Chylomicrons normally are cleared rapidly from plasma by lipoprotein lipase with apolipoprotein (apo) C-II as a cofactor. Familial chylomicronemia (hyperlipoproteinemia type 1, in the Fredrickson system) and primary mixed hyperlipidemia (type 5) are each characterized by the pathologic presence of chylomicrons after a 12–14-hour period of fasting. Clinical features observed in both familial chylomicronemia and primary mixed hyperlipidemia include eruptive xanthomata (A), lipemia retinalis (C), hepatosplenomegaly, focal neurologic symptoms such as irritability, and recurrent epigastric pain with increased risk of pancreatitis. Samples of lipemic plasma develop a creamy supernatant when refrigerated overnight (B); when the plasma is tested, fasting triglyceride measurements are typically above 10 mmol/L in cases of either familial chylomicronemia or primary mixed hyperlipidemia.
Fig. 1: Clinical manifestations of primary hypertriglyceridemia. A: Eruptive cutaneous xanthomas (here on a patient's knee) are filled with foam cells that appear as yellow morbiliform eruptions 2–5 mm in diameter, often with erythematous areolae. (more ...)
Key distinguishing features of familial chylomicronemia and primary mixed hyperlipidemia include initial manifestation during childhood for the former and in adulthood for the latter; biochemically proven deficiency of lipoprotein lipase, apo CII activity or homozygous gene mutations in the former, with less severe functional deficiency and infrequent detection of gene mutations in the latter; a much lower population prevalence of the former (about 1:106) than of the latter (about 1:103); frequent presence of secondary factors in the latter; and a greater elevation of total cholesterol in the latter, relative to that in familial chylomicronemia. In biochemical diagnosis, familial chylomicronemia features a loss of lipoprotein lipase activity in plasma collected after an intravenous dose of heparin; however, few laboratories still perform this test.
Familial hypertriglyceridemia (hyperlipoproteinemia type 4) is defined by an isolated elevation of VLDL, which is not as triglyceride-rich as chylomicrons are. This familial disorder has a population prevalence of some 5%–10%. Its molecular basis is still largely unknown but is likely to be polygenic, requiring a secondary factor for expression.1
Typically, patients with this disorder have moderately elevated plasma measurements of triglycerides (3–10 mmol/L), often with low levels of high-density lipoprotein–cholesterol (HDL-C). Familial hypertriglyceridemia is associated with increased risk of cardiovascular disease, obesity, insulin resistance, diabetes, hypertension and hyperuricemia.
The inheritance pattern of familial combined hyperlipoproteinemia (type 2B) is one of an autosomal dominant with variable penetrance, with a population prevalence of 2%–5%.4
The defining lipoprotein abnormalities are increased VLDL and low-density lipoprotein (LDL) with depressed HDL, associated with an abnormal lipoprotein profile in at least one first-degree relative. Affected people occasionally have obligate heterozygosity for LPL
gene mutations, but the molecular basis underlying familial combined hyperlipoproteinemia is unknown in most instances.1
A recently defined gene that may be causative for this disorder is USF1
, which encodes an upstream stimulatory factor,5
although several other genes (including APOA5
) have been variably claimed as causative.6
Finally, familial dysbetalipoproteinemia (hyperlipoproteinemia type 3) has a population prevalence of 1–2 in 20 000.7
The main observable lipoprotein abnormality is an increase in triglyceride-rich lipoprotein remnants, also known as intermediate-density lipoproteins or β-VLDL, which produce an equimolar elevation of plasma total cholesterol and triglyceride measurements.7
People with this disorder typically are homozygotic for the binding-defective APOE
E2 isoform, which differs from the common E3 isoform by a substitution of cysteine for the normal arginine at residue 158 in the receptor-binding domain. Phenotypic expression, however, usually requires accompanying factors such as obesity, type 2 diabetes or hypothyroidism.7
Plasma levels of LDL are decreased because of interrupted processing of VLDL. An increased VLDL-C: triglyceride ratio and E2/E2 homozygosity are diagnostic. Affected people often have tuberous or tuberoeruptive xanthomata on the extensor surfaces of their extremities (D), planar-or palmar-crease xanthomata (E) and increased risk of cardiovascular disease.
Some metabolic conditions are frequently (but not universally) associated with high triglyceride results, suggesting that people who develop secondary hypertriglyceridemia might have a subtle inherited metabolic defect that confers susceptibility. Obesity is probably the metabolic stressor most frequently associated with hypertriglyceridemia, although associations with poorly controlled type 2 diabetes and excessive alcohol consumption are also common.
Obesity, metabolic syndrome, diabetes.
