Peer Reviewed

Review Article

Familial Hypertriglyceridemia With Concomitant Familial Hypobetalipoproteinemia

Evan J. Leonard, MS, PA-C; Christopher B. Scuderi, DO; and Martin M. Zenni, MD 

Evan J. Leonard, MS, PA-C; Christopher B. Scuderi, DO; and Martin M. Zenni, MD 

Consultant. 2017;57(1):12-15.



ABSTRACT: A 49-year-old man presented to our family medicine practice with the unique presentation of an elevated fasting triglyceride level and a very low low-density lipoprotein cholesterol level. We present the combined pathology associated with the concomitant diseases, as well as the diagnosis, management, and patient education. We also discuss the symptomatology of our patient, the incidence of the disease, and the associated comorbidities such as insulin resistance, obesity, hyperglycemia, hypertension, and hyperuricemia.

KEYWORDS: Familial hypertriglyceridemia, familial hypobetalipoproteinemia, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, insulin resistance, obesity, diabetes, prediabetes, hyperglycemia, hypertension, hyperuricemia


A 49-year-old man was seen in our family medicine clinic in 2006 to establish care. The patient was a retired veteran; while on active duty, he had been under the care of military clinicians, at which time he had been physically active and had weighed 84 kg, compared with his presenting weight of 113 kg (body mass index [BMI], 35 kg/m2). He now consumed 4 glasses of wine a week and was a former cigarette smoker who previously had smoked 0.25 packs a day for 15 years. His maternal family history was positive for hypertriglyceridemia, but he was unsure of any other lipid details.

Since an initial assessment in 1992, at age 25, the patient’s lipid levels had fluctuated; his highest recorded triglyceride (TG) level was 315 mg/dL in 2005, and his lowest recorded low-density lipoprotein cholesterol (LDL-C) level was 19.8 mg/dL in 2002. His high-density lipoprotein cholesterol (HDL-C) level was as low as 30 mg/dL during that time. Despite these values, from 1992 to 2005, the patient had not been placed on any lipid-lowering medication.

When he established care at our clinic in 2006, the patient had a fasting TG level of 371 mg/dL, a direct LDL-C level of 41 mg/dL, an aspartate aminotransferase level of 65 U/L, an alanine aminotransferase level of 105 U/L, and a glucose level of 130 mg/dL. He also was found to have fatty liver infiltrates on liver ultrasonography. He was started on gemfibrozil, which was ineffective. He subsequently was treated with fenofibrate, 145 mg, which also failed to help him reach his goal TG level.

His TG level remained in the 200s over the next few years. Upon reevaluation by our team in 2015, he was not taking fenofibrate, and his TG level was further elevated to 355 mg/dL, his HDL-C level was 30 mg/dL, his hemoglobin A1c level was 6.3%, and, surprisingly, his direct LDL-C was 11 mg/dL. Physical examination findings were normal except for obesity. While under our care, his highest fasting TG level was 401 mg/dL.

A diagnosis of familial hypertriglyceridemia (FHTG; likely heterozygous, with confirmation requiring genetic testing) and prediabetes (with insulin resistance) was made. He was placed on fenofibrate, 160 mg; a low-carbohydrate, low-fat diet; and over-the-counter fish oil, 1000 mg twice daily.

Over the course of 25 years, the patient had remained asymp​tomatic despite his dyslipidemia. He had experienced no symptoms of vitamin deficiency or steroid deficiency and no neurologic deficits secondary to his low LDL-C level. He traveled overseas for work and had been unable to visit for follow up until the summer of 2016. At this time, he was found to have reduced his weight by 20 kg pounds to 93.4 kg; his BMI had improved to 28 kg/m2. He had been adherent to the regimen of fenofibrate and fish oil, and he now had a TG level of 160 mg/dL, a direct LDL-C level of 15 mg/dL, an HDL-C level of 40 mg/dL, normal liver function test results, and a hemoglobin A1c level of 5.5%.

At this time, the patient became interested in why his LDL-C level was so low. A cardiologist consultant recommended stopping the fenofibrate and running advanced cardiovascular laboratory tests in order to more accurately assess his cardiac risk and dyslipidemia. Levels of apolipoprotein (apo) AI, apo B, apo E, lipoprotein(a) [Lp(a)], phospholipase A2, vitamin E (α-tocopherol and β-γ-tocopherol), and vitamin A were analyzed, and a lipid panel test was performed.

Laboratory test results obtained after holding fenofibrate for 2 weeks (during which time he had to go back overseas) showed that his TG level had increased to 223 mg/dL, his direct LDL-C level had increased to 45 mg/dL (reference range, 100-130 mg/dL), his liver function had remained normal, and his HDL-C level was low at 38 mg/dL. Most interestingly, his Lp(a), phospholipase A2, apo E, and apo AI levels were normal, while his apo B level was low at 42 mg/dL (reference range, 52-109 mg/dL). These laboratory test results and his clinical course confirmed the diagnosis of familial hypobetalipoproteinemia (FHBL).

Insofar as the patient had normal fat-soluble vitamin levels and was asymptomatic, one can conclude that he most likely has the heterozygous form of hypobetalipoproteinemia; however, a genetic test would be required to specify the detailed genetics of the patient’s condition.

