we engaged Mary in shared decision-making regarding statin initiation, and she agreed to start atorvastatin 10 milligrams per day. At her fourth visit, while taking atorvastatin 10mg, fenofibrate 134 mg, and the fish oil, the non-HDL-C had dropped from 194 to 169 mg/dl and LDL-C from 151 to 127 mg/dl. However, she complained of myalgia, and rosuvastatin 5 mg per day was substituted for atorvastatin. On this dual-therapy regimen, non-HDL-C was just above 130 mg/dl and LDL-C dropped to 105 mg/dl, about 45 points and 30% lower than her pre-statin level. We did not change therapy at the last visit.
However, given improvements in her diet, alcohol consumption and other lifestyle factors, future considerations for Mary could include a trial off the fibrate and a transition to high intensity statin dose.5 However, we also have considered that myalgia might recur on a higher statin dose and that she would require closer follow-up of TG levels. As she enters menopause, the possibility that any prescribed hormone therapy could worsen her TGs again also would require counseling and close follow-up.
This case illustrates the fundamental importance of making a clinical diagnosis, including assessment of family history, for all lipid clinic patients. It demonstrates the benefit of using an easy electronic tool to develop valid differential diagnosis in those with hypertriglyceridemia hyper-ApoB, which strongly supports a more intensive preventive strategy. It also illustrates the importance of targeting severe elevations of TGs as an initial strategy and using non-pharmacologic approaches to minimize factors contributing to TG elevation, including medications, alcohol, hormonal agents, diet, obesity and a sedentary lifestyle. Finally, it demonstrates the importance of assessing long-term ASCVD risk in all patients, particularly in hypercholesterolemic middle-age women who are not typically assigned to a “statin benefit group” using traditional risk- factor scoring. In this regard, obtaining a pregnancy history in all women is important and can assist in decision-making. Also applying the NLA risk assessment schema to target elevated non- HDL-C in all hypertriglyceridemic patients is essential. In this case, these steps led to our assessment of elevated future ASCVD risk, a statin was added and adjusted to tolerability.
- Obtain a family history and pregnancy history in all women
- In hypertriglyceridemic women, target non-HDL-C and/or elevated ApoB
- Narrow the diagnosis using the ApoB app or a paper-based algorithm
- Target severe hypertriglyceridemia first
- Identify and target all lifestyle factors contributing to hypertriglyceridemia
- Assess and target future ASCVD risk using the NLA risk assessment schema
Disclosure statement: Adina Gutstein has no financial disclosures to report.
References available here.
Preventive Cardiology and Risk Factor Management
Cardiovascular Medical Associates, PC
Diplomate, Accreditation Council of Clinical Lipidology