People with excess visceral adipose tissue often have elevated triglyceride and low HDL-C levels. About 80% of men with a waist girth of 90 cm or more and a plasma triglyceride level of 2 mmol/L or more typically have a metabolic triad of nontraditional cardiovascular-disease markers: hyperinsulinemia and increased levels of apo B and small, dense LDL particles. This triad can increase the risk of cardiovascular disease by up to 20 times.8
Impairment of the ability of insulin to stimulate glucose uptake and inadequate compensation for insulin insensitivity underlie type 2 diabetes. Moreover, among insulin-resistant people without type 2 diabetes, hyperinsulinemia is associated with a cluster of metabolic abnormalities called the metabolic syndrome.9
This syndrome, seen in people with central obesity, strongly predicts a future onset of type 2 diabetes. It is characterized by glucose intolerance, dyslipidemia (specifically, triglycerides > 1.7 mmol/L and low HDL-C concentrations) and hypertension.3
Hypertriglyceridemia, both in the metabolic syndrome and in type 2 diabetes, results from increased plasma concentrations of VLDL, with or without chylomicronemia;9
deficient lipoprotein lipase activity; increased cholesteryl ester transfer protein activity; and increased flux of free fatty acids to the liver.
A fatty liver is often associated with hypertriglyceridemia in people with obesity and insulin resistance. Several definitions of the metabolic syndrome exist,9
and it has been debated whether the clustered risk factors impart any risk above the simple sum of the individual components. However, the concept of the metabolic syndrome has proven to be useful in emphasizing the importance of obesity, insulin resistance and related lipoprotein disturbances in the assessment of cardiovascular disease risk. Hypertriglyceridemia of obesity, the metabolic syndrome and type 2 diabetes improves with weight loss and glycemic control.
Alcohol. Hypertriglyceridemia associated with alcohol intake also mainly results from increased plasma VLDL, with or without chylomicronemia. In some alcohol users, plasma triglyceride measurements can remain within the normal range because of an adaptive increase in lipolytic activity. However, alcohol can also impair lipolysis, especially when a patient has a pre-existing functional deficiency of lipoprotein lipase, which leads to markedly increased plasma triglycerides.
Although elevated LDL-C is the dominant abnormality, nephrotic syndrome is also characterized by increases in apo B–containing lipoproteins, including VLDL. The complex relation between renal disease and lipoprotein metabolism is reviewed in depth elsewhere,10
but the underlying mechanisms probably include overproduction by the liver, which concurrently increases albumin synthesis to compensate for renal protein wasting. Uremia is associated with elevated VLDL, which reflects impaired lipolysis, possibly from the toxic effect of uremic metabolites.
During the third trimester of pregnancy, plasma triglyceride levels normally rise to as much as threefold,11
but this physiologic triglyceride increase has little clinical consequence. Marked triglyceride increases also result, however, when lipoprotein lipase activity is compromised. Although chylomicronemia during pregnancy is very rare, it can be complicated by pancreatitis, which can be fatal to both mother and fetus.12
Nonalcoholic fatty-liver disorder.
This disorder may affect up to one-third of North Americans, which reflects the increasing prevalence of obesity, insulin resistance and metabolic syndrome.13,14
Among affected patients, up to one-third may also have nonalcoholic steatotic hepatitis.13,14
Lipotoxicity, oxidative stress, cytokines and proinflammatory mediators contribute to the progression from steatosis to nonalcoholic steatotic hepatitis. Elevated triglyceride and depressed HDL-C levels are the defining components of the dyslipidemia in nonalcoholic fatty-liver disorder. Small studies have indicated that treatment with statins is more effective than that with fibrates in correcting the dyslipidemia.15
Other medical conditions. Although hypothyroidism is usually associated with elevated LDL concentrations, triglycerides may also be elevated. Paraproteinemias (e.g., hypergammaglobulinemia in macroglobulinemia, myeloma, lymphoma and lymphocytic leukemias) and autoimmune disorders (e.g., systemic lupus erythematosis) can also cause hypertriglyceridemia, probably through immune-mediated interference of lipolysis.
Medications. Many drugs increase triglyceride concentrations (). If one is considered to cause hypertriglyceridemia, the indications for that medication should be reviewed. If dosage reductions, changes in route of administration or substitution with another class of medication are not practical, then marked elevations of triglycerides should be treated with diet or pharmacologic agents.
Patients taking highly active antiretroviral therapy, particularly protease inhibitors, frequently experience lipodystrophy, insulin resistance and dyslipidemia; up to 80% and 50% of patients develop hypertriglyceridemia and hypercholesterolemia, respectively.16
Combination highly active antiretroviral therapy was found to be associated with a 26% increase in relative risk of cardiovascular disease.17
Ritonavir and lopinavir are most strongly associated with dyslipidemias;16
3 reverse-transcriptase inhibitors, the nucleoside stavudine and the nonnucleoside nevirapine16
less consistently so. Often, triglyceride levels can improve when agents are switched (if there is no compromise in antiretroviral efficacy).18,19
In one study,19
for instance, a change from a protease inhibitor to nevirapine or efavirenz reduced triglyceride levels by about 25%; the addition of pravastatin or bezafibrate further reduced them by about 40%.
Second-generation antipsychotic medications are known to be associated with obesity, hypertriglyceridemia,20
hyperglycemia and type 2 diabetes.21
Clozapine and olanzapine disturb metabolism the most; risperidone and quetiapine have intermediate effects; and aripiprazole and ziprasidone, the fewest.20
Psychiatric disorders, because of associated lifestyles, may also predispose those affected to metabolic disturbances.22
Patients taking second-generation antipsychotics should be monitored regularly (every 8–12 months) for weight gain and changes in fasting plasma glucose and lipoprotein levels.21