The patient was educated about the diagnosis and prognosis and was placed back on the regimen of fish oil and fenofibrate, 160 mg daily. When the patient returns from overseas, repeat hepatic ultrasonography should be performed in order to help track the progress of the hepatic steatosis (HS).


NEXT: Pathology and Risk, Discussion


Pathology and Risk

Typically polygenic, heterozygous FHTG is an autosomal dominant disorder, is either monogenic or polygenic, and is associated with a moderate elevation in the fasting serum TG level (200-500 mg/dL). Insulin resistance, obesity, hyperglycemia, hypertension, and hyperuricemia often accompany the condition.

Homozygous mutations typically result in TG levels greater than 1000 mg/dL, which result in a significantly elevated risk of cardiovascular and pancreatic complications compared with the heterozygous form. The catabolism of HDL-C particles is enhanced in the setting of hypertriglyceridemia.1 Patients with FHTG are heterozygous for inactivating mutations of the lipoprotein lipase gene, LPL, and as noted typically have a low serum HDL-C level. The common LPL mutations raise serum TG levels by 20% to 80%.

FHTG is associated with increased coronary artery disease (CAD) risk and is common in patients with premature CAD. Among first-degree relatives of affected persons, the baseline serum TG level predicts cardiovascular mortality, independent of serum total cholesterol levels. FHTG occurs in approximately 1% of the general population.2

FHBL is associated with mutations that may occur at multiple genetic loci. The best-described cases show linkage to mutations in the gene encoding apo B (APOB). Apo B is the integral protein found in chylomicrons as well as in their remnants, including very low-density lipoprotein cholesterol (VLDL-C), LDL-C, and Lp(a). Patients with FHBL have a low level of plasma apo B (a building block of VLDL-C and LDL-C), with an LDL-C level between 25 and 40 mg/dL or below the fifth percentile of age- and sex-specific values, a low TG level, and a low VLDL-C level.

Heterozygous mutations typically result in an LDL-C level less than 30% of those of normal sex-matched individuals. The heterozygous form occurs in 1 in 500 to 1 in 1000 patients, although one group of authors places the frequency at 1 in 3000 in the general population.3 

Homozygous mutations result in an absence of or an extremely low level of LDL-C, a low level of TGs, and a very low level of vitamin E. Homozygous FHBL is typically indistinguishable from abetalipoproteinemia.

Another less-common mutation is a loss-of-function mutation in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9), which results in a decrease in the LDL-C and apo B levels, which are associated with a low lifetime risk of cardiovascular disease. This discovery has led to the development of new medications that affect this pathway—the PCSK9 inhibitors (evolocumab and alirocumab). PCSK9 is a protease that binds to the LDL-C receptor and targets it for lysosomal degradation within the hepatocytes. With an elevated PCSK9 level, there is a decrease in the LDL-C receptor density in the liver with a concomitant rise in LDL-C and in cardiovascular risk.4

Affected individuals are usually asymptomatic but are at an increased risk for HS. Coupled with a high TG level, the risk of HS increases substantially,4 as was seen in our patient. The most likely cause of the increased prevalence of HS in patients with FHBL is the impaired secretion of VLDL-C from the liver, leading to TG accumulation in the hepatocytes and not necessarily in the serum, hence the uniqueness of our patient’s condition. Sankatsing and colleagues5 observed that patients with FHBL can have an alanine aminotransferase level of more than twice the upper limit of normal, as well as a more severe degree of HS as visualized with hepatic ultrasonography. They did, however, also note a decrease in carotid arteriosclerosis compared with healthy patients and patients with diabetes. 

The clinical diagnosis of FHTG is typically made when the fasting TG level is greater than 200 mg/dL with or without the presence of insulin resistance, obesity, hyperglycemia, hypertension, and hyperuricemia. A definitive diagnosis can be made based on the results of a genetic analysis; however, this is relatively expensive and is generally not considered a diagnostic requisite.1,2,4

The diagnosis of FHBL is more involved. The first step in the diagnostic workup is assessment with a standard lipid panel after an 8-hour fast. If concern exists for a high TG level, then a direct LDL-C test can be ordered, as we did in our patient’s case. A comprehensive metabolic panel analysis should be performed to assess the functionality of the liver and kidneys and the patient’s glucose level. A medication review should be detailed to ensure patient safety if a new agent is needed for treatment. If the glucose level is elevated, a glucose tolerance test and/or a hemoglobin A1c test should be performed to assess for insulin resistance.

Once a low LDL-C level is observed, the clinician should then assess the levels apo B, apo AI, and Lp(a) with or without the phospholipases. The analysis of apo B should be performed in whole plasma or plasma lipoprotein fractions measured by Western blotting. Some of these patients may experience steatorrhea, thus fecal fat may be analyzed, although it is not necessary to confirm the diagnosis. A genetic analysis for APOB is not entirely necessary for the diagnosis, but it does confirm it and subsequently allows the patient to share this information with family members who may be affected.1,2,4 If there is complete absence of apo B, then microsomal triglyceride transfer protein (MTTP) gene analysis should be performed in order to diagnose abetalipoproteinemia.3

The apo E genotype has been reported to account for 15% to 60% of the variability in plasma LDL-C in patients with FHBL. The physiologic basis for this effect has yet to be determined.6 If an elevated TG level is present, coupled with elevated liver enzymes, the patient should have ultrasonography of the right upper quadrant to search for HS. If HS is present, a liver fibrosis panel (HepaScore) can be performed, including assessment of levels of bilirubin, γ-glutamyltransferase, hyaluronic acid, and α2-macroglobulin, along with transient elastography (FibroScan).7

NEXT: Discussion, References



This patient’s case demonstrates that in rare situations, more than one lipid disorder can occur simultaneously. This patient’s risk for HS was increased more so than a typical patient with FHBL; thus, the importance of lowering the TG level is more imperative. While a low LDL-C level is a negative cardiovascular risk factor and is cardioprotective, the elevated TG level warrants more scrutiny for the sake of the liver over time and to a lesser extent the heart. HS is a leading cause of liver cirrhosis, after alcohol-related hepatic cirrhosis. The elevated TG level still poses a threat to the cardiovascular system and warrants rigorous control in order to lessen cardiovascular risk from low HDL-C and elevated TG levels.

In our patient, lipid levels were assessed with the direct LDL-C method, which detects LDL-C and HDL-C levels regardless of an elevated TG level. Even when this patient weighed only 84 kg and was physically active, with no other metabolic abnormalities, he had a high TG level, an LDL-C level well below the reference range of 100 to 130 mg/dL, and a high fasting glucose level. The patient’s direct LDL-C level never went higher than 45 mg/dL, and this peak occurred when the TG level was lowered with medication.

This case highlights the need to do a full workup of lipoprotein levels in patients with hypocholesterolemia in order to appropriately treat them, as well as to inform their family members of a genetic predisposition. Our patient had a positive family history along with the other coexisting metabolic disturbances, thus confirming the diagnosis based on the current guidelines.2

Patients with abetalipoproteinemia and homozygous hypertriglyceridemia may benefit from consulting a genetic counselor. Familial (heterozygous) hypertriglyceridemia usually can be managed with lifestyle modifications such as a Mediterranean diet and a program of regular exercise. Patients can be referred to a dietitian if they need assistance with proper dietary planning. Aerobic training and weight training programs have been shown to be beneficial in lowering the plasma TG level. It is important to recommend that the patient exercise every day to every other day, because exercise reduces plasma TG concentrations the day after exercise but not 2 to 3 days later. We recommend that patients follow the American Heart Association guidelines of 30 to 60 minutes of aerobic exercise most days of the week and toning exercises 20 to 30 minutes twice a week.8

A prescription medication, usually a fibric acid derivative such as fenofibrate, typically is required, as well as high doses of ω-3 fatty acids. In cases of a severely elevated TG level, such as in the homozygous form of the disease, the patient may even require additional TG lowering medications such as a bile acid sequestrant. If there is a concomitant high LDL-C level, a statin may be necessary and can help lower both LDL-C and TG levels, however only minimally for the latter.

We recommend reassessing the patient with a lipid panel 5 to 6 weeks after beginning medication therapy and lifestyle modifications. The therapeutic target range for the TG level should be 130 to 150 mg/dL or less.

Additionally, ours was an isolated case of an LDL-C level of 11 mg/dL observed in an asymptomatic individual, including no symptoms of infertility (the patient has 2 children) or hypotestosteronemia. The literature contains no long-term studies detailing the complications related to hypocholesterolemia, and more research is required. The only currently available data suggest that having a very low LDL-C level is a negative risk factor for cardiovascular disease.4,5 Only in the complete absence of the lipoproteins do major complications arise, such as poor enteric absorption of fat-soluble vitamins.

In summary, we describe a case in which a formerly obese man with FHBL also presented with FHTG. Primary care providers, hepatologists, and cardiovascular specialists should be aware that more than one lipid disease may exist in a patient, and that the liver should be surveyed using biochemical and imaging techniques given the increased potential for progression to cirrhosis, particularly in a patient with 2 lipid disorders that can lead to HS. When a patient presents with hypocholesterolemia but with few cardiovascular risk factors, we recommend that a lipoprotein analysis be performed, because each deficiency carries specific risks. The complete absence of some lipoproteins can result in devastatingly low levels of vitamins E and A. It is beneficial to monitor and document the clinical course of these patients over time. Long-term studies are needed to assess the chronic ramifications of having such a low LDL-C level.

Evan J. Leonard, MS, PA-C, is a physician assistant in the Department of Emergency Medicine at University of Florida (UF) Health North in Jacksonville, Florida.

Christopher B. Scuderi, DO, is an associate professor in the Department of Community Health and Family Medicine at the UF College of Medicine and is the medical director of UF Health Family Medicine and Pediatrics–New Berlin in Jacksonville, Florida.

Martin M. Zenni, MD, is an associate professor in the Department of Medicine, Division of Cardiology, and director of Nuclear Cardiology at the UF College of Medicine in Jacksonville, Florida. 


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